JP4789289B2 - 3-aminobenzamide compound and vanilloid receptor type 1 (VR1) activity inhibitor - Google Patents

Description

  The present invention relates to novel 3-aminobenzamide compounds having an inhibitory action on vanilloid receptor type 1 (VR1) activity and pharmaceutical compositions containing these compounds as active ingredients, particularly therapeutic agents for painful diseases.

Capsaicin, the main component of pepper, is both a hot ingredient and a pain-causing substance. Many nociceptive nerves, especially unmyelinated C fibers, have been reported to have capsaicin sensitivity, and it is known that C fibers are selectively detached when capsaicin is administered to rodents in early childhood. . The site of action of capsaicin is widely distributed in the skin, cornea, and oral mucosa, and is also found in muscles, joints, and internal organs, especially in the cardiovascular system, respiratory system, and urinary bladder system, and is important for autonomic reflexes. It has also been reported. Capsaicin sensitivity has also been observed in nerves in the preoptic area of the thalamus, and it is presumed to be involved in thermoregulation. In nociceptive nerves, depolarization due to influx of Na ⁺ and Ca ²⁺ is observed when capsaicin is administered, and glutamate and neuropeptides (mainly substance P and calcitonin gene-related peptide from primary afferent fibers in the dorsal horn of the spinal cord). ) Is caused. It is considered that fat-soluble capsaicin acts on the receptor protein due to the fact that the specific binding activity of resiniferatoxin (RTX), which brings about the same action as capsaicin, was confirmed, and capsazepine was revealed as a competitive inhibitor. (For example, Szallasi A, Blumberg PM. (1999) Pharmacol. Rev. 51, 159-212).
reference. ).
In 1997, the capsaicin receptor gene was cloned (see, for example, Non-Patent Document 2). It was deduced from the amino acid sequence that it would be an ion channel with 6 transmembrane regions. Since capsaicin has a vanillyl group in its structure, it is collectively referred to as vanilloid together with analogs such as RTX, and the cloned receptor is vanilloid receptor type 1 (hereinafter referred to as VR1). (This VR1 is sometimes called TRPV1 (transient receptor potential vanilloid receptor 1).) Subsequently, VR1 was expressed in Xenopus oocytes and human-derived cultured cells, and electrophysiological functional analysis was performed using the patch clamp method. VR1 was directly activated by capsaicin without using an intracellular second messenger. (See, for example, Szallasi A, Blumberg PM. (1999) Pharmacol. Rev. 51, 159-212), and VR1 has an outward rectifying property and a highly selective Ca ²⁺ non-selective cation ion. It was found to be a channel (see Premkumar LS, Agarwal S, Steffen D. (2002) J. Physiol. 545, 107-117).
Capsaicin is a substance that causes pain, but is used as an analgesic for the purpose of reducing pain in diabetic neuropathy and rheumatic neuropathy (for example, Szallasi A, Blumberg PM. (1999) Pharmacol. Rev.). 51, 159-212.). This is understood to be due to the desensitization that sensory nerve endings exposed to capsaicin become unresponsive to other painful stimuli. The VR1 desensitization mechanism is thought to involve regulation via Ca ²⁺ , regulation depending on voltage, and regulation of VR1 activity by phosphorylation / dephosphorylation, but there are still many unclear points.
Like capsaicin, heat and acid cause pain, and capsaicin-sensitive nociceptive nerves are known to respond to multiple stimuli. It has been found that VR1 is directly activated not only by capsaicin but also by thermal stimulation at 43 ° C. or higher (see, for example, Yang D, Geeauu RW 4th. (2002) J. Neurosci. 22, 6388-6393). The temperature of 43 ° C. is almost the same as the temperature threshold that causes pain in humans and animals, suggesting that VR1 is involved in nociceptive heat stimulation reception.
Tissue acidification that occurs during inflammation and ischemia is known to cause and enhance pain (see, for example, Bevan S, Gepetti P. (1994) Trends Neurosci. 17, 509-512). ). It can be seen that when extracellular pH is lowered within the range of acidification caused by tissue damage, VR1 can be directly activated by acidification (proton) alone, and VR1 is stimulated by acidification of tissue that occurs during inflammation or ischemia. It is presumed to be the molecular reality of the receptor (see, for example, Yang D, Gereau RW 4th. (2002) J. Neurosci. 22, 6388-6398).
An increase in the number of unmyelinated C fibers expressing VR1 at the inflammatory site was confirmed by immunohistological analysis using specific antibodies (Carlton SM, Coggeshall RE. (2001) Neurosci). Lett. 310, 53-56). In fact, increased expression of VR1 in the submucosal plexus has been observed in human inflammatory bowel disease (eg, Yanyang Y, Facer P, Dyer NH, Chan CL, Knowles C, Williams NS, Anand P. (2001). ) See Lancet 357, 1338-1339.) Such an increase in VR1 expression level is thought to cause peripheral sensitization in inflamed tissues and contribute to the persistence of inflammatory hyperalgesia.
Inflammation-related substances extracellular ATP, bradykinin, and nerve growth factor have also been reported to increase VR1 activity (eg, Tominaga M, Wada M, Masu M. (2001) Proc. Natl. Acad. Sci. USA 98, 6951-6965, Shu X, Mendell LM. (1999) Neurosci. Lett. 274, 159-162, Chuang HH, Prescott ED, Kong H, Shields S, Jordt SE, Basbaum A, Basbaum A Julius D. (2001) Nature 411, 957-962, Sugiura T, Tominaga M, Katsura H, Mizumura K. (2002) J. Neuro. hysiol.88, 544-548), and VR1 is said to be undoubtedly involved in pain such as inflammation and hyperalgesia (for example, Numazaki M, Tominaga M (2003) Biochemistry). 75, 359-371.).
Sensory neurons of VR1-deficient mice did not respond to any of capsaicin, proton, or heat stimulus. Also in behavioral analysis, VR1-deficient mice have been reported not to show a pain response due to capsaicin administration, to decrease the sensitivity to heat stimulation, and to observe no inflammatory hyperalgesia (for example, Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J, Peterson-Zeitz KR, Koltzenburg M, Basbaum AI, Julius D. (2000) Science 288, 306, 313, Davis LB, Grat. 183-187). Thus, analysis of VR1-deficient mice has confirmed that VR1 functions as a wide range of pain stimulating receptors even at the individual level.
In addition, regarding the relationship between vanilloid receptor (VR1) and diseases, it has already been reported that substances that inhibit VR1 activity are useful as therapeutic agents for various diseases.
In particular, with regard to pain therapeutic agents, it has been reported that capsazepine, which is known as a VR1 antagonist, has shown significant analgesic effects in animal models (eg, Ikeda Y, Ueno A, Naraba H, Oh-shi S, (2001) Life). Science 69), and is highly expected to be used as a new therapeutic agent for pain having VR1 activity inhibitory action.
Regarding bladder hypertonia and urinary incontinence, it has been confirmed that the bladder contractile function of VR1-deficient mice is reduced, and it has an inhibitory effect on VR1 or a compound having a capsaicin-like medicinal mechanism. It has been reported that a compound, ie, a substance that inhibits vanilloid receptor (VR1) activity is also useful as an effective therapeutic agent for improving bladder function, for example, frequent urination, urinary incontinence (for example, (2002)). Nat. Neurosci. 5, 856-860.).
According to another document, a substance having antagonistic activity of vanilloid receptor (VR1), particularly an antagonist of VR1 receptor, prevents and treats a disease involving VR1 activity, particularly urge urinary incontinence, bladder overactivity, Chronic pain, neuropathic pain, postoperative pain, rheumatoid arthritis pain, neuralgia, neuropathy, hyperalgesia, nerve injury, ischemia, neurodegeneration, stroke, incontinence, inflammatory disease, urge incontinence (UUI), and It has also been reported that it is useful for the prevention and treatment of symptoms and diseases including bladder overactivity (see, for example, JP-A-2003-192673).
Diseases associated with vanilloid receptor activity include pain, acute pain, chronic pain, neuropathic pain, postoperative pain, migraine, joint pain, neuropathy, nerve damage, diabetic neuropathy, neurodegenerative disease , Neurological skin disease, stroke, bladder hypersensitivity, irritable bowel syndrome, respiratory abnormalities such as asthma and chronic obstructive pulmonary disease, skin, eye or mucous membrane irritation, fever, stomach-duodenal ulcer, inflammatory bowel disease It is also known that inflammatory diseases and the like can be included (see, for example, JP-T-2004-506714).
Thus, a substance having a vanilloid receptor (VR1) antagonistic activity is a pathological condition involving C fibers, such as pruritus, allergic and allergic rhinitis, bladder overactive frequent urination / urinary incontinence, Stroke, irritable bowel syndrome, respiratory diseases such as asthma / chronic obstructive pulmonary disease, dermatitis, mucositis, gastric / duodenal ulcer and inflammatory bowel syndrome, pain, acute pain, chronic pain, Neuropathic pain, postoperative pain, migraine, joint pain, neuropathy, nerve damage, diabetic neuropathy, neurodegenerative disease, rheumatoid arthritis pain, neuralgia, neuropathy, hyperalgesia, neurodermal disease, stroke, imminent It can be said that it is useful as a therapeutic agent for urinary incontinence, ischemia, inflammatory diseases and the like.
Next, known vanilloid receptor (VR1) antagonists and compounds that are considered to be relatively close to the compounds of the present invention will be described.
The following compounds are known as compounds similar in structure to the present invention.
For example, JP9059236 discloses that the following piperidine compounds are useful as antiallergic agents.
However, the piperidine structure of the compound is different from the structure of the present invention. Further, there is no disclosure that the compound has a VR1 receptor activity inhibitory activity as in the present invention or that the compound is useful as a therapeutic and / or prophylactic agent for pain as in the present invention (Japanese Patent Laid-Open No. Hei 9). -059236.
Further, WO04 / 009552 and WO02 / 074726 disclose that the following compounds are useful as PDE4 inhibitors.
However, the substitution position of the alkoxy group on the phenyl group of the compound is different from the structure of the present invention. Further, there is no disclosure that the compound has a VR1 receptor activity inhibitory activity as in the present invention, or that the compound is useful as a therapeutic and / or prophylactic agent for pain as in the present invention.
In addition, US3773936A discloses that the following compounds are useful as anti-inflammatory agents.
However, the phenyl group of the N-phenylacetamide structure of the compound has no substituent other than a hydrogen atom and is different from the structure of the present invention. Further, there is no disclosure that the compound has a VR1 receptor activity inhibitory activity as in the present invention or that the compound is useful as a therapeutic and / or prophylactic agent for pain as in the present invention (for example, US Pat. No. 3,737,936A). No., US Pat. No. 3,678,094A, Japanese Patent Publication No. 48-42054).
In addition, WO02 / 064545 discloses that the following benzimidazole compounds are useful as NOS inhibitors.
However, the benzimidazole structure of the compound is different from the structure of the present invention. Further, there is no disclosure that the compound has a VR1 receptor activity inhibitory activity as in the present invention, or that the compound is useful as a therapeutic and / or prophylactic agent for pain as in the present invention.
WO97 / 48697 discloses that the following indole compounds are useful as PDE4 inhibitors.
However, the indole structure of the compound is different from the structure of the present invention. Further, there is no disclosure that the compound has a VR1 receptor activity inhibitory activity as in the present invention, or that the compound is useful as a therapeutic and / or prophylactic agent for a disease accompanied by pain symptoms as in the present invention. .
Next, compounds that have a known VR1 receptor activity inhibitory action and are considered to be relatively close to the compounds of the present invention will be described.
WO02 / 16318 discloses a compound represented by the following general formula as a compound having an antagonistic action against VR1.
The feature of the invention resides in having a thiourea structure.
However, the feature of the present invention is that it has a thiourea structure, and these compounds have a structure in which a phenyl group or a pyridyl group is substituted on the amino group substituted at the 3-position of the benzamide structure, which is a feature of the compound of the present invention. Is different.
Furthermore, this document does not disclose specific examples of the compound having a benzamide structure as in the present invention, and there is no description suggesting the compound of the present invention.
In WO 03/99284, compounds represented by the following general formula are described as compounds exhibiting antagonistic action against VR1.
The feature of the present invention is that it has a structure including a ring containing a pyridine ring and an amino group having one hydrogen atom on the ring.
However, these compounds are different in structure from the amino group substituted with an alkyl group, which is a feature of the compound of the present invention.
Furthermore, there is no disclosure of specific examples of the compound having a benzamide structure as in the present invention, and no description suggesting the compound of the present invention is found.
Thus, the above compounds are different in structure from the compounds of the present invention, and there is no description suggesting the compounds of the present invention.

Currently, narcotic analgesics (such as morphine), non-narcotic analgesics (NSAID (nonsteroidal anti-inflammatory drug)) and the like are mainly used as analgesics. However, the use of narcotic analgesics is severely restricted due to the development of tolerance / dependence or other serious side effects. It is well known that non-narcotic analgesics cause a high rate of upper gastrointestinal tract disorders and liver disorders with long-term administration, and analgesics with higher analgesic effects and fewer side effects are desired. Furthermore, no effective analgesics have yet been found for neuropathic pain (neuropathic pain) such as diabetic neuropathic pain, postherpetic neuralgia, and trigeminal neuralgia. Drug development is also expected.
A capsaicin-like compound that acts on VR1 is thought to exhibit an analgesic effect based on a completely different medicinal mechanism (suppression of capsaicin-sensitive nerves) from existing analgesics, and a neuropathic pain that does not respond to existing analgesics. The effectiveness is greatly expected as a therapeutic agent for pain caused by various pathological conditions such as rheumatoid arthritis.
The fact that VR1 is the ultimate target of various inflammation-related substances indicates that drugs that act on VR1 may be effective in various inflammatory pains and interstitial cystitis, replacing these existing drugs It is highly expected to be effective as an analgesic.
Accordingly, an object of the present invention is to provide a new analgesic, that is, a VR1 activity inhibitor based on a medicinal effect mechanism (suppression of capsaicin-sensitive nerves) completely different from existing analgesics.
As a result of earnest research to develop analgesics based on a new action mechanism replacing conventional analgesics such as non-narcotic analgesics, pilin-type analgesics, non-pyrine-type analgesics, NSAIDs and the like, In addition, the present inventors have found a 3-aminobenzamide compound having VR1 action inhibitory activity and completed the present invention.
The present invention is as follows in more detail.
1. A 3-aminobenzamide compound represented by the following general formula [1] or a pharmaceutically acceptable salt thereof.
[Where:
R ¹ Is
A C1-6 alkyl group which may be substituted with one or more substituents which may be the same or different from the following group A;
[Group A]
1) a halogen atom,
2) a hydroxyl group,
3) a C1-6 alkoxy group,
4) a halo C1-6 alkoxy group,
5) -NR ⁷ R ⁸ (Wherein R ⁷ And R ⁸ Are the same or different,
(A) a hydrogen atom, or
(B) a C1-6 alkyl group which may be substituted with a hydroxyl group, or
(C) R ⁷ , R ⁸ And a nitrogen-containing saturated heterocyclic group consisting of a single ring formed by combining adjacent nitrogen atoms. ),
6) -CONR ⁷ R ⁸ (Wherein R ⁷ And R ⁸ Is the same as above. ),
7)-COR ⁹ (Wherein R ⁹ Is
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C1-6 alkyl group, or
(D) C1-6 alkoxy group. ),
8) -NR ⁷¹ COR ⁹ (Wherein R ⁹ Is the same as above. R ⁷¹ Is
(A) a hydrogen atom, or
(B) a C1-6 alkyl group. )
9) -NR ⁷¹ CONR ⁷ R ⁸ (Wherein R ⁷ , R ⁸ And R ⁷¹ Is the same as above. ),
10) -NR ⁷¹ SO ₂ R ¹⁰ (Wherein R ⁷¹ Is the same as above. R ¹⁰ Is a C1-6 alkyl group. ),as well as
11) -SO ₂ R ¹⁰ (Wherein R ¹⁰ Is the same as above. );
[Wherein the nitrogen-containing saturated heterocycle consisting of a C1-6 alkyl group, a C1-6 alkoxy group, a halo C1-6 alkoxy group and a monocycle in the above 1) to 11) is further selected from group A It may be substituted with a substituent. ]
R ² Is
One or more substituents which may be the same or different from the following group B;
[Group B]
1) a halogen atom,
2) a hydroxyl group,
3) a C1-6 alkyl group which may be substituted with one or more substituents which may be the same or different and selected from the group A;
4) a C1-6 alkoxy group which may be substituted with one or more substituents which may be the same or different and selected from the group A;
5) a cycloalkylalkoxy group (the cycloalkylalkoxy group is
(A) one or more substituents selected from the group A, which may be the same or different, or
(B) It may be substituted with a C1-6 alkyl group which may be substituted with one or more substituents which may be the same or different and selected from the group A. ),
6) Aralkyl group (the aralkyl group is
(A) one or more substituents selected from the group A, which may be the same or different, or
(B) It may be substituted with a C1-6 alkyl group which may be substituted with one or more substituents which may be the same or different and selected from the group A. ),
7) Aralkoxy group (the aralkoxy group is
(A) one or more substituents selected from the group A, which may be the same or different, or
(B) It may be substituted with a C1-6 alkyl group which may be substituted with one or more substituents which may be the same or different and selected from the group A. ),
8)-COR ¹¹ (Wherein R ¹¹ Is
(A) a hydroxyl group,
(B) a C1-6 alkyl group which may be substituted with one or more substituents which may be the same or different and selected from the group A;
(C) one or more substituents which may be the same or different selected from the group A, or a C1-6 alkoxy group which may be substituted with a C1-6 alkyl group which may be substituted with these substituents,
(D) one or more substituents which may be the same or different selected from the group A, or a C 3-6 alkyl group which may be substituted with a C 1-6 alkyl group which may be substituted with these substituents; A cycloalkyl group,
(E) a cycloalkylalkoxy group which may be substituted with one or more substituents which may be the same or different selected from the group A, or a C1-6 alkyl group which may be substituted with these substituents;
(F) one or more substituents which may be the same or different selected from the group A, or an aralkyl group which may be substituted with a C1-6 alkyl group which may be substituted with these substituents, or
(G) an aralkoxy group which may be substituted with one or more substituents which may be the same or different selected from the group A, or a C1-6 alkyl group which may be substituted with these substituents;
(H) Saturation having 3 to 14 carbon atoms which may be substituted with one or more substituents which may be the same as or different from each other selected from Group A, or a C1-6 alkyl group which may be substituted with these substituents Or it is an unsaturated carbocyclic group. ),
9) -NR ¹² R ¹³ (Wherein R ¹² And R ¹³ Are the same or different,
(A) a hydrogen atom, or
(B) a C1-6 alkyl group which may be substituted with one or more substituents which may be the same or different from the group A, or
(C) R ¹² , R ¹³ And a nitrogen-containing saturated heterocyclic group consisting of a single ring formed by combining adjacent nitrogen atoms. ),
10) -CONR ¹² R ¹³ (Wherein R ¹² And R ¹³ Is the same as above. ),
11) -NR ¹²¹ COR ¹¹ (Wherein R ¹²¹ Is
(A) a hydrogen atom, or
(B) a C1-6 alkyl group which may be substituted with one or more substituents which may be the same or different from the group A, and R ¹¹ Is the same as above. ),
12) -NR ¹²¹ CONR ¹² R ¹³ (Wherein R ¹² , R ¹³ And R ¹²¹ Is the same as above. ),
13) -SR ¹⁴ (Wherein R ¹⁴ Is
(A) a C1-6 alkyl group which may be substituted with one or more substituents which may be the same or different from the group A, or
(B) a cycloalkyl group having 3 to 8 carbon atoms which may be substituted with one or more substituents which may be the same or different and selected from the group A. ),
14) -SOR ¹⁴ (Wherein R ¹⁴ Is the same as above. ),
15) -SO ₂ R ¹⁴ (Wherein R ¹⁴ Is the same as above. ),
16) -SO ₂ NR ¹² R ¹³ (Wherein R ¹² And R ¹³ Is the same as above. ),
17) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (the carbocyclic group is
(A) one or more substituents selected from the group A, which may be the same or different, or
(B) It may be substituted with a C1-6 alkyl group which may be substituted with one or more substituents which may be the same or different and selected from the group A. ),
18) a saturated or unsaturated heterocyclic group having at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom (the heterocyclic group is
(A) one or more substituents selected from the group A, which may be the same or different, or
(B) It may be substituted with a C1-6 alkyl group which may be substituted with one or more substituents which may be the same or different and selected from the group A. ),as well as
19) Aryloxy group (the aryloxy group is
(A) one or more substituents selected from the group A, which may be the same or different, or
(B) It may be substituted with a C1-6 alkyl group which may be substituted with one or more substituents which may be the same or different and selected from the group A. );
Or R ¹ And R ² Together, between adjacent nitrogen and carbon atoms, —CH ₂ -CH ₂ A -O- bond may be formed;
R ³ Is
(1) a hydrogen atom, or
(2) a C1-6 alkyl group which may be substituted with one or more substituents which may be the same or different and selected from the group A;
m is an integer from 1 to 5;
n is 0 or an integer from 1 to 4;
R ⁴ Is one or more substituents which may be the same or different and selected from the group B,
When m is 2 or more,
(1) Two R ⁴ The groups may form ═O together, or
(2) Two R ⁴ Together with the adjacent carbon atom of ring P1,
(Wherein R ¹⁵ Are 1 to 4 substituents selected from the group B);
R ⁵ And R ⁶ Are the same or different,
(1) a hydrogen atom, or
(2) a substituent selected from the group B;
Or R ² And R ⁵ May form an —O— bond with adjacent carbon atoms;
X is
(1) CH or
(2) N;
Ring P1 is
(1) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms, or
(2) A saturated or unsaturated heterocyclic group having at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom. ]
2. In the general formula [1], R ¹ And R ² Together with adjacent nitrogen and carbon atoms —CH ₂ -CH ₂ -O- is not formed and R ² And R ⁵ The 3-aminobenzamide compound or the pharmaceutically acceptable salt thereof according to 1, wherein does not form —O— with an adjacent carbon atom.
3. The 3-aminobenzamide compound according to the above 1 represented by the following general formula [2] or a pharmaceutically acceptable salt thereof.
[Wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , M, n, X and ring P1 are the same as described above. However, n is not 0 at this time. ]
4). 3. The 3-aminobenzamide compound of the above 1 represented by the following general formula [3] or a pharmaceutically acceptable salt thereof.
[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁶ , M, n, X and ring P1 are the same as described above. However, n is not 0 at this time. ]
5. The 3-aminobenzamide compound or a pharmaceutically acceptable salt thereof according to any one of 1 to 4 above, wherein the carbocyclic group or heterocyclic group of ring P1 is a monocyclic ring.
6). R ¹ Is a hydroxyl group, a C1-6 alkoxy group, -CONR ⁷ R ⁸ And -COR ⁹ A C1-6 alkyl group which may be substituted with one or more substituents selected from: n is 0, or n is an integer of 1 to 4 and R ² Is defined as a halogen atom, a hydroxyl group, a C1-6 alkyl group defined as the group B, a C1-6 alkoxy group defined as the group B, a carbocyclic group defined as the group B, or a group B as defined above. An aralkoxy group, R ³ 6. The 3-aminobenzamide compound or a pharmaceutically acceptable salt thereof according to 1, 2, 4 or 5, wherein is a hydrogen atom.
7). n is 0 or n is an integer from 1 to 4 and R ² Is a halogen atom, a hydroxyl group, a C1-6 alkyl group, a phenyl group, a phenoxy group, or a hydroxyl group, a C1-6 alkoxy group, -CONR ¹² R ¹³ (Wherein R ¹² And R ¹³ Is the same as above. ) And -COR ¹¹ (Wherein R ¹¹ Is the same as above. The 3-aminobenzamide compound according to 6, or a pharmaceutically acceptable salt thereof, which is a C1-6 alkoxy group which may be substituted with a substituent selected from:
8). R ⁴ Is a heterocyclic group which is a halogen atom, a C1-6 alkyl group, a halo C1-6 alkyl group, a C1-6 alkoxy group, a halo C1-6 alkoxy group, or a saturated monocyclic ring having a nitrogen atom as a hetero atom The 3-aminobenzamide compound or a pharmaceutically acceptable salt thereof according to 1 to 7.
9. X is CH or N and R ¹ Is a hydroxyl group, a C1-6 alkoxy group, -NR ⁷ R ⁸ (Where R ⁷ And R ⁸ Are the same or different and a C1-6 alkyl group which may be substituted with a hydrogen atom or a hydroxyl group. ), -CONR ⁷ R ⁸ And (where R ⁷ And R ⁸ Are the same or different and a C1-6 alkyl group which may be substituted with a hydrogen atom or a hydroxyl group. ) And -COR ⁹ (Where R ⁹ Is a hydroxyl group or a C1-6 alkoxy group. ) Is a C1-6 alkyl group which may be substituted with one or more substituents selected from: n is 0 or an integer of 1 to 2, and R ² Is a halogen atom, a hydroxyl group, a C1-6 alkyl group, an aryl group, an aryloxy group or a C1-6 alkoxy group (the alkoxy group is a hydroxyl group, a C1-6 alkoxy group, -CONR ⁷ R ⁸ And (where R ⁷ And R ⁸ Are the same or different and a C1-6 alkyl group which may be substituted with a hydrogen atom or a hydroxyl group. ) And -COR ⁹ (Where R ⁹ Is a hydroxyl group or a C1-6 alkoxy group. ) May be substituted with 1 to 2 substituents selected from ) And R ³ Is a hydrogen atom, m is an integer of 1 to 3, and R ⁴ Is a halogen atom, C1-6 alkyl group, halo C1-6 alkyl group, C1-6 alkoxy group, halo C1-6 alkoxy group, -CONR ¹² R ¹³ (Where R ¹² And R ¹³ Are the same or different and are a hydrogen atom or a C1-6 alkyl group. Or a saturated monocyclic heterocyclic group having a nitrogen atom as a hetero atom, and R ⁵ And R ⁶ Are the same or different and each is a hydrogen atom, a halogen atom, a C1-6 alkoxy group, a hydroxyl group, or a C1-6 alkyl group optionally substituted with a C1-6 alkoxy group, a halo C1-6 alkyl group, -CONR ¹² R ¹³ (Where R ¹² And R ¹³ Are the same or different and are a hydrogen atom or a C1-6 alkyl group. ) Or -COR ¹¹ (Where R ¹¹ Is a hydroxyl group or a C1-6 alkoxy group. The 3-aminobenzamide compound or the pharmaceutically acceptable salt thereof according to 1, wherein ring P1 is a phenyl group or a pyridyl group.
10. 3. The 3-aminobenzamide compound according to 1 or a pharmaceutically acceptable salt thereof selected from the following group.
(1) N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] benzamide hydrochloride,
(2) N- (4-tert-butylphenyl) -3- [N- (pyridin-2-yl) -N-methyl-amino] benzamide hydrochloride,
(3) N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-ethyl-amino] benzamide,
(4) N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl] amino-4-methoxybenzamide,
(5) N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl] amino-4-phenoxybenzamide,
(6) N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] -2-methylbenzamide,
(7) N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] -4-methylbenzamide,
(8) N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] -4-phenylbenzamide,
(9) N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] -4-fluorobenzamide,
(10) N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-ethyl] amino-4-methoxybenzamide,
(11) N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-isopropyl] amino-4-methoxybenzamide,
(12) N- (4-tert-butylphenyl) -4-chloro-3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] benzamide,
(13) N- (4-tert-butylphenyl) -4-chloro-3- [N- (pyridin-2-yl) -N-methyl-amino] benzamide,
(14) N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] -4-methoxymethyloxybenzamide,
(15) N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] -4-hydroxybenzamide,
(16) N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] -4-isopropoxybenzamide,
(17) N- (4-tert-butylphenyl) -10-methyl-10H-benzo [b] pyrido [2,3-e] [1,4] oxazine-8-carboxamide,
(18) N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] -4- (2-hydroxyethyl) oxybenzamide,
(19) {4- (4-tert-butylphenyl) aminocarbonyl-2- [N- (3-chloropyridin-2-yl) -N-methyl] amino-phenoxy} acetic acid,
(20) N- (4-tert-butylphenyl) -4-carbamoylmethyloxy-3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] benzamide,
(21) N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] -4- (N-methylcarbamoylmethyl) oxybenzamide,
(22) N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] -4- (N, N-dimethylcarbamoylmethyl) oxybenzamide ,
(23) N- (4-tert-butylphenyl) -5-chloro-3- [N- (3-chloropyridin-2-yl) -N-methyl] aminobenzamide,
(24) N- (4-tert-butylphenyl) -2-chloro-5- [N- (3-chloropyridin-2-yl) -N-methyl] aminobenzamide,
(25) N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl] amino-2-hydroxybenzamide,
(26) N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl] amino-2-methoxybenzamide,
(27) N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] -2- (2-hydroxyethyl) oxybenzamide,
(28) N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N- (2-hydroxyethyl)] amino-4-methoxybenzamide,
(29) N- (4-tert-butylphenyl) -4-chloro-3- [N- (3-chloropyridin-2-yl) -N- (2-methoxyethyl) amino] benzamide,
(30) N- (4-tert-butylphenyl) -4-chloro-3- [N- (3-chloropyridin-2-yl) -N- (2-hydroxyethyl) amino] benzamide,
(31) 4-chloro-3- [N- (3-chloropyridin-2-yl) -N- (2-hydroxyethyl) amino] -N- (4-trifluoromethylphenyl) -benzamide hydrochloride,
(32) 4-chloro-3- [N- (3-chloropyridin-2-yl) -N- (2-hydroxyethyl) amino] -N- (4-trifluoromethoxyphenyl) -benzamide hydrochloride,
(33) N- (4-tert-butylphenyl) -3- [N- (2-chlorophenyl) -N-methyl-amino] benzamide, and
(34) N- (4-tert-butylphenyl) -4- (3-chloropyridin-2-yl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-carboxamide.
(35) 4-Chloro-3- [N- (3-chloropyridin-2-yl) -N- (2-hydroxyethyl) amino] -N- (4-isobutyloxyphenyl) -benzamide hydrochloride
(36) 4-Chloro-N- (4-chlorophenyl) -3- [N- (3-chloropyridin-2-yl) -N- (2-hydroxyethyl) amino] -benzamide
(37) 4-Chloro-3- [N- (3-chloropyridin-2-yl) -N- (2-hydroxyethyl) amino] -N- (4-isopropylphenyl) -benzamide
(38) 4-Chloro-3- [N- (3-chloropyridin-2-yl) -N- (2-hydroxyethyl) amino] -N- (1-methyl-1,2,3,4-tetrahydro Isoquinolin-7-yl) -benzamide
(39) 4-Chloro-3- [N- (3-chloropyridin-2-yl) -N- (2-hydroxyethyl) amino] -N- (4-chloro-3-trifluoromethylphenyl) -benzamide
(40) 4-Chloro-3- [N- (3-chloropyridin-2-yl) -N- (2-hydroxyethyl) amino] -N- (2-trifluoromethylpyridin-5-yl) -benzamide
(41) 4-Chloro-3- [N- (3-chloropyridin-2-yl) -N- (2-hydroxyethyl) amino] -N- (4-isopropyloxyphenyl) -benzamide
(42) 4-Chloro-3- [N- (3-chloropyridin-2-yl) -N- (2-hydroxyethyl) amino] -N- (5-trifluoromethylpyridin-2-yl) -benzamide
(43) 4-Chloro-3- [N- (3-chloropyridin-2-yl) -N- (2-hydroxyethyl) amino] -N- (3-fluoro-4-piperidinylphenyl) -benzamide
(44) 4-Chloro-3- [N- (3-chloropyridin-2-yl) -N- (2-hydroxyethyl) amino] -N- (4-isobutyloxyphenyl) -benzamide
(45) 4-Chloro-3- [N- (3-chloropyridin-2-yl) -N- (3-hydroxypropyl) amino] -N- (4-tert-butylphenyl) -benzamide
(46) N- (3-chloropyridin-2-yl) -N- {2-chloro-5- [N- (4-tert-butylphenyl) carbamoyl] phenyl} -aminoacetic acid
(47) 4-Chloro-3- [N- (3-chloropyridin-2-yl) -N- (carbamoylmethyl) amino] -N- (4-tert-butylphenyl) -benzamide
(48) 4-Chloro-3- [N- (3-chloropyridin-2-yl) -N- (N-methylcarbamoylmethyl) amino] -N- (4-tert-butylphenyl) -benzamide
(49) 4-Chloro-3- [N- (3-chloropyridin-2-yl) -N- (N, N-dimethylcarbamoylmethyl) amino] -N- (4-tert-butylphenyl) -benzamide
(50) 3- [N- (3-chloropyridin-2-yl) -N- (2-hydroxyethyl) amino] -N- (4-isobutyloxyphenyl) -4-methoxy-benzamide,
(51) N- (4-isobutyloxyphenyl) -4-methoxy-3- [N- (5-methylpyridin-2-yl) -N- (2-hydroxyethyl) amino] -benzamide,
(52) 3- [N- (3-chloropyridin-2-yl) -N- (2-hydroxyethyl) amino] -N- (4-isobutyloxyphenyl) -benzamide;
(53) N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N- (2-hydroxyethyl) amino] -benzamide,
(54) 3- [N- (3-chloropyridin-2-yl) -N- (2-hydroxyethyl) amino] -N- (4-trifluoromethylphenyl) -benzamide,
(55) 4-Chloro-3- [N- (3-chloropyridin-2-yl) -N- (2-hydroxyethyl) amino] -N- (4-isobutyloxy-3-methylcarbamoylphenyl) -benzamide ,
(56) 4-Chloro-3- [N- (3-chloropyridin-2-yl) -N- (2-hydroxyethyl) amino] -N- (3-dimethylcarbamoyl-4-isobutyloxyphenyl) -benzamide ,
(57) N- (4-tert-butylphenyl) -4-chloro-3- {N- (3-chloropyridin-2-yl) -N- [N- (2-hydroxyethyl) carbamoylmethyl] amino} -Benzamide,
(58) 3- [N- (2-aminoethyl) -N- (3-chloropyridin-2-yl) amino] -4-chloro-N- (4-tert-butylphenyl) -benzamide,
(59) 4-chloro-3- [N- (3-chloropyridin-2-yl) -N- (carbamoylmethyl) amino] -N- (4-trifluoromethylphenyl) -benzamide;
(60) 4-chloro-3- [N- (3-chloropyridin-2-yl) -N- (carbamoylmethyl) amino] -N- (4-trifluoromethoxyphenyl) -benzamide,
(61) 4-chloro-3- [N- (3-chloropyridin-2-yl) -N- (carbamoylmethyl) amino] -N- (4-isobutyloxyphenyl) -benzamide;
(62) 4-chloro-3- [N- (3-chloropyridin-2-yl) -N- (carbamoylmethyl) amino] -N- (3-fluoro-4-piperidinophenyl) -benzamide;
(63) 3- [N- (3-chloropyridin-2-yl) -N- (carbamoylmethyl) amino] -4-methyl-N- (4-trifluoromethylphenyl) -benzamide;
(64) 3- [N- (3-chloropyridin-2-yl) -N- (carbamoylmethyl) amino] -4-methyl-N- (4-trifluoromethoxyphenyl) -benzamide;
(65) 3- [N- (3-chloropyridin-2-yl) -N- (carbamoylmethyl) amino] -N- (4-isobutyloxyphenyl) -4-methyl-benzamide,
(66) 4-chloro-3- [N- (3-chloropyridin-2-yl) -N- (N-methylcarbamoylmethyl) amino] -N- (4-trifluoromethylphenyl) -benzamide;
(67) 4-Chloro-3- [N- (3-chloro-5-trifluoromethylpyridin-2-yl) -N- (carbamoylmethyl) amino] -N- (4-trifluoromethoxyphenyl) -benzamide ,
(68) 4-Chloro-3- [N- (3-chloro-5-trifluoromethylpyridin-2-yl) -N- (carbamoylmethyl) amino] -N- (4-trifluoromethylphenyl) -benzamide ,
(69) 4-chloro-3- [N- (3-chloropyridin-2-yl) -N- (carbamoylmethyl) amino] -N- (trifluoromethoxyphenyl) -benzamide;
(70) 4-chloro-3- [N- (3-chloropyridin-2-yl) -N- (carbamoylmethyl) amino] -N- (trifluoromethylphenyl) -benzamide;
(71) 4-chloro-3- [N- (3-chloro-5-methoxymethylpyridin-2-yl) -N- (carbamoylmethyl) amino] -N- (trifluoromethoxyphenyl) -benzamide;
(72) 4-chloro-3- [N- (3-chloro-5-methoxymethylpyridin-2-yl) -N- (carbamoylmethyl) amino] -N- (trifluoromethylphenyl) -benzamide;
(73) 6-{[5- (4-tert-butylphenylcarbamoyl) -2-chlorophenyl] -methyl-amino} -5-chloronicotinic acid ethyl;
(74) 6-{[5- (4-tert-butylphenylcarbamoyl) -2-chlorophenyl] -methyl-amino} -5-chloronicotinic acid,
(75) 6-{[5- (4-tert-butylphenylcarbamoyl) -2-chlorophenyl] -methyl-amino} -5-chloronicotinamide,
(76) 6-{[5- (4-tert-butylphenylcarbamoyl) -2-chlorophenyl] -methyl-amino} -5-chloro-N-methylnicotinamide,
(77) 6-{[5- (4-tert-butylphenylcarbamoyl) -2-chlorophenyl] -methyl-amino} -5-chloro-N, N-dimethylnicotinamide,
(78) N- (4-tert-butylphenyl) -4-chloro-3- [N- (3-chloro-5-hydroxymethylpyridin-2-yl) -N-methyl-amino] benzamide,
(79) 4-chloro-3- [N- (3-chloro-5-hydroxymethylpyridin-2-yl) -N-methyl-amino] -N- (4-trifluoromethylphenyl) -benzamide;
(80) 4-chloro-3- [N- (3-chloro-5-hydroxymethylpyridin-2-yl) -N-methyl-amino] -N- (4-chlorophenyl) -benzamide;
(81) 4-chloro-3- [N- (3-chloro-5-hydroxymethylpyridin-2-yl) -N-methyl-amino] -N- (4-trifluoromethoxyphenyl) -benzamide;
(82) 3- [N- (3-chloro-5-hydroxymethylpyridin-2-yl) -N-methyl-amino] -4-fluoro-N- (4-trifluoromethylphenyl) -benzamide, and
(83) 3- [N- (3-Chloro-5-hydroxymethylpyridin-2-yl) -N-methyl-amino] -4-fluoro-N- (4-trifluoromethoxyphenyl) -benzamide.
11. 11. A pharmaceutical composition comprising the 3-aminobenzamide compound according to any one of 1 to 10 above or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
12 Pain, acute pain, chronic pain, neuropathy comprising the 3-aminobenzamide compound according to any one of 1 to 10 above or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier Pain, rheumatoid arthritis pain, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, acute postherpetic neuralgia, postherpetic neuralgia, chronic postherpetic neuralgia, postoperative neuralgia, cancer pain, inflammatory pain, Interstitial cystitis, posttraumatic neuralgia, diabetic neuropathy, neurodegeneration, stroke, ischemia, nerve injury, neurological skin disease, inflammatory disease, pruritus, allergic rhinitis, stroke, hypersensitivity Treatment and / or treatment of diseases selected from bowel syndrome, asthma, chronic obstructive pulmonary disease, dermatitis, mucositis, gastric / duodenal ulcer and inflammatory bowel syndrome, bladder hypersensitivity, bladder overactivity, frequent urination and urinary incontinence Medicine for prevention Narubutsu.
13. A medicament for treating and / or preventing pain comprising the 3-aminobenzamide compound according to any one of 1 to 10 above or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Composition.
14 Pain is pain, acute pain, chronic pain, neuropathic pain, rheumatoid arthritis pain, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, acute postherpetic neuralgia, postherpetic neuralgia, chronic postherpetic neuralgia 14. The pharmaceutical composition according to 13 above, which is postoperative neuralgia, cancer pain, inflammatory pain, interstitial cystitis, posttraumatic neuralgia, diabetic neuropathy, or neurodegeneration.
15. Vanilloid receptor type 1 (VR1) activity inhibitor comprising the 3-aminobenzamide compound according to any one of 1 to 10 above or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. .
16. Pain, acute pain, chronic pain, neuropathic pain characterized by administering a pharmaceutically effective amount of the 3-aminobenzamide compound according to any one of 1 to 10 above or a pharmaceutically acceptable salt thereof Rheumatoid arthritis pain, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, acute postherpetic neuralgia, postherpetic neuralgia, chronic postherpetic neuralgia, postoperative neuralgia, cancer pain, inflammatory pain, between Cystitis, posttraumatic neuralgia, diabetic neuropathy, neurodegeneration, stroke, ischemia, nerve injury, neurological skin disease, inflammatory disease, pruritus, allergic rhinitis, stroke, irritable bowel A method of treating a disease selected from syndrome, asthma, chronic obstructive pulmonary disease, dermatitis, mucositis, gastric / duodenal ulcer and inflammatory bowel syndrome, bladder hypersensitivity, bladder overactivity, urinary incontinence and / or Prevention method.
17. A method for treating and / or preventing pain, comprising administering a pharmaceutically effective amount of the 3-aminobenzamide compound according to any one of 1 to 10 above or a pharmaceutically acceptable salt thereof.
18. Pain is pain, acute pain, chronic pain, neuropathic pain, rheumatoid arthritis pain, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, acute postherpetic neuralgia, postherpetic neuralgia, chronic postherpetic neuralgia 18. The method of treatment and / or prevention according to 17 above, which is postoperative neuralgia, cancer pain, inflammatory pain, interstitial cystitis, posttraumatic neuralgia, diabetic neuropathy, or neurodegeneration.
19. The pharmaceutical composition according to 11-14 above, and the pharmaceutical composition comprising pain, acute pain, chronic pain, neuropathic pain, rheumatoid arthritis pain, neuralgia, neuropathy, hyperalgesia, migraine, arthralgia, acute Postherpetic neuralgia, Postherpetic neuralgia, Chronic postherpetic neuralgia, Postoperative neuralgia, Cancer pain, Inflammatory pain, Interstitial cystitis, Posttraumatic neuralgia, Diabetic neuropathy, Neurodegenerative disease, Stroke, False , Neurological injury, neurological skin disease, inflammatory disease, pruritus, allergic rhinitis, stroke, irritable bowel syndrome, asthma, chronic obstructive pulmonary disease, dermatitis, mucositis, gastric / duodenal ulcer and Said medicament which can be used or should be used for the treatment and / or prevention of diseases selected from inflammatory bowel syndrome, bladder hypersensitivity, bladder overactivity type urination and urinary incontinence Descriptions related to the composition Commercial package that includes.
20. 12. Pain, acute pain, chronic pain, neuropathic pain, rheumatoid arthritis pain, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, acute postherpetic neuralgia, postherpetic neuralgia, chronic zoster Post-herpetic neuralgia, postoperative neuralgia, cancer pain, inflammatory pain, interstitial cystitis, posttraumatic neuralgia, diabetic neuropathy, neurodegeneration, stroke, ischemia, nerve injury, neurological skin disease, Inflammatory disease, pruritus, allergic rhinitis, stroke, irritable bowel syndrome, asthma, chronic obstructive pulmonary disease, dermatitis, mucositis, gastric / duodenal ulcer and inflammatory bowel syndrome, bladder hypersensitivity, bladder overactivity 11. The 3-aminobenzamide compound according to any one of 1 to 10 above or a pharmaceutically acceptable salt thereof for producing a pharmaceutical composition for treating and / or preventing a disease selected from frequent urination and urinary incontinence Use of salt .
21. Use of the 3-aminobenzamide compound according to any one of 1 to 10 above or a pharmaceutically acceptable salt thereof for producing a pharmaceutical composition for treating and / or preventing pain according to the above 13.
22. Pain is pain, acute pain, chronic pain, neuropathic pain, rheumatoid arthritis pain, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, acute postherpetic neuralgia, postherpetic neuralgia, chronic postherpetic neuralgia The 3-aminobenzamide compound according to 21 above, which is postoperative neuralgia, cancer pain, inflammatory pain, interstitial cystitis, posttraumatic neuralgia, diabetic neuropathy, or neurodegeneration, or a pharmaceutically acceptable salt thereof Salt used.
23. A pharmaceutical composition comprising the 3-aminobenzamide compound or a pharmaceutically acceptable salt thereof according to any one of 1 to 10 above and a pharmaceutically acceptable carrier, an antiviral agent, and an antidepressant Drugs, anticonvulsants, antiarrhythmic drugs, local anesthetics, anesthetics, N-methyl-D-aspartate antagonists, corticosteroids, nerve blocks, nonsteroidal anti-inflammatory drugs Analgesics, narcotics, antagonistic analgesics, α ₂ A medicament comprising a combination of one or more drugs selected from the group consisting of an adrenergic receptor agonist, an external preparation, a calcium channel antagonist and a potassium channel opener.
24. Use of the 3-aminobenzamide compound according to any one of 1 to 10 or a pharmaceutically acceptable salt thereof for producing the medicament according to 23.
25. Antiviral agent, antidepressant, anticonvulsant, antiarrhythmic agent, local anesthetic, anesthetic, N-methyl-D-aspartate antagonist, corticosteroid, nerve Block, non-steroidal anti-inflammatory analgesic, narcotic, antagonistic analgesic, alpha ₂ Use of one or more drugs selected from the group consisting of adrenergic receptor agonists, topical drugs, calcium channel antagonists and potassium channel openers in combination with a pharmaceutically effective amount of vanilloid receptor type 1 (VR1) activity inhibitor. Pain, acute pain, chronic pain, neuropathic pain, rheumatoid arthritis pain, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, acute postherpetic neuralgia, postherpetic neuralgia, chronic herpes zoster Post Neuralgia, Postoperative Neuralgia, Cancer Pain, Inflammatory Pain, Interstitial Cystitis, Posttraumatic Neuralgia, Diabetic Neuropathy, Neurodegeneration, Stroke, Ischemia, Nerve Injury, Nervous Skin Disease, Inflammation Sex diseases, pruritus, allergic rhinitis, stroke, irritable bowel syndrome, asthma, chronic obstructive pulmonary disease, dermatitis, mucositis, gastric / duodenal ulcer and inflammatory bowel syndrome, bladder hypersensitivity, Method for the treatment and / or prevention of diseases selected from 胱過 activity type frequent urination and urinary incontinence.
26. 26. The method for treatment and / or prevention according to 25 above, wherein the vanilloid receptor type 1 (VR1) activity inhibitor is the 3-aminobenzamide compound according to any one of 1 to 10 above or a pharmaceutically acceptable salt thereof. .
27. Administration of vanilloid receptor type 1 (VR1) inhibitor and acupuncture, transcutaneous electrical acupuncture, transcutaneous electrical nerve stimulation, silver spike point (SSP) therapy, peripheral nerve stimulation, spinal cord stimulation A method for treating and / or preventing a disease accompanied by pain symptoms, characterized by using a combination of stimulation and analgesia selected from electroconvulsive therapy, laser therapy, and low-frequency therapy.
28. 28. The therapeutic and / or prophylactic method according to the above 27, wherein the vanilloid receptor type 1 (VR1) activity inhibitor is the 3-aminobenzamide compound according to any one of 1 to 10 above or a pharmaceutically acceptable salt thereof. .
29. Inhibition of vanilloid receptor type 1 (VR1) activity after surgery selected from scar resection, nerve cryocoagulation, peripheral nerve resection, dorsal root resection, sympathectomy, dorsal root approach tract destruction, cord tomy, frontal lobe resection A method for treating and / or preventing postoperative pain, comprising administering an agent.
30. 29. The method for treatment and / or prevention according to 29 above, wherein the vanilloid receptor type 1 (VR1) activity inhibitor is the 3-aminobenzamide compound according to any one of 1 to 10 above or a pharmaceutically acceptable salt thereof. .
Since the 3-aminobenzamide compound of the present invention effectively inhibits the activity of vanilloid receptor type 1 (VR1), pain, acute pain, chronic pain, neuropathic pain, rheumatoid arthritis pain, neuralgia, neuropathy, Hyperalgesia, migraine, joint pain, acute postherpetic neuralgia, postherpetic neuralgia, chronic postherpetic neuralgia, postoperative neuralgia, cancer pain, inflammatory pain, interstitial cystitis, posttraumatic neuralgia, diabetes Neuropathy, neurodegeneration, stroke, ischemia, nerve injury, neurological skin disease, inflammatory disease, pruritus, allergic rhinitis, stroke, irritable bowel syndrome, asthma, chronic obstructive pulmonary disease, It is effective for the treatment and / or prevention of diseases such as dermatitis, mucositis, gastric / duodenal ulcer and inflammatory bowel syndrome, bladder hypersensitivity, bladder overactivity, frequent urination and urinary incontinence. In particular, pain, acute pain, chronic pain, neuropathic pain, rheumatoid arthritis pain, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, acute postherpetic neuralgia, postherpetic neuralgia, chronic herpes zoster Neuralgia, postoperative neuralgia, cancer pain, inflammatory pain, interstitial cystitis, posttraumatic neuralgia, diabetic neuropathy, neurodegenerative disease, and the like are effective as a therapeutic agent and preventive agent. Moreover, the effect by the mechanism different from the conventional analgesic is also anticipated.

The definition of each term used in this specification is as follows.
The “C 1-6 alkyl group” represents a linear or branched alkyl group having 1 to 6 carbon atoms,
Specific examples include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a tert-pentyl group, and a hexyl group. R ¹ , R ² , R ⁴ , R ⁵ And R ⁶ A preferred “C 1-6 alkyl group” is a C 1-4 alkyl group.
The “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom or a chlorine atom. R ² , R ⁴ , R ⁵ And R ⁶ Preferred “halogen atom” is a chlorine atom or a fluorine atom.
The “halo C1-6 alkyl group” is a group in which the “C1-6 alkyl group” defined above is substituted with the “halogen atom” defined above, and preferably the alkyl group moiety has 1 to 4 carbon atoms. It is a halogenated alkyl group which is a linear or branched alkyl group. Specifically, fluoromethyl group, difluoromethyl group, trifluoromethyl group, bromomethyl group, chloromethyl group, 1,2-dichloromethyl group, 2,2-dichloromethyl group, 2,2,2-trifluoroethyl Groups and the like.
The “C1-6 alkoxy group” is an alkoxy group whose alkyl moiety is the “C1-6 alkyl group” defined above, specifically, a methoxy group, an ethoxy group, a propoxy group, an isopropyloxy group, a butoxy group. , Isobutyloxy group, tert-butyloxy group, pentyloxy group, hexyloxy group and the like. Preferably, the alkyl group moiety is an alkoxy group having a linear or branched alkyl group having 1 to 4 carbon atoms. R ² And R ⁴ A preferred “C 1-6 alkoxy group” is a C 1-4 alkoxy group.
The term “carbocyclic group” or “saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms” means an unsaturated group having 3 to 14 carbon atoms, preferably 3 to 8 carbon atoms or preferably having a double bond in part. A saturated cyclic hydrocarbon group, specifically, an aryl group, a cycloalkyl group, a cycloalkenyl group, or a condensed carbocyclic ring in which those rings are condensed as described below.
Here, the “aryl group” is an aromatic hydrocarbon group having 6 to 14 carbon atoms, specifically, a phenyl group, a naphthyl group, a biphenyl group, an anthryl group, an indenyl group, a pentarenyl group, an azulenyl group, Examples include a fluorenyl group and a phenanthryl group. Preferably, it is a phenyl group.
Here, the “cycloalkyl group” is a saturated cycloalkyl group having 3 to 8 carbon atoms, and specifically includes a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group. Can be mentioned.
The “cycloalkenyl group” is a cycloalkenyl group having 3 to 8 carbon atoms and contains at least one, preferably 1 or 2 double bonds. Specifically, cyclopropenyl group, cyclobutenyl group, cyclopentenyl group, cyclopentadienyl group, cyclohexenyl group, cyclohexadienyl group (2,4-cyclohexadien-1-yl group, 2,5-cyclohexadiene-1 -Yl group, etc.), cycloheptenyl group, cyclooctenyl group and the like.
Specific examples of the “condensed carbocycle” obtained by condensing these “aryl group”, “cycloalkyl group”, and “cycloalkenyl group” include indenyl group, indanyl group, 1,4-dihydronaphthyl group, 1,2,3 , 4-tetrahydronaphthyl group (1,2,3,4-tetrahydro-2-naphthyl group, 5,6,7,8-tetrahydro-2-naphthyl group, etc.), perhydronaphthyl group and the like.
Ring P1 and R ² A preferred “carbocyclic group” is an aryl group, more preferably a phenyl group.
An “aralkyl group” is an arylalkyl group in which the aryl moiety is the above-described aryl group, particularly a phenyl group, and the alkyl moiety is the “C1-6 alkyl group” defined above, specifically, Include benzyl group, phenethyl group, 3-phenylpropyl group, 4-phenylbutyl group, 6-phenylhexyl group and the like.
“Aralkoxy group” means an arylalkoxy group in which the aryl moiety is the aforementioned aryl group, particularly a phenyl group, and the alkoxy moiety is the “C1-6 alkoxy group” defined above, specifically Benzyloxy group, 3-phenylpropyloxy group, 4-phenylbutyloxy group, 6-phenylhexyloxy group and the like. R ² A preferable “aralkoxy group” is a benzyloxy group.
The “cycloalkylalkoxy group” is a cycloalkylalkoxy group in which the cycloalkyl moiety is the “cycloalkyl group” defined above and the alkoxy moiety is the “C1-6 alkoxy group” defined above. Specific examples include a cyclopropylmethoxy group, a cyclobutylmethoxy group, a cyclopentylmethoxy group, a cyclohexylmethoxy group, and the like.
The “aryloxy group” is an aryloxy group whose aryl moiety is the “aryl group” defined above, specifically a phenoxy group, a naphthyloxy group, or a biphenyloxy group.
“Heterocyclic group” or “saturated or unsaturated heterocyclic group having at least one heteroatom selected from nitrogen atom, oxygen atom and sulfur atom” means a nitrogen atom, oxygen atom and sulfur in addition to carbon atom A saturated or unsaturated (including partially and fully unsaturated) monocyclic 5- or 6-membered heterocycle containing at least one, preferably 1 to 4 heteroatoms selected from atoms, or It means a condensed ring of these heterocyclic rings, or a condensed ring of these heterocyclic rings and a carbocyclic ring selected from benzene, cyclopentane and cyclohexane.
Examples of the “saturated monocyclic heterocyclic group” include pyrrolidinyl group, tetrahydrofuryl group, tetrahydrothienyl group, imidazolidinyl group, pyrazolidinyl group, 1,3-dioxolanyl group, 1,3-oxathiolanyl group, oxazolidinyl group, thiazolidinyl group , Piperidinyl group, piperazinyl group, tetrahydropyranyl group, tetrahydrothiopyranyl group, dioxanyl group, morpholinyl group, thiomorpholinyl group, 2-oxopyrrolidinyl group, 2-oxopiperidinyl group, 4-oxopiperidinyl group 2,6-dioxopiperidinyl group and the like. The “nitrogen-containing saturated heterocyclic group” means these “saturated monocyclic heterocyclic groups” having at least one nitrogen atom as a ring-constituting atom.
Examples of the “unsaturated monocyclic heterocyclic group” include pyrrolyl group, furyl group, thienyl group, imidazolyl group, 1,2-dihydro-2-oxoimidazolyl group, pyrazolyl group, diazolyl group, oxazolyl group, isoxazolyl group , Thiazolyl group, isothiazolyl group, 1,2,4-triazolyl group, 1,2,3-triazolyl group, tetrazolyl group, 1,3,4-oxadiazolyl group, 1,2,4-oxadiazolyl group, 1,3, 4-thiadiazolyl group, 1,2,4-thiadiazolyl group, furazanyl group, pyridyl group, pyrimidinyl group, 3,4-dihydro-4-oxopyrimidinyl group, pyridazinyl group, pyrazinyl group, 1,3,5-triazinyl group, Imidazolinyl group, pyrazolinyl group, oxazolinyl group (2-oxazolinyl group, 3-oxazolinyl group, -Oxazolinyl group), isoxazolinyl group, thiazolinyl group, isothiazolinyl group, pyranyl group, 2-oxopyranyl group, 2-oxo-2,5-dihydrofuranyl group, 1,1-dioxo-1H-isothiazolyl group It is done. The “heterocyclic group that is an unsaturated monocyclic ring” preferable as the ring P1 is a piperidinyl group, a thiazolyl group, a pyridyl group, or a quinolyl group, and particularly preferably a pyridyl group.
Examples of the “heterocyclic group that is a condensed ring” include an indolyl group (eg, 4-indolyl group, 7-indolyl group, etc.), isoindolyl group, 1,3-dihydro-1,3-dioxoisoindolyl group, Benzofuranyl group (for example, 4-benzofuranyl group, 7-benzofuranyl group, etc.), indazolyl group, isobenzofuranyl group, benzothiophenyl group (for example, 4-benzothiophenyl group, 7-benzothiophenyl group, etc.) Benzoxazolyl group (for example, 4-benzoxazolyl group, 7-benzoxazolyl group, etc.), benzimidazolyl group (for example, 4-benzimidazolyl group, 7-benzimidazolyl group, etc.), benzothiazolyl. Group (for example, 4-benzothiazolyl group, 7-benzothiazolyl group, etc.), indolizinyl group, quinolyl group, isoquino Group, 1,2-dihydro-2-oxoquinolyl group, quinazolinyl group, quinoxalinyl group, cinnolinyl group, phthalazinyl group, quinolidinyl group, prill group, pteridinyl group, indolinyl group, isoindolinyl group, 5,6,7,8-tetrahydro Quinolyl group, 1,2,3,4-tetrahydroquinolyl group, 2-oxo-1,2,3,4-tetrahydroquinolyl group, benzo [1,3] dioxolyl group, 3,4-methylenedioxy Examples include pyridyl group, 4,5-ethylenedioxypyrimidinyl group, chromenyl group, chromanyl group, and isochromanyl group. A “heterocyclic group which is a condensed ring” preferable as the ring P1 is a 1,2,3,4-tetrahydroquinolyl group.
“It may be substituted with one or more substituents” means that it may be substituted with at least one substituent and at most, the maximum number of permissible substituents. For example, a methyl group means that it may be substituted with 1 to 3 substituents, and an ethyl group means that it may be substituted with 1 to 5 substituents.
“C 1-6 alkyl group which may be substituted with one or more substituents which may be the same or different and selected from group A” means, for example, a methyl group which may be substituted with 1 to 3 substituents; It means an ethyl group which may be substituted with 1 to 5 substituents.
"R ⁷ , R ⁸ And a nitrogen-containing saturated heterocyclic group formed of a single ring formed by combining adjacent nitrogen atoms has at least one nitrogen atom such as, for example, a piperidino group, a morpholino group, a piperazino group, or a pyrrolidino group. It means a heterocyclic ring consisting of a saturated 5-membered or 6-membered monocycle.
“Two R ⁴ The groups may form ═O together ”means that when m is 2 or more, two R ⁴ It means that the groups together form ═O.
In the group A, the nitrogen-containing saturated heterocycle consisting of a C1-6 alkyl group, a C1-6 alkoxy group, a halo C1-6 alkoxy group and a monocycle in the above 1) to 11) is further selected from group A May be substituted with a substituent of, for example, R ⁷ , R ⁸ Or R ⁹ It means that the alkyl group in may be further substituted with a halogen atom or a hydroxyl group.
"R ¹ And R ² Together, between adjacent nitrogen and carbon atoms, —CH ₂ -CH ₂ “O— bond may be formed” means that R ¹ Nitrogen atom adjacent to R and R ² -CH between the carbon atom of the benzene ring adjacent to ₂ -CH ₂ It means forming a 2H-benzo [1,4] oxazine ring together with an adjacent benzene ring by forming an —O— bond.
m is an integer of 1 to 5, preferably 1 to 3, and more preferably 1 to 2.
n is 0 or an integer of 1 to 4, preferably 0 or 1 to 2.
"R ⁵ And R ⁶ Are the same or different and each is (1) a hydrogen atom, or (2) one or two substituents selected from the group B ”. ⁵ And R ⁶ Both are hydrogen atoms, one is a hydrogen atom and the other is a substituent selected from group B, or both are the same or different two substituents selected from group B .
In the general formula [1], X is preferably —N═, m is preferably 1 to 3, particularly 1 or 2, and the ring P1 is preferably a monocyclic aromatic carbocyclic group such as a phenyl group. Or a heterocyclic group which is an aromatic heterocyclic group such as a pyridyl group or a condensed ring such as a 1,2,3,4-tetrahydroquinolyl group, and R ¹ Preferably a hydroxyl group, a C1-6 alkoxy group, -NR ⁷ R ⁸ , -CONR ⁷ R ⁸ (Where R ⁷ , R ⁸ Is preferably a C1-6 alkyl group which may be substituted with a hydrogen atom or a hydroxyl group. ) And -COR ⁹ (Here, R ⁹ Preferred is a hydroxyl group or a C1-6 alkoxy group. ) Is a C1-6 alkyl group which may be substituted with one or more substituents selected from: n is preferably 0 or an integer of 1 to 2, and R ² Preferably, a halogen atom, a hydroxyl group, a C1-6 alkyl group defined in the group B, a C1-6 alkoxy group defined in the group B, a carbocyclic group defined in the group B, or the group B An aralkoxy group, particularly preferably a halogen atom, a hydroxyl group, a C1-4 alkyl group, a phenyl group, a phenoxy group, or a C1-4 alkoxy group (the alkoxy group is a hydroxyl group, a C1-4 alkoxy group, -CONR ⁷ R ⁸ (Where R ⁷ , R ⁸ Is preferably a hydrogen atom or a C1-6 alkyl group. ) Or -COR ⁹ (Where R ⁹ Is preferably a hydroxyl group. ) May be substituted. ) And R ³ Preferably a hydrogen atom or a C1-4 alkyl group, particularly a hydrogen atom, and R ⁴ As a halogen atom, C1-4 alkyl group, halo C1-4 alkyl group, C1-4 alkoxy group, halo C1-4 alkoxy group, -CONR ¹² R ¹³ (Where R ¹² , R ¹³ Is preferably a hydrogen atom or a C1-6 alkyl group. Or a 6-membered nitrogen-containing saturated heterocyclic group consisting of a single ring.
The “pharmaceutically acceptable salt thereof” may be any salt that forms a non-toxic salt with the compound represented by the above general formula [1]. For example, hydrochloric acid, sulfuric acid, phosphoric acid, hydrogen bromide Inorganic acids such as acids; or oxalic acid, malonic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, gluconic acid, ascorbic acid, methylsulfonic acid, benzylsulfonic acid, etc. Organic acids; or inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, ammonium hydroxide; or methylamine, diethylamine, triethylamine, triethanolamine, ethylenediamine, tris (hydroxymethyl) methylamine, Organic bases such as guanidine, choline and cinchonine; or aldehydes such as lysine, arginine and alanine It can be obtained by reacting the Amino Acids. In the present invention, a hydrate or hydrate or solvate of each compound is also included.
In the compound represented by the general formula [1], various isomers exist. For example, E isomer and Z isomer exist as geometric isomers, and when an asymmetric carbon atom exists, enantiomers and diastereomers as stereoisomers based on these exist, tautomers Can exist. Accordingly, the scope of the present invention includes all these isomers and mixtures thereof. In addition to the compound represented by the general formula [1], the present invention also includes prodrug compounds and metabolic compounds of these compounds as equivalent compounds.
"Prodrug" is a derivative of a compound of the present invention having a group that can be chemically or metabolically decomposed and chemically changed to a compound having pharmaceutical activity after administration to a living body and exhibiting the original medicinal effect And non-covalent complexes and salts.
Prodrugs are used, for example, for improving absorption in oral administration or for targeting to a target site. Examples of the modification site for prodrug formation include highly reactive functional groups such as a hydroxyl group, a carboxyl group, an amino group, and a thiol group in the compound of the present invention. Specific examples of the hydroxyl-modifying group include an acetyl group, a propionyl group, an isobutyryl group, a pivaloyl group, a benzoyl group, a 4-methylbenzoyl group, a dimethylcarbamoyl group, and a sulfo group. Specific examples of the modifying group for the carboxyl group include an ethyl group, a pivaloyloxymethyl group, a 1- (acetyloxy) ethyl group, a 1- (ethoxycarbonyloxy) ethyl group, and a 1- (cyclohexyloxycarbonyloxy) ethyl group. Carboxylmethyl group, (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl group, phenyl group, o-tolyl group and the like. Specific examples of the amino group-modifying group include hexylcarbamoyl group, 3-methylthio-1- (acetylamino) propylcarbonyl group, 1-sulfo-1- (3-ethoxy-4-hydroxyphenyl) methyl group, (5 -Methyl-2-oxo-1,3-diokyl-4-yl) methyl group and the like.
The “pharmaceutical composition” includes, in addition to the so-called “composition” composed of a pharmaceutical active ingredient and a compounding agent and the like, a combination with other drugs and the like. Of course, the present pharmaceutical composition may be used in combination with any other drug within a range acceptable in the medical field. Therefore, it can also be said that this pharmaceutical composition is a pharmaceutical composition for combined use with other drugs.
The “vanilloid receptor type 1 (VR1) activity inhibitor” refers to a substance that inhibits the function of vanilloid receptor type 1 as an ion channel and loses or attenuates its activity. Specific examples include vanilloid receptor type 1 antagonists. The vanilloid receptor type 1 antagonist refers to a substance that inhibits the function of an agonist acting on the vanilloid receptor type 1 to inhibit the function of the vanilloid receptor type 1 as an ion channel. Moreover, this inhibitor may inhibit the binding of ligands such as VR1 and capsaicin.
Specific examples of agonists acting on vanilloid receptor type 1 include capsaicin, capsaicin derivatives, acid stimulation (proton), heat stimulation and the like, but vanilloid receptor type 1 (VR1) activity inhibitors are Capsaicin, acid-stimulated (proton) or heat-stimulated agonist-stimulated intracellular Ca ²⁺ It may be a substance that inhibits inflow.
The pharmaceutical composition of the present invention can be administered not only to humans but also to other mammals (mouse, rat, hamster, rabbit, cat, dog, cow, horse, sheep, monkey, etc.). Therefore, the pharmaceutical composition of the present invention is useful not only for humans but also for veterinary drugs.
When the compound of the present invention is used as a pharmaceutical preparation, it is usually a pharmaceutically acceptable carrier, excipient, diluent, extender, disintegrant, stabilizer, preservative, buffer, emulsifier, fragrance, coloring. Agents, sweeteners, thickeners, flavoring agents, solubilizing agents, other additives, specifically water, vegetable oils, alcohols such as ethanol or benzyl alcohol, polyethylene glycol, glycerol triacetate, gelatin, lactose, starch and other carbohydrates Tablets, pills, powders, granules, suppositories, injections, eye drops, solutions, capsules, troches, aerosols, elixirs, etc., mixed with magnesium stearate, talc, lanolin, petrolatum, etc. Can be administered systemically or locally, orally or parenterally, in the form of suspensions, emulsions, syrups, etc. .
The dosage varies depending on age, body weight, symptoms, therapeutic effects, administration method, etc., but is usually in the range of 0.01 mg to 1 g per adult, once or several times a day, orally or intravenously. Etc.
“Prevention” refers to prophylactically suppressing the onset of neuralgia or chronicity of neuralgia. Specifically, acute postherpetic neuralgia, postherpetic neuralgia, transition from acute herpes zoster pain to postherpetic neuralgia, chronic postherpetic neuralgia, postoperative neuralgia, postoperative neuralgia Chronic, cancer pain, chronic cancer pain, inflammatory pain, interstitial cystitis, chronic inflammatory pain, posttraumatic neuralgia or posttraumatic neuralgia And the like are prevented prophylactically.
The compound and pharmaceutical composition of the present invention can be used in combination with one or a plurality of other drugs by a general method performed in a normal medical field.
The “medicament comprising a combination” is a pharmaceutical comprising a pharmaceutical composition or a combination containing a drug to be combined, or a pharmaceutical comprising a pharmaceutical composition or a kit containing the combination , Or a pharmaceutical or the like, wherein the combined pharmaceutical composition or drug is administered by the same or different administration route.
There are various drugs that can be used in combination with the compounds of the present invention, and in particular, antiviral agents, antidepressants, anticonvulsants, antiarrhythmic agents, local anesthetics, anesthetics, N-methyl-D-aspartate receptor antagonists, Corticosteroid, nerve block, non-steroidal anti-inflammatory analgesic, narcotic, antagonistic analgesic, alpha ₂ Adrenergic receptor agonists, stimulant analgesics, topical drugs, calcium channel antagonists, potassium channel openers are preferred.
Specific examples of the antiviral agent include vidarabine, acyclovir, ganciclovir, zidovudine, didanosine, amantadine, idoxuridine, interferon and the like.
Specific examples of the antidepressant include amitriptin, imipramine, clomipramine, trimipramine, lofepramine, dosrepin, desipramine, amoxapine, nortriptyline, fluoxetine, fluvoxamine, maprotiline, mianserin, cetiptiline, and trazodone.
Specific anticonvulsants include gabapentin, pregabalin, phenobarbital, primidone, phenytoin, mephenytoin, nilvanol, etotoin, trimetadione, ethosuximide, acetylphenetride, carbamazepine, zonisamide, acetazolamide, diazepam, clonazepam, tranazepam, Examples include phenylhydantoin, valproic acid, and baclofen.
Specific examples of antiarrhythmic drugs include quinidine, disopyramide, procainamide, ajmarin, prazimalium, cibenzoline, lidocaine, mexiletine, aprindine, tonicoid, phenytoin, flecainide, pyrushicainide, propafenone, propranolol, amiodarone, verapamil, and bepridil. Can be mentioned.
Specific examples of the local anesthetic include lidocaine, mexiletine, cocaine, procaine, bupivacaine, mepivacaine, prilocaine, tetracaine, dibucaine, ethyl aminobenzoate and the like.
Specific examples of the anesthetic include benzodiazepine, diazepam, midazolam, thiopental, thiamylal, propofol, baclofen, droperirole, sufentanil and the like.
Specific examples of the N-methyl-D-aspartate receptor antagonist include ketamine, dextromethorphan, memantine, amantadine and the like.
Specific examples of corticosteroids include cortisol, cortisone, prednisolone, triamcinolone, dexamethasone, betamethasone, parameterzone, fluocinolone acetonide, fluocinonide, beclomethasone, flucortisone, and the like.
Nerve blocks include stellate ganglion block, epidural block, brachial plexus block, nerve root block, chest / lumbar sympathetic ganglion block, trigger point block, subarachnoid block, trigeminal block, sympathetic block, local Examples include infiltration blocks and peripheral nerve blocks.
Specific examples of non-steroidal anti-inflammatory analgesics include celecoxib, rofecoxib, etodolac, meloxicam, nimesulide, diclofenac sodium, mefenamic acid, zaltoprofen, loxoprofen sodium, sulindac, nabumetone, diflunisal, piroxicam, ibuprofen, nafenxenfen Acetylsalicylic acid, tolmethine, indomethacin, flurbiprofen, oxaprozin, ketoprofen, mofezolac, acetaminophen, ketorolac, zomepirac, nitroaspirin, thiaprofen, ampiroxicam, thiaramide, epilysole and the like.
Specific examples of narcotics include morphine, fentanyl, oxycodone, methadone, codeine, cocaine, pethidine, opium, and tocone.
Specific examples of the antagonistic analgesic include pentadine, buprenorphine, nalorphine, cyclazocine, butophanol and the like.
α ₂ Specific examples of adrenergic receptor agonists include clonidine, dexmedetomidine, tizanidine, guanfacine, and guanabenz.
Specific examples of the external medicine include capsaicin cream.
Specific examples of the stimulation and analgesia include acupuncture, transcutaneous electrical acupuncture, transcutaneous electrical nerve stimulation, silver spike point (SSP) therapy, peripheral nerve stimulation, spinal cord electrical stimulation, electroconvulsive therapy, Laser treatment, low frequency therapy, etc. are mentioned.
Moreover, the compound of this invention can be used in order to prevent or treat pain by administering after performing surgery by the general method normally performed with the medicine. There are various types of surgery that can be used in combination with the compound of the present invention, and scar excision, nerve cryocoagulation, peripheral nerve resection, spinal dorsal root excision, sympathectomy, spinal dorsal root approach tract destruction, cordotomy, and frontal lobe resection are particularly preferable.
In addition, although the above description demonstrated the application of the compound of this invention mainly as a use for the prevention or treatment of pain, the pathological condition in which C fiber is involved, for example, pruritus, allergic and allergic rhinitis , Bladder overactive frequent urination / urinary incontinence, stroke, irritable bowel syndrome, respiratory diseases such as asthma / chronic obstructive pulmonary disease, dermatitis, mucositis, gastric / duodenal ulcer and inflammatory bowel syndrome The compounds of the present invention can also be applied to prevention or treatment.
Next, a method for producing the compound represented by the general formula (1) according to the present invention will be specifically described. However, it goes without saying that the present invention is not limited to these production methods. In the production of the compound of the present invention, the order of the reaction may be carried out from a site where it can be appropriately performed. Moreover, a substituent conversion (substituent conversion or further modification) step may be appropriately inserted between the steps. Moreover, in order to accelerate | stimulate progress of reaction, reagents other than the illustrated reagent can be used suitably. In addition, raw material compounds whose production methods are not described are commercially available or can be easily prepared by combining known synthetic reactions.
All of the compounds obtained in each step can be isolated and purified by a conventional method, but in some cases, the next step can be proceeded without isolation and purification.
Manufacturing method A;
(In the formula, R represents an alkyl group, which forms an ester that is easily led to carboxylic acid by hydrolysis or catalytic hydrogenation reaction. E is a halogen atom or 3-nitrobenzenesulfonyloxy group, p-toluenesulfonyl) Represents a sulfonyloxy group such as an oxy group, a benzenesulfonyloxy group, a p-bromobenzenesulfonyloxy group, a methanesulfonyloxy group or a trifluoromethanesulfonyloxy group; ¹ Is the same as defined above, but when a reactive substituent is included, for example, in the case of a hydroxyl group, a substituted substituent such as a tetrahydropyranyl group or a tert-butyldimethylsilyl group is also included. Other symbols are as defined above. )
First step;
In this reaction, compound (IIIA) is obtained from compounds (IA) and (IIA) by a palladium-catalyzed Buchwald / Hartwig-type amination reaction.
Compound (IA) is palladium such as palladium acetate, bis (diphenylphosphino) ferrocene palladium chloride (II), tris (dibenzylideneacetone) dipalladium in toluene, 1,4-dioxane, tetrahydrofuran or the like or a mixed solvent thereof. A mixture of catalyst and 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, and sodium carbonate, tripotassium phosphate (K ₃ PO ₄ ), Potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, potassium tert-butoxide, sodium tert-butoxide and the like to react with compound (IIA) to give compound (IIIA).
Second step;
In this step, R of compound (IIIA) is removed to obtain carboxylic acid (IVA).
When R is a methyl, ethyl, propyl group or the like, compound (IIIA) is dissolved in water, methanol, ethanol, propanol, tetrahydrofuran or the like, or a mixed solvent thereof, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, carbonic acid. The compound (IVA) is obtained by hydrolysis using sodium or the like or a base of these aqueous solutions.
When R is a tert-butyl group, the compound (IIIA) is reacted with an acid such as hydrochloric acid or trifluoroacetic acid in a solvent-free or water, methanol, ethanol, propanol, tetrahydrofuran, or the like or a mixed solvent thereof. (IVA) is obtained.
When R is benzyl, paramethoxybenzyl, etc., the compound (IVA) is reacted with hydrogen, ammonium formate or the like in the presence of a palladium carbon catalyst or the like in methanol, ethanol, propanol, tetrahydrofuran or the like or a mixed solvent thereof. ) Is obtained.
Third step;
In this reaction, compound (1) is obtained by a condensation reaction of compounds (IVA) and (VA). The condensation reaction includes a method using a condensing agent and a method using an acid chloride.
When the direct condensation reaction is carried out using a condensing agent, compound (IVA) is mixed with N, N-dimethylformamide, methylene chloride, chloroform or the like, or a mixed solvent thereof, dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylamino). Compound (1) is obtained by reacting with compound (VA) using a condensing agent such as propyl) -carbodiimide. In this case, it is preferable to add additives such as hydroxybenzotriazole and N-hydroxysuccinimide.
In the case of passing through an acid chloride, the compound (IVA) is reacted with thionyl chloride, oxalyl chloride, etc. in chloroform, methylene chloride, tetrahydrofuran, pyridine or the like or a mixed solvent thereof to obtain an acid chloride of (IVA). Is reacted with compound (VA) in the presence of a base such as triethylamine or pyridine in toluene, chloroform, tetrahydrofuran or the like or a mixed solvent thereof to give compound (1).
A substituent conversion step;
R during the manufacturing process ¹ , R ² , R ⁵ Or R ⁶ Can be inserted after the first step or the third step.
For example R ¹ Is an acetoxyethyl group, after completion of the first step, the reaction is carried out by adding sodium hydroxide water, potassium hydroxide water, lithium hydroxide water or the like under a mixed solvent such as tetrahydrofuran, methanol, etc. ¹ Can be converted to hydroxyethyl groups.
For example R ² Is a methoxyethyloxy group, after the completion of the first step or the third step, the reaction is carried out by adding hydrochloric acid under tetrahydrofuran, methanol, etc. and a mixed solvent to react. ² Can be converted to hydroxyl groups.
For example R ² In the case where is a hydroxyl group, after completion of the first step or the third step, R is reacted with an alkyl halide in the presence of a base such as sodium carbonate or triethylamine in a solvent such as N, N-dimethylformamide or acetone. ² Can be converted to an alkoxy group.
Production method B;
This is another method of (IIIA) production method in production method A. The symbols in the formula are the same as above.
First step;
In this reaction, compound (IIIB) is obtained from compounds (IB) and (IIB) by a palladium-catalyzed Buchwald / Hartwig-type amination reaction.
Compound (IB) is palladium, such as palladium acetate, bis (diphenylphosphino) ferrocene palladium chloride (II), tris (dibenzylideneacetone) dipalladium, in toluene, 1,4-dioxane, tetrahydrofuran, or a mixed solvent thereof. A mixture of catalyst and 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, and sodium carbonate, tripotassium phosphate (K ₃ PO ₄ ), Potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, potassium tert butoxide, sodium tert butoxide and the like to react with compound (IIB) to give compound (IIIB).
Second step;
In this step, compound (IIIB) is N-alkylated.
Alkylating reagents such as alkyl halide, alkyl p-toluenesulfonate, alkyl methanesulfonate, alkyl trifluoromethanesulfonate, dialkylsulfuric acid and the like (IIIB) are mixed with N, N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran, acetone, water. Or in a mixed solvent thereof, sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine, Compound (IIIA) is obtained by reacting in the presence of a base such as 4-dimethylaminopyridine at 0 ° C. to reflux temperature.
Production method C;
(In the formula, G means an easily removable amino protecting group generally used in organic synthesis reaction, that is, tert-butoxycarbonyl group, benzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group, chloroacetyl group, etc. A protecting group that is convenient for the conditions of each step or for the conversion of substituents is selected and used (other symbols are as defined above).
First step;
In this step, the compound (IC) is N-alkylated.
Alkylating reagents such as alkyl halides, alkyl p-toluenesulfonate, alkyl methanesulfonate, alkyl trifluoromethanesulfonate, dialkylsulfuric acid and the like (IC) are mixed with N, N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran, acetone, water. Or in a mixed solvent thereof, sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine, Compound (IIC) is obtained by reacting in the presence of a base such as 4-dimethylaminopyridine at 0 ° C. to reflux temperature.
Second step;
In this step, R of compound (IIC) is removed to obtain carboxylic acid (IIIC).
When R is methyl, ethyl, propyl group or the like, G is tert-butoxycarbonyl group, benzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group, chloroacetyl group or the like. The compound (IIC) is hydrolyzed with water, methanol, ethanol, propanol, tetrahydrofuran or the like or a mixed solvent thereof using sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate or the like or a base of these aqueous solutions. The compound (IIIC) is obtained by decomposition.
When R is a tert-butyl group, G is a benzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group, a chloroacetyl group, or the like. Compound (IIIC) is obtained by reacting compound (IIC) with an acid such as hydrochloric acid or trifluoroacetic acid in a solvent-free or water, methanol, ethanol, propanol, tetrahydrofuran, chloroform or the like or a mixed solvent thereof.
When R is benzyl, paramethoxybenzyl group or the like, G is a tert-butoxycarbonyl group, a chloroacetyl group or the like. Compound (IIIC) is obtained by reacting compound (IIC) with methanol, ethanol, propanol, tetrahydrofuran or the like or a mixed solvent thereof in the presence of a palladium carbon catalyst or the like using hydrogen or ammonium formate.
Third step;
In this reaction, compound (VC) is obtained by condensation reaction of compounds (IIIC) and (IVC). The condensation reaction includes a method using a condensing agent and a method using an acid chloride.
When the direct condensation reaction is carried out using a condensing agent, compound (IIIC) is mixed with N, N-dimethylformamide, methylene chloride, chloroform or the like, or a mixed solvent thereof, dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylamino). Compound (VC) is obtained by reacting with compound (IVC) using a condensing agent such as propyl) -carbodiimide. In this case, it is preferable to add additives such as 1-hydroxybenzotriazole and N-hydroxysuccinimide.
When passing through an acid chloride, G is a benzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group, a chloroacetyl group, or the like. Compound (IIIC) is reacted with thionyl chloride, oxalyl chloride or the like in chloroform, methylene chloride, tetrahydrofuran or the like or a mixed solvent thereof to obtain an acid chloride of (IIIC), which is toluene, chloroform, tetrahydrofuran or the like. Compound (VC) is obtained by reacting with compound (IVC) in the presence of a base such as triethylamine or pyridine in a mixed solvent.
4th process;
In this step, the protecting group G is removed.
When G is a tert-butoxycarbonyl group, the compound (VC) is reacted with an acid such as hydrochloric acid or trifluoroacetic acid in no solvent or in water, methanol, ethanol, propanol, tetrahydrofuran, chloroform or the like or a mixed solvent thereof. This gives compound (VIC).
When G is a benzyloxycarbonyl group or a p-methoxybenzyloxycarbonyl group, the compound (VC) is hydrogen, ammonium formate, etc. in the presence of a palladium carbon catalyst or the like in methanol, ethanol, propanol, tetrahydrofuran or the like or a mixed solvent thereof. To give compound (VIC).
When G is a chloroacetyl group, compound (VIC) is obtained by reacting compound (VC) with thiourea in water, methanol, ethanol, propanol, tetrahydrofuran, or the like or a mixed solvent thereof.
5th step;
In this reaction, compound (1) is obtained from compounds (VIC) and (VIIC) by a palladium-catalyzed Buchwald / Hartwig-type amination reaction.
Compound (VIC) is palladium such as palladium acetate, bis (diphenylphosphino) ferrocene palladium chloride (II), tris (dibenzylideneacetone) dipalladium in toluene, 1,4-dioxane, tetrahydrofuran or the like or a mixed solvent thereof. A mixture of catalyst and 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, and sodium carbonate, tripotassium phosphate (K ₃ PO ₄ ), Potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, potassium tert butoxide, sodium tert butoxide and the like to react with compound (VIIC) to give compound (1).

Preparation of N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] benzamide hydrochloride;
Step 1;
Preparation of methyl 3- (tert-butoxycarbamido) benzoate;
Methyl 3-aminobenzate (3.02 g) was dissolved in tetrahydrofuran (30 mL), triethylamine (2.79 mL) and di-tert-butyl dicarbonate (4.47 g) were added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was partitioned between ethyl acetate and water, and the ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 2: 1) to obtain the title compound (2.86 g).
Step 2;
Preparation of methyl 3- (N-tert-butoxycarbonyl-N-methyl) aminobenzoate;
Sodium hydride (60%) (530 mg) was suspended in tetrahydrofuran (5 mL), and methyl 3- (tert-butoxycarbamido) benzoate (2.86 g) N, N- A dimethylformamide (20 mL) solution was added dropwise, and then the mixture was stirred at room temperature for 1 hour. The reaction mixture was ice-cooled, methyl iodide (1.12 mL) was added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was partitioned between water and ethyl acetate, and the ethyl acetate layer was washed with saturated brine, dried over saturated brine and concentrated to give a residue containing the title compound.
Step 3;
Preparation of 3- (N-tert-butoxycarbonyl-N-methyl) aminobenzoic acid;
The residue containing methyl 3- (N-tert-butoxycarbonyl-N-methyl) aminobenzoate obtained in the previous step was dissolved in methanol (15 mL), 4M sodium hydroxide (5 mL) was added, and 30 ° C. was added at 30 ° C. Stir for minutes. The reaction solution was allowed to cool, neutralized with 1M hydrochloric acid (20 mL), and then separated between ethyl acetate and water. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give a residue containing the title compound.
Step 4;
Preparation of 3-[(N-tert-butoxycarbonyl-N-methyl) amino] -N- (4-tert-butylphenyl) benzamide;
The residue containing 3- (N-tert-butoxycarbonyl-N-methyl) aminobenzoic acid obtained in the previous step was dissolved in N, N-dimethylformamide (15 mL), and 4-tert-butylaniline (1.96 g) was dissolved. ), 1-hydroxybenzotriazole (2.02 g) and 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (2.53 g) were sequentially added and stirred at room temperature for 15 hours. Water was added to the reaction solution, and the white solid obtained by stirring was collected by filtration and dried to obtain the title compound (4.87 g).
Step 5;
Preparation of N- (4-tert-butylphenyl) -3- (N-methylamino) -benzamide;
3- [N-tert-butoxycarbonyl-N-methyl] amino] -N- (4-tert-butylphenyl) benzamide (4.87 g) obtained in the previous step was dissolved in chloroform (15 mL), and trifluoro Acetic acid (5 mL) was added and stirred at room temperature for 6 hours. The reaction mixture was concentrated and separated between saturated aqueous sodium hydrogen carbonate and ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate = 2: 1) to obtain the title compound (2.92 g).
Step 6;
Preparation of N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] benzamide hydrochloride;
N- (4-tert-butylphenyl) -3-methylamino-benzamide (687 mg) obtained in the previous step was dissolved in toluene (6 mL), 2,3-dichloropyridine (300 mg), tris (dibenzylideneacetone). ) Dipalladium (92 mg), 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (151 mg) and sodium tert-butoxide (390 mg) were sequentially added, and the mixture was heated at 70 ° C. for 6 hours and further at 90 ° C. Stir for 12 hours. The reaction mixture was allowed to cool and then partitioned between ethyl acetate and water. The resulting ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel chromatography (hexane-tetrahydrofuran = 2: 1, chloroform-methanol = 19: 1), and 4N hydrogen chloride / ethyl acetate was added to precipitate the title compound (265 mg) as a pale yellow solid. Obtained.

Preparation of N- (4-tert-butylphenyl) -3- [N- (pyridin-2-yl) -N-methyl-amino] benzamide hydrochloride;
The same reaction was performed in Step 6 of Example 1 using 2-bromopyridine instead of 2,3-dichloropyridine to obtain the title compound (373 mg).

Preparation of N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-ethyl-amino] benzamide;
Step 1;
Preparation of methyl 3- (3-chloropyridin-2-yl) amino-benzoate;
Methyl 3-aminobenzoate (1 g) was suspended in toluene (10 mL), 2,3-dichloropyridine (890 mg), tris (dibenzylideneacetone) dipalladium (275 mg), 2,2′-bis (diphenylphosphino). ) -1,1′-binaphthyl (450 mg) and cesium carbonate (2.94 g) were sequentially added, and the mixture was stirred at 80 ° C. overnight. The reaction mixture was allowed to cool, ethyl acetate-water was added, insolubles were filtered off, and the layers were separated. The obtained ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel chromatography (hexane-ethyl acetate system) to obtain the title compound (320 mg).
Step 2;
Preparation of methyl 3- [N- (3-chloropyridin-2-yl) -N-ethyl) amino-benzoate;
Methyl 3- (3-chloropyridin-2-yl) amino-benzoate (300 mg) obtained in the previous step was dissolved in N, N-dimethylformamide (5 mL), and 60% sodium hydride was stirred with ice cooling. (46 mg) was added, then ethyl iodide (0, 092 mL) was added, and the mixture was stirred at room temperature for 3 hr. A small amount of acetic acid was added to the reaction solution to stop the reaction, and the mixture was concentrated and then separated between ethyl acetate and water. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel chromatography (hexane-ethyl acetate = 5: 1, hexane-acetone = 8: 1) to obtain the title compound (80 mg).
Step 3;
Preparation of 3- [N- (3-chloropyridin-2-yl) -N-ethyl] aminobenzoic acid;
Methyl 3- [N- (3-chloropyridin-2-yl) -N-ethyl] amino-benzoate (80 mg) obtained in the previous step was dissolved in methanol (1 mL), and 4M aqueous sodium hydroxide (0. 5 mL) was added, and the mixture was stirred at 60 ° C. for 3 hours. The reaction mixture was allowed to cool and concentrated, and the mixture was partitioned between ethyl acetate and water. The obtained aqueous layer was acidified with dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated to give the title compound (60 mg).
Step 4;
Preparation of N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-ethyl-amino] benzamide;
The 3- [N- (3-chloropyridin-2-yl) -N-ethyl] aminobenzoic acid (60 mg) obtained in the previous step was subjected to the same reaction as in Step 4 of Example 1 to obtain a pale yellow solid. The title compound (30 mg) was obtained.

Preparation of N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl] amino-4-methoxybenzamide;
Step 1;
Preparation of methyl 3- (3-chloropyridin-2-yl) amino-4-methoxybenzoate;
In Step 1 of Example 3, methyl 3-amino-4-methoxybenzoate (399 mg) was used, and palladium acetate was used instead of tris (dibenzylideneacetone) dipalladium, and the title compound (273 mg) was prepared. )
Step 2;
Preparation of methyl 3- [N- (3-chloropyridin-2-yl) -N-methyl] amino-4-methoxybenzoate;
Using methyl 3- (3-chloropyridin-2-yl) amino-4-methoxybenzoate (273 mg) obtained in the previous step, using methyl iodide instead of ethyl iodide in step 2 of Example 3. The same reaction was performed to give the title compound (260 mg) as a white solid.
Step 3;
Preparation of N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl] amino-4-methoxybenzamide;
Similar to Step 3-4 of Example 3 using methyl 3- [N- (3-chloropyridin-2-yl) -N-methyl] amino-4-methoxybenzoate (259 mg) obtained in the previous step. The reaction was performed to give the title compound (297 mg) as a white solid.

Preparation of N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl] amino-4-phenoxybenzamide;
The title compound (351 mg) was obtained in the same manner as in Example 4 using methyl 3-amino-4-phenoxybenzoate (537 mg).

Preparation of N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] -2-methylbenzamide;
The title compound was obtained in the same manner as in Example 4 using methyl 3-amino-2-methylbenzoate.

Preparation of N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] -4-methylbenzamide;
The title compound was obtained in the same manner as in Example 4 using methyl 3-amino-4-methylbenzoate.

Preparation of N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] -4-phenylbenzamide;
The title compound was obtained in the same manner as in Example 4 using methyl 3-amino-4-phenylbenzoate.

Preparation of N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] -4-fluorobenzamide;
The title compound was obtained in the same manner as in Example 4 using methyl 3-amino-4-fluorobenzoate.

Preparation of N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-ethyl] amino-4-methoxybenzamide;
Using methyl 3- (3-chloropyridin-2-yl) amino-4-methoxybenzoate (293 mg) obtained by the method of Step 1 of Example 4, the same reaction as in Step 2-4 of Example 3 was performed. The title compound (331 mg) was obtained.

Preparation of N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-isopropyl] amino-4-methoxybenzamide;
Instead of ethyl iodide in Step 2 of Example 3, using methyl 3- (3-chloropyridin-2-yl) amino-4-methoxybenzoate (293 mg) obtained by the method of Step 1 of Example 4 The reaction was conducted in the same manner as in Step 3-4 of Example 3 using isopyl iodide to obtain the title compound (38 mg).

Preparation of N- (4-tert-butylphenyl) -4-chloro-3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] benzamide;
The title compound (293 mg) was obtained in the same manner as in Example 4 using methyl 3-amino-4-chlorobenzoate (611 mg).

Preparation of N- (4-tert-butylphenyl) -4-chloro-3- [N- (pyridin-2-yl) -N-methyl-amino] benzamide;
Methyl 3-amino-4-chlorobenzoate (611 mg) was used, and 2-bromopyridine was used in place of 2,3-dichloropyridine in Step 1 of Example 4, and the same as in Example 4 2-3 below. The title compound (377 mg) was obtained by the method.

Preparation of N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] -4-methoxymethyloxybenzamide;
The title compound (1.76 g) was obtained in the same manner as in Example 4 using methyl 3-amino-4-methoxymethyloxybenzoate (5.25 g).

Preparation of N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] -4-hydroxybenzamide;
N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] -4-methoxymethyloxybenzamide obtained in Example 14 (1. 48 g) was dissolved in tetrahydrofuran (10 mL) and methanol (10 mL), 6M hydrochloric acid (10 mL) was added, and the mixture was stirred at 60 ° C. for 2 hr. The reaction mixture was ice-cooled, made weakly alkaline with saturated aqueous sodium hydrogen carbonate, stirred at room temperature for 1 hour, and the white solid obtained was filtered and dried to give the title compound (1.24 g).

Preparation of N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] -4-isopropoxybenzamide;
N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] -4-hydroxybenzamide (146 mg) obtained in Example 15 was converted to N , N-dimethylformamide (3 mL), potassium carbonate (74 mg) and isopropyl bromide (0.037 mL) were added, and the mixture was stirred at 80 ° C. for 13 hours. The reaction mixture was allowed to cool, water was added, and the resulting white solid was collected by filtration and purified by silica gel chromatography (hexane-tetrahydrofuran system) to give Example 16 compound (66 mg).

Preparation of N- (4-tert-butylphenyl) -10-methyl-10H-benzo [b] pyrido [2,3-e] [1,4] oxazine-8-carboxamide;
When the method of the above Example was carried out, Example 17 Compound (20 mg) was obtained simultaneously with Example 16 Compound (66 mg).

Preparation of N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] -4- (2-hydroxyethyl) oxybenzamide;
Step 1;
Preparation of N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] -4- (2-acetoxyethyl) oxybenzamide;
N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] -4-hydroxybenzamide (205 mg) obtained in Example 15 was converted to N , N-dimethylformamide (2 mL), potassium carbonate (345 mg) and 2-promoethyl acetate (0.417 mL) were added, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was partitioned between water and ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (hexane-ethyl acetate = 1: 1) to obtain a white amorphous title compound (229 mg).
Step 2;
Preparation of N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] -4- (2-hydroxyethyl) oxybenzamide;
N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] -4- (2-acetoxyethyl) oxybenzamide obtained in the previous step (291 mg) was dissolved in methanol (1.5 mL), tetrahydrofuran (1.5 mL) and water (1 mL), lithium hydroxide hydrate (42 mg) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, washed with anhydrous sodium sulfate, and concentrated to give the title compound (200 mg).

Preparation of {4- (4-tert-butylphenyl) aminocarbonyl-2- [N- (3-chloropyridin-2-yl) -N-methyl] amino-phenoxy} acetic acid;
Step 1;
Preparation of N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] -4- (methoxycarbonylmethyl) oxybenzamide;
N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] -4-hydroxybenzamide (820 mg) obtained in Example 15 was converted to N , N-dimethylformamide (8 mL), potassium carbonate (1.38 g) and methyl bromoacetate (1.53 g) were added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was partitioned between water and ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (hexane-ethyl acetate = 1: 1) to give the title compound (1.04 g) as a white oil, step 2;
Preparation of {4- (4-tert-butylphenyl) aminocarbonyl-2- [N- (3-chloropyridin-2-yl) -N-methyl] amino-phenoxy} acetic acid;
N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] -4- (methoxycarbonylmethyl) oxybenzamide obtained in the previous step ( 1.04 g) was dissolved in methanol (5 mL), tetrahydrofuran (mL) and water (3 mL), lithium hydroxide hydrate (210 mg) was added, and the mixture was stirred at room temperature for 1 hr. 1M Hydrochloric acid (5 mL) was added to the reaction mixture and concentrated. The concentrate was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, washed with anhydrous sodium sulfate, and concentrated to give the title compound (816 mg).

Preparation of N- (4-tert-butylphenyl) -4-carbamoylmethyloxy-3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] benzamide;
The {4- (4-tert-butylphenyl) aminocarbonyl-2- [N- (3-chloropyridin-2-yl) -N-methyl] amino-phenoxy} acetic acid (200 mg) obtained in Example 19 was used. Dissolved in N, N-dimethylformamide (2 mL), ammonium chloride (114 mg), 1-hydroxybenzotriazole (72 mg), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (90 mg), triethylamine (0.357 mL) was sequentially added and stirred at room temperature for 48 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed successively with saturated aqueous sodium hydrogen carbonate, 5% aqueous citric acid and saturated brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel chromatography (chloroform-methanol = 9: 1), suspended and washed with hexane, and the white solid was collected by filtration and dried to give the title compound (88 mg).

Preparation of N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] -4- (N-methylcarbamoylmethyl) oxybenzamide;
The title compound was obtained in the same manner as in Example 20 using methylamine hydrochloride instead of ammonium chloride.

Preparation of N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] -4- (N, N-dimethylcarbamoylmethyl) oxybenzamide;
The title compound was obtained in the same manner as in Example 20 using dimethylamine hydrochloride instead of ammonium chloride.

Preparation of N- (4-tert-butylphenyl) -5-chloro-3- [N- (3-chloropyridin-2-yl) -N-methyl] aminobenzamide;
The title compound was obtained in the same manner as in Example 4 using methyl 3-amino-5-chlorobenzoate.

Preparation of N- (4-tert-butylphenyl) -2-chloro-5- [N- (3-chloropyridin-2-yl) -N-methyl] aminobenzamide;
The title compound was obtained in the same manner as in Example 4 using methyl 5-amino-2-chlorobenzoate.

Preparation of N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl] amino-2-hydroxybenzamide;
Step 1;
Production of 2-methoxymethyloxy-3-nitrobenzoic acid;
3-Nitrosalicylic acid (2.5 g) was dissolved in N, N-dimethylformamide (25 mL), potassium carbonate (3.5 g) was added, and the mixture was stirred at room temperature for 30 minutes, cooled on ice, and methoxymethyl chloride (1. 15 mL) and stirred overnight while returning to room temperature. The reaction mixture was partitioned between water and ethyl acetate, and the obtained ethyl acetate layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate and concentrated to give the title compound (2.64 g).
Step 2;
Production of methyl 3-amino-2-methoxymethyloxybenzoate;
2-methoxymethyloxy-3-nitrobenzoic acid (2.64 g) obtained in the previous step was dissolved in tetrahydrofuran (20 mL) and ethyl acetate (10 mL), and 5% palladium / activated carbon (0.25 g) was added. The mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated to obtain the title compound (2.38 g).
Step 3;
Preparation of methyl 3- (3-chloropyridin-2-yl) amino-2-methoxymethyloxybenzoate;
Methyl 3-amino-2-methoxymethyloxybenzoate (2.38 g) obtained in the previous step was suspended in toluene (20 mL), 2,3-dichloropyridine (1.62 g), palladium acetate (123 mg), 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (341 mg) and cesium carbonate (5.35 g) were sequentially added, and the mixture was stirred at 80 ° C. for 15 hours. The reaction mixture was allowed to cool, ethyl acetate-water was added, insolubles were filtered off, and the layers were separated. The obtained ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel chromatography (hexane-ethyl acetate = 4: 1) to obtain the title compound (3.46 g).
Step 4;
Production of 3- (3-chloropyridin-2-yl) amino-2-hydroxybenzoic acid;
Methyl 3- (3-chloropyridin-2-yl) amino-2-methoxymethyloxybenzoate (3.46 g) obtained in the previous step was dissolved in tetrahydrofuran (7.5 mL) and methanol (7.5 mL). 4M aqueous sodium hydroxide (4 mL) was added and the mixture was stirred at 60 ° C. for 1 hr. The reaction mixture was allowed to cool, and 1M hydrochloric acid was added with stirring to adjust to pH 4, followed by concentration. Water was added to the concentrated solution, and the mixture was stirred for 1 hour at room temperature. The resulting white solid was collected by filtration and dried to obtain the title compound (1.31 g).
Step 5;
Preparation of N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl] amino-2-hydroxybenzamide;
The 3- (3-chloropyridin-2-yl) amino-2-hydroxybenzoic acid (1.31 g) obtained in the previous step was subjected to the same reaction as in Step 4 of Example 1 to give the title compound ( 1.19 g) was obtained.

Preparation of N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl] amino-2-methoxybenzamide;
N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl] amino-2-hydroxybenzamide (150 mg) obtained in Example 25 was added to N, It melt | dissolved in N-dimethylformamide (1.5 mL), potassium carbonate (101 mg) and methyl iodide (0.046 mL) were added, and it stirred at room temperature for 4 hours. The reaction mixture was partitioned between water and ethyl acetate, and the ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound (151 mg) as a pale yellow resin.

Preparation of N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] -2- (2-hydroxyethyl) oxybenzamide;
Using N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl] amino-2-hydroxybenzamide (200 mg) obtained in Example 25 In the same manner as in Example 18, the title compound (145 mg) was obtained.

Preparation of N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N- (2-hydroxyethyl)] amino-4-methoxybenzamide;
Instead of ethyl iodide in Step 2 of Example 3, using methyl 3- (3-chloropyridin-2-yl) amino-4-methoxybenzoate (200 mg) obtained by the method of Step 1 of Example 4 Using tert-butyldimethylsilylethyl bromide, the same reaction as in Step 3-4 of Example 3 was carried out to obtain the title compound (162 mg).

Preparation of N- (4-tert-butylphenyl) -4-chloro-3- [N- (3-chloropyridin-2-yl) -N- (2-methoxyethyl) amino] benzamide;
Step 1;
Preparation of methyl 4-chloro-3- (3-chloropyridin-2-yl) aminobenzoate;
The title compound (5.5 g) was obtained in the same manner as in Step 1 of Example 4 using methyl 3-amino-4-chlorobenzoate (7 g).
Step 2;
Preparation of N- (4-tert-butylphenyl) -4-chloro-3- [N- (3-chloropyridin-2-yl) -N- (2-methoxyethyl) amino] benzamide;
Using methyl 4-chloro-3- (3-chloropyridin-2-yl) aminobenzoate (600 mg) obtained in the previous step, substituting methoxyethyl bromide for ethyl iodide in Step 2 of Example 3, Then, the reaction similar to step 3-4 in Example 3 was performed to obtain the title compound (250 mg).

Preparation of N- (4-tert-butylphenyl) -4-chloro-3- [N- (3-chloropyridin-2-yl) -N- (2-hydroxyethyl) amino] benzamide;
Using methyl 4-chloro-3- (3-chloropyridin-2-yl) aminobenzoate obtained in Step 1 of Example 29, 2-bromoethyl acetate instead of ethyl iodide in Step 2 of Example 3 Was used to carry out the same reaction as in Step 3-4 of Example 3 to obtain the title compound.

Preparation of 4-chloro-3- [N- (3-chloropyridin-2-yl) -N- (2-hydroxyethyl) amino] -N- (4-trifluoromethylphenyl) -benzamide hydrochloride;
Step 1;
Preparation of methyl 4-chloro-3- {N- (3-chloropyridin-2-yl) -N- [2- (tetrahydropyran-2-yl) oxyethyl] amino} benzoate;
Methyl 4-chloro-3- (3-chloropyridin-2-yl) aminobenzoate (2.15 g) obtained by the method of Step 1 of Example 29 was dissolved in N, N-dimethylformamide (30 mL). Under ice-cooling, 60% sodium hydride (320 mg) and 2-bromoethyl- (tetrahydropyran-2-yl) ether were sequentially added, and the mixture was stirred at 60 ° C. for 6 hours. The reaction solution was diluted, neutralized with acetic acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (hexane-ethyl acetate = 8: 1) to obtain the oily title compound (1.9 g).
Step 2;
Preparation of 4-chloro-3- {N- (3-chloropyridin-2-yl) -N- [2- (tetrahydropyran-2-yl) oxyethyl] amino} benzoic acid;
Methyl 4-chloro-3- {N- (3-chloropyridin-2-yl) -N- [2- (tetrahydropyran-2-yl) oxyethyl] amino} benzoate obtained in the previous step (1.9 g) Was dissolved in methanol (20 mL), 4M aqueous sodium hydroxide (1.5 mL) was added, and the mixture was stirred at 60 ° C. for 1 hr. Thereafter, 4M aqueous sodium hydroxide (1.5 mL) was added, and the mixture was further stirred at the same temperature for 1 hour. The reaction mixture was concentrated, and the concentrate was diluted with water, adjusted to pH 5 with hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. Hexane was added to the residue and the precipitated white solid was collected by filtration and dried to obtain the title compound (1.48 g).
Step 3;
4-chloro-3- {N- (3-chloropyridin-2-yl) -N- [2- (tetrahydropyran-2-yl) oxyethyl] amino} -N- (4-trifluoromethylphenyl) -benzamide Manufacturing of;
4-chloro-3- {N- (3-chloropyridin-2-yl) -N- [2- (tetrahydropyran-2-yl) oxyethyl] amino} benzoic acid (250 mg) obtained in the previous step and 4 -Trifluoromethylaniline was subjected to the same condensation reaction as in Step 4 of Example 1 to obtain the title compound (120 mg).
Step 4;
Preparation of 4-chloro-3- [N- (3-chloropyridin-2-yl) -N- (2-hydroxyethyl) amino] -N- (4-trifluoromethylphenyl) -benzamide hydrochloride;
4-chloro-3- {N- (3-chloropyridin-2-yl) -N- [2- (tetrahydropyran-2-yl) oxyethyl] amino} -N- (4-tri Fluoromethylphenyl) -benzamide (120 mg) was dissolved in methanol (2 mL), 6M hydrochloric acid (1 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction solution was partitioned between saturated aqueous sodium hydrogen carbonate and ethyl acetate, and the obtained ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel chromatography (hexane-ethyl acetate = 3: 1), concentrated, 4N-HCl / ethyl acetate was added and the precipitated white solid was collected by filtration and dried to give the title compound (45 mg). Got.

Preparation of 4-chloro-3- [N- (3-chloropyridin-2-yl) -N- (2-hydroxyethyl) amino] -N- (4-trifluoromethoxyphenyl) -benzamide hydrochloride;
4-chloro-3- {N- (3-chloropyridin-2-yl) -N- [2- (tetrahydropyran-2-yl) oxyethyl] amino} benzoic acid obtained in Step 2 of Example 31 ( 200 mg) and 4-trifluoromethoxyaniline were used to carry out the same reaction as in Step 3-4 of Example 31 to obtain the title compound (30 mg).

Preparation of N- (4-tert-butylphenyl) -3- [N- (2-chlorophenyl) -N-methyl-amino] benzamide;
Step 1;
Production of ethyl 3- (2-chlorophenyl) aminobenzoate;
2-Bromo-1-chlorobenzene (383 mg) and ethyl 3-aminobenzoate (661 mg) are dissolved in toluene (6 mL), tris (dibenzylideneacetone) dipalladium (18 mg), 2,2′-bis (diphenylphosphine). Fino) -1,1′-binaphthyl (12 mg) and potassium tert-butoxide (450 mg) were sequentially added, and the mixture was stirred at reflux for 16 hours. The reaction solution was allowed to cool and then diluted with diethyl ether, the insoluble material was removed by filtration, and the filtrate was concentrated. The residue was purified by silica gel chromatography (hexane-ethyl acetate = 5: 1) to give the title compound (156 mg) as a colorless oil.
Step 2;
Preparation of ethyl 3- [N- (2-chlorophenyl) -N-methyl] aminobenzoate;
Dissolve ethyl 3- (2-chlorophenyl) aminobenzoate (156 mg) obtained in the previous step in N, N-dimethylformamide (2 mL) and add 60% sodium hydride (10 mg) to room temperature until foaming subsides. Then, methyl iodide (0.028 mL) was added and stirred for 1 hour. The reaction mixture was partitioned between water and ethyl acetate, and the obtained ethyl acetate layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give the title compound (171 mg) as a yellow oil. .
Step 3;
Preparation of N- (4-tert-butylphenyl) -3- [N- (2-chlorophenyl) -N-methyl-amino] benzamide;
Using ethyl 3- [N- (2-chlorophenyl) -N-methyl] aminobenzoate (170 mg) obtained in the previous step, the same reaction as in step 3-4 of Example 3 was carried out to obtain a white solid. Of 26 mg) was obtained.

Preparation of N- (4-tert-butylphenyl) -4- (3-chloropyridin-2-yl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-carboxamide;
Step 1;
Production of methyl 4-hydroxy-3-nitrobenzoate;
4-hydroxy-3-nitrobenzoic acid (10 g) was dissolved in methanol (100 mL), concentrated sulfuric acid (1.5 mL) was added, and the mixture was stirred at reflux for 5 hours. The reaction mixture was concentrated and separated between water and ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give the title compound (7.6 g).
Step 2;
Production of methyl 4-ethoxycarbonylmethyloxy-3-nitrobenzoate;
Methyl 4-hydroxy-3-nitrobenzoate (7.6 g) obtained in the previous step was dissolved in N, N-dimethylformamide (100 mL), potassium carbonate (5.4 g), ethyl bromoacetate (4.3 mL). ) And stirred at 110 ° C. for 1.5 hours. The reaction solution was concentrated and separated between water and ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate, and concentrated. Hexane was added to the concentrated residue, and the precipitated solid was collected by filtration and dried to obtain the title compound (10.14 g).
Step 3;
Preparation of methyl 3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-6-carboxylate;
4-Ethoxycarbonylmethyloxy-3-nitrobenzoate (10 g) obtained in the previous step was dissolved in methanol (50 mL) and tetrahydrofuran (50 mL), 5% palladium on carbon (2 g) was added, and room temperature under a hydrogen atmosphere. Stir with. The reaction solution was filtered, and the filtrate was concentrated and purified by silica gel chromatography (hexane-ethyl acetate system) to obtain the title compound (4 g).
Step 4;
Preparation of methyl 3,4-dihydro-2H-benzo [1,4] oxazine-6-carboxylate;
Methyl 3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-6-carboxylate (3 g) obtained in the previous step was dissolved in tetrahydrofuran (50 mL), and 1M borane / tetrahydrofuran solution (17 4 mL) and stirred at reflux for 1.5 hours. The reaction mixture was ice-cooled, 6M hydrochloric acid was added with stirring until pH = 2, and then stirring was continued for 1 hour. The reaction mixture was partitioned between ethyl acetate and aqueous sodium hydrogen carbonate, and the ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (hexane-ethyl acetate = 3: 1) to give the title compound (2 g).
Step 5;
Preparation of methyl 4- (3-chloropyridin-2-yl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-carboxylate;
Methyl 3,4-dihydro-2H-benzo [1,4] oxazine-6-carboxylate (1 g) obtained in the previous step was dissolved in toluene (10 mL), and 2,3-dichloropyridine (1.5 g) was dissolved. , Tris (dibenzylideneacetone) dipalladium (356 mg), 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (242 mg), cesium carbonate (1.42.53 g) were sequentially added, and And stirred overnight. The reaction mixture was allowed to cool, ethyl acetate-water was added, insolubles were filtered off, and the layers were separated. The obtained ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel chromatography (hexane-tetrahydrofuran = 3: 1) to give the title compound (250 mg) as an oil.
Step 6;
Preparation of 4- (3-chloropyridin-2-yl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-carboxylic acid;
Methyl 4- (3-chloropyridin-2-yl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-carboxylate (240 mg) obtained in the previous step was dissolved in methanol (2.5 mL). 4M lithium hydroxide aqueous solution (0.3 mL) was added and stirred with heating at 60 ° C. for 1.5 hours. After cooling, the mixture was neutralized with 1M hydrochloric acid (4 mL), water (20 mL) was added, and the precipitated solid was collected by filtration and dried to obtain the title compound (180 mg).
Step 7;
Preparation of N- (4-tert-butylphenyl) -4- (3-chloropyridin-2-yl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-carboxamide;
4- (3-Chloropyridin-2-yl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-carboxylic acid (170 mg) obtained in the previous step was converted to N, N-dimethylformamide (170 mg). 1.7 mL) and 4-tert-butylaniline (0.094 mL), 1-hydroxybenzotriazole (90 mg), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (112 mg). Sequentially added and stirred overnight at room temperature. Water and saturated aqueous sodium hydrogen carbonate were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel chromatography (hexane-ethyl acetate system), diisopropyl ether was added and the precipitated solid was collected by filtration and dried to give the title compound (45 mg).

Preparation of 4-chloro-3- [N- (3-chloropyridin-2-yl) -N- (2-hydroxyethyl) amino] -N- (4-isobutyloxyphenyl) -benzamide hydrochloride;
4-chloro-3- {N- (3-chloropyridin-2-yl) -N- [2- (tetrahydropyran-2-yl) oxyethyl] amino} benzoic acid obtained in Step 2 of Example 31 ( 150 mg) and 4-isobutyloxyaniline were used to carry out the same reaction as in Step 3-4 of Example 31 to obtain the title compound (40 mg).

Preparation of 4-chloro-N- (4-chlorophenyl) -3- [N- (3-chloropyridin-2-yl) -N- (2-hydroxyethyl) amino] -benzamide;
4-chloro-3- {N- (3-chloropyridin-2-yl) -N- [2- (tetrahydropyran-2-yl) oxyethyl] amino} benzoic acid obtained in Step 2 of Example 31 ( 200 mg) and 4-chloroaniline were used to carry out the same reaction as in Step 3-4 of Example 31 to obtain the title compound (205 mg).

Preparation of 4-chloro-3- [N- (3-chloropyridin-2-yl) -N- (2-hydroxyethyl) amino] -N- (4-isopropylphenyl) -benzamide;
4-chloro-3- {N- (3-chloropyridin-2-yl) -N- [2- (tetrahydropyran-2-yl) oxyethyl] amino} benzoic acid obtained in Step 2 of Example 31 ( 210 mg) and 4-isopropylaniline were used for the same reaction as in Step 3-4 of Example 31 to obtain the title compound (110 mg).

4-Chloro-3- [N- (3-chloropyridin-2-yl) -N- (2-hydroxyethyl) amino] -N- (1-methyl-1,2,3,4-tetrahydroisoquinoline-7 -Yl) -benzamide production;
4-chloro-3- {N- (3-chloropyridin-2-yl) -N- [2- (tetrahydropyran-2-yl) oxyethyl] amino} benzoic acid obtained in Step 2 of Example 31 ( 200 mg) and 1-methyl-1,2,3,4-tetrahydroisoquinolin-7-ylamine were used to carry out the same reaction as in Step 3-4 of Example 31 to obtain the title compound (89 mg).

Preparation of 4-chloro-3- [N- (3-chloropyridin-2-yl) -N- (2-hydroxyethyl) amino] -N- (4-chloro-3-trifluoromethylphenyl) -benzamide;
4-chloro-3- {N- (3-chloropyridin-2-yl) -N- [2- (tetrahydropyran-2-yl) oxyethyl] amino} benzoic acid obtained in Step 2 of Example 31 ( 200 mg) and 4-chloro-3-trifluoromethylaniline were used to carry out the same reaction as in Step 3-4 of Example 31 to obtain the title compound (175 mg).

Preparation of 4-chloro-3- [N- (3-chloropyridin-2-yl) -N- (2-hydroxyethyl) amino] -N- (2-trifluoromethylpyridin-5-yl) -benzamide;
4-chloro-3- {N- (3-chloropyridin-2-yl) -N- [2- (tetrahydropyran-2-yl) oxyethyl] amino} benzoic acid obtained in Step 2 of Example 31 ( 200 mg) and 3-fluoro-4-piperidinoaniline were used to carry out the same reaction as in Step 3-4 of Example 31 to obtain the title compound (105 mg).

Preparation of 4-chloro-3- [N- (3-chloropyridin-2-yl) -N- (2-hydroxyethyl) amino] -N- (4-isopropyloxyphenyl) -benzamide;
4-chloro-3- {N- (3-chloropyridin-2-yl) -N- [2- (tetrahydropyran-2-yl) oxyethyl] amino} benzoic acid obtained in Step 2 of Example 31 ( 200 mg) and 4-isopropyloxyaniline were used to carry out the same reaction as in Step 3-4 of Example 31 to obtain the title compound (13 mg).

Preparation of 4-chloro-3- [N- (3-chloropyridin-2-yl) -N- (2-hydroxyethyl) amino] -N- (5-trifluoromethylpyridin-2-yl) -benzamide;
Step 1;
4-chloro-3- {N- (3-chloropyridin-2-yl) -N- [2- (tetrahydropyran-2-yl) oxyethyl] amino} -N- (2-trifluoromethylpyridine-5- Yl) -benzamide;
4-chloro-3- {N- (3-chloropyridin-2-yl) -N- [2- (tetrahydropyran-2-yl) oxyethyl] amino} benzoic acid obtained in Step 2 of Example 31 ( 200 mg) was dissolved in pyridine (2 mL), thionyl chloride (0.04 mL) was added, and the mixture was stirred at room temperature for 1 hr. Subsequently, 2-trifluoromethylpyridin-5-ylamine (79 mg) was added and stirred for 2 hours. The reaction mixture was diluted with ethyl acetate, washed successively with aqueous potassium hydrogen sulfate solution, aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (hexane-ethyl acetate = 1: 1) to obtain the title compound (120 mg).
Step 2;
Preparation of 4-chloro-3- [N- (3-chloropyridin-2-yl) -N- (2-hydroxyethyl) amino] -N- (2-trifluoromethylpyridin-5-yl) -benzamide;
4-Chloro-3- {N- (3-chloropyridin-2-yl) -N- [2- (tetrahydropyran-2-yl) oxyethyl] amino} -N- (2-tri Fluoromethylpyridin-5-yl) -benzamide (120 mg) was dissolved in tetrahydrofuran (2 mL), 6M hydrochloric acid was added, and the mixture was stirred overnight at room temperature. The reaction mixture was neutralized with 2M sodium hydroxide and extracted with ethyl acetate. The ethyl acetate layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained solid was purified by silica gel chromatography (hexane-ethyl acetate = 3: 2) to obtain the title compound (5.8 mg).

Preparation of 4-chloro-3- [N- (3-chloropyridin-2-yl) -N- (2-hydroxyethyl) amino] -N- (3-fluoro-4-piperidinylphenyl) -benzamide;
In Step 1 of Example 42, 5-trifluoromethylpyridin-2-ylamine (53 mg) was used instead of 2-trifluoromethylpyridin-5-ylamine, and the title compound (79 mg) was obtained in the same manner.

Preparation of 4-chloro-3- [N- (3-chloropyridin-2-yl) -N- (2-hydroxyethyl) amino] -N- (4-isobutyloxyphenyl) -benzamide;
4-chloro-3- {N- (3-chloropyridin-2-yl) -N- [2- (tetrahydropyran-2-yl) oxyethyl] amino} benzoic acid obtained in Step 2 of Example 31 ( 180 mg) and 4-isobutyloxyaniline were used for the same reaction as in Step 3-4 of Example 31 to obtain the title compound (31 mg).

Preparation of 4-chloro-3- [N- (3-chloropyridin-2-yl) -N- (3-hydroxypropyl) amino] -N- (4-tert-butylphenyl) -benzamide;
Step 1;
Preparation of 4-chloro-3- {N- (3-chloropyridin-2-yl) -N- [3- (tetrahydropyran-2-yl) oxypropyl] amino} benzoic acid;
In the same manner as in Step 1 of Example 31, using 4-chloro-3- (3-chloropyridin-2-yl) aminobenzoate (6.5 g), 2-bromoethyl- (tetrahydropyran-2-yl) The reaction was conducted using 3-bromopropyl- (tetrahydropyran-2-yl) ether instead of ether, and the same reaction was carried out. Thereafter, the same reaction as in step 2 of Example 31 was carried out to give the title compound (4.7 g )
Step 2;
Preparation of 4-chloro-3- [N- (3-chloropyridin-2-yl) -N- (3-hydroxypropyl) amino] -N- (4-tert-butylphenyl) -benzamide;
4-chloro-3- {N- (3-chloropyridin-2-yl) -N- [3- (tetrahydropyran-2-yl) oxypropyl] amino} benzoic acid (280 mg) obtained in the previous step Using tert-butylaniline, the title compound (245 mg) was obtained in the same manner as in Step 3-4 of Example 31.

Preparation of N- (3-chloropyridin-2-yl) -N- {2-chloro-5- [N- (4-tert-butylphenyl) carbamoyl] phenyl} -aminoacetic acid;
Step 1;
production of tert-butyl 4-chloro-3-nitrobenzoate;
4-Chloro-3-nitrobenzoic acid (5.0 g) was suspended in chloroform (50 mL), oxalyl chloride (3.24 mL) and N, N-dimethylformamide (1 drop) were added, and the mixture was stirred at room temperature for 2 hours. . The reaction mixture was concentrated, tetrahydrofuran (50 mL) was added, a solution of potassium tert-butoxide (4.17 g) in tetrahydrofuran (30 mL) was added under ice cooling, and the mixture was stirred at room temperature for 1.5 hr. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give the title compound (6.35 g).
Step 2;
production of tert-butyl 3-amino-4-chlorobenzoate;
Tert-butyl 4-chloro-3-nitrobenzoate (6.35 g) obtained in the previous step was dissolved in methanol (65 mL), activated carbon (3 g), iron (III) chloride hexahydrate (666 mg), and then Hydrazine hydrate (5.97 mL) was added and stirred at reflux for 1 hour. The reaction solution was filtered and the filtrate was concentrated. The concentrated solution was partitioned between ethyl acetate and water, and the ethyl acetate layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (hexane-ethyl acetate = 8: 1) to give the title compound (4.14 g) as a white solid.
Step 3;
preparation of tert-butyl 4-chloro-3- (3-chloropyridin-2-yl) aminobenzoate;
The tert-butyl 3-amino-4-chlorobenzoate (1.48 g) obtained in the previous step was subjected to the same reaction as in Step 1 of Example 3 to obtain the title compound (3.13 g) as a white solid.
Step 4;
preparation of tert-butyl 4-chloro-3- [N- (3-chloropyridin-2-yl) -N-ethoxycarbonylmethyl] aminobenzoate;
The tert-butyl 4-chloro-3- (3-chloropyridin-2-yl) aminobenzoate (1.62 g) obtained in the previous step was dissolved in N, N-dimethylformamide (15 mL), and sodium hydride ( 229 mg) and ethyl bromoacetate (0.635 mL) were sequentially added, and the mixture was stirred at 60 ° C. for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (hexane-ethyl acetate = 8: 1) to give the title compound (1.55 g) as a white solid.
Step 5;
Preparation of 4-chloro-3- [N- (3-chloropyridin-2-yl) -N-ethoxycarbonylmethyl] aminobenzoic acid;
Tert-butyl 4-chloro-3- [N- (3-chloropyridin-2-yl) -N-ethoxycarbonylmethyl] aminobenzoate (500 mg) obtained in the previous step was dissolved in chloroform (1 mL), Fluoroacetic acid (1 mL) was added and stirred at room temperature for 6 hours. The reaction mixture was concentrated, and the residue containing the title compound was advanced to the next step without purification.
Step 6;
Preparation of 4-chloro-3- [N- (3-chloropyridin-2-yl) -N- (ethoxycarbonylmethyl) amino] -N- (4-tert-butylphenyl) -benzamide;
The residue containing 4-chloro-3- [N- (3-chloropyridin-2-yl) -N-ethoxycarbonylmethyl] aminobenzoic acid obtained in the previous step was dissolved in N, N-dimethylformamide (5 mL). 4-tert-butylaniline (192 mg), 1-hydroxybenzotriazole (216 mg) and 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (270 mg) were sequentially added for 2 days at room temperature. Stir. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel chromatography (hexane-ethyl acetate = 7: 1) to obtain a white amorphous title compound (408 mg).
Step 7;
Preparation of N- (3-chloropyridin-2-yl) -N- {2-chloro-5- [N- (4-tert-butylphenyl) carbamoyl] phenyl} -aminoacetic acid;
4-Chloro-3- [N- (3-chloropyridin-2-yl) -N- (ethoxycarbonylmethyl) amino] -N- (4-tert-butylphenyl) -benzamide (408 mg) obtained in the previous step ) Was dissolved in tetrahydrofuran (2 mL) and ethanol (2 mL), 1M aqueous sodium hydroxide (1.5 mL) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was neutralized with 1M hydrochloric acid and concentrated. Water was added to the residue and stirred, and the precipitated white solid was collected by filtration and dried to obtain the title compound (372 mg).

Preparation of 4-chloro-3- [N- (3-chloropyridin-2-yl) -N- (carbamoylmethyl) amino] -N- (4-tert-butylphenyl) -benzamide;
N- (3-chloropyridin-2-yl) -N- {2-chloro-5- [N- (4-tert-butylphenyl) carbamoyl] phenyl-aminoacetic acid (100 mg) obtained in Example 46 was Dissolved in N, N-dimethylformamide (2 mL), ammonium chloride (57 mg), triethylamine (0.177 mL), 1-hydroxybenzotriazole (39 mg), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide Hydrochloric acid salt (49 mg) was sequentially added and stirred at room temperature for 24 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel chromatography (chloroform-methanol = 20: 1) to obtain the title compound (56 mg) as a pale yellow solid.

Preparation of 4-chloro-3- [N- (3-chloropyridin-2-yl) -N- (N-methylcarbamoylmethyl) amino] -N- (4-tert-butylphenyl) -benzamide;
N- (3-chloropyridin-2-yl) -N- {2-chloro-5- [N- (4-tert-butylphenyl) carbamoyl] phenyl-aminoacetic acid (100 mg) obtained in Example 46 was Dissolve in N, N-dimethylformamide (2 mL), add 1-hydroxybenzotriazole (39 mg) and 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (49 mg) sequentially, and add 2 at room temperature. Stir for hours. The reaction mixture was ice-cooled, 40% aqueous methylamine solution (0.038 mL) was added, and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel chromatography (chloroform-methanol = 20: 1) to obtain the title compound (26 mg) as a pale yellow solid.

Preparation of 4-chloro-3- [N- (3-chloropyridin-2-yl) -N- (N, N-dimethylcarbamoylmethyl) amino] -N- (4-tert-butylphenyl) -benzamide;
N- (3-chloropyridin-2-yl) -N- {2-chloro-5- [N- (4-tert-butylphenyl) carbamoyl] phenyl-aminoacetic acid (150 mg) obtained in Example 46 was Dissolve in N, N-dimethylformamide (3 mL), add 1-hydroxybenzotriazole (58 mg), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (73 mg) sequentially and add 30 at room temperature. Stir for minutes. The reaction mixture was ice-cooled, 50% dimethylamine aqueous solution (0.066 mL) was added, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel chromatography (hexane-ethyl acetate = 3: 2) to give the title compound (136 mg) as a pale yellow solid.
Example 50-Example 56
The compounds of Examples 50 to 56 shown in the following table were obtained in the same manner as in the general production methods A to C and / or the methods described in Examples 28 to 32.
Examples 57-72
The compounds of Examples 57 to 72 shown in the following table were obtained in the same manner as in the general production methods A to C and / or the methods described in Examples 46 to 49.
Example 73
Production step 1 of ethyl 6-{[5- (4-tert-butylphenylcarbamoyl) -2-chlorophenyl] -methyl-amino} -5-chloronicotinate;
Preparation of ethyl 6-[(5-tert-butoxycarbonyl-2-chlorophenyl) amino] -5-chloronicotinate Ethyl 5,6-dichloronicotinate (1.64 g), 3-amino-4-chlorobenzoic acid tert -Butyl ester (1.70 g) was dissolved in toluene (15 mL), palladium acetate (84 mg), 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (232 mg), cesium carbonate (3. 65 g) was sequentially added, and the mixture was stirred at 80 ° C. for 20 hours. The reaction mixture was allowed to cool, ethyl acetate-water was added, insolubles were filtered off, and the layers were separated. The obtained ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel chromatography (hexane-ethyl acetate system) to obtain the title compound (2.37 g).
Step 2;
Preparation of ethyl 6-[(5-tert-butoxycarbonyl-2-chlorophenyl) -methyl-amino] -5-chloronicotinate 6-[(5-tert-butoxycarbonyl-2-chlorophenyl) obtained in the previous step Amino] -5-chloronicotinic acid ethyl (1.37 g) was dissolved in N, N-dimethylformamide (15 mL), sodium hydride (60%) (160 mg) was added under ice cooling, and the mixture was stirred at room temperature for 1 hr. Then, methyl iodide (0.311 mL) was added and stirred for 1 hour. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel chromatography to obtain the title compound (1.17 g).
Step 3;
Preparation of 4-chloro-3- (3-chloro-5-ethoxycarbonylpyridin-2-yl) -methyl-aminobenzoic acid 6-[(5-tert-butoxycarbonyl-2-chlorophenyl) obtained in the previous step Amino] -5-chloronicotinic acid ethyl (1.17 g) was dissolved in chloroform (5 mL), trifluoroacetic acid (5 mL) was added, and the mixture was stirred at room temperature for 5 hr. The reaction mixture was concentrated, water was added to the residue, and the solid obtained after neutralization with saturated aqueous sodium hydrogen carbonate was collected by filtration and dried to give the title compound (965 mg).
Step 4;
Preparation of ethyl 6-{[5- (4-tert-butylphenylcarbamoyl) -2-chlorophenyl] -methyl-amino} -5-chloronicotinate 4-chloro-3- (3-chloro obtained in the previous step -5-Ethoxycarbonylpyridin-2-yl) -methyl-aminobenzoic acid (965 mg) was dissolved in N, N-dimethylformamide (10 mL) and 4-tert-butylaniline (423 mg), 1-hydroxybenzotriazole ( 476 mg) and 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (595 mg) were sequentially added and stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound (1.33 g).
Example 74
Preparation of 6-{[5- (4-tert-butylphenylcarbamoyl) -2-chlorophenyl] -methyl-amino} -5-chloronicotinic acid 6-{[5- (4-tert -Butylphenylcarbamoyl) -2-chlorophenyl] -methyl-amino} -5-chloronicotinic acid ethyl (1.30 g) was dissolved in tetrahydrofuran (5 mL) and methanol (5 mL), and 4N sodium hydroxide (2 mL) was added. And stirred at room temperature for 1.5 hours. The reaction mixture was neutralized with 1N hydrochloric acid and concentrated. Water was added to the residue, and the precipitated solid was collected by filtration and dried. The obtained solid was dissolved in ethyl acetate, insoluble material was removed by filtration, and the filtrate was concentrated. Diethyl ether was added to the residue to suspend it, and the solid was collected by filtration and dried to obtain the title compound (1.03 g).
Example 75
Preparation of 6-{[5- (4-tert-butylphenylcarbamoyl) -2-chlorophenyl] -methyl-amino} -5-chloronicotinamide 6-{[5- (4-tert -Butylphenylcarbamoyl) -2-chlorophenyl] methyl-amino} -5-chloronicotinic acid (200 mg) dissolved in chloroform (5 mL), oxalyl chloride (0.055 mL), N, N-dimethylformamide (1 drop) And stirred at room temperature for 1 hour. The reaction mixture was concentrated, dissolved in tetrahydrofuran (5 mL), 28% aqueous ammonia (1 mL) was added, and the mixture was stirred for 1 hr at room temperature. The reaction solution was separated between water and ethyl acetate, and the ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography to obtain the title compound (46 mg).
Example 76
Preparation of 6-{[5- (4-tert-butylphenylcarbamoyl) -2-chlorophenyl] -methyl-amino} -5-chloro-N-methylnicotinamide 6-{[5- The title compound (106 mg) was obtained in the same manner as in Example 75 from (4-tert-butylphenylcarbamoyl) -2-chlorophenyl] -methyl-amino} -5-chloronicotinic acid (200 mg).
Example 77
Preparation of 6-{[5- (4-tert-Butylphenylcarbamoyl) -2-chlorophenyl] -methyl-amino} -5-chloro-N, N-dimethylnicotinamide 6-{[ The title compound (143 mg) was obtained in the same manner as in Example 75 from 5- (4-tert-butylphenylcarbamoyl) -2-chlorophenyl] -methyl-amino} -5-chloronicotinic acid (200 mg).
Example 78-Example 83
The compounds of Examples 78 to 83 shown in the following table were obtained in the same manner as in the general production methods A to C and / or the methods described in Examples 1 to 28.
Test Example Next, a method for evaluating the VR1 inhibitory action of the compound of the present invention will be described.
As an in vitro evaluation, an inhibitory effect on Ca ²⁺ influx into cells caused by protons that are VR1 agonists was examined.
Test Example [1] Examination of intracellular Ca ²⁺ influx inhibitory action;
Human VR1 stably expressing rat glioma (C6BU1) cells were treated with 20 mM MES buffer (pH 6.8 / 20 mM 2-morpholinoethanesulfonic acid (hereinafter MES), 115 mM NaCl, 5 mM KCl, 1 mM MgCl ₂ , 14 mM D-glucose). It suspended so that it might become * 10 < ⁶ > cells / mL. Fura2-AM solution (Dojindo Laboratories, Inc., Cat. No. 343-05401), which is a fluorescent dye, was added to the cell suspension to 5 μM, and Pluronic F-127 (Wako Pure Chemical Industries, Ltd.) was added. Company, Cat. No. P6866) was added to 0.1%, followed by incubation at 37 ° C. for 30 minutes. After washing 3 times with 20 mM MES buffer, resuspension was performed so that the number of cells was 5 × 10 ⁵ cells / mL. 500 μL of the cell suspension is weighed into a cuvette (MC Medical Co., Cat. No. SSR3121), and 10 μL of 20 mM MES buffer containing 250 mM CaCl ₂ is added to the cells to allow Ca ²⁺ to be taken up into the cells. It was. At the same time, add 5 μL of test substance (diluted to 100 μM to 10 nM with DMSO) (final concentration 1 μM to 0.1 nM), or 5 μL of DMSO alone as a control (final concentration 1% DMSO), and 10 minutes after addition It set to the ion measuring apparatus (CAF-110, JASCO Corporation). As an agonist, proton stimulation was given by adding 60 μL of 20 mM MES buffer having a pH of 1.1 to adjust the pH of the cell suspension to 5.5. The activity of the test substance was measured by the difference between the minimum value of the fluorescence intensity before stimulation with the agonist and the maximum value of the fluorescence intensity after stimulation, and the IC ₅₀ value was calculated as the inhibition rate relative to the control.
The results are shown in Tables 1 to 11 together with the structural formulas of the example compounds.
In the table, “++” indicates that the IC50 value is 100 nM or less, and “+” indicates that the IC50 value is 100 nM to 1000 nM.
Indicates that

  Since the 3-aminobenzamide compound of the present invention effectively inhibits the activity of vanilloid receptor type 1 (VR1), pain, acute pain, chronic pain, neuropathic pain, rheumatoid arthritis pain, neuralgia, neuropathy, Hyperalgesia, migraine, joint pain, acute postherpetic neuralgia, postherpetic neuralgia, chronic postherpetic neuralgia, postoperative neuralgia, cancer pain, inflammatory pain, interstitial cystitis, posttraumatic neuralgia, diabetes Neuropathy, neurodegeneration, stroke, ischemia, nerve injury, neurological skin disease, inflammatory disease, pruritus, allergic rhinitis, stroke, irritable bowel syndrome, asthma, chronic obstructive pulmonary disease, It is effective as a therapeutic and / or prophylactic agent for diseases such as dermatitis, mucositis, gastric / duodenal ulcer and inflammatory bowel syndrome, bladder hypersensitivity, bladder overactivity, urinary frequency and urinary incontinence.

Claims (24)

A 3-aminobenzamide compound represented by the following general formula [1] or a pharmaceutically acceptable salt thereof.
[Where:
R ¹ is
A C1-6 alkyl group which may be substituted with one or more substituents which may be the same or different from the following group A;
[Group A]
1) a halogen atom,
2) a hydroxyl group,
3) a C1-6 alkoxy group,
4) a halo C1-6 alkoxy group,
5) —NR ⁷ R ⁸ (wherein R ⁷ and R ⁸ are the same or different,
(A) a hydrogen atom, or (b) a C1-6 alkyl group that may be substituted with a hydroxyl group, or (c) a single-ring nitrogen formed by combining R ⁷ , R ⁸ and an adjacent nitrogen atom It is a containing saturated heterocyclic group. ),
6) -CONR ⁷ R ⁸ (wherein R ⁷ and R ⁸ are as defined above),
7) —COR ⁹ (wherein R ⁹ is
(A) a hydrogen atom,
(B) a hydroxyl group,
(C) a C1-6 alkyl group or (d) a C1-6 alkoxy group. ),
8) —NR ⁷¹ COR ⁹ (wherein R ⁹ is the same as defined above; R ⁷¹ represents
(A) a hydrogen atom, or (b) a C1-6 alkyl group. )
9) —NR ⁷¹ CONR ⁷ R ⁸ (wherein R ⁷ , R ⁸ and R ⁷¹ are the same as above),
10) —NR ⁷¹ SO ₂ R ¹⁰ (wherein R ⁷¹ is the same as defined above; R ¹⁰ represents
C1-6 alkyl group. ), And 11) —SO ₂ R ¹⁰ (wherein R ¹⁰ is the same as above);
[Wherein the nitrogen-containing saturated heterocycle consisting of a C1-6 alkyl group, a C1-6 alkoxy group, a halo C1-6 alkoxy group and a monocycle in the above 1) to 11) is further selected from group A It may be substituted with a substituent. ]
R ² is
One or more substituents which may be the same or different from the following group B;
[Group B]
1) a halogen atom,
2) a hydroxyl group,
3) a C1-6 alkyl group which may be substituted with one or more substituents which may be the same or different and selected from the group A;
4) a C1-6 alkoxy group which may be substituted with one or more substituents which may be the same or different and selected from the group A;
5) a cycloalkylalkoxy group (the cycloalkylalkoxy group is
(A) one or more substituents which may be the same or different selected from the group A, or (b) one or more substituents which may be the same or different and selected from the group A. It may be substituted with 6 alkyl groups. ),
6) Aralkyl group (the aralkyl group is
(A) one or more substituents which may be the same or different selected from the group A, or (b) one or more substituents which may be the same or different and selected from the group A. It may be substituted with 6 alkyl groups. ),
7) Aralkoxy group (the aralkoxy group is
(A) one or more substituents which may be the same or different selected from the group A, or (b) one or more substituents which may be the same or different and selected from the group A. It may be substituted with 6 alkyl groups. ),
8) -COR ¹¹ (wherein R ¹¹ is
(A) a hydroxyl group,
(B) a C1-6 alkyl group which may be substituted with one or more substituents which may be the same or different and selected from the group A;
(C) one or more substituents which may be the same or different selected from the group A, or a C1-6 alkoxy group which may be substituted with a C1-6 alkyl group which may be substituted with these substituents,
(D) one or more substituents which may be the same or different selected from the group A, or a C 3-6 alkyl group which may be substituted with a C 1-6 alkyl group which may be substituted with these substituents; A cycloalkyl group,
(E) a cycloalkylalkoxy group which may be substituted with one or more substituents which may be the same or different selected from the group A, or a C1-6 alkyl group which may be substituted with these substituents;
(F) an aralkyl group which may be substituted with one or more substituents which may be the same or different selected from the group A, or a C1-6 alkyl group which may be substituted with these substituents, or (g) An aralkoxy group which may be substituted with one or more substituents which may be the same or different selected from the group A, or a C1-6 alkyl group which may be substituted with these substituents;
(H) Saturation having 3 to 14 carbon atoms which may be substituted with one or more substituents which may be the same as or different from each other selected from Group A, or a C1-6 alkyl group which may be substituted with these substituents Or it is an unsaturated carbocyclic group. ),
9) —NR ¹² R ¹³ (wherein R ¹² and R ¹³ are the same or different,
(A) a hydrogen atom, or (b) a C1-6 alkyl group that may be substituted with one or more substituents that may be the same or different selected from the group A, or (c) R ¹² , R ^13, and adjacent groups A nitrogen-containing saturated heterocyclic group consisting of a single ring formed by combining nitrogen atoms. ),
10) -CONR ¹² R ¹³ (wherein R ¹² and R ¹³ are the same as above),
11) -NR ¹²¹ COR ¹¹ (wherein R ¹²¹ is
(A) a hydrogen atom, or (b) a C1-6 alkyl group which may be substituted with one or more substituents which may be the same or different from the group A, and R ¹¹ is the same as described above. ),
12) -NR ¹²¹ CONR ¹² R ¹³ (wherein R ¹² , R ¹³ and R ¹²¹ are the same as above),
13) -SR ¹⁴ (wherein R ¹⁴ is
(A) a C1-6 alkyl group which may be substituted with one or more substituents which may be the same or different selected from the group A, or (b) one or more which may be the same or different selected from the group A A cycloalkyl group having 3 to 8 carbon atoms which may be substituted with the above substituent. ),
14) -SOR ¹⁴ (wherein R ¹⁴ is as defined above),
15) —SO ₂ R ¹⁴ (wherein R ¹⁴ is as defined above),
16) —SO ₂ NR ¹² R ¹³ (wherein R ¹² and R ¹³ are the same as above),
17) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms (the carbocyclic group is
(A) one or more substituents which may be the same or different selected from the group A, or (b) one or more substituents which may be the same or different and selected from the group A. It may be substituted with 6 alkyl groups. ),
18) a saturated or unsaturated heterocyclic group having at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom (the heterocyclic group is
(A) one or more substituents which may be the same or different selected from the group A, or (b) one or more substituents which may be the same or different and selected from the group A. It may be substituted with 6 alkyl groups. ), And 19) an aryloxy group (the aryloxy group is
(A) one or more substituents which may be the same or different selected from the group A, or (b) one or more substituents which may be the same or different and selected from the group A. It may be substituted with 6 alkyl groups. );
Alternatively, R ¹ and R ² may be taken together to form a —CH ₂ —CH ₂ —O— bond between adjacent nitrogen and carbon atoms;
R ³ is
(1) a hydrogen atom, or (2) a C1-6 alkyl group which may be substituted with one or more substituents which may be the same or different from the group A;
m is an integer from 1 to 5;
n is 0 or an integer from 1 to 4;
R ⁴ is one or more substituents which may be the same or different and selected from the group B,
When m is 2 or more,
(1) two R ⁴ groups may form together to form ═O, or
(2) Two R ⁴ groups together with adjacent carbon atoms of ring P1,
(Wherein R ¹⁵ is 1 to 4 substituents selected from Group B);
R ⁵ and R ⁶ are the same or different,
(1) a hydrogen atom, or (2) a substituent selected from the group B;
Alternatively, R ² and R ⁵ may be taken together with adjacent carbon atoms to form an —O— bond;
X is
(1) CH or (2) N;
Ring P1 is
(1) a saturated or unsaturated carbocyclic group having 3 to 14 carbon atoms, or (2) a saturated or unsaturated heterocyclic group having at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom. . ] In the general formula [1], R ¹ and R ² do not form —CH ₂ —CH ₂ —O— together with the adjacent nitrogen and carbon atoms, and R ² and R ⁵ are adjacent. The 3-aminobenzamide compound or a pharmaceutically acceptable salt thereof according to claim 1, which does not form -O- with a carbon atom. The 3-aminobenzamide compound according to claim 1 represented by the following general formula [2] or a pharmaceutically acceptable salt thereof.
[Wherein, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , m, n, X and ring P 1 are the same as described above. However, n is not 0 at this time. ] The 3-aminobenzamide compound according to claim 1 represented by the following general formula [3] or a pharmaceutically acceptable salt thereof.
[Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁶ , m, n, X and ring P 1 are the same as described above. However, n is not 0 at this time. ] The 3-aminobenzamide compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein the carbocyclic group or heterocyclic group of ring P1 is monocyclic. R ¹ is a C 1-6 alkyl group which may be substituted with one or more substituents selected from a hydroxyl group, a C 1-6 alkoxy group, —CONR ⁷ R ⁸ and —COR ⁹ ; and n is 0, or n is an integer of 1 to 4 and R ² is a halogen atom, a hydroxyl group, a C 1-6 alkyl group defined in the group B, a C 1-6 alkoxy group defined in the group B, or defined in the group B The 3-aminobenzamide compound according to claim 1, 2, 4 or 5, or a pharmaceutically acceptable salt thereof, wherein R ³ is a hydrogen atom. Salt. n is 0, or n is an integer of 1 to 4, and R ² is a halogen atom, a hydroxyl group, a C 1-6 alkyl group, a phenyl group, a phenoxy group, or a hydroxyl group, a C 1-6 alkoxy group, —CONR ¹² C 1-6 alkoxy optionally substituted with a substituent selected from R ¹³ (wherein R ¹² and R ¹³ are the same as above) and —COR ¹¹ (wherein R ¹¹ is the same as above). The 3-aminobenzamide compound or a pharmaceutically acceptable salt thereof according to claim 6, which is a group. A heterocyclic group in which R ⁴ is a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, a C 1-6 alkoxy group, a halo C 1-6 alkoxy group, or a saturated monocyclic ring having a nitrogen atom as a hetero atom; A 3-aminobenzamide compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7. X is CH or N, R ¹ is a hydroxyl group, a C 1-6 alkoxy group, —NR ⁷ R ⁸ (wherein R ⁷ and R ⁸ are the same or different and may be substituted with a hydrogen atom or a hydroxyl group) A —6 alkyl group.), —CONR ⁷ R ⁸ and (wherein R ⁷ and R ⁸ are the same or different and are a C 1-6 alkyl group which may be substituted with a hydrogen atom or a hydroxyl group) and -COR ⁹ (wherein R ⁹ is a hydroxyl group or a C 1-6 alkoxy group) is a C 1-6 alkyl group which may be substituted with one or more substituents, and n is 0 or 1 to 2 R ² is a halogen atom, a hydroxyl group, a C 1-6 alkyl group, an aryl group, an aryloxy group or a C 1-6 alkoxy group (the alkoxy group is a hydroxyl group, a C 1-6 alkoxy group, —CONR ⁷ R ⁸ And (where R ⁷ and R ⁸ are the same or different and are a hydrogen atom or a C 1-6 alkyl group which may be substituted with a hydroxyl group.) And —COR ⁹ (where R ⁹ is a hydroxyl group or a C 1-6 alkoxy group). And R ³ is a hydrogen atom, m is an integer of 1 to 3, R ⁴ is a halogen atom, and C 1-6 alkyl. group, a halo C1-6 alkyl group, C1-6 alkoxy group, a halo C1-6 alkoxy group, ^-CONR 12 ^{R 13 (wherein, R 12} and ^{R 13} are the same or different and each represents a hydrogen atom or a C1-6 alkyl group in a.), or a monocyclic heterocyclic group, saturated with a nitrogen atom as a hetero atom, R ⁵ and R ⁶ are the same or different and each a hydrogen atom, a halogen atom, C1-6 alkoxy group, a hydroxyl group or a C1 6 which may be C1-6 alkyl group substituted with an alkoxy group, a halo C1-6 alkyl group, ^-CONR 12 ^{R 13 (wherein, R 12} and ^{R 13} are the same or different and each represents a hydrogen atom or a C1-6 alkyl group Or 3-COR ¹¹ (wherein R ¹¹ is a hydroxyl group or a C 1-6 alkoxy group), and the ring P 1 is a phenyl group or a pyridyl group. A compound or a pharmaceutically acceptable salt thereof. The 3-aminobenzamide compound according to claim 1 or a pharmaceutically acceptable salt thereof selected from the following group.
(1) N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] benzamide hydrochloride,
(2) N- (4-tert-butylphenyl) -3- [N- (pyridin-2-yl) -N-methyl-amino] benzamide hydrochloride,
(3) N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-ethyl-amino] benzamide,
(4) N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl] amino-4-methoxybenzamide,
(5) N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl] amino-4-phenoxybenzamide,
(6) N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] -2-methylbenzamide,
(7) N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] -4-methylbenzamide,
(8) N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] -4-phenylbenzamide,
(9) N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] -4-fluorobenzamide,
(10) N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-ethyl] amino-4-methoxybenzamide,
(11) N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-isopropyl] amino-4-methoxybenzamide,
(12) N- (4-tert-butylphenyl) -4-chloro-3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] benzamide,
(13) N- (4-tert-butylphenyl) -4-chloro-3- [N- (pyridin-2-yl) -N-methyl-amino] benzamide,
(14) N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] -4-methoxymethyloxybenzamide,
(15) N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] -4-hydroxybenzamide,
(16) N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] -4-isopropoxybenzamide,
(17) N- (4-tert-butylphenyl) -10-methyl-10H-benzo [b] pyrido [2,3-e] [1,4] oxazine-8-carboxamide,
(18) N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] -4- (2-hydroxyethyl) oxybenzamide,
(19) {4- (4-tert-butylphenyl) aminocarbonyl-2- [N- (3-chloropyridin-2-yl) -N-methyl] amino-phenoxy} acetic acid,
(20) N- (4-tert-butylphenyl) -4-carbamoylmethyloxy-3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] benzamide,
(21) N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] -4- (N-methylcarbamoylmethyl) oxybenzamide,
(22) N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] -4- (N, N-dimethylcarbamoylmethyl) oxybenzamide ,
(23) N- (4-tert-butylphenyl) -5-chloro-3- [N- (3-chloropyridin-2-yl) -N-methyl] aminobenzamide,
(24) N- (4-tert-butylphenyl) -2-chloro-5- [N- (3-chloropyridin-2-yl) -N-methyl] aminobenzamide,
(25) N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl] amino-2-hydroxybenzamide,
(26) N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl] amino-2-methoxybenzamide,
(27) N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N-methyl-amino] -2- (2-hydroxyethyl) oxybenzamide,
(28) N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N- (2-hydroxyethyl)] amino-4-methoxybenzamide,
(29) N- (4-tert-butylphenyl) -4-chloro-3- [N- (3-chloropyridin-2-yl) -N- (2-methoxyethyl) amino] benzamide,
(30) N- (4-tert-butylphenyl) -4-chloro-3- [N- (3-chloropyridin-2-yl) -N- (2-hydroxyethyl) amino] benzamide,
(31) 4-chloro-3- [N- (3-chloropyridin-2-yl) -N- (2-hydroxyethyl) amino] -N- (4-trifluoromethylphenyl) -benzamide hydrochloride,
(32) 4-chloro-3- [N- (3-chloropyridin-2-yl) -N- (2-hydroxyethyl) amino] -N- (4-trifluoromethoxyphenyl) -benzamide hydrochloride,
(33) N- (4-tert-butylphenyl) -3- [N- (2-chlorophenyl) -N-methyl-amino] benzamide, and (34) N- (4-tert-butylphenyl) -4- (3-Chloropyridin-2-yl) -3,4-dihydro-2H-benzo [1,4] oxazine-6-carboxamide.
(35) 4-Chloro-3- [N- (3-chloropyridin-2-yl) -N- (2-hydroxyethyl) amino] -N- (4-isobutyloxyphenyl) -benzamide hydrochloride (36) 4-chloro-N- (4-chlorophenyl) -3- [N- (3-chloropyridin-2-yl) -N- (2-hydroxyethyl) amino] -benzamide (37) 4-chloro-3- [ N- (3-chloropyridin-2-yl) -N- (2-hydroxyethyl) amino] -N- (4-isopropylphenyl) -benzamide (38) 4-chloro-3- [N- (3-chloro Pyridin-2-yl) -N- (2-hydroxyethyl) amino] -N- (1-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -benzamide (39) 4-chloro-3 -[N- ( -Chloropyridin-2-yl) -N- (2-hydroxyethyl) amino] -N- (4-chloro-3-trifluoromethylphenyl) -benzamide (40) 4-chloro-3- [N- (3 -Chloropyridin-2-yl) -N- (2-hydroxyethyl) amino] -N- (2-trifluoromethylpyridin-5-yl) -benzamide (41) 4-chloro-3- [N- (3 -Chloropyridin-2-yl) -N- (2-hydroxyethyl) amino] -N- (4-isopropyloxyphenyl) -benzamide (42) 4-chloro-3- [N- (3-chloropyridine-2) -Yl) -N- (2-hydroxyethyl) amino] -N- (5-trifluoromethylpyridin-2-yl) -benzamide (43) 4-chloro-3- [N- (3-chloropyridine) 2-yl) -N- (2-hydroxyethyl) amino] -N- (3-fluoro-4-piperidinylphenyl) -benzamide (44) 4-chloro-3- [N- (3-chloropyridine- 2-yl) -N- (2-hydroxyethyl) amino] -N- (4-isobutyloxyphenyl) -benzamide (45) 4-chloro-3- [N- (3-chloropyridin-2-yl)- N- (3-hydroxypropyl) amino] -N- (4-tert-butylphenyl) -benzamide (46) N- (3-chloropyridin-2-yl) -N- {2-chloro-5- [N -(4-tert-butylphenyl) carbamoyl] phenyl} -aminoacetic acid (47) 4-chloro-3- [N- (3-chloropyridin-2-yl) -N- (carbamoylmethyl) amino] -N- (4 -Tert-butylphenyl) -benzamide (48) 4-chloro-3- [N- (3-chloropyridin-2-yl) -N- (N-methylcarbamoylmethyl) amino] -N- (4-tert- (Butylphenyl) -benzamide (49) 4-chloro-3- [N- (3-chloropyridin-2-yl) -N- (N, N-dimethylcarbamoylmethyl) amino] -N- (4-tert-butyl Phenyl) -benzamide (50) 3- [N- (3-chloropyridin-2-yl) -N- (2-hydroxyethyl) amino] -N- (4-isobutyloxyphenyl) -4-methoxy-benzamide,
(51) N- (4-isobutyloxyphenyl) -4-methoxy-3- [N- (5-methylpyridin-2-yl) -N- (2-hydroxyethyl) amino] -benzamide,
(52) 3- [N- (3-chloropyridin-2-yl) -N- (2-hydroxyethyl) amino] -N- (4-isobutyloxyphenyl) -benzamide;
(53) N- (4-tert-butylphenyl) -3- [N- (3-chloropyridin-2-yl) -N- (2-hydroxyethyl) amino] -benzamide,
(54) 3- [N- (3-chloropyridin-2-yl) -N- (2-hydroxyethyl) amino] -N- (4-trifluoromethylphenyl) -benzamide,
(55) 4-Chloro-3- [N- (3-chloropyridin-2-yl) -N- (2-hydroxyethyl) amino] -N- (4-isobutyloxy-3-methylcarbamoylphenyl) -benzamide ,
(56) 4-Chloro-3- [N- (3-chloropyridin-2-yl) -N- (2-hydroxyethyl) amino] -N- (3-dimethylcarbamoyl-4-isobutyloxyphenyl) -benzamide ,
(57) N- (4-tert-butylphenyl) -4-chloro-3- {N- (3-chloropyridin-2-yl) -N- [N- (2-hydroxyethyl) carbamoylmethyl] amino} -Benzamide,
(58) 3- [N- (2-aminoethyl) -N- (3-chloropyridin-2-yl) amino] -4-chloro-N- (4-tert-butylphenyl) -benzamide,
(59) 4-chloro-3- [N- (3-chloropyridin-2-yl) -N- (carbamoylmethyl) amino] -N- (4-trifluoromethylphenyl) -benzamide;
(60) 4-chloro-3- [N- (3-chloropyridin-2-yl) -N- (carbamoylmethyl) amino] -N- (4-trifluoromethoxyphenyl) -benzamide,
(61) 4-chloro-3- [N- (3-chloropyridin-2-yl) -N- (carbamoylmethyl) amino] -N- (4-isobutyloxyphenyl) -benzamide;
(62) 4-chloro-3- [N- (3-chloropyridin-2-yl) -N- (carbamoylmethyl) amino] -N- (3-fluoro-4-piperidinophenyl) -benzamide;
(63) 3- [N- (3-chloropyridin-2-yl) -N- (carbamoylmethyl) amino] -4-methyl-N- (4-trifluoromethylphenyl) -benzamide;
(64) 3- [N- (3-chloropyridin-2-yl) -N- (carbamoylmethyl) amino] -4-methyl-N- (4-trifluoromethoxyphenyl) -benzamide;
(65) 3- [N- (3-chloropyridin-2-yl) -N- (carbamoylmethyl) amino] -N- (4-isobutyloxyphenyl) -4-methyl-benzamide,
(66) 4-chloro-3- [N- (3-chloropyridin-2-yl) -N- (N-methylcarbamoylmethyl) amino] -N- (4-trifluoromethylphenyl) -benzamide;
(67) 4-Chloro-3- [N- (3-chloro-5-trifluoromethylpyridin-2-yl) -N- (carbamoylmethyl) amino] -N- (4-trifluoromethoxyphenyl) -benzamide ,
(68) 4-Chloro-3- [N- (3-chloro-5-trifluoromethylpyridin-2-yl) -N- (carbamoylmethyl) amino] -N- (4-trifluoromethylphenyl) -benzamide ,
(69) 4-chloro-3- [N- (3-chloropyridin-2-yl) -N- (carbamoylmethyl) amino] -N- (trifluoromethoxyphenyl) -benzamide;
(70) 4-chloro-3- [N- (3-chloropyridin-2-yl) -N- (carbamoylmethyl) amino] -N- (trifluoromethylphenyl) -benzamide;
(71) 4-chloro-3- [N- (3-chloro-5-methoxymethylpyridin-2-yl) -N- (carbamoylmethyl) amino] -N- (trifluoromethoxyphenyl) -benzamide;
(72) 4-chloro-3- [N- (3-chloro-5-methoxymethylpyridin-2-yl) -N- (carbamoylmethyl) amino] -N- (trifluoromethylphenyl) -benzamide;
(73) 6-{[5- (4-tert-butylphenylcarbamoyl) -2-chlorophenyl] -methyl-amino} -5-chloronicotinic acid ethyl;
(74) 6-{[5- (4-tert-butylphenylcarbamoyl) -2-chlorophenyl] -methyl-amino} -5-chloronicotinic acid,
(75) 6-{[5- (4-tert-butylphenylcarbamoyl) -2-chlorophenyl] -methyl-amino} -5-chloronicotinamide,
(76) 6-{[5- (4-tert-butylphenylcarbamoyl) -2-chlorophenyl] -methyl-amino} -5-chloro-N-methylnicotinamide,
(77) 6-{[5- (4-tert-butylphenylcarbamoyl) -2-chlorophenyl] -methyl-amino} -5-chloro-N, N-dimethylnicotinamide,
(78) N- (4-tert-butylphenyl) -4-chloro-3- [N- (3-chloro-5-hydroxymethylpyridin-2-yl) -N-methyl-amino] benzamide,
(79) 4-chloro-3- [N- (3-chloro-5-hydroxymethylpyridin-2-yl) -N-methyl-amino] -N- (4-trifluoromethylphenyl) -benzamide;
(80) 4-chloro-3- [N- (3-chloro-5-hydroxymethylpyridin-2-yl) -N-methyl-amino] -N- (4-chlorophenyl) -benzamide;
(81) 4-chloro-3- [N- (3-chloro-5-hydroxymethylpyridin-2-yl) -N-methyl-amino] -N- (4-trifluoromethoxyphenyl) -benzamide;
(82) 3- [N- (3-Chloro-5-hydroxymethylpyridin-2-yl) -N-methyl-amino] -4-fluoro-N- (4-trifluoromethylphenyl) -benzamide; 83) 3- [N- (3-Chloro-5-hydroxymethylpyridin-2-yl) -N-methyl-amino] -4-fluoro-N- (4-trifluoromethoxyphenyl) -benzamide. A pharmaceutical composition comprising the 3-aminobenzamide compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Pain, acute pain, chronic pain, nerve comprising the 3-aminobenzamide compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier Disability pain, rheumatoid arthritis pain, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, acute postherpetic neuralgia, postherpetic neuralgia, chronic postherpetic neuralgia, postoperative neuralgia, cancer pain, inflammatory Pain, interstitial cystitis, post-traumatic neuralgia, diabetic neuropathy, neurodegeneration, stroke, ischemia, nerve injury, neurological skin disease, inflammatory disease, pruritus, allergic rhinitis, stroke, Treatment of diseases selected from irritable bowel syndrome, asthma, chronic obstructive pulmonary disease, dermatitis, mucositis, gastric / duodenal ulcer and inflammatory bowel syndrome, bladder hypersensitivity, bladder overactive frequent urination and urinary incontinence / Or for prevention Pharmaceutical compositions. For treatment and / or prevention of pain comprising the 3-aminobenzamide compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Pharmaceutical composition. Pain is pain, acute pain, chronic pain, neuropathic pain, rheumatoid arthritis pain, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, acute postherpetic neuralgia, postherpetic neuralgia, chronic postherpetic neuralgia The pharmaceutical composition according to claim 13, which is postoperative neuralgia, cancer pain, inflammatory pain, interstitial cystitis, posttraumatic neuralgia, diabetic neuropathy, or neurodegeneration. Vanilloid receptor type 1 (VR1) activity comprising the 3-aminobenzamide compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Inhibitor. Pain, acute pain, chronic pain, neuropathic pain, rheumatoid arthritis comprising a pharmaceutically effective amount of the 3-aminobenzamide compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof Pain, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, acute postherpetic neuralgia, postherpetic neuralgia, chronic postherpetic neuralgia, postoperative neuralgia, cancer pain, inflammatory pain, interstitial cystitis Post-traumatic neuralgia, diabetic neuropathy, neurodegeneration, stroke, ischemia, nerve injury, neurological skin disease, inflammatory disease, pruritus, allergic rhinitis, stroke, irritable bowel syndrome, asthma, A therapeutic or prophylactic agent for a disease selected from chronic obstructive pulmonary disease, dermatitis, mucositis, gastric / duodenal ulcer and inflammatory bowel syndrome, bladder hypersensitivity, bladder overactivity, frequent urination and urinary incontinence. A therapeutic or prophylactic agent for pain comprising a pharmaceutically effective amount of the 3-aminobenzamide compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof. Pain is pain, acute pain, chronic pain, neuropathic pain, rheumatoid arthritis pain, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, acute postherpetic neuralgia, postherpetic neuralgia, chronic postherpetic neuralgia The therapeutic or prophylactic agent according to claim 17, which is postoperative neuralgia, cancer pain, inflammatory pain, interstitial cystitis, posttraumatic neuralgia, diabetic neuropathy, or neurodegeneration. The pharmaceutical composition according to claim 11-14, and the pharmaceutical composition comprising pain, acute pain, chronic pain, neuropathic pain, rheumatoid arthritis pain, neuralgia, neuropathy, hyperalgesia, migraine, arthralgia Acute postherpetic neuralgia, postherpetic neuralgia, chronic postherpetic neuralgia, postoperative neuralgia, cancer pain, inflammatory pain, interstitial cystitis, posttraumatic neuralgia, diabetic neuropathy, neurodegeneration, stroke , Ischemia, nerve injury, neurological skin disease, inflammatory disease, pruritus, allergic rhinitis, stroke, irritable bowel syndrome, asthma, chronic obstructive pulmonary disease, dermatitis, mucositis, stomach / duodenum Described that it can or should be used for the treatment and / or prevention of diseases selected from ulcer and inflammatory bowel syndrome, bladder hypersensitivity, bladder overactivity type urination and urinary incontinence Relates to the pharmaceutical composition Commercial packages containing the Nobutsu. The pain according to claim 12, acute pain, chronic pain, neuropathic pain, rheumatoid arthritis pain, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, acute postherpetic neuralgia, postherpetic neuralgia, Chronic postherpetic neuralgia, postoperative neuralgia, cancer pain, inflammatory pain, interstitial cystitis, posttraumatic neuralgia, diabetic neuropathy, neurodegeneration, stroke, ischemia, nerve injury, nerve skin Disease, inflammatory disease, pruritus, allergic rhinitis, stroke, irritable bowel syndrome, asthma, chronic obstructive pulmonary disease, dermatitis, mucositis, gastric / duodenal ulcer and inflammatory bowel syndrome, bladder hypersensitivity, bladder The 3-aminobenzamide compound according to any one of claims 1 to 10 or a pharmacy thereof for producing a pharmaceutical composition for the treatment and / or prevention of a disease selected from overactive frequent urination and urinary incontinence Permissible The use of salt. The 3-aminobenzamide compound according to any one of claims 1 to 10 or a pharmaceutically acceptable product thereof for producing a pharmaceutical composition for the treatment and / or prevention of pain according to claim 13. Use of salt. Pain is pain, acute pain, chronic pain, neuropathic pain, rheumatoid arthritis pain, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, acute postherpetic neuralgia, postherpetic neuralgia, chronic postherpetic neuralgia The 3-aminobenzamide compound or pharmaceutical thereof according to claim 21, which is postoperative neuralgia, cancer pain, inflammatory pain, interstitial cystitis, posttraumatic neuralgia, diabetic neuropathy, or neurodegeneration Use of acceptable salts. A pharmaceutical composition comprising the 3-aminobenzamide compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, an antiviral agent, Antidepressant, anticonvulsant, antiarrhythmic, local anesthetic, anesthetic, N-methyl-D-aspartate receptor antagonist, corticosteroid, nerve block, non-steroid A drug comprising a combination of one or more drugs selected from the group consisting of a natural anti-inflammatory analgesic, narcotic, antagonistic analgesic, α ₂ adrenergic receptor agonist, topical drug, calcium channel antagonist and potassium channel opener. Use of the 3-aminobenzamide compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof for producing the medicament according to claim 23.