Patent Grant
8304547
This application is a 371 of International Patent Application No. PCT/JP2008/069263, filed on Oct. 23, 2008, and claims priority to Japanese Patent Application No. 2007-276894, filed on Oct. 24, 2007.
The present invention relates to an azolecarboxamide compound which is useful as a pharmaceutical, in particular, a therapeutic agent for urinary frequency, urinary urgency, urinary incontinence, and lower urinary tract pain associated with various lower urinary tract diseases including overactive bladder, and various diseases accompanied by pain.
An overactive bladder is a clinical condition showing urinary urgency regardless of incontinence, which is usually accompanied by urinary frequency and nocturia (Non-Patent Document 1). At present, for a treatment thereof, an anticholinergic agent is mainly used for a treatment thereof, and constant treatment results are given. However, it has been reported that the use thereof is difficult with patients with prostatic hypertrophy or elderly patients because it is known to cause side-effects such as dry mouth, constipation and blurred vision, as well as a risk of urinary retention. In addition, there are patients who show no improvement with the anticholinergic-treatment. From the above, there is great expectation of a drug with a new mechanism of action for overactive bladder.
A nerve growth factor (NGF) is one of the humoral factors named generically as a neurotrophic factor, which plays an important role in the development, differentiation and functional maintenance of neurons in the living body. As a receptor of NGF, a high-affinity trkA receptor (tyrosine kinase receptor) and a low-affinity p75 receptor have been known. It has been reported that p75 binds to all neurotrophic factors, and is involved in apoptosis in the process of neuron development, but the role has not yet been fully understood. It has been known that NGF and trkA receptor-knockout mice show the similar phenotype (Non-Patent Document 1), and it is believed that the physiological action of NGF is exhibited mainly through the trkA receptor.
It has been known that the NGF level in bladder is increased in a patient with overactive bladder or interstitial cystitis (Non-Patent Document 2), and there have been reports that an intravesical instillation of NGF reduces the bladder capacity of a rat and that the inhibition of NGF improves urination function in the urinary frequency-model rat (Non-Patent Document 3). In addition, it has been reported that the inhibition of NGF improved urinary frequency or urinary incontinence in a patient with interstitial cystitis (Non-Patent Document 4), and it is thus believed that a trkA receptor inhibitor is useful as a therapeutic agent for lower urinary tract diseases such as overactive bladder, interstitial cystitis, prostatitis, and the like.
Moreover, a trkA receptor inhibitor has different mechanisms of action, and thus the side effects specific to the anticholinergic agent are expected to be avoided as well as an effect on patients who showed no improvement with the anticholinergic treatment is expected. In addition, this agent is expected to have potent effects of improving the subjective symptoms by acting on sensory nerves. Furthermore, this agent has been reported to exhibit an effect of improving the clinical condition without lowering urinary pressure in the urinary frequency-model rat (Non-Patent Document 5), and thus is expected to be administered safely to a patient with prostatic hypertrophy or an elderly patient.
It has been known that when NGF is administered to a human or a rat, pain is induced, and that pain sensation in the trkA receptor-knockout mice is lost. Consequently, NGF is believed to be strongly related to expression of pain. An NGF inhibition shows efficacy in model animals with neuropathic pain or inflammatory pain, such as a model with pain induced by damage to the ischiadic nerves (Non-Patent Document 6) and a model with pain induced by damage to the knee joint (Non-Patent Document 7), and a trkA receptor inhibitor is believed to be useful as a therapeutic agent for various pains such as lower urinary tract disease accompanied by lower urinary tract pain, osteoarthritis, or the like.
As the compound mentioned above, there have been known an indolocarbazole derivative (Non-Patent Document 8), a pyrrolocarbazole derivative (Patent Document 1), a pyrazolone derivative (Patent Document 2), an oxyindole derivative (Patent Documents 3 and 4), an azaoxyindole derivative (Patent Document 5), a pyrazoryl condensed ring compound (Patent Document 6), a pyrazole derivative (Patent Documents 7 and 8), a tricyclic derivative (Patent Document 9), ALE-0540 (Patent Document 10), a benzo[de]isoquinoline derivative (Patent Document 11), a benzo[lmn]phenanthroline derivative (Patent Document 12), and a pyrrolotriazine derivative (Patent Document 13).
As described above, existing therapeutic agents for urinary frequency, urinary urgency, and urinary incontinence associated with overactive bladder, and various lower urinary tract diseases accompanied by lower urinary tract pain, such as interstitial cystitis, chronic prostatitis, and the like are not satisfactory from the viewpoint of efficacy, safety, or the like. Thus, there has been a strong demand for a therapeutic agent for lower urinary tract disease which is excellent in efficacy and safety.
As described above, a trkA receptor inhibitor can be expected to be a safe therapeutic agent for lower urinary tract disease, with few side effects such as dry mouth, urinary retention, and the like. The present inventors thoroughly investigated a compound having trkA receptor inhibitory activity for the purpose of providing a novel compound useful for treating lower urinary tract disease and so forth. As a result, the inventors found that an azolecarboxamide compound represented by the following formula (I) exhibits potent trkA receptor inhibitory action, thereby completing the present invention.
That is, the present invention relates to an azolecarboxamide compound represented by the following formula (I) or a salt thereof.
[1] An azolecarboxamide compound represented by the following formula (I) or a salt thereof:
(the symbols in the formula have the following meanings:
X: S or O,
R1: halogen, aryl, heteroaryl, cycloalkyl, 4-piperidyl, 4-tetrahydropyranyl, -Alk-aryl, -Alk-O-aryl, -Alk-O-lower alkyl, -Alk-NH—CO-lower alkyl, -Alk-NH—CO—O-lower alkyl, —NH-aryl, —NH-(4-piperidyl), a group represented by the formula (II), or a group represented by the formula (III):
wherein in R1, each aryl may be substituted with group(s) selected from the group consisting of halogen and halogeno-lower alkyl, the heteroaryl may be substituted with amino or —NH—CO—O-lower alkyl, the cycloalkyl may be substituted with —O-Alk-aryl or —O-heteroaryl, and the N atom of each 4-piperidyl may be substituted with lower alkyl, heteroaryl, —CO-lower alkyl, or —CO—O-lower alkyl,
Alk: the same as or different from each other, each representing lower alkylene,
R1a: lower alkyl substituted with one or two —OH, -Alk-O-lower alkyl, -Alk-SO2-lower alkyl, -Alk-O—SO2-lower alkyl, -Alk-aryl, -Alk-O-aryl, -Alk-heteroaryl, -Alk-O-heteroaryl, -Alk-CO-saturated hetero ring group, -Alk-NRARB, -Alk-CO—NRARB, saturated hetero ring group, wherein the saturated hetero ring group may be substituted with lower alkyl, lower alkenyl, -Alk-O-lower alkyl or -Alk-aryl, or -Alk-saturated hetero ring group, wherein the saturated hetero ring group in the -Alk-saturated hetero ring group may be substituted with lower alkyl or —OH,
RA and RB: the same as or different from each other, each representing —H or lower alkyl,
R1b: lower alkyl or -Alk-aryl,
Q: cyclic amino which may be substituted with group(s) selected from Group G1 below:
Group G1: halogen, —OH, —CN, lower alkyl, halogeno-lower alkyl, -Alk-OH, —O-lower alkyl, —O-halogeno-lower alkyl, -Alk-O-lower alkyl, —O-Alk-O-lower alkyl, —O-cycloalkyl, —O-Alk-cycloalkyl, —CO2H, —CO—O-lower alkyl, —CO-lower alkyl, —CO—NRARB, —CO—NH-Alk-OH, -Alk-CO—NRARB, —SO2-lower alkyl, —SO2—NRARB, aryl, —O-aryl, heteroaryl which may be substituted with (—O-lower alkyl), -Alk-heteroaryl, —O-(heteroaryl which may be substituted with group(s) selected from the group consisting of halogen, lower alkyl, —O-lower alkyl, —CN and —OH), -Alk-O-heteroaryl, —SO2-heteroaryl, —S-(heteroaryl which may be substituted with lower alkyl), oxo, —NRCRD, and -Alk-aryl,
wherein, in -Alk-aryl of Group G1, the Alk may be substituted with —OH, and the aryl may be substituted with —CO2H or —CO—O-lower alkyl,
and two substituents on the ring group Q may be combined to form -Alk-,
saturated hetero ring which may be substituted with group(s) selected from the group consisting of lower alkyl and oxo, or cycloalkane, may be spiro bonded on the ring group Q,
heteroarene which may be substituted with lower alkyl, arene, or cycloalkane, may be condensed with the ring group Q,
RC: —H or lower alkyl,
RD: lower alkyl, —CO-lower alkyl, —CO—O-lower alkyl, -Alk-CO—NRARB, or heteroaryl,
R2: a group selected from (i) or (ii) below,
(i) a group represented by the formula (IV) or (V),
R2a: —O—RE, —CH2—RF, —NRGRH, or heteroaryl,
RE: —H or lower alkyl,
RF: —H, heteroaryl, or saturated hetero ring group,
RG: —H or lower alkyl,
RH: (1) —H, (2) —O-lower alkyl, (3) cycloalkyl which may be substituted with group(s) selected from the group consisting of —OH, —NRARB, —NH—CO—O-lower alkyl, —CN, —CO2H, —CO—O-lower alkyl and —CONH2, (4) cycloalkenyl which may be substituted with -Alk-OH or —CONH2, (5) saturated hetero ring group which may be substituted with group(s) selected from the group consisting of —OH, lower alkyl, -Alk-cycloalkyl, —CO-lower alkyl and oxo, (6) aryl which may be substituted with group(s) selected from the group consisting of —OH, —CN and halogen, (7) heteroaryl, or (8) lower alkyl which may be substituted with group(s) selected from Group G2 below:
Group G2: halogen, halogeno-lower alkyl, —OH, cycloalkyl, —O-lower alkyl, —O-cycloalkyl, —O-Alk-OH, —CN, —S-lower alkyl, —SO2-lower alkyl, —CONH2, —CONH-lower alkyl, —NHCO-lower alkyl, —CO2H, —CO—O-lower alkyl, —NRARB, saturated hetero ring group, —CO-saturated hetero ring group, aryl, and heteroaryl,
wherein, in Group G2, the cycloalkyl may be substituted with —OH, —CO—O-lower alkyl, -Alk-OH or -Alk-NRARB, the saturated hetero ring group may be substituted with —OH, lower alkyl, -Alk-OH, -Alk-O-lower alkyl, -Alk-aryl, —NRARB, —CO—O-lower alkyl or oxo, and the heteroaryl may be substituted with —OH, lower alkyl, —CO2H or —CO—O-lower alkyl,
and RG and RH may be combined with the N atom to which they are bonded to form nitrogen-containing saturated hetero ring which may be substituted with group(s) selected from the group consisting of —OH, lower alkyl, —CO—O-lower alkyl, -Alk-aryl and —CO-saturated hetero ring group,
R2b: lower alkyl, halogeno-lower alkyl, -Alk-RK, —NRLRM, aryl or saturated hetero ring group, wherein the saturated hetero ring group may be substituted with —CO—O-Alk-aryl,
RK: —CN, —OH, —N3, —CONH2, —O—CO-lower alkyl, —NRARB, —NH—CO-lower alkyl, —O—SO2-lower alkyl, heteroaryl or saturated hetero ring group,
RL: —H or lower alkyl,
RM: heteroaryl or saturated hetero ring group,
(ii) —H, halogen, —OH, lower alkyl, halogeno-lower alkyl, —CN, —O-lower alkyl, —O-halogeno-lower alkyl, heteroaryl which may be substituted with lower alkyl, -Alk-OH, -Alk-CONH2, -Alk-saturated hetero ring group or —S—RN,
RN: (1) -Alk-OH, (2) -Alk-CONH2, (3) -Alk-heteroaryl, (4) -Alk-saturated hetero ring group, or (5) saturated hetero ring group which may be substituted with (—CO—O-Alk-aryl),
A:
R3: —H, halogen, lower alkyl, —O-lower alkyl or —CN,
R4: —H, halogen, —OH, —O-Alk-R4a, cycloalkyl which may be substituted with —CN, —CN, —CO2H, —CO—O-lower alkyl, —CO—NH-heteroaryl, —CO—NH—SO2-lower alkyl, —CO—NH—SO2—NRARB, saturated hetero ring group, —O-saturated hetero ring group, —CO-saturated hetero ring group, —SO2-saturated hetero ring group, —CO—NR4bR4c, or lower alkyl which may be substituted with group(s) selected from Group G3 below,
R4a: —H, —OH, —O-lower alkyl, —O-Alk-aryl, —S-lower alkyl, —SO2-lower alkyl or —NH—RO,
RO: —H, —CO—O-lower alkyl, —CO-lower alkyl or —SO2-lower alkyl,
R4b: the same as or different from each other, each representing —H or lower alkyl,
R4c: the same as or different from each other, each representing —H, lower alkyl, -Alk-O-lower alkyl, -Alk-NRARB, -Alk-aryl, -Alk-saturated hetero ring group, cycloalkyl, aryl or saturated hetero ring group,
Group G3: halogen, —OH, —O-lower alkyl, —O—CO-lower alkyl, —O-Alk-O-lower alkyl, —CN, —CO2H, —CO—O-lower alkyl, —NR4bR4c, cyclic amino and —CO-saturated hetero ring group,
wherein each saturated hetero ring group in R4, the saturated hetero ring group in the —CO-saturated hetero ring group of Group G3, and the cyclic amino in Group G3 may be substituted with group(s) selected from Group G4 below,
and two substituents on the cyclic amino in Group G3 may be combined to form -Alk-,
saturated hetero ring which may be substituted with group(s) selected from the group consisting of lower alkyl and oxo, or cycloalkane, may be spiro bonded on the cyclic amino,
and arene which may be substituted with group(s) selected from the group consisting of halogen, lower alkyl, and —O-lower alkyl, heteroarene, cycloalkane or saturated hetero ring, may be condensed with the cyclic amino,
Group G4: halogen, lower alkyl, halogeno-lower alkyl, —OH, —O-lower alkyl, —O-aryl, —O—CO-lower alkyl, —CO—O-lower alkyl, —NRARB, —NH—CO-lower alkyl, -Alk-OH, -Alk-O-lower alkyl, —CO-lower alkyl, —CO—NRARB, -Alk-aryl, -Alk-heteroaryl, -Alk-NRARB, -Alk-CO—NRARB, -Alk-cyclic amino, -Alk-NH-aryl, -Alk-S-lower alkyl, -Alk-halogeno-lower alkyl, cycloalkyl, aryl, heteroaryl, cyclic amino, —SO2-lower alkyl, —SO2—NRARB, oxo and —CN,
wherein each aryl and each heteroaryl in Group G4 may be substituted with group(s) selected from Group G5 below,
Group G5: halogen, lower alkyl, halogeno-lower alkyl, —O-lower alkyl, —NRARB and -Alk-O-lower alkyl,
R5: —H, halogen, lower alkyl, —OH, —O-lower alkyl, —CN, halogeno-lower alkyl, -Alk-OH, -Alk-O-lower alkyl, -Alk-CN, —O-Alk-NH2, —O-Alk-NH—CO—O-lower alkyl, —O-Alk-aryl or —CONH2,
wherein R4 and R5 may be combined with the carbon atom on the benzene ring to which they are bonded to form (1) pyrazole ring, (2) 2,3-dihydro-1,4-dioxine ring, or (3) cyclopentene ring which may be substituted with —OH or oxo,
R6: —H, halogen, lower alkyl, or —O-lower alkyl,
R7: —H, lower alkyl, —CO2H, —CO—O-lower alkyl, —CO-saturated hetero ring group or -Alk-saturated hetero ring group,
R8: —H or lower alkyl, and
R9: —H, lower alkyl or -Alk-saturated hetero ring group,
provided that 1) in the case where R2 is a group selected from (ii), R1 is a group represented by the formula (II) or (III), 2) in the case where R2 is —H, any one group of R3 to R6 and R7 are a group other than —H, and 3) in the case where R1 is heteroaryl, A is phenylene which may be substituted.
The same applies hereinafter.)
[2] The compound or a salt thereof of [1], wherein R1 is a group represented by the formula (II) or the formula (III), and R2 is a group represented by the formula (IV) or the formula (V).
[3] The compound or a salt thereof of [2], wherein R2 is a group represented by the formula (IV).
[4] The compound or a salt thereof of [3], wherein A is a ring group represented by the following formula:
A:
[5] The compound or a salt thereof of [4], wherein R3 and R5 are the same as or different from each other, and each represents —H, halogen, lower alkyl or —O-lower alkyl, R4 is (1) —H, (2) halogen, (3) —O-lower alkyl, (4) cycloalkyl which may be substituted with —CN, (5) saturated hetero ring group which may be substituted with group(s) selected from the group consisting of lower alkyl and -Alk-O-lower alkyl, (6) —O-saturated hetero ring group, or (7) lower alkyl which may be substituted with group(s) selected from Group G3A, R6 is —H or —O-lower alkyl, and R7 and R8 are the same as or different from each other, and each represents —H or -lower alkyl;
wherein
Group G3A: —O-lower alkyl, —O-Alk-O-lower alkyl, —NR4dR4e and cyclic amino,
R4d: lower alkyl,
R4e: lower alkyl, -Alk-O-lower alkyl, or -Alk-saturated hetero ring group,
and the cyclic amino in Group G3A may be substituted with group(s) selected from the group consisting of F, lower alkyl, —O-lower alkyl and -Alk-O-lower alkyl,
two substituents on the cyclic amino in Group G3A may be combined to form -Alk-,
saturated hetero ring which may be substituted with group(s) selected from the group consisting of lower alkyl and oxo, or cycloalkane, may be Spiro bonded on the cyclic amino,
and arene which may be substituted with group(s) selected from the group consisting of halogen, lower alkyl and —O-lower alkyl, heteroarene, cycloalkane or saturated hetero ring, may be condensed with the cyclic amino.
[6] The compound or a salt thereof of [5], wherein in R1, R1a of the group represented by the formula (II) is (1) -Alk-O-lower alkyl, (2) saturated hetero ring group which may be substituted with group(s) selected from the group consisting of lower alkyl, lower alkenyl, -Alk-O-lower alkyl and -Alk-aryl, or (3) -Alk-(saturated hetero ring group which may be substituted with lower alkyl or —OH), R1b is lower alkyl, and the cyclic amino represented by the formula (III) is cyclic amino which may be substituted with group(s) selected from Group G1A below;
Group G1A: F, —OH, lower alkyl, —O-lower alkyl, -Alk-O-lower alkyl and —O-(heteroaryl which may be substituted with group(s) selected from the group consisting of halogen, lower alkyl, —O-lower alkyl, —CN and —OH).
[7] The compound or a salt thereof of [6], wherein in R2, R2a of the group represented by the formula (IV) is —O—RE, —CH2—RF or —NRGRH, wherein RE is lower alkyl, RF is —H, heteroaryl or saturated hetero ring group, RG is —H, and RH is (1) —H, (2) cycloalkyl, (3) saturated hetero ring group which may be substituted with lower alkyl, (4) heteroaryl which may be substituted with lower alkyl, or (5) lower alkyl which may be substituted with group(s) selected from the group consisting of F, —OH, cycloalkyl, —O-lower alkyl, saturated hetero ring group, and heteroaryl.
[8] The compound or a salt thereof of [7], wherein R3, R6, R7, and R8 are —H.
[9] An azolecarboxamide compound represented by the following formula (I-A) or a salt thereof:
(the symbols in the formula have the following meanings:
X: S or O,
R1A: a group represented by the formula (II-A) or a group represented by the formula (III-A),
Alk: the same as or different from each other, each representing lower alkylene,
R1c: -Alk-O-lower alkyl, saturated hetero ring group which may be substituted with lower alkyl, or -Alk-saturated hetero ring group,
R1d: lower alkyl,
Q1: cyclic amino which may be substituted with group(s) selected from Group G1B below,
Group G1B: F, —OH, —O-lower alkyl, or —O-(heteroaryl which may be substituted with group(s) selected from the group consisting of halogen, lower alkyl, —O-lower alkyl, —CN, and —OH),
R2A:
R2C: —O-lower alkyl, —CH2—RW or —NH—RX,
RW: —H, heteroaryl or saturated hetero ring group,
RX: (1) —H, (2) cycloalkyl, (3) saturated hetero ring group, (4) heteroaryl, or (5) lower alkyl which may be substituted with group(s) selected from the group consisting of F, cycloalkyl, —O-lower alkyl and saturated hetero ring group,
A1:
R4A: (1) —H, (2) cycloalkyl substituted with one —CN, (3) saturated hetero ring group which may be substituted with group(s) selected from the group consisting of lower alkyl and -Alk-O-lower alkyl, (4) —O-lower alkyl, (5) —O-saturated hetero ring group, or (6) lower alkyl which may be substituted with one group selected from Group G3B below,
Group G3B: —O-lower alkyl, —NR4fR4g and cyclic amino,
R4f: lower alkyl,
R4g: lower alkyl which is the same as or different from R4f, which may be substituted with one group selected from the group consisting of —O-lower alkyl and saturated hetero ring group,
wherein the cyclic amino in Group G3B may be substituted with group(s) selected from the group consisting of F, lower alkyl, —O-lower alkyl and -Alk-O-lower alkyl,
and cycloalkane may be Spiro bonded on the cyclic amino in Group G3B, and arene or cycloalkane may be condensed with the cyclic amino in Group G3B, and
R5A: —H, lower alkyl or —O-lower alkyl.
The same applies hereinafter.)
[10] The compound or a salt thereof of [9], wherein R2C is —NH—RX.
[11] The compound of [1], which is selected from the group consisting of:
[12] A pharmaceutical composition comprising the compound or a salt thereof of [1], and a pharmaceutically acceptable excipient.
[13] The pharmaceutical composition of [12], which is a trkA receptor inhibitor.
[14] The pharmaceutical composition of [12], which is a prophylactic and/or therapeutic agent for urinary frequency, urinary urgency, urinary incontinence and lower urinary tract pain associated with various lower urinary tract diseases, and various diseases accompanied by pain.
[15] The pharmaceutical composition of [14], wherein the lower urinary tract disease is overactive bladder, interstitial cystitis, or chronic prostatitis.
[16] Use of the compound or a salt thereof of [1] for the manufacture of a prophylactic and/or therapeutic agent for urinary frequency, urinary urgency, urinary incontinence and lower urinary tract pain associated with various lower urinary tract diseases, and various diseases accompanied by pain.
[17] The use of [16], wherein the lower urinary tract disease is overactive bladder, interstitial cystitis, or chronic prostatitis.
[18] A method for preventing and/or treating urinary frequency, urinary urgency, urinary incontinence and lower urinary tract pain associated with various lower urinary tract diseases, and various diseases accompanied by pain, which comprises administering to a patient an effective amount of the compound or a salt thereof of [1].
[19] The method for preventing and/or treating of [18], wherein the lower urinary tract disease is overactive bladder, interstitial cystitis, or chronic prostatitis.
The compound of the present invention has potent trkA receptor inhibitory activity and excellent action for improving the condition of urinary frequency, and is expected to have effects of improving pain, and thus, it is useful as a therapeutic and/or prophylactic agent for urinary frequency, urinary urgency and urinary incontinence associated with various lower urinary tract diseases including overactive bladder, and various lower urinary tract diseases accompanied by lower urinary tract pain, such as interstitial cystitis, chronic prostatitis, and the like as well as various diseases accompanied by pain.
Hereinafter, the present invention will be described in more detail. Furthermore, in the present specification, the “azolecarboxamide compound represented by the formula (I) or a salt thereof” may be simply referred to as “the compound (I) of the present invention”, “the compound of the formula (I)”, or the like.
In the present specification, the term “lower” means a linear or branched carbon chain having 1 to 6 carbon atoms (hereinafter simply referred to as C1-6), unless otherwise specifically mentioned.
The “lower alkyl” is C1-6 alkyl, and preferably linear alkyl such as methyl, ethyl, n-propyl, n-butyl, and the like, and branched alkyl such as isopropyl, isobutyl, tert-butyl, neopentyl, and the like. More preferred is C1-4 alkyl, and particularly preferred is methyl, ethyl, n-propyl, isopropyl, or tert-butyl. The “lower alkylene” preferably refers to a divalent group formed by the removal of any hydrogen atoms of the C1-6 alkylene, and preferably C1-5 alkylene such as methylene, ethylene, methylmethylene, ethylmethylene, methylethylene, trimethylene, tetramethylene, dimethylethylene, pentamethylene, or 2,2-dimethyltrimethylene.
The “lower alkenyl” means C2-6 alkenyl, preferably vinyl, allyl, or 2-butenyl, and more preferably 2-butenyl.
The “halogen” means F, Cl, Br, and I.
The “halogeno-lower alkyl” means C1-6 alkyl substituted with one or more halogens, preferred is C1-6 alkyl substituted with one or more F or Cl, and more preferred is fluoroethyl, fluoropropyl, difluoromethyl, difluoroethyl, or trifluoromethyl.
The “cycloalkyl” is a C3-10 saturated hydrocarbon ring group, which may have a bridge. Preferred is C3-8 cycloalkyl, and more preferred is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. The cycloalkyl having a bridge is preferably a bicyclo[2.2.1]heptyl or adamantyl. In addition, the “cycloalkane” means a ring constituting the “cycloalkyl”, for example, a cyclohexane ring corresponding to cyclohexyl.
The “cycloalkenyl” is a C3-10 unsaturated hydrocarbon ring group, which may have a bridge. Preferred is C3-8 cycloalkenyl, and more preferred is cyclopentenyl or cyclohexenyl.
The “aryl” is a C6-14 mono- to tricyclic aromatic hydrocarbon ring group, preferred is a phenyl or naphthyl group, and more preferred is phenyl. The aryl may be condensed with a monocyclic saturated hetero ring or monocyclic cycloalkane. Further, the “arene” means a ring constituting the “aryl”, for example, a benzene ring corresponding to phenyl.
The “heteroaryl” is a generic term referring to i) a 5- to 6-membered monocyclic aromatic ring group (monocyclic heteroaryl) containing 1 to 4 hetero atoms selected from O, S, and N, and ii) a bicyclic or tricyclic heteroaryl, formed by condensation between monocyclic heteroaryls, between a benzene ring and monocyclic heteroaryl, or between saturated hetero ring as described later and monocyclic heteroaryl. The monocyclic heteroaryl is preferably pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, or thiadiazolyl, and more preferably pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, thiazolyl, oxadiazolyl, or tetrazolyl. The bicyclic or tricyclic heteroaryl formed by condensation between a benzene ring and monocyclic heteroaryl is preferably benzofuranyl, benzothienyl, indolyl, benzimidazolyl, indazolyl, benzothiazolyl, benzoisothiazolyl, benzoxazolyl, benzoisoxazolyl, quinolyl, isoquinolyl, quinazolyl, or quinoxalinyl, and more preferably indolyl, benzimidazolyl, or quinolyl.
Further, specific examples of the bicyclic or tricyclic heteroaryl formed by condensation between saturated hetero ring and monocyclic heteroaryl include 6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl and the like.
In the “heteroaryl”, the ring atom S may be oxidized to form an oxide or dioxide, and N may be oxidized to form an oxide.
The “heteroarene” means a ring constituting the “heteroaryl”, and examples thereof include a thiophene ring corresponding to thienyl.
The “saturated hetero ring group” is a 3- to 10-membered saturated hetero ring group containing 1 to 4 hetero atoms of N, O and/or S, and preferably the following groups.
(1) the groups containing 1 to 2 N atoms, specifically azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperadinyl, azepanyl, diazepanyl, and the like, and more preferably azetidinyl, pyrrolidinyl, piperidyl, piperadinyl, azepanyl, or diazepanyl;
(2) the groups containing one N atom, and one S atom and/or one O atom, specifically thiazolidinyl, isothiazolidinyl, oxazolidinyl, thiomorpholinyl, morpholinyl, oxazepanyl, and the like, and more preferably oxazolidinyl, morpholinyl, thiomorpholinyl, or oxazepanyl;
(3) the groups containing 1 to 2 S atoms, and specifically tetrahydrothienyl and the like;
(4) the groups containing one S atom and one O atom, and specifically oxathiolanyl and the like; and
(5) the groups containing 1 to 2 O atoms, specifically oxetanyl, tetrahydrofuryl, dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl, and the like, and more preferably oxetanyl, tetrahydrofuryl, tetrahydropyranyl, or 1,4-dioxanyl.
The “saturated hetero ring” means a ring constituting the “saturated hetero ring group”, for example, a tetrahydrofuran ring corresponding to tetrahydrofuryl.
In the “saturated hetero ring”, the saturated hetero ring may have a bridge, and may be condensed with arene, heteroarene, or cycloalkane. Further, the ring atom S may be oxidized to form an oxide or dioxide, and N may be oxidized to form an oxide.
The saturated hetero ring group having a bridge is specifically quinuclidinyl, 8-azabicyclo[3.2.1]octyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 7-azabicyclo[2.2.1]heptyl, or the like.
The saturated hetero ring group formed by condensation with arene, heteroarene, or cycloalkane is specifically indolinyl, isoindolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroisoquinolyl, tetrahydrothienopyridyl, tetrahydrothiazolopyridyl, chromanyl, isochromanyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrofuro[2,3-b]pyridyl, or the like, and more preferably 2,3-dihydrobenzofuranyl or 2,3-dihydropyridofuranyl.
The “nitrogen-containing saturated hetero ring group” means, among the “saturated hetero ring group”, a 3- to 8-membered saturated hetero ring group containing at least one N atom as in (1) and (2). It is preferably a 4- to 7-membered nitrogen-containing saturated hetero ring group, and specifically azetidinyl, pyrrolidinyl, piperidyl, piperadinyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, oxazepanyl, and the like.
The “nitrogen-containing saturated hetero ring” means a ring constituting the “nitrogen-containing saturated hetero ring group”, for example, a pyrrolidine ring corresponding to pyrrolidinyl.
The nitrogen-containing saturated hetero ring may have a bridge, and may be formed by condensation with arene, heteroarene, or cycloalkane.
The nitrogen-containing saturated hetero ring formed by condensation of arene, heteroarene, or cycloalkane is specifically indolinyl, isoindolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroisoquinolyl, tetrahydrothieno[3,2-c]pyridyl, tetrahydro[1,3]thiazolo[5,4-c]pyridyl, and the like.
The “cyclic amino” particularly means a ring group having a binding arm on an N atom among the “nitrogen-containing saturated hetero ring group”, the nitrogen-containing heteroaryl, and a partially saturated nitrogen-containing heteroaryl, and specifically 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, 1-piperadinyl, 4-morpholinyl, 4-thiomorpholinyl, 1-azepanyl, 1,4-diazepan-1-yl, 1,4-oxazepan-4-yl, 1-imidazolidinyl, 1,3-oxazolidin-3-yl, 1-dihydropyrrolyl, 1-tetrahydropyridyl, 1-azepinyl, 1-pyrrolyl, 1-imidazolyl, and the like. It is preferably a nitrogen-containing saturated hetero ring group having a binding arm on an N atom, and more preferably 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, 1-piperadinyl, 4-morpholinyl, 4-thiomorpholinyl, 1-azepanyl, or 1,4-diazepan-1-yl.
In the “cyclic amino”, the cyclic amino may have a bridge (the cyclic amino in which two substituents on the cyclic amino are combined to form -Alk-), may be condensed with arene, heteroarene, cycloalkane, or saturated hetero ring, or formed by the Spiro bonding with the cycloalkane or saturated hetero ring.
Specific examples of the cyclic amino having a bridge include 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, 8-azabicyclo[3.2.1]oct-8-yl, 7-azabicyclo[2.2.1]hept-7-yl, and the like.
Specific examples of the cyclic amino formed by condensation with arene, heteroarene, cycloalkane, or saturated hetero ring include 4-benzoxadinyl, 1-indolinyl, 1-tetrahydroquinolyl, 2-tetrahydroisoquinolyl, 1-tetrahydroquinoxalinyl, tetrahydrothieno[3,2-c]pyridin-5-yl, tetrahydro[1,3]thiazolo[5,4-c]pyridin-5-yl, tetrahydropyrrolo[1,2-a]pyradin-2-yl, 1-decahydroquinolyl, 2-decahydroquinolyl, octahydrocyclopenta[b][1,4]oxadin-4-yl, octahydropyrrolo[1,2-a]pyrazin-2-yl, octahydro-2H-pyrido[1,2-a]pyrazin-2-yl, and the like.
Specific examples of the cyclic amino formed by the spiro bonding with a cycloalkane or saturated hetero ring include 2-azaspiro[4.4]nonan-2-yl, 2-azaspiro[4.5]decan-2-yl, 8-azaspiro[4.5]decan-8-yl, 8-oxa-5-azaspiro[3.5]nonan-5-yl, 2-azaspiro[5.5]undecan-2-yl, 1-oxa-8-azaspiro[4.5]decan-8-yl, 2-oxa-8-azaspiro[4.5]decan-8-yl, 1-oxa-3,8-diazaspiro[4.5]decan-8-yl, 1,4-dioxa-8-azaspiro[4.5]decan-8-yl, 2,8-diazaspiro[4.5]decan-8-yl, and the like.
The expression “which may be substituted” represents “which is unsubstituted” or “which is substituted with 1 to 5 substituents and preferably 1 to 3 substituents, which are the same as or different from each other”. Further, if it has a plurality of substituents, the substituents may be the same as or different from each other, or the substitutions may be present at the same atom.
Preferred embodiments of the compound (I) of the present invention are presented below.
(1) X is preferably S. In other preferred embodiments, X is O.
(2) R1 is preferably a group represented by the formula (II) or the formula (III).
In this connection,
R1a in the formula (II) is preferably (a) -Alk-O-lower alkyl, (b) saturated hetero ring group which may be substituted with group(s) selected from the group consisting of lower alkyl, lower alkenyl, -Alk-O-lower alkyl, and -Alk-aryl, or (c) -Alk-(saturated hetero ring group which may be substituted with lower alkyl or —OH), more preferably -Alk-O-lower alkyl, saturated hetero ring group which may be substituted with lower alkyl, or an -Alk-saturated hetero ring group.
The saturated hetero ring group in the saturated hetero ring group and the -Alk-saturated hetero ring group of R1a is preferably azetidinyl, pyrrolidinyl, piperidyl, oxetanyl, tetrahydrofuryl or tetrahydropyranyl, each of which has a binding arm on a carbon atom of the ring.
R1b in the formula (II) is preferably lower alkyl, and more preferably methyl.
The ring group Q represented by the formula (III) is preferably cyclic amino which may be substituted with group(s) selected from the Group G1A, more preferably cyclic amino which may be substituted with group(s) selected from the Group G1B, still more preferably 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl or 4-morpholinyl, each of which may each be substituted with group(s) selected from the Group G1B, and yet still more preferably 1-pyrrolidinyl, 1-piperidyl or 4-morpholinyl, each of which may each be substituted with group(s) selected from the Group G1B.
(3) R2 is preferably a group represented by the formula (IV) or the formula (V), and more preferably a group represented by the formula (IV).
In this connection,
the compound wherein R2a in the formula (IV) is —O—RE, —CH2—RF or —NRGRH, in which RE is lower alkyl, RF is —H, heteroaryl or saturated hetero ring group, RG is —H, and RH is (1) —H, (2) cycloalkyl, (3) saturated hetero ring group which may be substituted with lower alkyl, (4) heteroaryl which may be substituted with lower alkyl, or (5) lower alkyl which may be substituted with group(s) selected from the group consisting of F, —OH, cycloalkyl, —O-lower alkyl, saturated hetero ring group and heteroaryl is preferable, the compound wherein R2a is —O-lower alkyl, methyl, —CH2-heteroaryl, —CH2-saturated hetero ring group, or —NH—Rx, in which Rx is (1) —H, (2) cycloalkyl, (3) saturated hetero ring group, (4) heteroaryl, or (5) lower alkyl which may be substituted with group(s) selected from the group consisting of F, cycloalkyl, —O-lower alkyl, and saturated hetero ring group is more preferable, and the compound wherein R2a is —NH—RX is still more preferable.
(4) A is preferably
and more preferably
In this connection,
R3 is preferably —H, halogen, lower alkyl, or —O-lower alkyl, and more preferably —H.
R4 is preferably (a) —H, (b) halogen, (c) —O-lower alkyl, (d) cycloalkyl which may be substituted with —CN, (e) saturated hetero ring group which may be substituted with group(s) selected from the group consisting of lower alkyl and -Alk-O-lower alkyl, (f) —O-saturated hetero ring group, or (g) lower alkyl which may be substituted with group(s) selected from the Group G3A, more preferably (a) —H, (b) cycloalkyl substituted with one —CN, (c) saturated hetero ring group which may be substituted with group(s) selected from the group consisting of lower alkyl and -Alk-O-lower alkyl, (d) —O-lower alkyl, (e) —O-saturated hetero ring group, or (f) lower alkyl substituted with one group selected from the Group G3B, and still more preferably —H, cycloalkyl substituted with one —CN, —O-lower alkyl, or lower alkyl substituted with one group selected from the Group G3B.
R5 is preferably —H, halogen, lower alkyl, or —O-lower alkyl, more preferably —H, lower alkyl, or —O-lower alkyl, and still more preferably —H.
R6 is preferably —H or —O-lower alkyl, and more preferably —H.
R7 is preferably —H or lower alkyl, and more preferably —H.
R8 is preferably —H or lower alkyl, and more preferably —H.
In particularly preferred embodiments, the compound (I) of the present invention is a compound formed by the combination of preferred groups as described in (1) to (4) above, and specific examples thereof include the compounds as described in [1] to [11] above.
Another preferred embodiment of the compound (I) of the present invention is a compound represented by the formula (I-A).
Further, a particularly preferred embodiment of the compound represented by the formula (I-A) is the compound in which R2C is —NH—RX.
The compound of the formula (I) may have tautomers or geometrical isomers in some cases, depending on the kind of substituents. In the present specification, the compound of the formula (I) shall be described in only one form of isomer, yet the present invention includes other isomers, isolated forms of the isomers, or a mixture thereof. Examples of the tautomers include tautomers between 3-hydroxypyridazine and 2,3-dihydropyridazin-3-one.
In addition, the compound of the formula (I) may have asymmetric carbon atom(s) or axial asymmetry in some cases, and correspondingly, it may exist in the form of optical isomers. The present invention includes both an isolated form of these optical isomers of the compound of the formula (I) or a mixture thereof.
In addition, the pharmaceutically acceptable prodrugs of the compound represented by the formula (I) are also included in the present invention. The pharmaceutically acceptable prodrug refers to a compound having a group which can be converted into amino group, hydroxyl group, carboxyl group, or the like, by solvolysis or under a physiological condition. Examples of the group for forming a prodrug include those as described in Prog. Med., 5, 2157-2161 (1985) or “Iyakuhin no Kaihatsu (Pharmaceutical Research and Development)” (Hirokawa Publishing Company, 1990), vol. 7, Bunshi Sekkei (Drug Design), 163-198.
Furthermore, the compound of the formula (I) may form an acid addition salt or a salt with a base, depending on the kind of substituents, and these salts are included in the present invention as long as they are pharmaceutically acceptable salts. Specifically, examples thereof include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and salts with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyl tartaric acid, ditolyl tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid, and the like, and salts with inorganic bases such as sodium, potassium, magnesium, calcium, aluminum, and the like or salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine, ornithine, and the like, salts with various amino acids or amino acid derivatives such as acetylleucine and the like, ammonium salts, and others.
In addition, the present invention also includes various hydrates or solvates, and any of crystalline polymorphs of the compound of the formula (I) and a pharmaceutically acceptable salt thereof. Also, the present invention includes compounds labeled with various radioactive or non-radioactive isotopes.
(Production Processes)
The compound of the formula (I) and a pharmaceutically acceptable salt thereof can be prepared by applying various known synthetic methods, using the characteristics based on their basic skeletons or the kind of substituents. At this time, depending on the type of the functional groups, it is in some cases effective, from the viewpoint of the preparation techniques, to substitute the functional group with an appropriate protective group (a group which is capable of being easily converted into the functional group), during the stage of starting material or intermediate. Examples of the protective group include the protective groups described in “Protective Groups in Organic Synthesis (3rd edition, 1999)”, written by Greene and Wuts, and the like, which may be appropriately selected and used depending on reaction conditions. In these methods, a desired compound can be obtained by introducing the protective group to carry out the reaction, and then, if desired, removing the protective group.
In addition, the prodrug of the compound of formula (I) can be prepared by introducing a specific group during the stage of starting material or intermediate, in the same manner as for the aforementioned protective groups, or by carrying out the reaction using the obtained compound of formula (I). The reaction can be carried out by applying a method known to a person skilled in the art, such as common esterification, amidation, dehydration, and the like.
Hereinbelow, the representative production processes for the compound of formula (I) will be described. Each of the production processes may also be carried out with reference to the References appended in the explanation. Further, the production processes of the present invention are not limited to the examples as shown below.
(First Production Process)
This step is a step for preparing the compound (I) of the present invention by subjecting a compound (2) or a reactive derivative thereof, and a compound (I) or a salt thereof to amidation by a conventional method, and then if desired, removing the protective group.
Examples of the reactive derivative of the compound (2) include a common ester such as methyl ester, ethyl ester, tert-butyl ester, and the like; an acid halide such as acid chloride, acid bromide, and the like; an acid azide; an active ester with 1-hydroxybenzotriazole, p-nitrophenol, N-hydroxysuccinimide, or the like; a symmetric acid anhydride; a mixed acid anhydride with a halocarboxylic acid alkyl ester such as an alkyl halocarbonate, a pivaloyl halide, a p-toluenesulfonic acid chloride, and the like; a mixed acid anhydride such as a phosphoric mixed acid anhydride obtained by the reaction of diphenylphosphoryl chloride, N-methylmorpholine, and the like; etc.
If the compound (2) is reacted as a free acid, or is reacted without isolation of an active ester, or the like, amidation usually used by a person skilled in the art can be used, but a method in which a condensing agent such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC-HCl), or dicyclohexylcarbodiimide (DCC), carbonyldiimidazole (CDI), diphenylphosphoryl azide (DPPA), diethylphosphorylcyanide (DEPC), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), N,N,N′,N′-tetramethylfluoroformamidinium hexafluorophosphate (TFFH), and the like are allowed to undergo the reaction in the presence of 1-hydroxybenzotriazole (HOBt), a method in which phosphorus oxychloride is allowed to undergo the reaction in a pyridine solvent, or a condensing agent-supported polystyrene resin, for example, PS-carbodiimide (Argonaut Technologies, Inc., USA) or PL-DCC resin (Polymer Laboratories, UK) is preferably used.
Also, in some cases, it is preferable to use an isocyanate-supported polystyrene resin, for example, PS-Isocyanate (Argonaut Technologies, Inc., USA) and the like in order to remove an excess amount of amine after completion of the reaction. Further, it is preferable in some cases to use a quaternary ammonium salt-supported polystyrene resin such as MP-Carbonate (Argonaut Technologies, Inc., USA) and the like in order to remove an excess amount of carboxylic acid, and the aforementioned additive such as HOBt and the like after completion of the reaction. In addition, it is preferable in some cases to use a primary ammine-supported polystyrene resin such as PS-Trisamine (Argonaut Technologies, Inc., USA) and the like in order to remove an excess amount of electrophilic reagents (acid chlorides and the like) after completion of the reaction.
Particularly, in the present invention, an acid chloride method, and a method for performing a reaction in the coexistence of an active esterifying agent and a condensing agent are convenient.
The reaction varies according to the reactive derivatives, condensing agents, or the like used, but usually, is carried out under cooling, from under cooling to at room temperature, or from at room temperature to under heating, in a organic solvent inert to the reaction, for example, halogenated hydrocarbons such as methylenechloride, dichloroethane, chloroform, and the like; aromatic hydrocarbons such as benzene, toluene, xylene, and the like; ethers such as ether, tetrahydrofuran (THF), and the like; esters such as ethyl acetate (EtOAc) and the like; acetronitrile, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), and the like.
Furthermore, in the reaction, it is in some cases advantageous in advancing the reaction smoothly to carry out the reaction with an excess amount of the compound (I) or in the presence of a base such as N-methylmorpholine, trimethylamine, triethylamine, diisopropylethylamine, N,N-dimethylaniline, pyridine, 4-(N,N-dimethylamino)pyridine, picoline, lutidine, and the like. Also, a salt formed from a weak base and a strong acid, such as pyridine hydrochloride, pyridine p-toluenesulfonate, N,N-dimethylaniline hydrochloride, and the like, may be used. Pyridine may be used as a solvent.
Particularly, it is preferable to carry out the reaction in the presence of a base such as triethylamine and the like in a solvent such as THF, DMF, and the like.
(Second Production Process)
(wherein Lv1 represents a leaving group, and preferably halogen, —SMe, —SOMe, —SO2Me, —SO3H, or —O—SO2CF3. The same applies hereinafter.)
This step is a step for preparing a compound (I-a) in which R1 is a group represented by the formula (II) or a compound (I-b) in which R1 is a group represented by the formula (III) in the compound (I) of the present invention, by reacting a compound (3) having a leaving group at the 2-position on the azole and a compound (4) or (5). Furthermore, the compound (3) can be prepared in accordance with the first production process, and in the case where Lv1 is halogen, it is included in the compound (I) of the present invention.
The nucleophilic substitution reaction of this step can be carried out in a organic solvent inert to the reaction, such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, esters, alcohols such as methanol, ethanol, isopropanol, and the like, acetonitrile, DMF, DMA, DMSO, and others in the presence of an organic base such as triethylamine, diisopropylethylamine, and the like and/or an inorganic base such as potassium carbonate, sodium carbonate, cesium carbonate, sodium hydrogen carbonate, sodium hydride, and the like. Further, in order to accelerate the reaction, a catalyst such as 4-(N,N-dimethylamino)pyridine and the like may be added. Also, instead of the organic base and/or the inorganic base, the compound (4) or (5) may be used in an excess amount. The reaction is carried out in a manner varying according to the base to be used, but it can be carried out from under cooling to at room temperature, from at room temperature to under heating, or from at room temperature to under reflux.
Also, depending on the case, it is preferable in some cases to use an isocyanate-supported polystyrene resin, for example, PS-Isocyanate (Argonaut Technologies, Inc., USA) or the like in order to remove an excess amount of amine after completion of the reaction.
(Third Production Process)
(wherein R represents lower alkyl. The same applies hereinafter.)
Step 1
This step is a step for preparing a compound (I-d) in which R2 is a carboxylic group by hydrolyzing a compound (I-c) in which R2 is an ester with respect to the compound (I) of the present invention. The hydrolysis reaction of this step can be carried out in accordance with, for example, the deprotection reaction as described in the “Protective Groups in Organic Synthesis (third edition)” above. Further, the compound (I-c) can be prepared in accordance with the first production process.
Step 2
This step is a step for preparing a compound (I-e) by subjecting a compound (I-d) and a compound (6) to an amidation reaction. The amidation reaction of this step can be carried out in accordance with the first production process.
(Fourth Production Process)
Step 1
This step is a step for preparing a compound (7) by subjecting the compound (I-d) synthesized according to the third production process or a reactive derivative thereof to an intramolecular cyclization reaction. The cyclization reaction of this step can be carried out by subjecting a condensing agent to react with a carboxylic acid, or by using the reactive derivative of carboxylic acid in accordance with the first production process. In order to accelerate the reaction, a catalyst such as 4-(N,N-dimethylamino)pyridine and the like may be added. The reaction can be carried out in an organic solvent inert to the reaction such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, esters, acetonitrile, DMF, DMA, DMSO, and the like, from under cooling to room temperature, from at room temperature to under heating, or from at room temperature to under reflux.
Step 2
This step is a step for preparing a compound (I-e) by allowing a compound (7) to undergo a reaction with a compound (6). The ring-opening reaction can be carried out in an organic solvent inert to the reaction, such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, esters, alcohols, acetonitrile, acetic acid, DMF, DMA, DMSO, and the like. Furthermore, in order to accelerate the reaction, a catalyst such as p-toluenesulfonic acid and the like may be added. The reaction can be carried out from under cooling to room temperature, from at room temperature to under heating, or from at room temperature to under reflux.
(Fifth Production Process)
This step is a step for preparing a compound (I-g) by oxidizing a compound (I-f). The oxidation reaction of this step can employ a sulfide oxidation reaction, which is usually employed by a person skilled in the art. For example, an oxidation reaction using peracids such as hydrogen peroxide, m-chloroperbenzoic acid, and the like may be mentioned. The reaction can be carried out, for example, with reference to a method as described in “Jikken Kagaku Koza (Courses in Experimental Chemistry) (4th edition)”, edited by The Chemical Society of Japan, vol. 23 (1992) (Maruzen).
(Sixth Production Process)
Moreover, the compounds of the present invention represented by formula (I) having various functional groups can be prepared from the compound of the present invention obtained by the first production process, the second production process, the third production process, the fourth production process, or the fifth production process, by any combination of the steps that can usually be employed by a person skilled in the art, such as alkylation, acylation, a substitution reaction, oxidation, reduction, hydrolysis, and the like. This step is not limited to a one-step reaction, but it may consist of a multi-step reaction. Further, the processes that can usually be employed by a person skilled in the art are not limited to the application for the compound of the present invention, but they may be used in the application for the preparation of synthetic intermediates.
Representative reactions are exemplified as below.
(1) Amidation
A compound having an amide group among the compounds (I) of the present invention can be prepared by reacting a compound having an amino group as a starting material with carboxylic acid and a reactive derivative thereof, or by reacting a compound having carboxylic acid as a starting material with an amine. The reaction can be carried out in accordance with Step 1 of First Production Process, for example, with reference to a method as described in “Jikken Kagaku Koza (Courses in Experimental Chemistry) (4th edition)”, vol. 22 (1992) (Maruzen), or “Compendium of Organic Synthetic Methods”, vols. 1 to 3, or the like.
(2) Sulfonylation
A compound having a sulfonamide group, sulfonic ester among the compounds (I) of the present invention can be prepared by reacting a corresponding compound having an amino group, hydroxyl group as a starting material with sulfonic acid and a reactive derivative thereof. The reaction can be carried out, for example, with reference to a method as described in “Jikken Kagaku Koza (Courses in Experimental Chemistry) (4th edition)”, edited by The Chemical Society of Japan, vol. 24 (1992) (Maruzen).
(3) Carbamation
A compound having a carbamate group among the compounds (I) of the present invention can be prepared by reacting a compound having an amino group as a starting material with a carbonate derivative. The reaction can be carried out, for example, with reference to a method as described in “Jikken Kagaku Koza (Courses in Experimental Chemistry) (4th edition)”, edited by The Chemical Society of Japan, vol. (1992) (Maruzen).
(4) O-Acylation
A compound having an ester group among the compounds (I) of the present invention can be prepared by reacting a compound having an hydroxyl group as a starting material with a carboxylic derivative. The reaction can be carried out, for example, with reference to a method as described in “Jikken Kagaku Koza (Courses in Experimental Chemistry) (4th edition)”, edited by The Chemical Society of Japan, vol. 22 (1992) (Maruzen).
(5) O-Alkylation
A compound having an ether skelton among the compounds (I) of the present invention can be prepared by reacting a compound having a hydroxyl group as a starting material with another alkylating agent. As the alkylating agents, an alkyl halide, an organic sulfonic ester of an alcohol, and the like are preferred. The reaction can be carried out, for example, with reference to a method as described in “Jikken Kagaku Koza (Courses in Experimental Chemistry) (4th edition)”, edited by The Chemical Society of Japan, vol. 20 (1992) (Maruzen).
(6) Amination
A compound having a secondary amine or a tertiary amine among the compounds (I) of the present invention can be prepared by reacting a compound having an alkyl halide, an organic sulfonic ester of an alcohol, and the like as a starting material with another compound having a primary amine or a secondary amine. The reaction can be carried out, for example, with reference to a method as described in “Jikken Kagaku Koza (Courses in Experimental Chemistry) (4th edition)”, edited by The Chemical Society of Japan, vol. 20 (1992) (Maruzen).
(7) N-alkylation
A compound having a secondary amine or a tertiary amine among the compounds (I) of the present invention can be prepared by reacting a compound having a primary amino group or a secondary amino group as a starting material with another alkylating agent. As the alkylating agent, alkyl halide, an organic sulfonic ester of alcohol, and the like are preferred. The reaction can be carried out, for example, with reference to a method as described in “Jikken Kagaku Koza (Courses in Experimental Chemistry) (4th edition)”, edited by The Chemical Society of Japan, vol. (1992) (Maruzen).
(8) Reductive Alkylation
A compound having a secondary amine or a tertiary amine among the compounds (I) of the present invention can have an alkyl group introduced thereinto by reacting a compound having a primary amine or a secondary amine as a starting material with an aldehyde and a ketone for performing reductive alkylation, in the presence of a reducing agent such as sodium borohydride, sodium triacetoxyborohydride, and the like, or under a catalytic reduction condition by palladium-carbon, under a hydrogen atmosphere. For example, a method as described in “Jikken Kagaku Koza (Courses in Experimental Chemistry) (4th edition)”, edited by The Chemical Society of Japan, vol. 20 (1992) (Maruzen), or the like, can be exemplified.
(9) Oxidation
A compound having a sulfonyl group among the compounds (I) of the present invention can be prepared by subjecting a compound having a sulfide group to an oxidation reaction. The reaction can be carried out, for example, with reference to a method as described in “Jikken Kagaku Koza (Courses in Experimental Chemistry) (4th edition)”, edited by The Chemical Society of Japan, vol. 23 (1992) (Maruzen).
(10) Reduction
A compound having a primary alcohol among the compounds (I) of the present invention can be prepared by subjecting a corresponding compound having a carboxyl group or ester group to a reduction reaction. The reaction can be carried out, for example, with reference to a method as described in “Jikken Kagaku Koza (Courses in Experimental Chemistry) (4th edition)”, edited by The Chemical Society of Japan, vol. 26 (1992) (Maruzen).
(11) Ipso Substitution
A compound having an alkoxypyridine or alkoxypyrimidine skelton among the compounds (I) of the present invention can be prepared by subjecting a corresponding compound having an alcohol as a starting material to an ipso substitution for chloropyridine, chloropyrimidine, or the like. This reaction can be carried out in an organic solvent inert to the reaction, such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, esters, acetonitrile, DMF, DMA, DMSO, and the like, in the presence of an inorganic base such as cesium carbonate, sodium hydride, and the like, from under cooling to room temperature, from at room temperature to under heating, or from at room temperature to under reflux.
(12) Hydrolysis
A compound having a carboxylic group or an amide group among the compounds (I) of the present invention can be prepared by hydrolyzing a corresponding compound having an ester group, an amide group, or a cyano group. The reaction can be carried out, for example, with reference to a method as described in “Protective Groups in Organic Synthesis (third edition)” or “Jikken Kagaku Koza (Courses in Experimental Chemistry) (4th edition)”, edited by The Chemical Society of Japan, vol. 22 (1992) (Maruzen).
(13) Dehydration
A compound having a cyano group among the compounds (I) of the present invention can be prepared by subjecting a corresponding compound having a carboxamide group to a dehydration reaction. The reaction can be carried out, for example, with reference to a method as described in “Jikken Kagaku Koza (Courses in Experimental Chemistry) (4th edition)”, edited by The Chemical Society of Japan, vol. 20 (1992) (Maruzen).
The starting compounds used in the preparation of the compounds (I) of the present invention can be prepared, for example, by using the following methods, methods described in Preparative Examples as described below, well-known methods, or methods apparent to a person skilled in the art, or variations thereof
(Starting Material Synthesis 1)
Step 1
This step is a step for preparing a compound (9) by esterification of a carboxylic acid group of a compound (8). The reaction can use a conventional esterification condition, and can use a method described, for example, in the protection reaction of a carboxylic group in “Protective Groups in Organic Synthesis (third edition)” above, or the like.
Step 2
This step is a step for preparing a compound (1a) by subjecting the nitro compound (9) to reduction. The reduction reaction of a nitro group of this step can be carried out by using a reduction reaction of a nitro group, which can be usually employed by a person skilled in the art. For example, it can be exemplified by a reduction reaction using a reducing agent such as reduced iron, tin chloride, and the like and a hydrogenation reaction using palladium-carbon, rhodium-carbon, or the like as a catalyst. The reaction can be carried out, for example, with reference to a method as described in “Jikken Kagaku Koza (Courses in Experimental Chemistry) (4th edition)”, edited by The Chemical Society of Japan, vol. 26 (1992) (Maruzen).
(Starting Material Synthesis 2)
(wherein RS represents —H or lower alkyl, and Y represents halogen. Further, RT represents —NR4bR4c or cyclic amino above.)
Step 1
This step is a step for preparing a compound (11) by halogenating a compound (10). The halogenation reaction of this step can be carried out by using a reaction which can usually be employed by a person skilled in the art, for example, a halogenation reaction using N-bromosuccinimide, N-chlorosuccinimide, or the like. The reaction can be carried out, for example, with reference to a method as described in “Jikken Kagaku Koza (Courses in Experimental Chemistry) (4th edition)”, edited by The Chemical Society of Japan, vol. 19 (1992) (Maruzen).
Step 2
This step is a step for preparing a compound (12) by allowing a compound (11) to undergo a reaction with an amine. The amination reaction of this step can be carried out, for example, with reference to a method as described in “Jikken Kagaku Koza (Courses in Experimental Chemistry) (4th edition)”, edited by The Chemical Society of Japan, vol. 20 (1992) (Maruzen).
Step 3
This step is a step for preparing a compound (1b) by reducing a nitro compound (12). The reduction reaction of a nitro group of this step can be carried out by the same method as in the step 2 in the starting material synthesis 1.
(Starting Material Synthesis 3)
(wherein RU represents -Alk-R4a or saturated hetero ring group above)
Step 1
This step is a step for preparing a compound (14) by alkylating a compound (13). The alkylation reaction of this step can use a reaction which can usually be employed by a person skilled in the art. For example, an alkylation reaction using an alkyl halide under basic condition and Mitsunobu reaction are exemplified. The reaction can be carried out, for example, with reference to a method as described in “Jikken Kagaku Koza (Courses in Experimental Chemistry) (4th edition)”, edited by The Chemical Society of Japan, vol. 20 (1992) (Maruzen).
Step 2
This step is a step for preparing a compound (1c) by reducing a nitro compound (14). The reduction reaction of a nitro group of this step can be carried out by the same method as in the step 2 in the starting material synthesis 1.
(Starting Material Synthesis 4)
Step 1
This step is a step for carrying out an amidation reaction from the compound (8) and the compound (6). The reaction can be carried out in accordance with step 1 in the first production process.
Step 2
This step is a step for preparing a compound (1d) by reducing a nitro compound (15). The reduction reaction of a nitro group of this step can be carried out by the same method as in step 2 in the starting material synthesis 1.
(Starting Material Synthesis 5)
(wherein Lv2 represents a leaving group, and preferably halogen or —O—SO2CF3. Rv represents —O—RE or —CH2—RF above.)
This synthesis method is a reaction in which a reaction with carbon monoxide or a coupling reaction is carried out in the presence of transition metal catalyst such as palladium and the like and suitable additives, and an ester or a ketone is introduced, to the compound (16). Examples of the representative methods include a method as described in “Jikken Kagaku Koza (Courses in Experimental Chemistry) (4th edition)”, edited by The Chemical Society of Japan, vol. 25 (1992) (Maruzen).
(Starting Material Synthesis 6)
This synthesis method is a reaction for preparing a compound (1d) by allowing a compound (17) to undergo a reaction with the compound (6). This ring-opening reaction can be carried out in accordance with step 2 of the fourth production process.
(Starting Material Synthesis 7)
(wherein L represents a protective group for a carboxylic acid. The same applies hereinafter.)
Step 1
This step is a method for constructing a thiazole ring by allowing a thioamide or thiourea (18) to undergo the reaction with an α-haloketone, representatively such as bromopyruvic ester and the like. A method described in “Comprehensive Organic Chemistry”, vol. 4, or an equivalent method thereof can be employed. In addition, it is preferable in some cases to add an acid such as anhydrous trifluoroacetic acid and the like in order to promote a cyclization reaction.
Step 2
This step is a step for preparing carboxylic acid (2a) by hydrolyzing carboxylic ester (19). For the reaction, hydrolysis condition of a conventional method can be used, and for example, a method as described in the deprotection reaction of a carboxyl group in “Protective Groups in Organic Synthesis (third edition)” as described above, or the like can be applied.
(Starting Material Synthesis 8)
Step 1
This step is a method for constructing an oxazole ring by allowing an amide or urea (20) to undergo the reaction with an α-haloketone, representatively such as bromopyruvic ester and the like. A method as described in “Heterocyclic Compounds” edited by Turchi, vol. 45, or “Heterocyclic Compounds” edited by Palmer, vol. 60, Part A, or an equivalent method thereof can be employed.
Step 2
This step is a step for preparing a compound (2b) by hydrolyzing a carboxylic ester (21). The hydrolysis reaction of this reaction can be carried out by the same method as in step 2 in the starting material synthesis 7.
(Starting Material Synthesis 9)
Step 1
This step is a step for carrying out an amidation reaction from a compound (22) and a compound (23). The reaction can be carried out in accordance with step 1 in the first production process.
Step 2
This step is a method for constructing an oxazoline ring by carrying out a dehydration-cyclization reaction from a compound (24). The cyclization reaction of this step can be carried out, for example, with reference to a method as described in Phillips, A. J.; Wipf, P.; Williams, D. R.; et al., Org Lett, 2000, 2(8), 1165-1168, or “Heterocyclic Compounds” as described above, vol. 60, Part A, Part B, or the like.
Step 3
This step is a method for constructing an oxazole ring by carrying out an oxidation reaction from a compound (25). The oxidation reaction of this step can be carried out, for example, with reference to a method as described in Phillips, A. J.; Wipf, P.; Williams, D. R.; et al., Org Lett, 2000, 2(8), 1165-1168, or “Heterocyclic Compounds”, vol. 60, Part A, etc. as described above, or the like.
Step 4
This step is a step for preparing a compound (2b) by hydrolyzing the carboxylic ester (21). The hydrolysis reaction of this step can be carried out by the same method as in step 2 in the starting material synthesis 7.
(Starting Material Synthesis 10)
Step 1
This step is a step for preparing compounds (27) and (28) by carrying out a substitution reaction at the 2-position on the thiazole ring of a compound (26). The substitution reaction of this step can be carried out by the same method as the second production process.
Step 2
This step is a step for preparing compounds (2c) and (2d) by hydrolyzing the carboxylic esters (27) and (28). The hydrolysis reaction of this step can be carried out by the same method as in step 2 in the starting material synthesis 7.
Further, in Starting Material Syntheses 1 to 10, the substituents which bonds to the compound (I) of the present invention can be converted in a suitable period of time in the above-described steps for proceeding in the next step. Examples of the method for conversion include a method in which in Starting Material Synthesis 2, an ester group is hydrolyzed at a suitable period of time, before Step 1, before Step 2, or before Step 3, and an amidation reaction is then carried out, for conversion into a partial structure R2 of the compound according to the present invention, and the like.
The compounds of formula (I) can be isolated and purified as their free compounds, pharmaceutically acceptable salts, hydrates, solvates, or crystalline polymorphorous substances thereof. The pharmaceutically acceptable salts of the compound of formula (I) can be prepared by subjecting the compound to a conventional salt formation reaction.
Isolation and purification can be carried out by employing general chemical operations such as extraction, fractional crystallization, various types of fractional chromatography, and the like.
Various isomers can be prepared by selecting an appropriate starting compound or separated by making use of the difference in the physicochemical properties among the isomers. For example, the optical isomers can be obtained by means of general optical resolution methods of racemic products (for example, by fractional crystallization converting the compound into diastereomer salts with optically active bases or acids, by chromatography using a chiral column or the like, and others), or can also be prepared from an appropriate optically active starting compound.
The pharmacological activity of the compound (I) of the present invention was confirmed by the following tests.
The trkA receptor inhibitory activity was measured by using the increase in a ligand-dependent calcium concentration in cells as an index. HEK293 cells (American Type Culture Collection) that stably expressed a human trkA receptor were dispensed onto a 96-well poly-D-lysine-coated plate (Product Name: Biocoat, PDL96W black/clear, by Nippon Becton Dickinson) to a 2×104 cells/well on the day before the experiment, and incubated overnight at 37° C. under 5% carbon dioxide (CO2) in a culture medium containing 10% fetal bovine serum (FBS) (Product Name: DMEM, Invitrogen Corporation). The culture medium was replaced by a loading buffer (a washing solution containing a 1.5 μM fluorescent-labelled indicator (Product Name: Fluo4-AM, Tong Ren Tang Technologies Co. Ltd.): a Hank's balanced salt solution (HBSS), 20 mM 2-[4-(2-hydroxyethyl)-1-piperazinyl]ethanesulfonic acid (HEPES)-sodium hydroxide (NaOH), 2.5 mM Probenecid, and 0.1% bovine serum albumin (BSA)), and left to stand at room temperature for 3 hours, and the cells were washed using a plate washer (Product Name: ELx405, BIO-TEK instrument Corporation) in which a washing solution had been set up. The compound that had been preliminarily dissolved and diluted in a washing solution was added thereto, and set up in a system for measuring a calcium (Ca) concentration in a cell (Product Name: FLIPR, Molecular Devices Corporation). After 5 minutes, a nerve growth factor (NGF, mouse derived 2.5S, Alomone) corresponding to 80% stimulation of a maximum response was added (to a final concentration of about 100 to 150 ng/ml) to measure the change in Ca concentrations in cells. The difference between a maximum value and a minimum value in the change of Ca concentrations in cells was determined, and kept as measurement data. With a response upon addition of NGF being set at 0%, and a response upon addition of a buffer being set at 100%, the concentration causing 50% inhibition was determined as an IC50 value. The results of several Example compounds are shown in Table 1 as below. In the table, Ex represents Example Compound No. as below (the same applies hereinafter). From the results of this test, it was confirmed that the representative compounds of the present invention as below have a trkA receptor inhibitory action.
The in vivo NGF inhibitory activity of the compound was examined. A Wistar female rat (Japan SLC) was forced to be orally administered with the compound (0.5% methylcellulose solution) 10 mg/3 ml/kg or a solvent (0.5% methylcellulose solution) 3 ml/kg. Under ether anesthesia performed at 60 minutes after administration, physiological saline or 1 μg/ml NGF (NGF, mouse derived 2.5 S, Alomone) was intracutaneously administered to the back at 50 μl/site, and then immediately a 1% Evans blue solution (dissolved in physiological saline) was administered through the caudal vein at 3 ml/kg. At a time point of 10 minutes after administration, the skin on the back was taken, and shaken in formamide for 16 hours. After shaking, an absorbance of Evans blue extracted in formamide was measured by an absorbance meter (wavelength: 620 nm), and the concentration was determined by a calibration curve method. A value obtained by subtracting the concentration of Evans blue at a site administered with physiological saline from the concentration of Evans blue at a site administered with NGF was determined as an NGF-dependent action, and an inhibitory rate of the compound group was determined with a group administered with a solvent being set at 100%. The results are shown in Table 2 below. In this test, it was confirmed that the representative compounds as below of the present invention have an excellent inhibitory action on enhanced vascular permeability caused by Rat NGF.
CPA (150 mg/5 ml/kg) was intraperitoneally administered to a Wistar female rat (Charles River Laboratories), and after 2 days, the experiment was carried out. It was forced to be orally administered with distilled water (30 ml/kg), and then confined in a metabolic cage, and urine weight and urination frequency were continuously measured for 1 hour. 3 or 10 mg/5 ml/kg of the compound (0.5% methylcellulose solution), or 5 ml/kg of a solvent (0.5% methylcellulose solution) was orally administered, and after 5 to 30 minutes, urination functions were measured after water-loading in the same manner as described above. A total urine weight was divided by the total urination frequency to determine an effective bladder capacity. With the value before administration of the compound being set at 100%, a rate of change in the effective bladder capacity caused by administration of the compound was determined. The results are shown in Table 3 below.
In this test, at 2 days after CPA treatment, the effective bladder capacity had decreased (about 0.5 ml), indicating urinary frequency. On the other hand, the representative compounds as below of the present invention improved the urinary frequency condition.
1% Acetic acid (99% distilled water) is intraperitoneally administered to a Wistar male rat (Charles River Laboratories), and the frequency of pain behavior (writhing) between 10 minutes and 20 minutes after administration is measured. The compound (10 mg/5 ml/kg) or a solvent (0.5% methylcellulose solution) is orally administered 5 minutes before the administration of 1% acetic acid. With the writhing frequency of the group administered with the solvent being set at 100%, the inhibition rate of the writhing frequency by the compound administration is determined. In this test, the pain-improving action of the compound of the present invention can be confirmed.
From the results the above-described tests, the compound of formula (I) has a potent in vitro trkA receptor inhibitory activity and a potent in vivo NGF inhibitory activity, and thus it is expected that the compound of the formula (I) has urinary frequency condition-ameliorating actions and pain-improving actions. Accordingly, it is clear that it is useful as a therapeutic and/or prophylactic agent for urinary frequency, urinary urgency, and urinary incontinence associated with lower urinary tract diseases including overactive bladder, various lower urinary tract diseases accompanied by lower urinary tract pain, such as interstitial cystitis, chronic prostatitis, and the like, and various diseases accompanied by pain, such as arthrosis osteoarthritis and the like.
A pharmaceutical composition containing one or two or more kinds of the compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient can be prepared in accordance with a generally used method, using an a pharmaceutical excipient, a pharmaceutical carrier, or the like, that is usually used in the art.
The administration can be carried out through any mode of oral administration via tablets, pills, capsules, granules, powders, liquid preparations, or the like, or parenteral administration via injections such as intraarticular, intravenous, intramuscular, or others, suppositories, eye drops, eye ointments, percutaneous liquid preparations, ointments, percutaneous patches, transmucosal liquid preparations, transmucosal patches, inhalations, and the like.
Regarding solid composition for oral administration, tablets, powders, granules, or the like are used. In such a solid composition, one or two or more active ingredients are mixed with at least one inactive excipient such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinyl pyrrolidone, magnesium aluminometasilicate, and/or the like. According to a conventional method, the composition may contain inactive additives such as lubricants such as magnesium stearate and the like, disintegrators such as sodium carboxymethyl starch and the like, stabilizers, and solubilizing agents. Tablets or pills may be coated with sugar coating, or with a film of gastric or enteric substance if necessary.
The liquid composition for oral administration includes pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, or the like, and contains a generally used inert diluent, such as purified water or ethanol. In addition to the inert diluent, the liquid composition may contain adjuvants such as solubilizing agents, moistening agents, and suspending agents, sweeteners, flavors, aromatics, and antiseptics.
Injections for parenteral administration include sterile, aqueous or non-aqueous solutions, suspensions, or emulsions. As the aqueous solvent, for example, distilled water for injection or physiological saline is included. Examples of the non-aqueous solvent include propylene glycol, polyethylene glycol, vegetable oils such as olive oil and the like, alcohols such as ethanol and the like, Polysorbate 80 (Pharmacopeia), etc. Such a composition may further contain tonicity agents, antiseptics, moistening agents, emulsifying agents, dispersing agents, stabilizers, or solubilizing agents. These are sterilized, for example, by filtration through a bacteria-retaining filter, blending with bactericides, or irradiation. In addition, these can also be used by producing sterile solid compositions, and dissolving or suspending it in sterile water or a sterile solvent for injection prior to their use.
Regarding transmucosal agents such as inhalations, transnasal agents, and the like, in solid, liquid or semi-solid state are used, and can be prepared in accordance with conventionally known methods. For example, known excipients, as well as pH adjusting agents, antiseptics, surfactants, lubricants, stabilizers, thickeners, or the like may be appropriately added thereto. For their administration, appropriate devices for inhalation or insufflation may be used. For example, a compound may be administered alone or as powders of formulated mixture, or as solution or suspension by combining it with pharmaceutically acceptable carriers, using conventionally known devices or sprayers, such as a measured administration inhalation device and the like. The dry powder inhalers or the like may be for single or multiple administration use, and dry powders or powder-containing capsules may be used. Alternatively, this may be in a form of a pressurized aerosol spray which uses an appropriate propellant such as chlorofluoroalkane or hydrofluoroalkane, or a suitable gas such as carbon dioxide, or the like.
In the case of oral administration, it is appropriate that the daily dose may be usually from about 0.001 to 100 mg/kg, preferably from 0.1 to 30 mg/kg, and more preferably 0.1 to 10 mg/kg per body weight, and this is administered in a single portion or divided into 2 to 4 portions. Also, in the case of intravenous administration, the daily dose is from about 0.0001 to 10 mg/kg per body weight, and administration is made once a day or two or more times a day. In addition, a transmucosal agent is administered at a dose from about 0.001 to 100 mg/kg per body weight, once a day or two or more times a day. The dose is appropriately determined in response to an individual case by taking the symptoms, age, and sex, and the like into consideration.
The compound of formula (I) can be used in combination with various therapeutic or prophylactic agents for the diseases, in which the compound of the formula (I) is considered effective, as described above. The combined preparation may be administered simultaneously or separately and continuously, or at a desired time interval. The preparations to be co-administered may be a blend, or prepared individually.
Hereinbelow, the production processes for the compound (I) of the present invention will be described in more detail with reference to the following Examples. Further, the present invention is not limited to the compounds described in the Examples as described below. Furthermore, the production processes for the starting compounds will be described in Preparative Examples. Further, the production processes for the compound of formula (I) are not limited to the production processes of the specific Examples as below, but the compound of formula (I) can be prepared by any combination of the production processes or the methods that are apparent to a person skilled in the art.
The following abbreviations may be used in some cases in the Examples, Preparative Examples, and Tables below.
Me: methyl, Et: ethyl, Ac: acetyl, Ms: mesyl, Ph: phenyl, Bn: benzyl, Cbz: benzyloxycarbonyl, Boc: tert-butoxycarbonyl, TBS: tert-butyldimethylsilyl, Tf: trifluoromethanesulfonyl, CF3: trifluoromethyl.
5-[(4-Hydroxypiperidin-1-yl)methyl]-2-nitro-N-(tetrahydro-2H-pyran-4-yl)benzamide was allowed to undergo a reaction with acetyl chloride in pyridine to prepare 1-[4-nitro-3-(tetrahydro-2H-pyran-4-ylcarbamoyl)benzyl]piperidin-4-yl acetate.
Methyl 5-(bromomethyl)-2-nitrobenzoate was allowed to undergo a reaction with morpholine in DMF to prepare methyl 5-(morpholin-4-ylmethyl)-2-nitrobenzoate.
Methyl 2-[4-(pyrimidin-2-yloxy)piperidin-1-yl]-1,3-thiazole-4-carboxylate was allowed to undergo a reaction with a 1 M aqueous sodium hydroxide solution in a methanol-THF mixed solution to prepare 2-[4-(pyrimidin-2-yloxy)piperidin-1-yl]-1,3-thiazole-4-carboxylic acid.
Methyl 2-amino-5-ethylbenzoate was allowed to undergo a reaction with di-tert-butyldicarbonate in tert-butanol to prepare methyl 2-[(tert-butoxycarbonyl)amino]-5-ethylbenzoate.
3-Fluoropiperidine hydrochloride was allowed to undergo a reaction with benzoylthioisocyanate in methylenechloride in the presence of triethylamine to prepare N-[(3-fluoropiperidin-1-yl)carbonothioyl]benzamide.
N-(cis-4-Carbamoylcyclohexyl)-2-nitrobenzamide was allowed to undergo a reaction with anhydrous trifluoroacetic acid in THF in the presence of triethylamine to prepare N-(cis-4-cyanocyclohexyl)-2-nitrobenzamide.
1-(4-Amino-3-iodophenyl)cyclopropanecarbonitrile was allowed to undergo a reaction with a 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride dichloromethane complex in an acetonitrile-methanol mixed solution in the presence of potassium carbonate and triethylamine under a carbon monoxide atmosphere to prepare methyl 2-amino-5-(1-cyanocyclopropyl)benzoate.
Under an argon atmosphere, tert-butyl 4-(vinyloxy)piperidine-1-carboxylate was allowed to undergo a reaction with diethyl zinc and diiodomethane to prepare tert-butyl 4-(cyclopropyloxy)piperidine-1-carboxylate.
Under an argon atmosphere, ethyl 2-bromo-1,3-thiazole-4-carboxylate was allowed to undergo a reaction with copper iodide (I), N,N-dimethylethane-1,2-diamine, and pyrrolidin-2-one in 1,4-dioxane in the presence of potassium carbonate to prepare ethyl 2-(2-oxopyrrolidin-1-yl)-1,3-thiazole-4-carboxylate.
Ethyl 2-[(3S)-3-hydroxypyrrolidin-1-yl]-1,3-oxazole-4-carboxylate was allowed to undergo a reaction with 2-methoxy-N-(2-methoxyethyl)-N-(trifluorosulfanyl)ethanamine in methylenechloride to prepare ethyl 2-[(3R)-3-fluoropyrrolidin-1-yl]-1,3-oxazole-4-carboxylate.
2-Amino-4,6-difluorobenzoic acid was subjected to an esterification reaction in ethanol in the presence of sulfuric acid to prepare ethyl 2-amino-4,6-difluorobenzate.
Methyl 4-(chloromethyl)-2-nitrobenzoate was allowed to undergo a reaction with sodium methoxide in methanol to prepare methyl 4-(methoxymethyl)-2-nitrobenzoate.
Methyl 5-(morpholin-4-ylmethyl)-2-nitrobenzoate was allowed to undergo a reaction with iron and ammonium chloride in an ethanol-water mixed solvent to obtain methyl 2-amino-5-(morpholin-4-ylmethyl)benzoate.
1-(4-Aminophenyl)cyclopropanecarbonitrile was allowed to undergo a reaction with bis(pyridine)iodonium tetrafluoroboric acid in methylenechloride to prepare 1-(4-amino-3-iodophenyl)cyclopropanecarbonitrile.
Isatoic anhydride was allowed to undergo a reaction with 4-aminotetrahydropyrane hydrochloride in DMF in the presence of triethylamine and 4-(N,N-dimethylamino)pyridine to prepare 2-amino-N-(tetrahydro-2H-pyran-4-yl)benzamide.
tert-Butyl [(1R)-2-methoxy-1-methylethyl]carbamate was allowed to undergo a reaction with lithium aluminum hydride in THF to prepare (2R)-1-methoxy-N-methylpropane-2-amine hydrochloride.
3-(Benzyloxy)cyclopentanecarboxamide was allowed to undergo a reaction with 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane2,4-sulfide in THF to prepare 3-(benzyloxy)cyclopentane carbothioamide.
1-tert-Butyl 2-methyl (2R,4S)-4-methoxypyrrolidine-1,2-dicarboxylate was allowed to undergo a reaction with lithium borohydride in THF to prepare tert-butyl (2R,4S)-2-(hydroxymethyl)-4-methoxypyrrolidine-1-carboxylate.
tert-Butyl 4-(ethylsulfanyl)piperidine-1-carboxylate was allowed to undergo a reaction with m-chloroperbenzoic acid in chloroform to prepare tert-butyl 4-(ethylsulfonyl)piperidine-1-carboxylate.
tert-Butyl [(1R)-2-hydroxy-1-methylethyl]carbamate was allowed to undergo a reaction with methyl iodide in acetonitrile in the presence of silver oxide (I) to prepare tert-butyl [(1R)-2-methoxy-1-methylethyl]carbamate.
Methyl 2-nitro-5-pyridin-2-yl benzoate was allowed to undergo a reaction with methyl iodide in acetonitrile. Subsequently, this was allowed to undergo a reaction with platinum oxide in acetic acid under a hydrogen atmosphere to prepare methyl 2-amino-5-(1-methylpiperidin-2-yl)benzoate.
Ethyl 2-piperidin-4-yl-1,3-thiazole-4-carboxylate was allowed to undergo a reaction with propanoyl chloride in methylenechloride in the presence of pyridine to prepare ethyl 2-(1-propionylpiperidin-4-yl)-1,3-thiazole-4-carboxylate.
3-Methyl-4-nitrobenzonitrile was allowed to undergo a reaction with a mixed aqueous solution of nickel (II) chloride hexahydrate and 2,2′-bipyridyl, and a sodium hydrochlorite solution in acetonitrile to prepare 5-cyano-2-nitrobenzoic acid.
5-Methyl-2-nitro-N-(tetrahydro-2H-pyran-4-yl)benzamide was allowed to undergo a reaction with benzoyl peroxide and N-bromosuccinimide in chloroform to prepare 5-(bromomethyl)-2-nitro-N-(tetrahydro-2H-pyran-4-yl)benzamide.
(S)-1-Methoxy-2-propyl amine was allowed to undergo a reaction with ethyl chloroformate in THF in the presence of triethylamine to prepare ethyl [(1S)-2-methoxy-1-methylethyl]carbamate.
1-(4-Aminophenyl)cyclopropanecarbonitrile was allowed to undergo a reaction with N-chlorosuccinimide in 2-propanol to prepare 1-(4-amino-3-chlorophenyl)cyclopropanecarbonitrile.
Methyl 3-hydroxycyclopentanecarboxylate was allowed to undergo a reaction with benzyl bromide in THF in the presence of sodium hydride to prepare benzyl 3-(benzyloxy)cyclopentanecarboxylate.
Benzyl 4-hydroxypiperidine-1-carboxylate was allowed to undergo a reaction with difluoro(fluorosulfonyl)acetic acid and sodium sulfate in acetonitrile to prepare benzyl 4-(difluoromethoxy)piperidine-1-carboxylate.
2-Fluoropyridine was allowed to undergo a reaction with a mixture of 2,2,6,6-tetramethylpiperidine and n-butyl lithium, and tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate in THF to prepare tert-butyl 4-[(2-fluoropyridin-3-yl)methyl]-4-hydroxypiperidine-1-carboxylate.
tert-Butyl {[1-(hydroxymethyl)cyclobutyl]methyl}carbamate was allowed to undergo a reaction with phthalimide, triphenyl phosphine, and diethyl azodicarboxylate in THF to prepare tert-butyl({1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]cyclobutyl}methyl)carbamate.
tert-Butyl 4-hydroxypiperidine-1-carboxylate was allowed to undergo a reaction with tert-butyl vinyl ether in the presence of palladium acetate and 4,7-diphenyl-1,10-phenanthroline to prepare tert-butyl 4-(vinyloxy)piperidine-1-carboxylate.
2-Fluoro-6-nitro-N-pyridin-3-yl benzamide was allowed to undergo a reaction with palladium-carbon in a methanol-DMF mixed solution under a hydrogen atmosphere to prepare 2-amino-6-fluoro-N-pyridin-3-yl benzamide.
Benzyl 4-(difluoromethoxy)piperidine-1-carboxylate was allowed to undergo a reaction with palladium-carbon in methanol under a hydrogen atmosphere to prepare 4-(difluoromethoxy)piperidine.
4-[(5-Bromopyridin-2-yl)methyl]morpholine was allowed to undergo a reaction with benzophenoneimine in toluene in the presence of sodium tert-butoxide, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, and tris(dibenzylideneacetone)dipalladium to prepare N-(diphenylmethylene)-6-(morpholin-4-ylmethyl)pyridin-3-amine. Then, this was allowed to undergo a reaction with an aqueous hydrochloric acid solution in THF to prepare 6-(morpholin-4-ylmethyl)pyridin-3-amine dihydrochloride.
Methyl 4-nitro-1H-pyrazole-3-carboxylate was allowed to undergo a reaction with 4-(2-chloroethyl)morpholine hydrochloride in DMF in the presence of potassium carbonate and potassium iodide to prepare methyl 1-(2 morpholin-4ylethyl)-4-nitro-1H-pyrazole-5-carboxylate and methyl 1-(2 morpholin-4ylethyl)-4-nitro-1H-pyrazole-3-carboxylate.
Ethyl 2-piperidin-4-yl-1,3-thiazole-4-carboxylate was allowed to undergo a reaction with formaldehyde, and sodium triacetoxyborohydride in methylenechloride in the presence of acetic acid to prepare ethyl 2-(1-methylpiperidin-4-yl)-1,3-thiazole-4-carboxylate.
1-(Morpholin-4-ylmethyl)-1H-benzotriazole was allowed to undergo a reaction with zinc and methyl 5-(bromomethyl)-2-nitrobenzoate in DMF to prepare methyl 5-(2-morpholin-4-ylethyl)-2-nitrobenzoate.
Benzyl cis-3-fluoro-4-hydroxypiperidine-1-carboxylate was allowed to undergo a reaction with 2-chloropyrimidine in THF-DMSO in the presence of sodium hydride to prepare benzyl cis-3-fluoro-4-(pyrimidin-2-yloxy)piperidine-1-carboxylate.
1-Fluoro-2-nitrobenzene was allowed to undergo a reaction with 2-mercaptoacetamide in methanol in the presence of ammonia to prepare 2-[(2-nitrophenyl)sulfanyl]acetamide.
tert-Butyl (3R)-3-(hydroxymethyl)pyrrolidine-1-carboxylate was allowed to undergo a reaction with methyl iodide in THF in the presence of sodium hydride to prepare tert-butyl (3R)-3-(methoxymethyl)pyrrolidine-1-carboxylate.
Ethyl 2-(chloromethyl)-1,3-thiazole-4-carboxylate was allowed to undergo a reaction with 2-bromophenol in DMF in the presence of potassium carbonate to prepare ethyl 2-[(2-bromophenoxy)methyl]-1,3-thiazole-4-carboxylate.
tert-Butyl 4-[(methylsulfonyl)oxy]piperidine-1-carboxylate was allowed to undergo a reaction with sodium ethanethiolate in a THF-DMF mixed solution to prepare tert-butyl 4-(ethylsulfanyl)piperidine-1-carboxylate.
2-Aminobenzenethiol was allowed to undergo a reaction with 5-{[tert-butyl(dimethyl)silyl]oxy}-n-pentylmethanesulfonate in DMF in the presence of sodium hydride. This was allowed to undergo a reaction with tetrabutyl ammonium fluoride in THF to prepare 5-[(2-aminophenyl)sulfanyl]pentan-1-ol.
Methyl (2S)-2-({2-[(tert-butoxycarbonyl)amino]isonicotinoyl}amino)-3-hydroxypropionate was allowed to undergo a reaction with 2-methoxy-N-(2-methoxyethyl)-N-(trifluorosulfanyl)ethanamine in methylenechloride. Subsequently, this was allowed to undergo a reaction with bromotrichloromethan in the presence of 1,8-diazabicyclo[5.4.0]-7-undecene to prepare methyl 2-{2-[(tert-butoxycarbonyl)amino]pyridin-4-yl}-1,3-oxazole-4-carboxylate.
2-[(tert-Butoxycarbonyl)amino]isonicotinic acid was allowed to undergo a reaction with L-serine methyl ester hydrochloride, WSC-HCl, and HOBt in DMF in the presence of triethylamine to prepare methyl (2S)-2-({2-[(tert-butoxycarbonyl)amino]isonicotinoyl}amino)-3-hydroxypropionate.
Tetrahydro-2H-pyran-4-amine hydrochloride was allowed to undergo a reaction with 2-nitrobenzenesulfonyl chloride in methylenechloride in the presence of triethylamine to prepare 2-nitro-N-(tetrahydro-2H-pyran-4-yl)benzenesulfonamide.
1-(4-Amino-3-iodophenyl)cyclopropanecarbonitrile was allowed to undergo a reaction with tributyl(1-ethoxy vinyl) tin, tetrakistriphenyl phosphine palladium in toluene, and the reaction liquid was concentrated. This was allowed to undergo a reaction with an aqueous hydrochloric acid solution in ethanol to prepare 1-(3-acetyl-4-aminophenyl)cyclopropanecarbonitrile.
Methyl 2-nitro-5-{[(trifluoromethyl)sulfonyl]oxy}benzoate was allowed to undergo a reaction with 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaboronate, and 1,1′-bis(diphenylphosphino)ferrocene palladium in 1,4-dioxane in the presence of potassium carbonate to prepare methyl 2-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate.
Methyl 2-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate was allowed to undergo a reaction with 2-chloropyridine in dimethoxyethane in the presence of tetrakis(triphenylphosphine)palladium and cesium fluoride to prepare methyl 2-nitro-5-pyridin-2-yl benzoate.
Methyl 1-(2-morpholin-4-ylethyl)-4-nitro-1H-pyrazole-5-carboxylate was allowed to undergo a reaction with an aqueous sodium hydroxide solution in methanol to prepare 1-(2-morpholin-4-ylethyl)-4-nitro-1H-pyrazole-5-carboxylic acid.
Methyl 5-hydroxy-2-nitrobenzoate was allowed to undergo a reaction with trifluoromethanesulfonic anhydride in pyridine to prepare methyl 2-nitro-5-{[(trifluoromethyl)sulfonyl]oxy}benzoate.
3-Fluoropiperidine-1-carbothioamide was allowed to undergo a reaction with ethyl 3-bromo-2-oxopropanoate in ethanol to prepare ethyl 2-(3-fluoropiperidin-1-yl)-1,3-thiazole-4-carboxylate.
Methyl 2-bromo-1,3-thiazole-4-carboxylate was allowed to undergo a reaction with 2-(piperidin-4-yloxy)pyrimidine in DMA in the presence of triethylamine to prepare methyl 2-[4-(pyrimidin-2-yloxy)piperidin-1-yl]-1,3-thiazole-4-carboxylate.
N-[(3-Fluoropiperidin-1-yl)carbothioyl]benzamide was allowed to undergo a reaction with methylamine in methanol to prepare 3-fluoropiperidine-1-carbothioamide.
3-Methoxyazetidine hydrochloride was allowed to undergo a reaction with trimethylsilyl isocyanate in DMF in the presence of triethylamine to prepare 3-methoxyazetidine-1-carboxamide.
4-[(6-Methoxypyridazin-3-yl)oxy]piperidine-1-carboxamide was allowed to undergo a reaction with ethyl 3-bromo-2-oxopropanoate in ethanol to prepare ethyl 2-{4-[(6-oxo-1,6-dihydropyridazin-3-yl)oxy]piperidin-1-yl}-1,3-oxazole-4-carboxylate.
N-(2-Methoxyethyl)-N-methylurea was allowed to undergo a reaction with ethyl 3-bromo-2-oxopropanoate in ethanol to prepare ethyl 2-[(2-methoxyethyl)(methyl)amino]-1,3-oxazole-4-carboxylate.
Methyl 5-formyl-2-nitrobenzoate was allowed to undergo a reaction with (methoxymethyl)(triphenyl)phosphonium chloride in THF in the presence of lithium bis(trimethylsilyl)amide to prepare methyl 5-[(E)-2-methoxy vinyl]-2-nitrobenzoate.
1-(4-Aminophenyl)cyclopropanecarbonitrile was allowed to undergo a reaction with 2-bromo-1,3-thiazole-4-carboxylic acid, WSC-HCl, and HOBt in DMF to prepare 2-bromo-N-[4-(1-cyanocyclopropyl)phenyl]-1,3-thiazole-4-carboxamide.
2-Fluoro-6-nitrobenzoic acid was allowed to undergo a reaction with oxalyl chloride and a catalytic amount of DMF in dichloroethane to prepare an acid chloride. This was allowed to undergo a reaction with 3-aminopyridine in pyridine to prepare 2-fluoro-6-nitro-N-pyridin-3-yl benzamide.
2-Nitrobenzoic acid was allowed to undergo a reaction with 1-(3-methyloxetan-3-yl)methanamine, WSC-HCl, and HOBt in DMF to prepare N-[(3-methyloxetan-3-yl)methyl]-2-nitrobenzamide.
Methyl 2-amino-5-hydroxybenzoate was allowed to undergo a reaction with tert-butyl(3-hydroxy propyl)carbamate, triphenyl phosphine, and diethyl azodicarboxylate in THF to prepare methyl 2-amino-5-{3-[(tert-butoxycarbonyl)amino]propoxy}benzoate.
Methyl 5-[(E)-2-methoxyvinyl]-2-nitrobenzoate was allowed to undergo a reaction with p-toluene sulfonic acid monohydrate and silica gel in methylenechloride. Subsequently, it was allowed to undergo a reaction with pyrrolidine and sodium triacetoxyborohydride in methylenechloride in the presence of acetic acid to prepare methyl 2-nitro-5-(2-pyrrolidin-1-ylethyl)benzoate.
tert-Butyl 4-(ethylsulfonyl)piperidine-1-carboxylate was allowed to undergo a reaction with hydrogen chloride in 1,4-dioxane to prepare 4-(ethylsulfonyl)piperidine hydrochloride.
tert-Butyl({1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]cyclobutyl}methyl)carbamate was allowed to undergo a reaction with hydrazine monohydrate in ethanol to prepare tert-butyl {[1-(aminomethyl)cyclobutyl]methyl}carbamate.
2-[({2-[Methyl(tetrahydro-2H-pyran-4-ylmethyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-5-(morpholin-4-ylmethyl)benzoic acid hydrochloride was allowed to undergo a reaction with WSC-HCl and HOBt in DMF in the presence of triethylamine to prepare 2-{2-[methyl(tetrahydro-2H-pyran-4-ylmethyl)amino]-1,3-thiazol-4-yl}-6-(morpholin-4-ylmethyl)-4H-3,1-benzoxazin-4-one.
tert-Butyl {4-(aminomethyl)-2-[(2-methoxyethyl)carbamoyl]-5-methylphenyl}carbamate was allowed to undergo a reaction with bis(2-chloroethyl)ether in a THF-DMF mixed solution in the presence of diisopropylethylamine to prepare tert-butyl {2-[(2-methoxyethyl)carbamoyl]-5-methyl-4-(morpholin-4-ylmethyl)phenyl}carbamate.
Methyl 2-[(tert-butoxycarbonyl)amino]-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-4-methylbenzoate was allowed to undergo a reaction with 2-methoxyethylamine in ethanol to prepare tert-butyl {4-(aminomethyl)-2-[(2-methoxyethyl)carbamoyl]-5-methylphenyl}carbamate.
Methyl 2-amino-4-methylbenzoate was allowed to undergo a reaction with N-(hydroxymethyl)phthalimide in sulfuric acid solution to prepare methyl 2-amino-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-4-methylbenzoate.
Methyl 5-(bromomethyl)-2-nitrobenzoate was allowed to undergo a reaction with sodium hydride and pyrrolidin-2-one in THF to prepare methyl 2-nitro-5-[(2-oxopyrrolidin-1-yl)methyl]benzoate.
Methyl 5-{[(2-hydroxyethyl)amino]methyl}-2-nitrobenzoate was allowed to undergo a reaction with CDI and triethylamine in THF to prepare methyl 2-nitro-5-[(2-oxo-1,3-oxazolidin-3-yl)methyl]benzoate.
Benzyl cis-3-fluoro-4-hydroxypiperidine-1-carboxylate was allowed to undergo a reaction with (2R)-3,3,3-trifluoro-2-methoxy-2-phenyl propanoic acid, dicyclohexylcarbodiimide, and 4-(N,N-dimethylamino)pyridine in methylenechloride to prepare benzyl (3S,4R)-3-fluoro-4-{[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]oxy}piperidine-1-carboxylate.
Methyl 5-chloro-2-nitrobenzoate was allowed to undergo a reaction with (2R)-2-(methoxymethyl)pyrrolidine in DMA in the presence of potassium carbonate to prepare methyl 5-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]-2-nitrobenzoate.
Methyl 2-nitro-5-vinylbenzoate was allowed to undergo a reaction with N-benzyl-1-methoxy-N-[(trimethylsilyl)methyl]methanamine and trifluoroacetic acid in toluene to prepare methyl 5-(1-benzylpyrrolidin-3-yl)-2-nitrobenzoate.
(2-Chloroethoxy)cyclopropane was allowed to undergo a reaction with a phthalimide potassium salt in DMF, and then with hydrazine monohydrate in EtOH. This was allowed to undergo a reaction with a 4 M hydrogen chloride/EtOAc solution to prepare 2-(cyclopropyloxy)ethanamine hydrochloride.
Methyl 5-[(tert-butoxycarbonyl)amino]-2-chloroisonicotinate was allowed to undergo a reaction with trimethylboroxin, triphenyl phosphine palladium, and cesium fluoride in dimethoxyethane to prepare methyl 5-[(tert-butoxycarbonyl)amino]-2-methyl isonicotinate.
5-Benzyl-8-oxa-5-azaspiro[3,5]nonane was allowed to undergo a reaction with 10% palladium-carbon in methanol under 4 atm a hydrogen atmosphere. This was allowed to undergo a reaction with a 4 M hydrogen chloride/EtOAc solution to prepare 8-oxa-5-azaspiro[3,5]nonane hydrochloride.
(3-Endo)-8-methyl-3-(pyrimidin-2-yloxy)-8-azabicyclo[3.2.1]octane was allowed to undergo a reaction with M-chloroperbenzoic acid and a 1 M aqueous iron dichloride solution in methylenechloride to prepare (3-endo)-3-(pyrimidin-2-yloxy)-8-azabicyclo[3.2.1]octane.
(2R,3S)-1-(Diphenylmethyl)-3-methoxy-2-methylazetidine was allowed to undergo a reaction with palladium hydroxide in ethanol under a hydrogen atmosphere and then with a 4 M hydrogen chloride/1,4-dioxane solution to prepare (2R,3S)-3-methoxy-2-methylazetidine hydrochloride.
Methyl 5-(bromomethyl)-2-nitrobenzoate was allowed to undergo a reaction with ethanol and silver oxide (I) in 1,2-dichloroethane to prepare methyl 5-(ethoxymethyl)-2-nitrobenzoate.
Methyl 2-nitro-5-oxylan-2-yl benzoate was allowed to undergo a reaction with 2-(methylamino)ethanol in methanol to prepare methyl 5-{1-hydroxy-2-[(2-hydroxyethyl)(methyl)amino]ethyl}-2-nitrobenzoate.
Methyl 5-{1-hydroxy-2-[(2-hydroxyethyl)(methyl)amino]ethyl}-2-nitrobenzoate was allowed to undergo a reaction with triphenyl phosphine and diethyl azodicarboxylate in THF to prepare methyl 5-(4-methylmorpholin-2-yl)-2-nitrobenzoate.
A mixture of methyl dichloroacetate, morpholine, and methyl 2-nitrobenzoate was allowed to undergo a reaction with potassium tert-butoxide in DMF, and then treated with a 1 M aqueous HCl solution to prepare methyl 5-(1-chloro-2-morpholin-4-yl-2-oxoethyl)-2-nitrobenzoate.
In the same manner as the methods of Preparative Examples 1 to 70 and 435 to 448, the compounds of Preparative Examples 71 to 434 and 449 to 534 shown in Tables 4 to 61 below were prepared, respectively, using a corresponding starting materials. For Tables 4 to 61, Pre denotes Preparative Example numbers and Str denotes the structural formulae. The structural formulae marked with * in the tables indicate that the compounds are optically active. The head in each cell of the right columns of Tables 4 to 61 shows the Preparative Example numbers which were referred to for the production processes as Syn, with numbers marked by P in front. For example, in the production process including “P30-P66” as described therein means that the same Production Process as Preparative Example 30 is performed, and then the same Production Process as in Preparative Example 66 is performed. The materials horizontally described in the right hand of Syn (Sal) represent salts, and the materials without such a description represent free compounds. (HCl) represents hydrochloride, (2HCl) represents dihydrochloride, and (Na) represents sodium salt. The bottom in the right hand columns show values by mass spectrum (MS) as Dat (physicochemical data).
Furthermore, as for the description of MS data, for example, in the columns of the compound of Preparative Example 1, MS (ESI) m/z: 406 ([M+H]+) is described, which means MS (ESI) m/z: 406 ([M+H]+). Similarly, in the case of Preparative Example 71, MS (ESI) m/z: 214 ([M−H]−) is described, which means MS (ESI) m/z: 214 ([M−H]−) (the description of the MS data applies in similarly in Tables 62 to 211 below having the description of Examples 1 to 1767).
To 128 mg of 2-{methyl[(3R)-pyrrolidin-3-yl]amino}-N-[2-(pyridin-3-ylcarbamoyl)phenyl]-1,3-thiazole-4-carboxamide were added 1 ml of DMA, 88 mg of 2-chloroethylmethyl ether, 50 mg of potassium iodide, and 158 μl of diisopropylethylamine, followed by stirring at 100° C. for 8 hours. To the reaction mixture was added water, followed by extraction with chloroform. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography (chloroform:methanol=9:1). This was dissolved in chloroform, and a 4 M hydrogen chloride/EtOAc solution and hexane was added thereto, followed by stirring at room temperature. The precipitate was collected by filtration to prepare 92 mg of 2-{[(3R)-1-(2-methoxyethyl)pyrrolidin-3-yl](methyl)amino}-N-[2-(pyridin-3-ylcarbamoyl)phenyl]-1,3-thiazole-4-carboxamide dihydrochloride.
To 110 mg of methyl 5-(morpholin-4-ylmethyl)-2-[({2-[4-(pyrimidin-2-yloxy)piperidin-1-yl]-1,3-thiazol-4-yl}carbonyl)amino]benzoate was added 2.1 ml of a 9.8 M methylamine/methanol solution, followed by leaving to stand at room temperature for 14 days. The reaction mixture was concentrated under reduced pressure, and the obtained residue was then purified by preparative thin layer chromatography (chloroform:methanol=9:1). A 4 M hydrogen chloride/EtOAc solution was added thereto, followed by stirring, and the solid in the system was collected by filtration to prepare 76.5 mg of N-[2-(methylcarbamoyl)-4-(morpholin-4-ylmethyl)phenyl]-2-[4-(pyrimidin-2-yloxy)piperidin-1-yl]-1,3-thiazole-4-carboxamide hydrochloride.
To 500 mg of 3-chloro-4-[({2-[4-(pyrimidin-2-yloxy)piperidin-1-yl]-1,3-thiazol-4-yl}carbonyl)amino]benzoic acid were added 5 ml of THF and 1.0 g of CDI, followed by heating under reflux for 2 hours. The reaction liquid was ice-cooled, and a solution of 200 mg of sodium borohydride in 1 ml of water was added thereto, followed by stirring at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and then water was added to the residue, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1) to prepare 226 mg of N-[2-chloro-4-(hydroxymethyl)phenyl]-2-[4-(pyrimidin-2-yloxy)piperidin-1-yl]-1,3-thiazole-4-carboxamide.
To a reaction mixture of 200 mg of N-[5-(hydroxymethyl)-2-(tetrahydro-2H-pyran-4-ylcarbamoyl)phenyl]-2-[(2-methoxyethyl)(methyl)amino]-1,3-thiazole-4-carboxamide, 0.1 ml of triethylamine, and 4 ml of methylenechloride was added 0.05 ml of methanesulfonylchloride under ice-cooling, followed by stirring at room temperature for 3 hours. To the reaction liquid was added water, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in 5 ml of acetonitrile, and 180 mg of tetrabutylammonium cyanide was added thereto, followed by stirring at room temperature for 6 hours. The insoluble materials generated in the reaction liquid were collected by filtration and washed with water and ethanol to prepare 142 mg of N-[5-(cyanomethyl)-2-(tetrahydro-2H-pyran-4-ylcarbamoyl)phenyl]-2-[(2-methoxyethyl)(methyl)amino]-1,3-thiazole-4-carboxamide.
To a solution of 200 mg of rel-N-(2-{[(1R,3S)-3-carbamoylcyclohexyl]carbamoyl}phenyl)-2-morpholin-4-yl-1,3-thiazole-4-carboxamide in 2 ml of DMF was added 105 mg of 2,4,6-trichloro-1,3,5-triazine under ice-cooling, followed by stirring at 0° C. for 1 hour and at room temperature for 1 hour. To the reaction liquid was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=100:1). This was heated and dissolved in 2-propanol, and then cooled to room temperature. The precipitate was collected by filtration to prepare 122 mg of rel-N-(2-{[(1R,3S)-3-cyanocyclohexyl]carbamoyl}phenyl)-2-morpholin-4-yl-1,3-thiazole-4-carboxamide.
To a suspension of 598 mg of 2-[4-(pyrimidin-2-yloxy)piperidin-1-yl]-1,3-thiazole-4-carboxylic acid in 6 ml of methylenechloride were added 0.51 ml of oxalyl chloride and 7.5 μl of DMF, followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and then to the residue were added 6 ml of THF, 631 mg of methyl 2-amino-5-(morpholin-4-ylmethyl)benzoate dihydrochloride, and 1 ml of diisopropylethylamine, followed by stirring at room temperature overnight. To the reaction liquid was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with EtOAc. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To the residue were added ethanol and diisopropyl ether, followed by stirring at 100° C., and then cooled to room temperature. The solid in the system was collected by filtration to prepare 700 mg of methyl 5-(morpholin-4-ylmethyl)-2-[({2-[4-(pyrimidin-2-yloxy)piperidin-1-yl]-1,3-thiazol-4-yl}carbonyl)amino]benzoate.
To a solution of 202 mg of methyl 5-(morpholin-4-ylmethyl)-2-[({2-[4-(pyrimidin-2-yloxy)piperidin-1-yl]-1,3-thiazol-4-yl}carbonyl)amino]benzoate in 8.1 ml of THF was added 6.7 mg of lithium hydride, followed by stirring for 1 hour while heating under reflux. To the reaction mixture was added 0.56 ml of a 1 M methyl magnesium bromide/THF solution at 0° C., followed by stirring at 45° C. for 3 hours. Further, 1.69 ml of a 1 M methyl magnesium bromide/THF solution was added thereto at 0° C., followed by stirring at 45° C. for 2 hours. To the reaction liquid was added a saturated aqueous ammonium chloride solution, followed by extraction with EtOAc. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography (chloroform:methanol=9:1 and chloroform:acetone=7:3). To this was added a 4 M hydrogen chloride/EtOAc solution, and ethanol and diisopropyl ether were then added thereto, followed by stirring. The solid in the system was collected by filtration to prepare 15.5 mg of N-[2-(1-hydroxy-1-methylethyl)-4-(morpholin-4-ylmethyl)phenyl]-2-[4-(pyrimidin-2-yloxy)piperidin-1-yl]-1,3-thiazole-4-carboxamide hydrochloride.
Under an argon atmosphere, to 1.3 g of trimethylsulfoxonium chloride were added 20 ml of THF and 1.2 g of potassium tert-butoxide, followed by stirring at 50° C. for 4 hours. The reaction mixture was cooled to room temperature, and 700 mg of methyl 2-[({2-[(2-methoxyethyl)(methyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]benzoate was then added thereto, followed by stirring at room temperature for 3 days. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 451 mg of N-(2-{[dimethyl(oxide)-λ4-sulfanylidene]acetyl}phenyl)-2-[(2-methoxyethyl)(methyl)amino]-1,3-thiazole-4-carboxamide.
To this were added 5 ml of THF, 700 μl of a 4 M hydrogen chloride/1,4-dioxane solution, and 1.5 ml of DMSO, followed by stirring at 70° C. for 2 hours, and 800 μl of morpholine was added thereto, followed by stirring at room temperature for 3 days. To the reaction mixture was added EtOAc, the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=1000:1, 500:1). This was dissolved in EtOAc, a 0.4 M hydrogen chloride/EtOAc solution was added thereto, and the solvent was evaporated. The residue was heated and dissolved in EtOH, and then cooled to room temperature. The precipitate was collected by filtration to prepare 43 mg of 2-[(2-methoxyethyl)(methyl)amino]-N-[2-(morpholin-4-ylacetyl)phenyl]-1,3-thiazole-4-carboxamide hydrochloride.
To a solution of 115 mg of 2-(3-fluoropiperidin-1-yl)-1,3-thiazole-4-carboxylic acid in 3 ml of DMF was added 110 mg of 2-amino-N-pyridin-3-yl benzamide, and 228 mg of HATU, followed by stirring at room temperature for 7 days. To the reaction liquid was added water, and the precipitate was collected by filtration. This was purified by silica gel column chromatography (chloroform:methanol=99:1-30:1). This was heated and dissolved in 2-propanol, and then cooled to room temperature. The precipitate was collected by filtration to prepare 102 mg of 2-(3-fluoropiperidin-1-yl)-N-[2-(pyridin-3-ylcarbamoyl)phenyl]-1,3-thiazole-4-carboxamide.
To a solution of 193 μl of diisopropylamine in 8 ml of THF was added 790 μl of a 1.6 M n-butyl lithium/hexane solution under ice-cooling, followed by stirring for 15 minutes, and 123 μl of 3-methylpyridine was added thereto, followed by stirring at 0° C. for 15 minutes. Subsequently, a solution of 400 mg of methyl 2-[({2-[(2-methoxyethyl)(methyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]benzoate in 4 ml of THF was added thereto, followed by stirring at 0° C. for 20 minutes. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with EtOAc. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:EtOAc=2:1 and chloroform:methanol=100:1-50:1). This was washed with 1 ml of EtOAc to prepare 46 mg of 2-[(2-methoxyethyl)(methyl)amino]-N-[2-(pyridin-3-ylacetyl)phenyl]-1,3-thiazole-4-carboxamide.
To a solution of 397 mg of 2-morpholin-4-yl-1,3-oxazole-4-carboxylic acid and 450 μl of 4-methylmorpholine in 10 ml of THF was added 260 μl of isobutyl chloroformate under ice-cooling, followed by stirring at room temperature for 30 minutes. Under ice-cooling, a solution of 426 mg of 2-amino-N-pyridin-3-yl benzamide in 8 ml of THF was added thereto, followed by stirring at room temperature for 1 hour and at 60° C. overnight. The reaction mixture was concentrated under reduced pressure, water was then added thereto, and the precipitated solid was collected by filtration. This was suspended in ethanol, and 1.5 ml of a 4 M hydrogen chloride/EtOAc solution was added thereto, followed by stirring for 2 hours. The solid in the system was collected by filtration to prepare 250 mg of 2-morpholin-4-yl-N-[2-(pyridin-3-ylcarbamoyl)phenyl]-1,3-oxazole-4-carboxamide hydrochloride.
To a solution of 578 mg of N-{2-[(5-hydroxypentyl)sulfanyl]phenyl}-2-morpholin-4-yl-1,3-thiazole-4-carboxamide in 5.78 ml of chloroform was added 734 mg of m-chloroperbenzoic acid, followed by stirring at room temperature for 6 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and an aqueous sodium thiosulfate solution, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=92:8), and then by preparative thin layer chromatography (chloroform:methanol=95:5) to prepare 560 mg of N-{2-[(5-hydroxypentyl)sulfonyl]phenyl}-2-morpholin-4-yl-1,3-thiazole-4-carboxamide.
To 168 mg of 2-[methyl(4-{[2-(pyridin-3-ylcarbamoyl)phenyl]carbamoyl}-1,3-thiazol-2-yl)amino]ethylmethanesulfonate were added 0.84 ml of DMA, 0.58 ml of pyrrolidine and 58 mg of potassium iodide, followed by stirring at 70° C. for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was then purified by preparative thin layer chromatography (chloroform:methanol=80:20). To this were added chloroform and diisopropyl ether, followed by stirring. The solid in the system was collected by filtration to prepare 122 mg of 2-[methyl(2-pyrrolidin-1-ylethyl)amino]-N-[2-(pyridin-3-ylcarbamoyl)phenyl]-1,3-thiazole-4-carboxamide.
To a solution of 114 mg of 2-(cis-3-fluoro-4-hydroxypiperidin-1-yl)-N-[2-(tetrahydro-2H-pyran-4-ylcarbamoyl)phenyl]-1,3-thiazole-4-carboxamide in 5 ml of methylenechloride were added 180 mg of (2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropionic acid, 160 mg of WSC-HCl, and 60 mg of 4-(N,N-dimethylamino)pyridine, followed by stirring at room temperature for 15 hours. The reaction liquid was purified by silica gel column chromatography (hexane:ether=1:3) as it is to prepare 10 mg of (2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropionic acid (3S,4R)-3-fluoro-1-(4-{[2-(tetrahydro-2H-pyran-4-ylcarbamoyl)phenyl]carbamoyl}-1,3-thiazol-2-yl)piperidin-4-yl ester and 10 mg of (2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropionic acid (3R,4S)-3-fluoro-1-(4-{[2-(tetrahydro-2H-pyran-4-ylcarbamoyl)phenyl]carbamoyl}-1,3-thiazol-2-yl)piperidin-4-yl ester.
Among these, to a solution of 10 mg of (2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropionic acid (3S,4R)-3-fluoro-1-(4-{[2-(tetrahydro-2H-pyran-4-ylcarbamoyl)phenyl]carbamoyl}-1,3-thiazol-2-yl)piperidin-4-yl ester in 1 ml of methanol was added 0.06 ml of a 1 M aqueous sodium hydroxide solution, followed by leaving to stand for 1 day. The reaction liquid was concentrated under reduced pressure, and then to the residue was added 0.06 ml of a 1 M aqueous hydrochloric acid solution. The insoluble materials were collected by filtration to prepare 3.8 mg of 2-[(3S,4R)-3-fluoro-4-hydroxypiperidin-1-yl]-N-[2-(tetrahydro-2H-pyran-4-ylcarbamoyl)phenyl]-1,3-thiazole-4-carboxamide.
Similarly, 5.5 mg of 2-[(3R,4S)-3-fluoro-4-hydroxypiperidin-1-yl]-N-[2-(tetrahydro-2H-pyran-4-ylcarbamoyl)phenyl]-1,3-thiazole-4-carboxamide was prepared from 10 mg of (2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropionic acid (3R,4S)-3-fluoro-1-(4-{[2-(tetrahydro-2H-pyran-4-ylcarbamoyl)phenyl]carbamoyl}-1,3-thiazol-2-yl)piperidin-4-yl ester.
To a solution of 315 mg of 5-[(2-{[(2-morpholin-4-yl-1,3-thiazol-4-yl)carbonyl]amino}phenyl)sulfonyl]pentylmethanesulfonate in 1.9 ml of DMF was added 119 mg of sodium azide, followed by stirring at 60° C. for 6 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with EtOAc. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography (EtOAc) to prepare 261 mg of N-{2-[(5-azidepentyl)sulfonyl]phenyl}-2-morpholin-4-yl-1,3-thiazole-4-carboxamide.
To a solution of 261 mg of N-{2-[(5-azidepentyl)sulfonyl]phenyl}-2-morpholin-4-yl-1,3-thiazole-4-carboxamide in 2.61 ml of ethanol and 1.305 ml of THF was added palladium-carbon, followed by stirring at room temperature for 6 hours under a hydrogen atmosphere. After filtering the catalyst, the filtrate was concentrated. This was purified by preparative thin layer chromatography (chloroform:methanol:aqueous ammonia=4:1:0.1) to prepare 133 mg of N-{2-[(5-aminopentyl)sulfonyl]phenyl}-2-morpholin-4-yl-1,3-thiazole-4-carboxamide.
To a mixture of 115 mg of N-[4-(3-aminopropoxy)-2-(tetrahydro-2H-pyran-4-ylcarbamoyl)phenyl]-2-[(2-methoxyethyl)(methyl)amino]-1,3-thiazole-4-carboxamide hydrochloride in 2 ml of THF were added 17 μl of acetyl chloride and 64 μl of triethylamine, followed by stirring at room temperature for 2 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform. The organic layer was washed with saturated brine, and the solvent was then evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform:methanol=20:1) to prepare 81 mg of N-[4-(3-acetamidepropoxy)-2-(tetrahydro-2H-pyran-4-ylcarbamoyl)phenyl]-2-[(2-methoxyethyl)(methyl)amino]-1,3-thiazole-4-carboxamide.
To a mixture of 220 mg of N-(3-carbonyl-1-methyl-1H-pyrazol-4-yl)-2-phenyl-1,3-thiazole-4-carboxamide in 10 ml of acetic acid were added 10 ml of concentrated sulfuric acid and 3 ml of an aqueous solution of 116 mg of sodium nitrite under ice-cooling, followed by stirring at room temperature for 5 hours. To the reaction mixture was added water, and the resulting insoluble materials were collected by filtration to prepare 220 mg of 1-methyl-4-{[(2-phenyl-1,3-thiazol-4-yl)carbonyl]amino}-1H-pyrazole-3-carboxylic acid.
To a mixture of 115 mg of N-[4-(3-aminopropoxy)-2-(tetrahydro-2H-pyran-4-ylcarbamoyl)phenyl]-2-[(2-methoxyethyl)(methyl)amino]-1,3-thiazole-4-carboxamide hydrochloride in 2 ml of THF were added 19 μl of methanesulfonylchloride and 64 μl of triethylamine, followed by stirring at room temperature for 2 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform. The organic layer was washed with saturated brine, and the solvent was then evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform:methanol=20:1) to prepare 96 mg of 2-[(2-methoxyethyl)(methyl)amino]-N-[4-{3-[(methylsulfonyl)amino]propoxy}-2-(tetrahydro-2H-pyran-4-ylcarbamoyl)phenyl]-1,3-thiazole-4-carboxamide.
To a solution of 90 mg of N-{2-[(5-hydroxypentyl)sulfonyl]phenyl}-2-morpholin-4-yl-1,3-thiazole-4-carboxamide in 1.8 ml of methylenechloride were added 58 μl of acetic anhydride, 0.33 ml of pyridine, and 25 mg of 4-(N,N-dimethylamino)pyridine, followed by stirring at room temperature for 3 days. The reaction liquid was concentrated under reduced pressure, and the residue was then purified by preparative thin layer chromatography (EtOAc). To this were added EtOAc and hexane, followed by stirring at room temperature. The solid in the system was collected by filtration to prepare 72 mg of 5-[(2-{[(2-morpholin-4-yl-1,3-thiazol-4-yl)carbonyl]amino}phenyl)sulfonyl]pentyl acetate.
To a solution of 508 mg of 2-[(2-hydroxyethyl)(methyl)amino]-N-[2-(pyridin-3-ylcarbamoyl)phenyl]-1,3-thiazole-4-carboxamide in 5.08 ml of methylenechloride were added 0.36 ml of triethylamine and 0.2 ml of methanesulfonylchloride under ice-cooling, followed by stirring for 1 hour. To the reaction mixture was added water, followed by extraction with methylenechloride. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to prepare 608 mg of 2-[methyl(4-{[2-(pyridin-3-ylcarbamoyl)phenyl]carbamoyl}-1,3-thiazol-2-yl)amino]ethylmethanesulfonate.
Under an argon atmosphere, a mixture of 380 mg of 2-[(2-methoxyethyl)(methyl)amino]-1,3-oxazole-4-carboxylic acid and 476 mg of methyl 2-amino-5-(morpholin-4-ylmethyl)benzoate in 11 ml of pyridine was cooled to −15° C., and 195 μl of phosphorous oxychloride was added slowly thereto, followed by stirring for 2 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform. The organic layer was washed with saturated brine and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform:methanol=20:1) to prepare 288 mg of methyl 2-[({2-[(2-methoxyethyl)(methyl)amino]-1,3-oxazol-4-yl}carbonyl)amino]-5-(morpholin-4-ylmethyl)benzoate.
To a mixture of 95 mg of 2-(methyl[(3R)-pyrrolidin-3-yl]amino}-N-[2-(pyridin-3-ylcarbamoyl)phenyl]-1,3-thiazole-4-carboxamide in 3.8 ml of methylenechloride and 1.9 ml of acetonitrile were added 375 μl of a 36% aqueous formaldehyde solution and 143 mg of sodium triacetoxyborohydride, followed by stirring at room temperature overnight. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, followed by filtration with granular Presep diatomaceous earth (Wako Pure Chemical Industries, Ltd.), and the filtrate was concentrated. The residue was purified by preparative thin layer chromatography (chloroform:methanol=80:20). To a solution thereof in chloroform was added a 4 M hydrogen chloride/EtOAc solution, and hexane was added thereto, followed by stirring. The precipitate was collected by filtration to prepare 78 mg of 2-(methyl[(3R)-1-methylpyrrolidin-3-yl]amino}-N-[2-(pyridin-3-ylcarbamoyl)phenyl]-1,3-thiazole-4-carboxamide dihydrochloride.
Under an argon atmosphere, to a suspension of 172 mg of 2-cyano-6-{[(2-morpholin-4-yl-1,3-thiazol-4-yl)carbonyl]amino}benzoic acid in 3 ml of THF were added 53 μl of 4-methylmorpholine and 62 μl of isobutyl chloroformate, followed by stirring at room temperature for 10 minutes. Subsequently, 45 mg of pyridin-3-amine was added thereto, followed by stirring at 50° C. for 15 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform. The organic layer was washed with saturated brine and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=50:1). This was suspended in 1 ml of ethanol, and 37 μl of 4 M hydrogen chloride/EtOAc was added thereto, followed by stirring for 1 hour. The precipitated solid was collected by filtration and washed with EtOAc to prepare 13 mg of N-[3-cyano-2-(pyridin-3-ylcarbamoyl)phenyl]-2-morpholin-4-yl-1,3-thiazole-4-carboxamide hydrochloride.
To a solution of 80 mg of 5-(morpholin-4-ylmethyl)-2-[({2-[4-(pyrimidin-2-yloxy)piperidin-1-yl]-1,3-thiazol-4-yl}carbonyl)amino]benzoic acid in 1.1 ml of DMF were added 40 mg of WSC-HCl, 30 mg of HOBt, 16 mg of ethylamine hydrochloride, and 0.04 ml of diisopropylethylamine, followed by stirring at room temperature for 2 days. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with EtOAc. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1) to prepare 74 mg of N-[2-(ethylcarbamoyl)-4-(morpholin-4-ylmethyl)phenyl]-2-[4-(pyrimidin-2-yloxy)piperidin-1-yl]-1,3-thiazole-4-carboxamide.
To a suspension of 200 mg of 2-(3-methoxyazetidin-1-yl)-1,3-thiazole-4-carboxylic acid in 9 ml of DMF were added 250 mg of fluoro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate, 219 mg of 2-amino-N-(cis-4-hydroxy cyclohexyl)benzamide, and 260 μl of triethylamine under ice-cooling, followed by stirring at 0° C. for 30 minutes and at room temperature for 3 hours. Further, 250 mg of fluoro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate was added thereto, followed by stirring under ice-cooling for 45 minutes and at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and then water and an aqueous hydrochloric acid solution were added thereto, followed by extraction with chloroform. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=100:0-90:10). This was heated and dissolved in 2-propanol, and then cooled to room temperature. The precipitate was collected by filtration to prepare 126 mg of N-{2-[(cis-4-hydroxy cyclohexyl)carbamoyl]phenyl}-2-(3-methoxyazetidin-1-yl)-1,3-thiazole-4-carboxamide.
To a solution of 148 mg of 4-ethoxypiperidine hydrochloride in 2 ml of DMA were added 339 μl of triethylamine and 200 mg of 2-bromo-N-[2-(tetrahydro-2H-pyran-4-ylcarbamoyl)phenyl]-1,3-thiazole-4-carboxamide, followed by stirring at 100° C. for 8 hours. After air-cooling, water was added thereto and the precipitate was collected by filtration. This was purified by silica gel column chromatography (hexane:EtOAc=1:1). This was heated and dissolved in methanol, and then cooled to room temperature. The precipitate was collected by filtration to prepare 127 mg of 2-(4-ethoxypiperidin-1-yl)-N-[2-(tetrahydro-2H-pyran-4-ylcarbamoyl)phenyl]-1,3-thiazole-4-carboxamide.
A solution of 800 mg of 2-bromo-N-[2-(pyridin-3-ylcarbamoyl)phenyl]-1,3-thiazole-4-carboxamide, 1.38 g of (3R)—N-methyl-1-(trifluoroacetyl)pyrrolidin-3-amine hydrochloride, and 1.73 ml of diisopropylamine in 6 ml of 1-methyl-2-pyrrolidinone was radiated with microwave (Biotage, Infinity Sixty) at 200° C. for 45 minutes. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=90:10).
To a solution thereof in 10 ml of methanol was added 4 ml of a 1 M aqueous sodium hydroxide solution, followed by stirring at room temperature overnight. To a reaction mixture was added water and brine, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography (chloroform:methanol:aqueous ammonia=4:1:0.1) to prepare 445 mg of 2-(methyl[(3R)-pyrrolidin-3-yl]amino}-N-[2-(pyridin-3-ylcarbamoyl)phenyl]-1,3-thiazole-4-carboxamide.
To a solution of 180 mg of 2-[methyl(tetrahydro-2H-pyran-4-ylmethyl)amino]-1,3-thiazole-4-carboxylic acid in 1.2 ml of DMF were added 117 mg of 2-amino-N-pyridin-3-yl benzamide, 110 mg of WSC-HCl, and 100 mg of HOBt, followed by stirring at 60° C. for 3 days. To the reaction liquid was added an aqueous sodium hydrogen carbonate solution, and the resulting insoluble materials were collected by filtration. This was washed with acetonitrile to prepare 195 mg of 2-[methyl(tetrahydro-2H-pyran-4-ylmethyl)amino]-N-[2-(pyridin-3-ylcarbamoyl)phenyl]-1,3-thiazole-4-carboxamide.
To a solution of 35 mg of 2-{2-[methyl(tetrahydro-2H-pyran-4-ylmethyl)amino]-1,3-thiazol-4-yl}-6-(morpholin-4-ylmethyl)-4H-3,1-benzoxazin-4-one in 5 ml of acetonitrile was added 41 mg of 1-pyridin-3-yl methanamine, followed by heating under reflux for 6 hours. The reaction mixture was concentrated under reduced pressure, and then to the residue was added water, followed by extraction with EtOAc. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was heated and dissolved in EtOAc and then cooled to room temperature. The precipitate was collected by filtration to prepare 31 mg of 2-[methyl(tetrahydro-2H-pyran-4-ylmethyl)amino]-N-{4-(morpholin-4-ylmethyl)-2-[(pyridin-3-ylmethyl)carbamoyl]phenyl}-1,3-thiazole-4-carboxamide.
To a solution of 174 mg of 2-{2-[methyl(tetrahydro-2H-pyran-4-ylmethyl)amino]-1,3-thiazol-4-yl}-4H-3,1-benzoxadin-4-one in 2.6 ml of THF was added 1.41 ml of a 0.96 M methyl magnesium bromide/THF solution at 0° C., followed by stirring at room temperature overnight. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by extraction with EtOAc. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography (chloroform:methanol=95:5 and chloroform) to prepare 5.3 mg of N-(2-acetylphenyl)-2-[methyl(tetrahydro-2H-pyran-4-ylmethyl)amino]-1,3-thiazole-4-carboxamide.
To a suspension of 464 mg of methyl 5-(morpholin-4-ylmethyl)-2-[({2-[4-(pyrimidin-2-yloxy)piperidin-1-yl]-1,3-thiazol-4-yl}carbonyl)amino]benzoate in 5 ml of THF was added 1.03 ml of a 1 M aqueous sodium hydroxide solution, followed by stirring at room temperature for 13 hours and at 50° C. for 4 hours with heating. To the reaction mixture were added 1.03 ml of a 1 M aqueous hydrochloric acid solution and 5 ml of water, and the precipitated solid was collected by filtration to prepare 325 mg of 5-(morpholin-4-ylmethyl)-2-[({2-[4-(pyrimidin-2-yloxy)piperidin-1-yl]-1,3-thiazol-4-yl}carbonyl)amino]benzoic acid.
To a solution of 141 mg of 1-{4-[({2-[4-(pyrimidin-2-yloxy)piperidin-1-yl]-1,3-thiazol-4-yl}carbonyl)amino]-3-tetrahydro-2H-pyran-4-ylcarbamoyl)benzyl}piperidin-4-yl acetate hydrochloride in 3 ml of methanol was added 56 mg of potassium carbonate, followed by stirring for 2 hours. To the reaction mixture was added water, followed by extraction with chloroform. The organic layer was washed with saturated brine, and the solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=30:1). This was dissolved in ethanol, and 4 M hydrogen chloride/EtOAc was added thereto, followed by stirring for 1 hour. The precipitate was collected by filtration to prepare 95 mg of N-{4-[(4-hydroxypiperidin-1-yl)methyl]-2-(tetrahydro-2H-pyran-4-ylcarbamoyl)phenyl}-2-[4-(pyrimidin-2-yloxy)piperidin-1-yl]-1,3-thiazole-4-carboxamide hydrochloride.
To 302 mg of tert-butyl (3-{4-[({2-[(2-methoxyethyl)(methyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]-3-(tetrahydro-2H-pyran-4-ylcarbamoyl)phenoxy}propyl)carbamate was added 3 ml of 4 M hydrogen chloride/EtOAc, followed by stirring at room temperature for 40 minutes.
To the reaction liquid was added 3 ml of ethanol, and the solvent was evaporated under reduced pressure. The residue was washed with EtOAc to prepare 259 mg of N-[4-(3-aminopropoxy)-2-(tetrahydro-2H-pyran-4-ylcarbamoyl)phenyl]-2-[(2-methoxyethyl)(methyl)amino]-1,3-thiazole-4-carboxamide hydrochloride.
To 179 mg of N-[5-(benzyloxy)-2-(tetrahydro-2H-pyran-4-ylcarbamoyl)phenyl]-2-morpholin-4-yl-1,3-thiazole-4-carboxamide were added 253 mg of 1,2,3,4,5-pentamethylbenzene and 5 ml of trifluoroacetic acid, followed by stirring at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, and then a 1 M aqueous hydrochloric acid solution was added thereto, followed by extraction with chloroform. The organic layer was washed with saturated brine, and the solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=80:20) to prepare 93 mg of N-[5-hydroxy-2-(tetrahydro-2H-pyran-4-ylcarbamoyl)phenyl]-2-morpholin-4-yl-1,3-thiazole-4-carboxamide.
Under an argon atmosphere, to a solution of 91 mg of N-{4-[3-(benzyloxy) propoxy]-2-(tetrahydro-2H-pyran-4-ylcarbamoyl)phenyl}-2-[(2-methoxyethyl)(methyl)amino]-1,3-thiazole-4-carboxamide and 116 mg of 1,2,3,4,5-pentamethylbenzene in 4 ml of methylenechloride was added slowly 780 μl of a 1.0 M trichloroborane/heptane solution at −78°, followed by warming to room temperature and stirring for 2 hours. To the reaction mixture were added MeOH and water, followed by extraction with chloroform. The organic layer was washed with saturated brine, and the solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=30:1). This was washed with hexane to prepare 41 mg of N-[4-(3-hydroxypropoxy)-2-(tetrahydro-2H-pyran-4-ylcarbamoyl)phenyl]-2-[(2-methoxyethyl)(methyl)amino]-1,3-thiazole-4-carboxamide.
To a solution of 400 mg of benzyl 4-[(2-{[(2-morpholin-4-yl-1,3-thiazol-4-yl)carbonyl]amino}phenyl)sulfonyl]piperidine-1-carboxylate in 10 ml of acetonitrile and 10 ml of methylenechloride was added 700 mg of trimethylsilyl iodide, followed by stirring at room temperature for 2 hours. To the reaction liquid was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform. The organic layer was washed with an aqueous sodium thiosulfate solution and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by washed with acetonitrile to prepare 35 mg of 2-morpholin-4-yl-N-[2-(piperidin-4-ylsulfonyl)phenyl]-1,3-thiazole-4-carboxamide.
To a solution of 160 mg of 2,5-difluoro-4-[({2-[4-(pyrimidin-2-yloxy)piperidin-1-yl]-1,3-thiazol-4-yl}carbonyl)amino]benzoic acid in 5 ml of methanol was added 0.05 ml of thionyl chloride under ice-cooling, followed by stirring at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure, and the residue was then purified by silica gel column chromatography (chloroform:methanol=20:1). This was heated and dissolved in a mixed solvent of EtOAc and acetonitrile, and then cooled to room temperature. The precipitate was collected by filtration to prepare 52 mg of methyl 2,5-difluoro-4-[({2-[4-(pyrimidin-2-yloxy)piperidin-1-yl]-1,3-thiazol-4-yl}carbonyl)amino]benzoate.
A solution of 7.3 mg of N-methyl-1-phenyl methanamine, 12.1 mg of 2-bromo-N-[2-(pyridin-3-ylcarbamoyl)phenyl]-1,3-thiazole-4-carboxamide, and 20.9 μl of triethylamine in 0.2 ml of DMA was stirred at 100° C. for 5 days. The reaction mixture was cooled to room temperature and filtrated, and the filtrate was then purified by preparative high performance liquid chromatography (methanol-aqueous 0.1% formic acid solution) to prepare 4.7 mg of 2-[benzyl(methyl)amino]-N-[2-(pyridin-3-ylcarbamoyl)phenyl]-1,3-thiazole-4-carboxamide.
To a solution of 2.6 mg of N,N-dimethylethane-1,2-diamine in 60 μl of 1-methyl-2-pyrrolidinone were added 8.1 mg of 2-{[(2-phenyl-1,3-thiazol-4-yl)carbonyl]amino}benzoic acid, 3.5 μl of triethylamine, a solution of 3.4 mg of HOBt in 1 ml of DMF, and 75 mg of PL-DCC Resin (Polymer Laboratories Ltd.), followed by stirring at room temperature overnight. To the reaction mixture was added 50 mg of MP-Carbonate (Argonaut Technologies, Inc.) and 50 mg of PS-Isocyanate (Argonaut Technologies, Inc.), followed by stirring at room temperature for 4 hours, and the insoluble materials were filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by preparative high performance liquid chromatography (methanol-aqueous 0.1% formic acid solution) to prepare 2.1 mg of N-(2-{[2-(dimethylamino)ethyl]carbamoyl}phenyl)-2-phenyl-1,3-thiazole-4-carboxamide.
To a solution of 4.1 mg of 2-aminobenzamide, 5.3 mg of 2-(2-thienyl)-1,3-thiazole-4-carboxylic acid, and 3.4 mg of HOBt in 1 ml of DMF was added 100 mg of PS-carbodiimide (Argonaut Technologies, Inc.), followed by stirring at room temperature overnight. To the reaction liquid were added 50 mg of MP-carbonate (Argonaut Technologies, Inc.) and 50 mg of PS-Isocyanate (Argonaut Technologies, Inc.), followed by stirring at room temperature for 4 hours, and the insoluble materials were filtered. The filtrate was concentrated under reduced pressure to prepare 7.5 mg of N-(2-carbamoylphenyl)-2-(2-thienyl)-1,3-thiazole-4-carboxamide.
To a solution of 821 mg of 2-phenyl-1,3-thiazole-4-carboxylic acid in 30 ml of methylenechloride were added dropwise 520 μl of oxalyl chloride and 15 μl of DMF at 0° C., followed by stirring at room temperature for 3 hours. From this reaction liquid, 300 μl portion was collected, a solution of 8.3 mg of 2-(methylsulfonyl)aniline hydrochloride and 11 μl of triethylamine in 200 μl of methylenechloride was added thereto at room temperature, followed by stirring overnight. To the reaction liquid were added 100 mg of PS-Isocyanate (Argonaut Technologies, Inc.), 75 mg of PS-Trisamine (Argonaut Technologies, Inc.), and 1 ml of DMF, followed by stirring at room temperature overnight, and the insoluble materials were filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by preparative high performance liquid chromatography (methanol-aqueous 0.1% formic acid solution) to prepare 8.4 mg of N-[2-(methylsulfonyl)phenyl]-2-phenyl-1,3-thiazole-4-carboxamide.
To 100 mg of N-{4-(chloromethyl)-2-[(2-methoxyethyl)carbamoyl]phenyl}-2-[(3S)-3-methoxypyrrolidin-1-yl]-1,3-thiazole-4-carboxamide were added 2 mL of DMF, 61 mg of (2S)-2-methylmorpholine hydrochloride, and 92 μl of triethylamine, followed by stirring at room temperature for 4 days. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=100:0-30:1). This was dissolved in ethanol, and 26 mg of fumaric acid was then added thereto, followed by concentration. Acetonitrile was added thereto, followed by stirring, and then the solid was collected by filtration to prepare 88 mg of N-(2-[(2-methoxyethyl)carbamoyl]-4-{[(2S)-2-methylmorpholin-4-yl]methyl}phenyl)-2-[(3S)-3-methoxypyrrolidin-1-yl]-1,3-thiazole-4-carboxamide fumarate.
Under an argon atmosphere, to 388 mg of N-{2-[(2-methoxyethyl)carbamoyl-4-(morpholin-4-ylmethyl)phenyl}-2-[(3S)-3-methoxypyrrolidin-1-yl]-1,3-thiazole-4-carboxamide were added 10 mL of 1,2-dichloroethane, 0.11 mL of ethyl chloroformate, and 0.18 mL of isopropanol, followed by heating under reflux at 100° C. for 3 hours. After air-cooling, to the reaction mixture was added water, followed by extraction with chloroform. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=99:1-10:1) to prepare 11 mg of N-{4-(isopropoxymethyl)-2-[(2-methoxyethyl)carbamoyl]phenyl}-2-[(3S)-3-methoxypyrrolidin-1-yl]-1,3-thiazole-4-carboxamide.
To a suspension of 120 mg of N-(1-oxo-2,3-dihydro-1H-inden-5-yl)-2-[4-(pyrimidin-2-yloxy)piperidin-1-yl]-1,3-thiazole-4-carboxamide in 2 ml of methanol-3 ml of THF was added 21 mg of sodium borohydride, followed by stirring at room temperature for 15 hours. The reaction mixture was concentrated, and a saturated aqueous sodium hydrogen carbonate solution was then added thereto, followed by extraction with chloroform. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=100/1-50/1) to prepare 89 mg of N-(1-hydroxy-2,3-dihydro-1H-inden-5-yl)-2-[4-(pyrimidin-2-yloxy)piperidin-1-yl]-1,3-thiazole-4-carboxamide.
To 131 mg of 5-(morpholin-4-ylmethyl)-2-[({2-[4-(pyrimidin-2-yloxy)piperidin-1-yl]-1,3-thiazol-4-yl}carbonyl)amino]benzoic acid were added 25 ml of methylenechloride and 75 mg of (isocyanoimino)triphenylphosphorane, followed by stirring at room temperature for 18 hours. The reaction mixture was purified by preparative thin layer chromatography (chloroform:methanol=94:6) to prepare 16 mg of N-[4-(morpholin-4-ylmethyl)-2-(1,3,4-oxadiazol-2-yl)phenyl]-2-[4-(pyrimidin-2-yloxy)piperidin-1-yl]-1,3-thiazole-4-carboxamide.
To 100 mg of 5-[(3,3-dimethylmorpholin-4-yl)methyl]-2-[({2-[(3S)-3-methoxypyrrolidin-1-yl]-1,3-thiazol-4-yl}carbonyl)amino]benzoic acid were added 2 mL of methylenechloride and 51 mg of CDI, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated, and then to the residue were added toluene (2 mL) and 31 mg of N-hydroxyacetamidine, followed by stirring at room temperature for 3 hours and then heating under reflux for 3 days. After air-cooling, the reaction mixture was concentrated. The residue was purified by silica gel column chromatography (chloroform:methanol=99:1) to prepare 35 mg of N-{4-[(3,3-dimethylmorpholin-4-yl)methyl]-2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl}-2-[(3S)-3-methoxypyrrolidin-1-yl]-1,3-thiazole-4-carboxamide.
To 100 mg of 4-[({2-[4-(pyrimidin-2-yloxy)piperidin-1-yl]-1,3-thiazol-4-yl}carbonyl)amino]-3-(trifluoromethoxy)benzoic acid were added 1 ml of DMF, 61 mg of 1,8-diazabicyclo[5.4.0]-7-undecene, 100 mg of CDI, and 100 mg of methanesulfonamide, followed by stirring at 60° C. for 1 hour. The reaction mixture was concentrated, and then to the resulting residue were added water and a 1 M aqueous hydrochloric acid solution. The resulting insoluble materials were collected by filtration. This was washed with acetonitrile to prepare 110 mg of N-{4-[(methanesulfonyl)carbamoyl]-2-(trifluoromethoxy)phenyl}-2-[4-pyrimidin-2-yloxy)piperidin-1-yl]-1,3-thiazole-4-carboxamide.
To 110 mg of 5-[(3,3-dimethylmorpholin-4-yl)methyl]-2-[({2-[(3S)-3-methoxypyrrolidin-1-yl]-1,3-thiazol-4-yl}carbonyl)amino]benzoic acid were added 2 mL of DMF, 106 mg of HATU, 162 μL of triethylamine, and 79 mg of 3-fluoropropylamine hydrochloride, followed by stirring at room temperature for 24 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform). This was dissolved in 2 mL of ethanol, and 22 mg of fumaric acid was added thereto, followed by stirring, heating, and dissolving, and then cooling by leaving to stand. After addition of diisopropyl ether, the precipitated solid was collected by filtration to prepare 41 mg of N-{4-[(3,3-dimethylmorpholin-4-yl)methyl]-2-[(3-fluoropropyl)carbamoyl]phenyl}-2-[(3S)-3-methoxypyrrolidin-1-yl]-1,3-thiazole-4-carboxamide fumarate.
To 2.0 g of N-{2-[(2-methoxyethyl)carbamoyl-4-(morpholin-4-ylmethyl)phenyl}-2-[(3S)-3-methoxypyrrolidin-1-yl]-1,3-thiazole-4-carboxamide was added 0.57 ml of ethyl chloroformate in 50 ml of 1,2-dichloroethane, followed by heating under reflux for 1.5 hours. To the reaction liquid was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=100/0-40/1) to prepare 740 mg of N-{4-(chloromethyl)-2-[(2-methoxyethyl)carbamoyl]phenyl}-2-[(3S)-3-methoxypyrrolidin-1-yl]-1,3-thiazole-4-carboxamide.
To 292 mg of N-{4-(1-benzylpyrrolidin-3-yl)-2-[(2-methoxyethyl)carbamoyl]phenyl-2-[(3S)-3-methoxypyrrolidin-1-yl]-1,3-thiazole-4-carboxamide was added 84 μl of 1-chloroethyl chlorocarbonate in 6 ml of 1,2-dichloroethane, followed by heating under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, and then 6 ml of methanol was added thereto, followed by heating under reflux for 1 hour. The reaction mixture was concentrated under reduced pressure, and then 130 mg of di-tert-butyl dicarbonate in 3 ml of methylenechloride and 166 μl of triethylamine, followed by stirring at room temperature for 16 hours. To the reaction liquid was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=100/0-20/1) to prepare 68 mg of tert-butyl 3-{3-[(2-methoxyethyl)carbamoyl]-4-[({2-[(3S)-3-methoxypyrrolidin-1-yl]-1,3-thiazol-4-yl}carbonyl)amino]phenyl}pyrrolidine-1-carboxylate.
To 172 mg of N-{4-(2-chloroethyl)-2-[(2-methoxyethyl)carbamoyl]phenyl}-2-[(3S)-3-methoxypyrrolidin-1-yl]-1,3-thiazole-4-carboxamide were added 87 mg of potassium acetate and 6 mg of potassium iodide in DMF, followed by stirring at 70° C. for 6 days. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=100/0-40/1) to prepare 120 mg of 2-{3-[(2-methoxyethyl)carbamoyl]-4-[({2-[(3S)-3-methoxypyrrolidin-1-yl]-1,3-thiazol-4-yl}carbonyl)amino]phenyl}ethyl acetate.
To 64 mg of N-{4-(2-hydroxyethyl)-2-[(2-methoxyethyl)carbamoyl]phenyl}-2-[(3S)-3-methoxypyrrolidin-1-yl]-1,3-thiazole-4-carboxamide were added 10 μl of methyl iodide in acetonitrile and 36 mg of silver carbonate, followed by stirring at room temperature with light-shielding for 10 days. The reaction mixture was filtered through Celite, and then the solvent was evaporated from the filtrate under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=100/0-30/1) to prepare 5 mg of N-{4-(2-methoxyethyl)-2-[(2-methoxyethyl)carbamoyl]phenyl}-2-[(3S)-3-methoxypyrrolidin-1-yl]-1,3-thiazole-4-carboxamide.
A solution of 11.3 mg of N-{4-(chloromethyl)-2-[(2-methoxyethyl)carbamoyl]phenyl}-2-[(3S)-3-methoxypyrrolidin-1-yl]-1,3-thiazole-4-carboxamide, 3.6 mg of pyrrolidine, and 10.5 μl of triethylamine in 0.25 ml of DMF was stirred at room temperature for 3 days. To the reaction mixture was added an aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform, and the organic layer was concentrated under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography (methanol-aqueous 0.1% formic acid solution) to prepare 3.5 mg of N-{2-[(2-methoxyethyl)carbamoyl]-4-(pyrrolidin-1-ylmethyl)phenyl}-2-[(3S)-3-methoxypyrrolidin-1-yl]-1,3-thiazole-4-carboxamide.
To a solution of 11.3 mg of N-{4-(chloromethyl)-2-[(2-methoxyethyl)carbamoyl]phenyl}-2-[(3S)-3-methoxypyrrolidin-1-yl]-1,3-thiazole-4-carboxamide and 5.4 mg of N-methyl aniline in 0.25 ml of DMF was added 24.4 mg of cesium carbonate, followed by stirring at room temperature for 3 days and then stirring at 50° C. for 1 hour. To the reaction mixture was added water, followed by extraction with chloroform, and the organic layer was concentrated under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography (methanol-aqueous 0.1% formic acid solution) to prepare 3.5 mg of N-(2-[(2-methoxyethyl)carbamoyl]-4-{[methyl(phenyl)amino]methyl}phenyl)-2-[(3S)-3-methoxypyrrolidin-1-yl]-1,3-thiazole-4-carboxamide.
To a solution of 11.3 mg of N-{4-(chloromethyl)-2-[(2-methoxyethyl)carbamoyl]phenyl}-2-[(3S)-3-methoxypyrrolidin-1-yl]-1,3-thiazole-4-carboxamide and 4.1 mg of 2-methyl imidazole in 0.25 ml of DMF was added 2.0 mg of 60% sodium hydride, followed by stirring at room temperature for 3 days and then stirring at 50° C. for 1 hour. To the reaction mixture was added water, followed by extraction with chloroform, and the organic layer was concentrated under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography (methanol-aqueous 0.1% formic acid solution) to prepare 1.6 mg of N-{2-[(2-methoxyethyl)carbamoyl]-4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-2-[(3S)-3-methoxypyrrolidin-1-yl]-1,3-thiazole-4-carboxamide.
To a solution of 11.3 mg of N-{4-(chloromethyl)-2-[(2-methoxyethyl)carbamoyl]phenyl}-2-[(3S)-3-methoxypyrrolidin-1-yl]-1,3-thiazole-4-carboxamide and 13.1 mg of tert-butyl 3-phenyl-piperazine-1-carboxylate in 0.25 ml of DMF was added 24.4 mg of cesium carbonate, followed by stirring at room temperature for 3 days and then stirring at 50° C. for 1 hour. To the reaction mixture was added water, followed by extraction with chloroform, and the organic layer was concentrated under reduced pressure. This was dissolved in 0.5 ml of 1,4-dioxane, and then 0.5 ml of a 4 M hydrogen chloride/1,4-dioxane solution was added thereto, followed by stirring at room temperature for 2 hours. The reaction solvent was evaporated under reduced pressure, and to the resulting residue was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform. The organic layer was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (methanol-aqueous 0.1% formic acid solution) to prepare 2.5 mg of N-{2-[(2-methoxyethyl)carbamoyl]-4-[(2-phenyl piperazin-1-yl)methyl]phenyl}-2-[(3S)-3-methoxypyrrolidin-1-yl]-1,3-thiazole-4-carboxamide.
In the same manner as the methods of Examples 1 to 43 and 1181 to 1195 above, the compounds of Examples 44 to 1180 and 1196 to 1767 shown in Tables 62 to 211 below were prepared, respectively, using a corresponding starting materials. For Tables 62 to 211, Str denotes the structural formulae. The structural formulae marked with * in the tables indicate that the compounds are optically active. Further, in Examples 1234 and 1269, the substituents on carbon adjacent on piperidine ring are in cis configuration, giving a mixture of two diastereomers. The head in each cell of in the right columns of Tables 62 to 211 shows the Example numbers which were referred to for the production processes as Syn, with numbers marked by E in front. For example, in the production process including “E33→E26” as described therein means that the same Production Process as in Example 33 is performed, and then the same Production Process as in Example 26 is performed. The materials horizontally described in the right hand of Syn (Sal) represent salts, and the materials without such a description represent free compounds. (HCl) represents hydrochloride, (2HCl) represents dihydrochloride, (3HCl) represents trihydrochloride, (Fum) represents fumarate, (1.5Fum) represents 1.5 fumarate, (2Fum) represents 2 fumarate, (3Fum) represents 3 fumarate, (0.5 L-Tart) represents 0.5 L-tartrate, (L-Tart) represents L-tartrate, and (Na) represents sodium salt. The bottom in the right hand columns show values by mass spectrum as Dat (physicochemical data).
Hereinafter, the NMR data of several Example compounds are shown in Tables 212 to 215. The data represents δ (ppm) of peaks in 1H-NMR where tetramethylsilane is used as internal standard, unless particularly described, DMSO-d6 is used as a solvent for measuring.
Further, (CDCl3) represents δ (ppm) of peaks in 1H-NMR in CDCl3.
The compound of the present invention has potent trkA receptor inhibitory action, and therefore, it is useful as a pharmaceutical, particularly as a therapeutic agent for urinary frequency, urinary urgency, urinary incontinence, and lower urinary tract pain associated with various lower urinary tract diseases including overactive bladder, and various diseases accompanied by pain.
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| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/JP2008/069263 | 10/23/2008 | WO | 00 | 4/23/2010 |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO2009/054468 | 4/30/2009 | WO | A |
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