# Patent

## Title
Tetrahydroisoquinolin-1-one derivative or salt thereof

## Abstract

[Problems] To provide a pharmaceutical, in particular a compound which can be used as a therapeutic agent for irritable bowel syndrome (IBS).
[Means for Solving Problems] It was found that a tetrahydroisoquinolin-1-one derivative having an amide group at the 4-position or a pharmaceutically acceptable salt thereof has an excellent bombesin 2 (BB2) receptor antagonistic action. It is also found that the tetrahydroisoquinolin-1-one derivative is highly effective on bowel movement disorders. From the above, the tetrahydroisoquinolin-1-one derivative of the present invention is useful as a therapeutic agent for diseases associated with a BB2 receptor, in particular IBS.

## Background
TECHNICAL FIELD
The present invention relates to a pharmaceutical, in particular, a tetrahydroisoquinolin-1-one derivative or a salt thereof, which is useful as a therapeutic agent for irritable bowel syndrome.
BACKGROUND ART
Irritable bowel syndrome (IBS) is a syndrome which causes chronic symptoms such as abdominal pain, bloating, and the like, bowel movement disorders such as diarrhea, constipation, and the like, defecation trouble, defecation straining, and the like. It is caused by functional abnormality of the lower digestive tract, mainly the large intestine, despite the absence of organic disorders such as inflammation, tumors, and the like, and is classified based on the conditions of stool into diarrhea-predominant, constipation-predominant, and alternating IBS which alternately repeats diarrhea and constipation. IBS is a disease which has a relatively high frequency occupying from 20 to 50% of bowel disease patients who consult outpatient cares, which is predominant in females with a male to female ratio of 1:2 regardless of race, and which has a high prevalence rate in the younger generation. Since mental stress correlates strongly with the state of the disease, it is regarded as a representative stress-related somatic disease and it is said that the stress management is important for the improvement of symptoms. Actually, it is known that abnormal motility of gastrointestinal tract is significantly accelerated and the symptoms are aggravated when emotional stress is applied to IBS patients. In addition, since the symptoms continue, a vicious circle is likely to form in which increased patient anxiety further aggravates the symptoms.
As the drug therapy of IBS, an anticholinergic is used for abdominal pain, and a tricyclic antidepressant for the improvement of pain threshold value reduction in the digestive tracts, and for the improvement of abnormal bowel motility, a stegnotic, a drug for controlling intestinal function, and the like in the case of diarrhea, and a saline cathartic and the like in the case of constipation, however these are merely symptomatic therapies and their effects are not clear. As an agent from which effects can be expected for both diarrhea and constipation, there is polycarbophil calcium, which regulates the hardness of feces by gelating in the intestines, however it exerts very limited effects because not only there is a bloating at the initial stage of its administration but also it requires time to exhibit the effects. Anxiolytics and antidepressants are used when anxiety and tension are considerably increased due to stress, however they are administered at a dose lower than the dose in the psychiatric field, so that there are cases in which the mental symptoms are not improved or cases in which these are improved but they do not exhibit any effects on the bowel movement disorder. Generally, among the symptoms of IBS, anxiolytics are effective for diarrhea and abdominal pain in some cases, but they have a tendency to exhibit little effect on constipation.
There are a 5-HT3 receptor antagonist alosetron and a 5-HT4 receptor agonist tegaserod as the agents, which have been drawing attention in recent years, and they are used in the diarrhea-predominant and the constipation-predominant, respectively. These agents improve the bowel movement by regulating the movement of intestines, and exhibit an effect quickly. However, though alosetron shows a relatively high improving rate of from 40 to 60% for abdominal symptoms and diarrhea, constipation occurs in 30 to 35% of the patients and it causes ischemic colitis (including mortal cases) as a serious side effect, so that its use is limited (Non-Patent Document 1). In addition, it cannot be said that the effect of tegaserod on the constipation-predominant is sufficient, and there is a possibility of causing tachyphylaxis (a phenomenon in which resistance is generated when a drug is repeatedly administered within a short period of time).
Apropos, when the living body receives a stress, it generates a hypothalamic-pituitary-adrenal system (HPA system) reaction, in which an adrenocorticotropic hormone (ACTH) is released through the secretion of a stress-related substance from the hypothalamus and a subsequent action upon the anterior hypophysis, and the ACTH released into the blood secretes corticosterone from the adrenal cortex, and thereby shows various stress responses such as increase in the blood pressure and the like. As the stress-related substance, corticotropin releasing hormone (CRH), bombesin (BB)/gastrin releasing peptide (GRP), vasopressin, neuropeptide Y, substance P, neurotensin, and the like are known. Secretion of these substances from the hypothalamus is accelerated when a stress is applied to an animal. Particularly regarding the CRH, it has been reported that it reinforces ACTH release and large bowel movement when administered to IBS patients (Non-Patent Document 2).
The bombesin/GRP as one of the stress-related substances is a brain-gut peptide and expresses various physiological actions via bombesin receptors. The bombesin receptor is classified into 3 subtypes of BB1, BB2 and BB3/BRS3 (bombesin receptor subtype-3), and as intrinsic ligands of mammals for the BB1 and BB2 receptors, neuromedin B and GRP have been identified respectively. It has been reported that the GRP and BB2 receptors are present ubiquitously in the brain, the digestive tracts, and the like, but GRP is markedly increased in the amygdala and hypothalamus when stress is applied to an animal (Non-Patent Document 3). In addition, it has been reported also that a BB2 receptor antagonist inhibits the increase in ACTH when administered into the cerebral ventricle in a restraint stress-added rat (Non-Patent Document 4).
As the role of the GRP/BB2 receptor in the digestive tract functions, it has been reported that it enhances the contraction in isolated human and rabbit ileum longitudinal muscle specimens (Non-Patent Documents 5 and 6), and enhances the water secretion in guinea pigs with the coexistence of a vasoactive intestinal peptide (VIP) (Non-Patent Document 7). In addition, it has been reported that BB2 receptor antagonists including RC-3095 that is a peptidic BB2 receptor antagonist, is effective for an abnormal bowel motility in a stress-induced defecation model. It has also been reported that, using an abdominal muscle contraction reaction as the index, RC-3095 is effective for an abdominal symptom in an abdominal pain model induced by large intestinal distension. Accordingly the BB2 receptor antagonist shows excellent efficacy on both the abdominal symptom and abnormal bowel motility (Patent Document 1).
As shown above, the BB2 receptor antagonist is expected to be a therapeutic agent for IBS, showing excellent efficacy on both the abdominal symptom and abnormal bowel motility.
Furthermore, since the bombesin/GRP also has a function as a cell growth factor and the expression of the GRP/BB2 receptor is increased in various cancer cells of lung cancer, prostate cancer, and the like, the efficacy of RC-3095 has been reported in a large number of antitumor tests (Non-Patent Documents 8 to 10). From this viewpoint, the BB2 receptor antagonist can also be expected to be effective against various cancers.
The tetrahydroisoquinolin-1-one derivative has been reported in Patent Documents 2 to 4.
Patent Document 2 describes that a 3,4-dihydroisoquinolin-1-one derivative represented by the following formula (A) has a caspase activating action and an apoptosis inducing action, and is effective for cancers, autoimmune diseases, rheumatoid arthritis, inflammatory bowel syndrome, psoriasis, and the like. However, there is no description of its antagonistic action on a bombesin type 2 receptor or of its efficacy regarding IBS.




(for the symbols in the formula, refer to the publication)
Patent Document 3 describes that a tetrahydroisoquinolin-1-one derivative represented by the following formula (B) is a ligand of an HDM2 protein, has an apoptosis inducing activity and a proliferation inhibitory activity, and is effective against cancers. However, there is no description of its antagonistic action on a bombesin type 2 receptor or of its efficacy regarding IBS.




(for the symbols in the formula, refer to the publication)
Patent Document 4 describes that a tetrahydroisoquinolin-1-one derivative represented by the following formula (C) is a neurotensin-2 (NT-2) receptor antagonist and is effective against pain. However, for R5 corresponding to R1 of the present invention, there is no description on the R1 group of the present invention. In addition, there is no description of its antagonistic action on a bombesin type 2 receptor or of its efficacy regarding IBS.




(wherein R5 means (C1-C8)alkyl which is optionally substituted with a group selected from trifluoromethyl, halogen, saturated or partially unsaturated (C3-C8)cycloalkyl, and (C6-C10)aryl. For the other symbols, refer to the publication.)
The compounds described in the following Tables 1 to 11 below are reported as Catalog Compounds. However, there is no description of the antagonistic action on a bombesin type 2 receptor and the efficacy for IBS, of these compounds. Further, in the following Tables, the abbreviations below are used. Me: Methyl, Et: Ethyl, iPr: Isopropyl, nBu: Normal Butyl, Ph: Phenyl.







TABLE 1







 








 








CAS Registry



No.
RaRbN—





931939-66-1






 


931315-65-0






 


902607-43-6
Me2N—


902450-09-3
Ph—(CH2)2—NH—


891914-00-4
PhCH2—NH—


 


891913-84-1






 


891913-76-1






 


891913-68-1






 


891913-28-3






 


891913-04-5






 


891912-88-2
EtNH—


 


891912-80-4






















TABLE 2








891912-64-4






 



891912-56-4






 



891912-48-4






 



891912-40-6






 



891912-16-6






 



891912-08-6






 



891912-00-8






 



891911-84-5






 



891911-60-7






 



891911-52-7






 



891911-44-7






 



891911-36-7





















TABLE 3







891911-29-8






 


891911-22-1






 


891911-07-2






 


891910-93-3






 


891910-86-4






 


891910-72-8






 


891910-65-9






 


891910-58-0






 


891910-23-9






 


891910-07-9






 


891909-99-2






 


891909-91-4
EtO—(CH2)3—NH—


 


891909-83-4






















TABLE 4








891909-75-4






 



891909-67-4






 



891909-59-4
iPrO—(CH2)3—NH—


 



891909-51-6






 



891909-27-6
PhN(Et)—(CH2)3—NH—


 



891909-11-8






 



891909-03-8






 



891908-95-5






 



891908-55-7
Et2N—


 



891907-99-6






 



891907-91-8






 



891907-83-8






 



891907-75-8






 



891907-43-0
MeO—(CH2)3—NH—



891907-35-0
nBuNH—



891907-27-0
iPrNH—


 



891907-19-0






 



891907-11-2
MeO—(CH2)2—NH—


















TABLE 5








891907-03-2






 



891906-95-9






 



891906-87-9






 



891906-79-9






 



891906-71-1






 



891906-55-1






 



891906-39-1






 



891905-75-2






 



891904-87-3




















TABLE 6













 










CAS Registry No.
RaRbN—







685520-62-1







 



685520-61-0







 



442858-62-0
EtO2C—CH2—NH—



 



442858-61-9







 



442858-27-7
MeO2C—(CH3)2—NH—



442858-05-1
MeO2C—CH2—NH—



 



442858-04-0







 



442857-76-3







 



442857-73-0







 



442856-86-2







 



442856-85-1







 



442856-80-6
Et2N—




















TABLE 7









442856-71-5







 



442856-34-0







 



442856-31-7







 



442856-30-6







 



442856-29-3
iPrNH—



 



442856-28-2







 



442856-17-9







 



442856-15-7
PhN(Et)-(CH2)3—NH—



 



442855-08-5







 



442854-93-5







 



442854-92-4







 



442854-57-1
MeO—(CH2)2—NH—



 



442854-41-3





















TABLE 8













 










CAS Registry No.
RaRbN—







685520-63-2







 



442859-46-3







 



442859-42-9







 



442859-40-7







 



442859-39-4







 



442859-38-3







 



442859-36-1







 



442859-27-0







 



442859-26-9
























TABLE 9









442859-25-8







 



442859-20-3
Et2N—



 



442859-13-4







 



442859-12-3







 



442859-11-2
MeO—(CH2)3—NH—



442859-09-8
nBuN(Et)—



 



442859-06-5







 



442859-05-4
nBuNH—



 



442859-03-2







 



442859-02-1
EtO2C—CH2—NH—



442859-01-0
MeO—(CH2)2—NH—



442858-99-3
nBuN(Me)NH—



 



442858-98-2







 



442858-93-7







 



442858-91-5
PhCH2N(Me)—



 



442858-86-8







 



442858-79-9
























TABLE 10









442858-77-7







 



442858-76-6







 



442858-72-2







 



442858-67-5







 



442858-56-2
iPrNH—



 



442858-55-1





















TABLE 11













 










CAS Registry No.
RaRbN—







442888-72-4







 



442888-70-2







 



442888-60-0







 



442888-49-5







 



442888-41-7







 



442888-39-3







 



442888-37-1







 



442888-35-9














Non-Patent Document 1: “American Journal of Gastroenterology”, (USA), 2003, vol. 98, p. 750-758
Non-Patent Document 2: “Gut”, (England), 1998, vol. 42, p. 845-849
Non-Patent Document 3: “The Journal of Neuroscience”, (USA), 1998, vol. 18, p. 4758-4766
Non-Patent Document 4: “Life Sciences”, (Holland), 2002, vol. 70, p. 2953-2966
Non-Patent Document 5: “Gastroenterology”, (USA), 1991, vol. 100, p. 980-985
Non-Patent Document 6: “Neurogastroenterology and Motility”, (England), 1997, vol. 9, p. 265-270
Non-Patent Document 7: “Annals of the New York Academy of Science”, (USA), 2000, vol. 921, p. 420-424
Non-Patent Document 8: “Cancer”, (USA), 1998, vol. 83, p. 1335-1343
Non-Patent Document 9: “British Journal of Cancer”, 2000, vol. 83, p. 906-913,
Non-Patent Document 10: “Cancer”, (USA), 2000, vol. 88, p. 1384-1392
Patent Document 1: Pamphlet of International Publication No. 2006/115135
Patent Document 2: Pamphlet of International Publication No. 2004/04727
Patent Document 3: Pamphlet of International Publication No. 2006/97323
Patent Document 4: Pamphlet of International Publication No. 03/29221
DISCLOSURE OF THE INVENTION
Problem that the Invention is to Solve
It is an object of the present invention to provide a novel pharmaceutical having a BB2 receptor antagonistic action, in particular, a novel compound which is useful as a therapeutic agent for IBS.
Means for Solving the Problems
The present inventors have conducted extensive studies on BB2 receptor antagonists, and as a result, we have found that a novel tetrahydroisoquinolin-1-one derivative having an amide group as a substituent at the 4-position has an excellent BB2 receptor antagonistic action, thus completing the present invention.
Namely the present invention relates to a tetrahydroisoquinolin-1-one derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof:




[the symbols in the formula represent the following meanings:
R1: lower alkylene-OH, lower alkylene-N(R0)(R6), lower alkylene-CO2Ro, cycloalkyl, cycloalkenyl, aryl, heterocyclic group, -(lower alkylene substituted with —OR0)-aryl or lower alkylene-heterocyclic group,
wherein the lower alkylene, cycloalkyl, cycloalkenyl, aryl and heterocyclic group in R1 may each be substituted,
R0: the same as or different from each other, each representing —H or lower alkyl,
R6: R0, —C(O)—R0, —CO2-lower alkyl or —S(O)2-lower alkyl,
R2: lower alkyl, lower alkylene-ORo, lower alkylene-aryl, lower alkylene-heterocyclic group, lower alkylene-N(R0)CO-aryl, lower alkylene-O-lower alkylene-aryl, —CO2Ro, —C(O)N(R0)2, —C(O)N(R0)-aryl, —C(O)N(R0)-lower alkylene-aryl, aryl or heterocyclic group,
wherein the aryl and heterocyclic group in R2 may each be substituted,
R3: —H or lower alkyl,
or R2 and R3 may be combined to form C2-6 alkylene,
R4: —N(R7)(R8), —N(R0)—OH, —N(R0)—N(R0)(R7), —N(R0)—N(R0)(R7), —N(R0)—S(O)2-aryl, or —N(R0)—S(O)2—R7,
wherein the aryl in R4 may be substituted,
R7: lower alkyl, halogeno-lower alkyl, lower alkylene-CN, lower alkylene-OR0, lower alkylene-CO2R0, lower alkylene-C(O)N(R0)2, lower alkylene-C(O)N(R0)N(R0)2, lower alkylene-C(═NH)NH2, lower alkylene-C(═NOH)NH2, heteroaryl, lower alkylene-X-aryl, or lower alkylene-X-heterocyclic group,
wherein the lower alkylene, aryl, heteroaryl, and heterocyclic group in R7 may each be substituted,
X: single bond, —O—, —C(O)—, —N(R0)—, —S(O)p—, or *—C(O)N(R0)—,
wherein * in X represents a bond to lower alkylene,
m: an integer of 0 to 3,
p: an integer of 0 to 2,
R8: —H or lower alkyl,
or R7 and R8 may be combined to form lower alkylene-N(R9)-lower alkylene, lower alkylene-CH(R9)-lower alkylene, lower alkylene-arylene-lower alkylene, or lower alkylene-arylene-C(O)—,
R9: aryl and heteroaryl which may each be substituted,
R10: —H, lower alkyl, or —C(O)R0,
R5: lower alkyl, halogeno-lower alkyl, halogen, nitro, —OR0, —O-halogeno-lower alkyl, —N(R0)2, —O-lower alkylene-CO2R0, or —O-lower alkylene-aryl,
wherein the aryl in R5 may be substituted,
provided that, when R4 is —N(R7)(R8),
(1) a compound wherein R1 is unsubstituted cyclopentyl and R2 is unsubstituted 2-thienyl;
(2) a compound wherein R1 is unsubstituted cyclohexyl and R2 is 4-methoxyphenyl;
(3) a compound wherein R1 is 4-methoxyphenyl and R2 is 4-methoxyphenyl; and
(4) a compound wherein R1 is (morpholin-4-yl)ethyl and R2 is 4-ethoxyphenyl are excluded,
furthermore, 2,3-bis(4-chlorophenyl)-N-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
3-(4-chlorobenzyl)-2-(4-chlorophenyl)-N-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
3-[3,5-bis(trifluoromethyl)phenyl]-2-cyclopropyl-N-(2-furylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
3-[3,5-bis(trifluoromethyl)phenyl]-2-cyclopropyl-N-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
ethyl 3-{3-[3,5-bis(trifluoromethyl)phenyl]-4-{[2-(4-methoxyphenyl)ethyl]carbamoyl}-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl}propanoate,
N-benzyl-3-[3,5-bis(trifluoromethyl)phenyl]-1-oxo-2-(tetrahydrofuran-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
3-[3,5-bis(trifluoromethyl)phenyl]-N-(2-methoxyethyl)-2-(2-morpholin-4-ylethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
3-[3,5-bis(trifluoromethyl)phenyl]-2-(2-furylmethyl)-N-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
3-[3,5-bis(trifluoromethyl)phenyl]-N-(2-furylmethyl)-2-(2-morpholin-4-ylethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, and
(4-chlorophenyl)[3-(4-chlorophenyl)-4-[(2-methoxyethyl)carbamoyl]-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl]acetic acid
are excluded.
The symbols hereinafter represent the same meanings].
Further, the present application relates to a pharmaceutical comprising a tetrahydroisoquinolin-1-one derivative represented by the general formula (I) or a salt thereof as an active ingredient, in particular a BB2 receptor antagonist, a therapeutic agent for irritable bowel syndrome or a therapeutic agent for cancers.
Furthermore, the present application relates to the use of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a BB2 receptor antagonist, a therapeutic agent for irritable bowel syndrome, or a therapeutic agent for cancers, and to a method for treating irritable bowel syndrome or cancers, comprising administering to a patient an effective amount of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
Namely, the present application relates to:
(1) a pharmaceutical composition comprising the compound described in the general formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier,
(2) the pharmaceutical composition as described in (1), which is a BB2 receptor antagonist,
(3) the pharmaceutical composition as described in (1), which is a therapeutic agent for irritable bowel syndrome,
(4) the pharmaceutical composition as described in (1), which is a therapeutic agent for cancers,
(5) use of the compound as described in the general formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a BB2 receptor antagonist, a therapeutic agent for irritable bowel syndrome, or a therapeutic agent for cancers, and
(6) a method for treating irritable bowel syndrome or cancers, comprising administering to a patient a therapeutically effective amount of the compound as described in the general formula (I) or a pharmaceutically acceptable salt thereof.
Effects of the Invention
The compound of the present invention is useful as a therapeutic agent for IBS since it has an excellent antagonistic action on a BB2 receptor.


BEST MODE FOR CARRYING OUT THE INVENTION
The present invention will be described in more detail as follows.
The “lower alkyl” is preferably a linear or branched alkyl having 1 to 6 carbon atoms (which is hereinafter simply referred to as C1-6), and specifically, it includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl group, and the like. More preferably, it is C1-4 alkyl, and more preferably, it includes methyl, ethyl, n-propyl, and isopropyl.
The “lower alkylene” is preferably a linear or branched C1-6 alkylene, and specifically, it includes methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, propylene, methylmethylene, ethylethylene, 1,2-dimethylethylene, 1,1,2,2-tetramethylethylene group, and the like. Preferably, it is C1-4 alkylene, and more preferably, it includes methylene, ethylene, and trimethylene.
The “halogen” means F, Cl, Br, or I.
The “halogeno-lower alkyl” refers to C1-6 alkyl substituted with one or more halogens. It is preferably lower alkyl substituted with 1 to 5 halogens, and more preferably trifluoromethyl.
The “halogeno-lower alkylene” refers to C1-6 alkylene substituted with one or more halogens. It is preferably lower alkylene substituted with 1 to 5 halogens, and more preferably, it includes difluoromethylene and difluoroethylene.
The “cycloalkyl” refers to a C3-10 saturated hydrocarbon ring group, which may have a bridge. Specifically, it includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl group, and the like. It is preferably C3-8 cycloalkyl, and more preferably C3-6 cycloalkyl, and even more preferably, it includes cyclopentyl and cyclohexyl.
The “cycloalkenyl” refers to C3-15 cycloalkenyl, which may have a bridge, and it includes a ring group condensed with a benzene ring at a double bond site. Specifically, it includes cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, 1-tetrahydronaphthyl, 1-indenyl, 9-fluorenyl group, and the like. Preferably, it is C5-10 cycloalkenyl, and more preferably, it includes cyclopentenyl and cyclohexenyl.
The “aryl” refers to a C6-14 monocyclic to tricyclic aromatic hydrocarbon ring group, and preferably, it includes phenyl and naphthyl, and more preferably phenyl.
The “arylene” refers to a divalent group formed by removing an arbitrary hydrogen atom from aryl, and it is preferably phenylene, and more preferably orthophenylene.
The “heteroaryl” means a ring group consisting of i) monocyclic 5- to 6-membered heteroaryl containing 1 to 4 hetero atoms selected from O, S, and N, and ii) bicyclic a 8- to 10-membered heterocycle and a tricyclic 11- to 14-membered heterocycle, each containing 1 to 5 hetero atoms selected from O, S, and N, which are formed by condensation of the monocyclic heteroaryl, and one or two rings selected from the group consisting of monocyclic heteroaryl and a benzene ring. The ring atom S or N may be oxidized to form an oxide or a dioxide.
The “heteroaryl” preferably includes pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, furyl, thienyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, indolyl, indazolyl, benzoimidazolyl, imidazopyridyl, quinolyl, quinazolyl, quinoxalinyl, naphthylidinyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, and carbazolyl, and more preferably pyrrolyl, pyridyl, furyl, thienyl, and thiazolyl.
The “heterocyclic group” means a ring group consisting of i) a monocyclic 3- to 8-membered (preferably 5- to 7-membered) heterocycle containing 1 to 4 hetero atoms selected from O, S, and N, and ii) a bicyclic 8- to 14-membered (preferably 9- to 11-membered) heterocycle and a tricyclic 11- to 20-membered (preferably 12- to 15-membered) heterocycle, each containing 1 to 5 hetero atoms selected from O, S, and N, which are formed by the condensation of the monocyclic heterocycle, and one or two rings selected from the group consisting of a monocyclic heterocycle, a benzene ring, C5-8 cycloalkane, and C5-8 cycloalkene. The ring atom S or N may be oxidized to form an oxide or a dioxide, or may have a bridge.
The “heterocyclic group” preferably includes aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, oxiranyl, oxetanyl, tetrahydropyranyl, tetrahydropyranyl, morpholinyl, homomorpholinyl, tetrahydrothienyl, tetrahydrothiopyranyl, thiomorpholinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, furyl, thienyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, indolyl, indazolyl, benzimidazolyl, imidazopyridyl, quinolyl, quinazolyl, quinoxalinyl, naphthylidinyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, dihydroindolyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, tetrahydroquinolyl, benzodioxolyl, dihydrobenzodioxynyl, dihydrobenzoxazinyl, tetrahydronaphthylidinyl, carbazolyl, and quinuclidinyl, and more preferably pyrrolidyl, piperidyl, tetrahydrofuryl, tetrahydropyranyl, pyrrolyl, pyridyl, furyl, thienyl, and thiazolyl.
The expression “which may be substituted” means “which is not substituted” or “which is substituted with 1 to 5 substituents which may be the same as or different from each other”. The expression “which is substituted” refers to “which is substituted with 1 to 5 substituents which are the same as or different from each other”. Further, if a plurality of substituents are contained, the substituents may be the same as or different from each other.
The substituent for the “lower alkylene” which may be substituted in R1 is preferably a group selected from Group G1, and more preferably —OH or phenyl.
Group G1: halogen, —OR0, —N(R0)(R6), and aryl.
Provided that, the “aryl” in Group G1 may be substituted with a group selected from the group consisting of halogen, lower alkyl, halogeno-lower alkyl, —OR0, and —O-halogeno-lower alkyl.
The substituent for the “cycloalkyl”, “cycloalkenyl”, and “heterocyclic group” which may be each substituted in R1 is preferably a group selected from Group G2, more preferably —OR0, —CO2Ro, —N(R0)2, —N(R0)C(O)Ro, —N(R0)C(O)-lower alkylene—OR0, or —N(R0)S(O)2-lower alkyl, and even more preferably —ORo, —N(Ro)C(O)Ro, or —N(Ro)S(O)2-lower alkyl.
Group G2: halogen, lower alkyl, halogeno-lower alkyl, lower alkylene-OR0, —OR0, —O-halogeno-lower alkyl, —N(R0)2, —N(R0)-lower alkylene-OR0, —N(R0)-lower alkylene-CO2Ro, —N(R0)C(O)Ro, —N(R0)C(O)OR0, —N(R0)C(O)-aryl, —N(R0)C(O)-lower alkylene-ORo, —N(R0)C(O)-lower alkylene-N(R0)2, —N(R0)C(O)N(R0)2, —N(R0)C(═NR0)-lower alkyl, —N(R0)S(O)2-lower alkyl, —N(lower alkylene-OR0)—S(O)2-lower alkyl, —N(lower alkylene-CO2Ro)—S(O)2-lower alkyl, —N(R0)S(O)2-lower alkylene-CO2Ro, —N(R0)S(O)2-lower alkylene-S(O)2-lower alkyl, —N(R0)S(O)2-aryl, —N(R0)S(O)2N(R0)2, —S(O)2-lower alkyl, —CO2Ro, —CO2-lower alkylene-Si(lower alkyl)3, —C(O)N(R0)2, —C(O)N(R0)-lower alkylene-ORo, —C(O)N(R0)-lower alkylene-N(R0)2, —C(O)N(R0)-lower alkylene-CO2Ro, —C(O)N(R0)—O-lower alkylene-heterocyclic group, heterocyclic group, —C(O)R0, —C(O)-lower alkylene-OR0, —C(O)-lower alkylene-N(R0)2, —C(O)-heterocyclic group, and oxo.
Provided that the “aryl” and the “heterocyclic group” in Group G2 may be each substituted with a group selected from the group consisting of halogen, lower alkyl, halogeno-lower alkyl, —OR0, —O-halogeno-lower alkyl, and oxo.
The substituent for the “aryl” which may be substituted in R1 is preferably a group selected from Group G3, and more preferably —OR0 or lower alkylene-OR0.
Group G3: halogen, lower alkyl, halogeno-lower alkyl, —OR0, —O-halogeno-lower alkyl, lower alkylene-OR0, and —CO2Ro.
The substituent for the “aryl” and the “heterocyclic group” which may be substituted in R2 is preferably a group selected from Group G4, more preferably halogen, lower alkyl, or —OR0, and even more preferably halogen.
Group G4: halogen, —CN, nitro, lower alkyl, halogeno-lower alkyl, —OR0, —N(R0)2, —CO2R0, —C(O)N(R0)2, —OS(O)2-lower alkyl, and oxo.
The substituent for the “lower alkylene” which may be substituted in R7 is preferably a group selected from Group G5, more preferably halogen.
Group G5: halogen, —OR0, —N(R0)2, and aryl.
Provided that the “aryl” in Group G5 may be substituted with a group selected from the group consisting of halogen, lower alkyl, halogeno-lower alkyl, —OR0, and —O-halogeno-lower alkyl.
The substituent for the “aryl” and the “heterocyclic group” which may each be substituted in R7 is preferably a group selected from Group G6, and more preferably halogen, —OR0, lower alkylene-OR0, —CO2R0, lower alkylene-CO2R0, —O-lower alkylene-CO2R0, or oxo.
Group G6: halogen, lower alkyl which may be substituted with —OR0, halogeno-lower alkyl which may be substituted with —OR0, —OR0, —CN, —N(R0)2, —CO2R0, —CO2-lower alkylene-aryl, —C(O)N(R0)2, lower alkylene-OC(O)R0, lower alkylene-OC(O)aryl, lower alkylene-CO2R0, halogeno-lower alkylene-CO2R0, lower alkylene-CO2-lower alkylene-aryl, lower alkylene-C(O)N(R0)2, halogeno-lower alkylene-C(O)N(R0)2, —O-lower alkylene-CO2R0, —O-lower alkylene-CO2-lower alkylene-aryl, —O-lower alkylene-C(O)N(R0)2, —O-halogeno-lower alkylene-CO2R0, —O-halogeno-lower alkylene-C(O)N(R0)2, —C(O)N(R0)S(O)2-lower alkyl, lower alkylene-C(O)N(R0)S(O)2-lower alkyl, —S(O)2-lower alkyl, —S(O)2N(R0)2, heterocyclic group, —C(═NH)NH2, —C(—NH)═NO—C(O)O—C1-10 alkyl, —C(═NOH)NH2, —C(O)N═C(N(R)2)2, —N(R0)C(O)R0, —N(R0)C(O)-lower alkylene-OR0, —N(R0)C(O)OR0, —N(R0)S(O)2-lower alkyl, —C(aryl)3, and oxo.
Provided that the “aryl” and the “heterocyclic group” in Group G6 may each be substituted with a group selected from the group consisting of halogen, lower alkyl, halogeno-lower alkyl, —OR0, —O-halogeno-lower alkyl, oxo, and thioxo (═S).
The substituent for the “aryl” which may be substituted in R4; and the substituent for the “heteroaryl” which may be substituted in R7 are preferably a group selected from the group consisting of halogen, lower alkyl, halogeno-lower alkyl, —OR0, and —O-halogeno-lower alkyl.
The substituent for the “aryl” and “heteroaryl” which may be each substituted in R9 is preferably a group selected from the group consisting of halogen, lower alkyl, halogeno-lower alkyl, —OR0, and —O-halogeno-lower alkyl.
The substituent for the “aryl” which may each be substituted in R5 is preferably a group selected from the group consisting of halogen, lower alkyl, halogeno-lower alkyl, —OR0, and —O-halogeno-lower alkyl.
Preferred embodiments of the present invention will be described below.
(a) R1 is preferably -(lower alkylene which may be substituted)-OH, or cycloalkyl, aryl, or a heterocyclic group, which may each be substituted. More preferably, it is (lower alkylene which may be substituted)-OH, or cyclopentyl, cyclohexyl, phenyl, tetrahydrofuryl, tetrahydropyranyl, pyrrolidyl, or piperidyl, which may be each substituted. More preferably, it is (lower alkylene which may be substituted with a group selected from the group consisting of phenyl which may be substituted with halogen, lower alkyl, or —OR0, and —OH)—OH, or cycloalkyl substituted with a group selected from the group consisting of —ORo, —N(Ro)2, —N(Ro)C(O)Ro, —N(Ro)C(O)-lower alkylene-ORo, —N(R)S(O)2-lower alkyl, and a heterocyclic group. Even more preferably, it is (lower alkylene which may be substituted with a group selected from the group consisting of phenyl which may be substituted with halogen, lower alkyl or —OR0, and —OH)—OH, or cyclopentyl or cyclohexyl, which is each substituted with a group selected from the group consisting of —ORo, —N(Ro)2, —N(Ro)C(O)Ro, —N(Ro)C(O)-lower alkylene-ORo, —N(Ro)S(O)2-lower alkyl and a heterocyclic group. Particularly preferably, it is cyclohexyl substituted with a group selected from the group consisting of —ORo, —N(Ro)C(O)Ro, and —N(Ro)S(O)2-lower alkyl.
(b) R2 is preferably aryl which may be substituted, and more preferably phenyl which may be substituted with halogen, lower alkyl, or —OR0, and even more preferably phenyl substituted with halogen.
(c) R3 is preferably —H.
(d) R4 is preferably —N(R0)-lower alkylene-(aryl or heteroaryl, which may be each substituted) or —N(R0)—O-lower alkylene-(aryl or heteroaryl, which may be each substituted). More preferably, it is —NH-lower alkylene-(phenyl, pyridyl, N-oxidopyridyl, thienyl, or thiazolyl, which may each be substituted) or —NH—O-lower alkylene-(phenyl, pyridyl, N-oxidopyridyl, thienyl, or thiazolyl, which may be each substituted). More preferably, it is —NH-lower alkylene-(phenyl, pyridyl, N-oxidopyridyl, thienyl, or thiazolyl, which may each be substituted with a group selected from the group consisting of halogen, —OR0, lower alkylene-OR0, —CO2R0, lower alkylene-CO2R0, and —O-lower)alkylene-CO2R0) or —NH—O-lower alkylene-(phenyl, pyridyl, N-oxidopyridyl, thienyl, or thiazolyl, which may each be substituted with a group selected from the group consisting of halogen, —OR0, lower alkylene-OR0, —CO2R0, lower alkylene-CO2R0, and —O-lower alkylene-CO2R0). Even more preferably, it is —NH-lower alkylene-(phenyl which may be substituted with a group selected from the group consisting of halogen, —OR0, lower alkylene-OR0, —CO2R0, lower alkylene-CO2R0, and —O-lower alkylene-CO2R0) or —NH—O-lower alkylene-(phenyl which may be substituted with a group selected from the group consisting of halogen, —OR0, lower alkylene-OR0, —CO2R0, lower alkylene-CO2R0, and —O-lower alkylene-CO2R0).
(e) R5 is preferably halogen or —OR0.
(f) m is preferably 0 or 1, and more preferably 0.
In further preferred embodiments, the compounds having any combination of each of the preferable groups as described in (a) to (f) above are preferred.
Furthermore, other preferred embodiments for the compound of the present invention represented by the general formula (I) are shown below.
(1) A compound represented by the general formula (I), wherein R3 is —H.
(2) The compound as described in (1), wherein R2 is phenyl which may be substituted with halogen, lower alkyl, or —OR0.
(3) The compound as described in (2), wherein R4 is —N(R0)-lower alkylene-(aryl or heteroaryl, which may each be substituted), or —N(R0)—O-lower alkylene-(aryl or heteroaryl, which may each be substituted).
(4) The compound as described in (3), wherein R1 is (lower alkylene which may be substituted with a group selected from the group consisting of phenyl which may be substituted with halogen, lower alkyl or —OR0, and —OH)—OH; or cycloalkyl substituted with a group selected from the group consisting of —OR0, —N(R0)2, —N(R0)C(O)R0, —N(R0)-lower alkylene-OR0, —N(R0)S(O)2-lower alkyl, and a heterocyclic group.
(5) A compound represented by the general formula (I) selected from the group consisting of:
(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-(pyridin-2-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-N-[(1-oxidopyridin-2-yl)methoxy]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
3-{[({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}benzoic acid,
(4-{[({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}phenyl)acetic acid,
(3-{[({[(3R,4R)-3-(2,4-dichlorophenyl-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}phenoxy)acetic acid,
{3-[2-({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)ethyl]phenyl}(difluoro)acetic acid,
(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-N-(2-{3-[(methylsulfonyl)carbamoyl]phenyl}ethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
{4-[2-({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)ethyl]phenyl}acetic acid, and
4-(3-{[({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}phenoxy)butanoic acid;
or a pharmaceutically acceptable salt thereof.
Furthermore, in the present specification, the “irritable bowel syndrome” (which is hereinafter referred to as IBS) includes diarrhea type IBS, constipation type IBS, and alternating type IBS. The disease to which the therapeutic agent of the present invention is applied is preferably diarrhea type IBS or alternating type IBS, and particularly preferably diarrhea type IBS.
The compounds of the present invention may exist in the form of other tautomers or geometrical isomers depending on the kind of the substituents. In the present specification, the compound may be described in only one form of an isomer, but the present invention includes the isomers, an isolated form or a mixture of the isomers.
Furthermore, the compound (I) may have asymmetric carbons or axial asymmetries, and correspondingly, it may exist in the form of optical isomers such as an (R)-form, an (S)-form, and the like. The compound of the present invention includes both a mixture and an isolated form of these optical isomers.
In addition, a pharmaceutically acceptable prodrug of the compound (I) is also included in the present invention. The pharmaceutically acceptable prodrug refers to a compound, having a group which can be converted into an amino group, OH, CO2H, and the like of the present invention, by solvolysis or under a physiological condition. Examples of the group which forms the prodrug include those as described in Prog. Med., 5, 2157-2161 (1985), or “Pharmaceutical Research and Development” (Hirokawa Publishing Company, 1990), vol. 7, Drug Design, 163-198.
Furthermore, the compound of the present invention may form an acid-addition salt or a salt with a base, depending on the kind of the substituents, and these salts are included in the present invention as long as they are pharmaceutically acceptable salts. Specifically, examples thereof include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid, or the like, and salts with inorganic bases such as sodium, potassium, magnesium, calcium, aluminum, and the like, and with organic bases such as methylamine, ethylamine, ethanolamine, lysine, ornithine, and the like, ammonium salts.
In addition, the present invention also includes various hydrates and solvates, and polymorphism of the compound of the present invention and a pharmaceutically acceptable salt thereof. Furthermore, the present invention also includes the compounds that are labeled with various radioactive or non-radioactive isotopes.
(Production Process)
The compound of the present invention and a pharmaceutically acceptable salt thereof may be prepared by applying various known synthetic methods, by the use of the characteristics based on their basic backbones or the kind of the substituents. Here, depending on the kind of the functional groups, it is in some cases effective from the viewpoint of the preparation techniques to substitute the functional group with an appropriate protecting group (a group which may be easily converted into the functional group), during the steps from starting materials to intermediates. Examples of such functional groups include an amino group, a hydroxyl group, a carboxyl group, and the like, and examples of a protecting group thereof include those as described in “Protective Groups in Organic Synthesis” (3rd edition, 1999), edited by Greene and Wuts, which may be optionally selected and used in response to the reaction conditions. By such a method, a desired compound can be obtained by introducing the protecting group and carrying out the reaction, and then, if desired, removing the protecting group.
In addition, a prodrug of the compound (I) can be prepared by introducing a specific group during the steps from starting materials to intermediates, in the same manner as for the aforementioned protecting groups, or by carrying out the reaction using the obtained compound (I). The reaction may be carried out by employing a method known to a person skilled in the art, such as general esterification, amidation, and dehydration.
Hereinbelow, the representative production processes of the compounds of the present invention will be described. Each of the production processes can also be carried out with reference to the reference documents attached to the present description. Further, the production processes of the present invention are not limited to the examples as shown below.
(Production Process 1)




This production process is a process for obtaining the compound (I) of the present invention by subjecting a carboxylic acid compound (1) and an amine compound (2) to amidation.
The reaction can be carried out using equivalent amounts of the carboxylic acid compound (1) and the amine compound (2), or an excess amount of either, and stirring them from under cooling to under heating, preferably at −20° C. to 60° C., usually for 0.1 hour to 5 days, in a solvent which is inert to the reaction, in the presence of a condensing agent. The solvent as used herein is not particularly limited, but examples thereof include aromatic hydrocarbons such as benzene, toluene, xylene, and the like, halogenated hydrocarbons, such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, ethers such as diethyl ether, tetrahydrofuran (THF), dioxane, dimethoxyethane, and the like, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidin-2-one (NMP), dimethyl sulfoxide (DMSO), ethyl acetate, acetonitrile, water, and the like, or mixture thereof. Examples of the condensing agent include 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (WSC), dicyclohexylcarbodiimide, 1,1′-carbonyldiimidazole (CDI), diphenyl phosphoryl azide, phosphorous oxychloride, and the like, but are not limited to these. An additive (for example, 1-hydroxybenzotriazole (HOBt), and the like) may be preferable for the reaction in some cases. It may be advantageous for the smooth progress of the reaction to carry out the reaction in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine, pyridine, N,N-dimethyl-4-aminopyridine (DMAP), and the like, or an inorganic base such as potassium carbonate, sodium carbonate, potassium hydroxide, and the like in some cases.
In addition, a process in which the carboxylic acid compound (1) is derived into a reactive derivative, and then reacted with the amine compound (2) can also be used. Examples of the reactive derivative of the carboxylic acid as used herein include an acid halide obtained by the reaction with a halogenating agent such as phosphorous oxychloride, thionyl chloride, and the like, a mixed acid anhydride obtained by the reaction with isobutyl chloroformate, or the like, an active ester obtained by the condensation with 1-hydroxybenzotriazole or the like, and others. The reaction of the reactive derivative and the amine compound (2) can be carried out from under cooling to under heating, preferably at −20° C. to 60° C., in a solvent which is inert to the reaction, such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, and the like.
Production Process 2: Other Production Processes
Furthermore, some compounds represented by the formula (I) can also be prepared by subjecting the compound of the present invention obtained as above to any combination of the processes that are usually employed by a skilled person in the art, such as conventional amidation, hydrolysis, N-oxidation, reductive amination, sulfonylation, oxidation, reduction, N-alkylation, O-alkylation, and the like. For example, they can be prepared by the reactions as below, the methods described in Examples to be described later, a method apparent to a skilled person in the art, or a modified method thereof.
2-1: Amidation
An amide compound can be obtained by subjecting a carboxylic acid compound and an amine compound to amidation.
The amidation can be carried out in the same manner as in Production Process 1.
2-2: Hydrolysis
A compound having a carboxyl group can be prepared by hydrolyzing a compound having an ester group.
The reaction can be carried out from under cooling to under heating in a solvent such as aromatic hydrocarbons, ethers, halogenated hydrocarbons, alcohols, DMF, DMA, NMP, DMSO, pyridine, water, and the like in the presence of an acid including mineral acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, and the like, and organic acids such as formic acid, acetic acid, and the like; or in the presence of a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, ammonia, and the like.
2-3: N-Oxidation
An N-oxide compound can be prepared by oxidating the nitrogen atom of a heterocycle having a nitrogen atom, such as pyridine and the like, with various oxidants.
The reaction can be carried out from under cooling, at room temperature to under heating, using an equivalent amount or excess amount of m-chloroperbenzoic acid, peracetic acid, aqueous hydrogen peroxide, and the like as an oxidant, in a solvent such as halogenated hydrocarbons, acetic acid, water, and the like.
2-4: Reductive Amination
An amine compound can be alkylated by reducing an imine compound which is prepared from a primary or secondary amine compound and a carbonyl compound.
The reaction can be carried out using equivalent amounts of an amine compound and a carbonyl compound, or an excessive amount of either thereof, in the presence of a reducing agent, in a solvent such as halogenated hydrocarbons, alcohols, ethers, and the like. As the reducing agent, sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, and the like can be used. The reaction may be preferably carried out in the presence of an acid such as acetic acid, hydrochloric acid, titanium(IV)isopropoxide complexes, and the like in some cases.
2-5: Sulfonylation
A sulfonamide compound can be obtained by the sulfonylation of an amine compound.
The reaction can be carried out, for example, from under cooling, at room temperature to under heating, by using equivalent amounts of an amine compound and a sulfonyl halide, or an excessive amount of either thereof, in a solvent such as aromatic hydrocarbons, ethers, halogenated hydrocarbons, pyridine, and the like. It may be advantageous for the smooth progress of the reaction to carry out the reaction in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine, pyridine, and the like, or an inorganic base such as potassium carbonate, sodium carbonate, potassium hydroxide, and the like in some cases.
(Production Processes for Starting Compounds)
The starting material used for the preparation of the compound of the present invention can be prepared, for example, by applying the methods described below, the methods described in Production Examples to be described later, a known method, a method apparent to a skilled person in the art, or a modified method thereof.
(Starting Material Synthesis 1)




Step 1:

A compound (5) can be obtained by reacting a compound (3) with a compound (4).
The reaction can be carried out from at room temperature to under heating, using equivalent amounts of the compound (3) and the compound (4) or an excessive amount of either thereof, in a solvent such as ethers, halogenated hydrocarbons, aromatic hydrocarbons, and the like.
Step 2:
When R3 is —H, a compound (6) in which the substituents at the 3- and 4-positions are trans can be obtained by isomerizing the compound (5).
The reaction can be carried out by treating the compound (5) with a base such as sodium hydroxide, potassium hydroxide, and the like, from at room temperature to under heating, in a solvent such as halogenated hydrocarbons, alcohols, water, and the like.
(Starting Material Synthesis 2)




The compound (3) can be obtained by carrying out dehydration-condensation of a compound (7) with a compound (8).
The reaction can be carried out from at room temperature to under heating, using equivalent amounts of the compound (7) and the compound (8) or an excessive amount of either thereof, in a solvent such as halogenated hydrocarbons, aromatic hydrocarbons, and the like. It may be advantageous for the smooth progress of the reaction to use a dehydrating agent such as anhydrous sodium sulfate, anhydrous magnesium sulfate, Molecular Sieves, and the like in some cases.
(Starting Material Synthesis 3)




Step 1:

A compound (10) can be obtained by reacting a compound (9) with a nitrite.
The reaction can be carried out from under cooling, at room temperature to under heating in a solvent such as ethers, halogenated hydrocarbons, alcohols, and the like in the presence of a nitrite such as ethyl nitrite, butyl nitrite, isoamyl nitrite, and the like. According to the compounds, it is advantageous for the progress of the reaction to carry out the reaction in the presence of an acid such as acetic acid, hydrochloric acid, and the like, or a base such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, and the like in some cases.
Step 2
A compound (11) can be prepared by subjecting the compound (10) to rearrangement and then to hydrolysis.
The rearrangement reaction can be carried out by treating the compound (10) with thionyl chloride, or the like under cooling.
The hydrolysis reaction can be carried out from at room temperature to under heating, in a solvent such as alcohols, water, and the like, using a base such as sodium hydroxide, potassium hydroxide, and the like.
Step 3
The compound (4) can be obtained by the dehydration of the compound (11).
The dehydration reaction can be carried out from at room temperature to under heating, using acetyl chloride or the like as a dehydrating agent.
The compound of the present invention is isolated and purified as a free compound, a pharmaceutically acceptable salt, hydrate, solvate, or polymorphism thereof. The pharmaceutically acceptable salt of the compound (I) of the present invention can be prepared by a salt formation reaction within a conventional technology.
The isolation and purification can be carried out by employing general chemical operations such as extraction, fractional crystallization, various types of fractional chromatography, and the like.
Various isomers can be separated by selecting an appropriate starting compound, or by making use of the difference in the physicochemical properties between isomers. For example, the optical isomer can be derived into a stereochemically pure isomer by means of general optical resolution methods (for example, fractional crystallization for inducing to diastereomeric salts with optically active bases or acids, chromatography using a chiral column, etc., and the like). In addition, the isomers can also be prepared from an appropriate optically active starting compound.
The pharmacological activity of the compound of the present invention was confirmed by the following test.
Test Example 1
BB2 Receptor Antagonistic Activity
A BB2 receptor binding test was carried out using a membrane sample prepared from a human prostate cancer-derived PC-3 cell. The PC-3 cell was cultured using an RPMI-1640 medium containing 5% fetal bovine serum, and then a membrane sample was prepared by the following methods. The cells detached by a trypsin treatment were added with a 50 mM Tris-HCl buffer (pH 7.4, containing 0.2 mg/ml trypsin inhibitor and 0.2 mg/ml benzamidine), and homogenized by Polytron. The cell suspension was centrifuged at 1,500 rpm for 10 minutes, and the supernatant thus obtained was subjected to 1 hour of ultracentrifugation at 37,000×g. The precipitate was suspended in the aforementioned buffer to a concentration of 0.4 mg protein/ml, and stored at −80° C.
The BB2 receptor binding test was carried out by the following method, and the receptor antagonistic activity of a compound to be tested was calculated. A 50 μl of the membrane sample, 50 μl of an assay buffer (20 mM HEPES-HBSS containing 0.1% bovine serum albumin and 0.1 mg/ml bacitracin, pH 7.4), 125I [Tyr4] bombesin (0.075 nM) and 2 μl of the compound to be tested dissolved in dimethyl sulfoxide were added to a 96 well assay plate, and incubated at room temperature for 2 hours. Non-specific binding was measured using 1 μM of bombesin. After completion of the incubation, the reaction solution was filtered through a Whatman GF/B filter which had been soaked in 0.5% polyethyleneimine. The radioactivity on the filter was measured using a microplate scintillation counter (Top Count, Perkin-Elmer Co., Ltd.). The 50% binding inhibition concentrations of the representative Example Compounds are shown in Table 12. Further, Ex represents the number of the Example compound.










TABLE 12







Ex
IC50 (nM)



















61
12.8



62
18.3



236
3.0



542
4.7



560
4.8



589
5.7



631
4.5



700
6.7



701
7.4



709
8.9



712
6.7



856
6.8










Test Example 2
Restraint Stress-induced Defecation Model
The compound to be tested of the present test was used by dissolving in water for injection containing 20% propylene glycol+20% Tween 80 or a 0.5% MC (methyl cellulose) solution.
Fifteen minutes after oral administration of the compound to be tested to a fed male Wistar rat, the animal was put into a restraint stress cage (KN-468, Natsume Seisakusho Co Ltd.). The number of feces excreted during a period from the restriction commencement to 1 hour thereafter was measured. Normal group was put into a separate cage, and number of feces excreted during 1 hour was measured in the same manner.
The inhibitory rates (%) of the representative Example Compounds when they were orally administered at a dose of 1 mg/kg are shown in Table 13. As a result, it was confirmed that the compound of the present invention exhibited an excellent action to improve the bowel movement symptom.










TABLE 13







Ex
Inhibitory Rate (%)









542
40.0



560
62.1



589
73.9



631
53.8



700
69.8



701
41.3



709
41.5



712
55.0



856
61.4










As a result of the test as described above, it was confirmed that the compound of the present invention has a BB2 receptor inhibitory action. From this point, it is obvious that the compound is useful as a therapeutic agent for the diseases associated with the BB2 receptors, in particular, IBS, cancers, functional dyspepsia, diabetic gastroparesis, reflux esophagitis, peptic ulcer, and the like.
The preparation containing one or two or more of the compound (I) of the present invention or a salt thereof as an active ingredient can be prepared in accordance with a generally used method, using a pharmaceutical carrier, an excipient, and the like, which are generally employed in the art.
The administration can be accompanied by any mode of oral administration via tablets, pills, capsules, granules, powders, liquid preparations, or the like; or parenteral administration via injections such as intraarticular, intravenous, or intramuscular injections, suppositories, eye drops, eye ointments, transdermal liquid preparations, ointments, transdermal patches, transmucosal liquid preparations, transmucosal patches, inhalations, and the like.
Regarding the solid composition for oral administration according to the present invention, tablets, powders, granules, or the like are used. In such a solid composition, one or two or more of active ingredients are mixed with at least one inactive excipient such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinyl pyrrolidone, and/or magnesium aluminometasilicate, and the like. According to a conventional method, the composition may contain inert additives such as a lubricant such as magnesium stearate, a disintegrator such as carboxymethyl starch sodium, a stabilizing agent, and a solubilizing agent. As necessary, tablets or pills may be coated with a sugar coating, or a film of a gastric or enteric material.
The liquid composition for oral administration includes pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, or the like, and contains a generally used inert diluent such as purified water and ethanol. In addition to the inert solvent, this liquid composition may contain an auxiliary agent such as a solubilizing agent, a moistening agent, and a suspending agent, a sweetener, a flavor, an aroma, and an antiseptic.
The injections for parenteral administration include sterile aqueous or non-aqueous liquid preparations, suspensions, and emulsions. As the aqueous solvent, for example, distilled water for injection and physiological saline are included. Examples of the non-aqueous solvent include propylene glycol, polyethylene glycol, plant oils such as olive oil, alcohols such as ethanol, and Polysorbate 80 (Japanese Pharmacopeia), and the like. Such a composition may further contain a tonicity agent, an antiseptic, a moistening agent, an emulsions, a dispersant, a stabilizer, or a solubilizing agent. These are sterilized, for example, by filtration through a bacteria retaining filter, blending of a bactericide, or irradiation. In addition, these can also be used by preparing a sterile solid composition, and dissolving or suspending in sterile water or a sterile solvent for injection prior to its use.
The drug for external use includes ointments, plasters, creams, jellies, cataplasms, sprays, lotions, eye drops, eye ointments, and the like. The drug contains generally used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions, and the like. Examples of the ointment or lotion bases include polyethylene glycol, propylene glycol, white vaseline, bleached beeswax, polyoxyethylene hydrogenated castor oil, glyceryl monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, sorbitan sesquioleate, and the like.
Regarding a transmucosal agent such as an inhalation, a transnasal agent, and the like, those in a solid, liquid, or semi-solid state are used, and may be produced in accordance with a conventionally known method. For example, a known excipient, and in addition, a pH adjusting agent, an antiseptic, a surfactant, a lubricant, a stabilizing agent, a thickening agent, and the like may be added thereto, if desired. For their administration, an appropriate device for inhalation or blowing may be used. For example, a compound may be administered alone or as a powder of formulated mixture, or as a solution or suspension in combination with a pharmaceutically acceptable carrier, using a conventionally known device or sprayer, such as a measured administration inhalation device and the like. The dry powder inhaler or the like may be for single or multiple administration use, and a dry powder or a powder-containing capsule may be used. Alternatively, this may be in a form such as a high pressurized aerosol spray which uses an appropriate propellant, for example, a suitable gas such as chlorofluoroalkane, hydrofluoroalkane, carbon dioxide, and the like.
In the case of conventional oral administration, the daily dose may be generally from about 0.001 to 100 mg/kg, preferably from 0.1 to 30 mg/kg, and even more preferably 0.1 to 10 mg/kg, per body weight, and this is administered in one portion or in 2 to 4 divided portions. Also, in the case of intravenous administration, the daily dose is from about 0.0001 to 10 mg/kg per body weight, once a day or twice or more times a day. In addition, a transmucosal agent is administered at a dose from about 0.001 to 100 mg/kg per body weight, once a day or twice or more times a day. The dose is appropriately decided in response to an individual case by taking symptoms, age, gender, or the like into consideration.
The compound of the present invention can be used in combination with various therapeutic or prophylactic agents for the diseases, for which the compound of the present invention is considered effective. The combined preparation may be administered simultaneously, or separately and continuously or at a desired time interval. The preparations to be co-administered may be a blend, or prepared individually.
EXAMPLES
Hereinbelow, the production processes for the compound (I) of the present invention will be described in more detail with reference to Examples. The compound of the present invention is not limited to the compounds described in Examples below. Further, the production processes for the starting compounds will be described in Production Examples.
In addition, the following abbreviations are used in Examples, Production Examples, and Tables to be described later.
PEx: Production Example, Ex: Example, No: Compound No., Data: Physicochemical Data (EI+: m/z value in E1-MS (cation) (unless otherwise mentioned, (M)+.), FAB+: m/z value in FAB-MS (cation) (unless otherwise mentioned, (M+H)+.), FAB−: m/z value in FAB-MS (anion) (unless otherwise mentioned, (M−H)−.), ESI+: m/z value in ESI-MS (cation) (unless otherwise mentioned, (M+H)+.), ESI−: m/z value in ESI-MS (anion) (unless otherwise mentioned, (M−H)−.), CI+: m/z value in CI-MS (cation) (unless otherwise mentioned, (M+H)+.), APCI+: m/z value in APCI-MS (cation) (unless otherwise mentioned, (M+H)+.), APCI−: m/z value in APCI-MS (anion) (unless otherwise mentioned, (M−H)−.), NMR1: δ (ppm) of characteristic peak in δ (ppm) by 1H-NMR in DMSO-d6), Structure: Structural Formula (a case where HCl, HBr, fum, or TFA is described in the structural formula indicates that the compound is hydrochloride, hydrobromide, fumarate, or trifluoroacetate, respectively. In the case where a numeral is attached before a salt component, the numeral means a molar ratio of the compound to the salt component. For example, a case where 2HCl is described means that the compound is dihydrochloride. Further, a case where H2O is described in the structural formula indicates that the compound is a hydrate in each case.), Syn: Production Process (the numeral shows that it was prepared using a corresponding starting material, similar to the case of an Example Compound having its number as the Example No.). In the case where P is attached before the numeral, the number shows that it was produced using a corresponding starting material, similar to the case of a Production Example Compound having its number as the Prosuction Example No. A case where a plurality of the numerals is described indicates that the compound was prepared by carrying out the reaction in order starting from the front numeral, using a corresponding starting material. Note: (the racemic mixture means a racemic mixture, the diastereo mixture means a diastero mixture, and the chiral compound means a chiral compound, in which a part of its stereochemistry is not clear. Further, less polar and more polar mean a low polarity product and a high polarity product, respectively, as compared with the corresponding diastereomers, in thin layer chromatography. Further, 3,4-trans, 1′,2′-cis, and the like mean the relative configurations of the substituents or the like. Provided that the numeral which is not dashed means the position substituted in the tetrahydroisoquinolin-1-one ring, and the dashed numeral means the position substituted in the substituent at the 2-position in a tetrahydroisoquinolin-1-one ring. For example, 3,4-trans indicates that the substituents at the 3- and 4-positions in the tetrahydroisoquinolin-1-one ring are trans.) Boc: a tert-butoxycarbonyl group, DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene.
In addition,




indicates that the double bond is cis or trans, or a mixture thereof.

Production Example 1
10 g of 5-(benzyloxy)-1H-indene-1,2(3H)-dione 2-oxime was added to 20 ml of thionyl chloride at 0° C., followed by stirring for 20 minutes under the same condition. After warming to room temperature, thionyl chloride was evaporated under reduced pressure. To the residue was added 20 ml of a 40% aqueous potassium hydroxide solution, followed by heating under reflux overnight. After cooling to room temperature, and neutralizing by the addition of concentrated hydrochloric acid, the precipitated solid was collected by filtration to obtain 9.9 g of 4-(benzyloxy)-2-(carboxymethyl)benzoic acid as a dark brown powder.
Production Example 2
To a mixture of 2.01 g of diethyl [3-(1,3-dioxolan-2-yl)phenyl]malonate, 2.89 g of calcium chloride, and 50 ml of ethanol was added 2.47 g of sodium borohydride under ice-cooling, followed by stirring at the same temperature for 2 hours and at room temperature for 4 hours. To the reaction solution was added 10 ml of water at room temperature, followed by stifling for 30 minutes. The insoluble material was separated by filtration using Celite, and the filtrate was concentrated under reduced pressure to obtain 0.76 g of 2-[3-(1,3-dioxolan-2-yl)phenyl]propane-1,3-diol as a colorless oily substance.
Production Example 3
A mixture of 1.83 g of 2-[3-(1,3-dioxolan-2-yl)phenyl]propane-1,3-diyl diacetate and 60 ml of a 83% aqueous acetic acid solution was stirred at 50° C. for 2 hours. The reaction solution was concentrated under reduced pressure to obtain 1.59 g of 2-(3-formylphenyl)propane-1,3-diyl diacetate as a colorless oily substance.
Production Example 4
To a solution of 958 mg of (6-methylpyridin-3-yl)methanol, 1.3 ml of triethylamine, and 95 mg of DMAP in 40 ml of dichloromethane was added dropwise 1.08 ml of benzoyl chloride, followed by stirring at room temperature. To the reaction solution was added water, followed by carrying out an extraction operation with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain 1767 mg of (6-methylpyridin-3-yl)methyl benzoate.
Production Example 5
To a solution of 1767 mg of (6-methylpyridin-3-yl)methyl benzoate in 26.5 ml of chloroform was added 2440 mg of m-chloroperbenzoic acid under ice-cooling, followed by stirring for 1 hour. An aqueous potassium carbonate solution was added thereto to carry out a liquid separation operation, and the organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The residue was concentrated under reduced pressure to obtain 1891 mg of (6-methyl-1-oxidopyridin-3-yl)methyl benzoate.
Production Example 6
To a solution of 1891 mg of (6-methyl-1-oxidopyridin-3-yl)methyl benzoate in 38 ml of DMF was added 11 ml of trifluoroacetic anhydride, followed by stirring at room temperature overnight. After evaporating trifluoroacetic anhydride under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain 3.675 g of [6-(hydroxymethyl)pyridin-3-yl]methyl benzoate.
Production Example 7
To a solution of 858 mg of pyrazine-2,5-diyl bis(methylene) diacetate in 8.6 ml of methanol was added 600 mg of zeolite, followed by heating under reflux for 4 days. Zeolite was removed by filtration and then concentrated, and the residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain 209 mg of [5-(hydroxymethyl)pyrazine-2-yl]methyl acetate.
Production Example 8
To a mixture of 313 mg of 6-(hydroxymethyl)nicotinamide, 540 mg of triphenylphosphine, 503 mg of N-hydroxyphthalimide, and 4.7 ml of THF was added dropwise 0.53 ml of diisopropyl azodicarboxylate, followed by stirring overnight. After concentration, the solid thus produced was suspended in water, and ethyl acetate was added thereto. After stirring for 30 minutes, the solid was collected by filtration to obtain 292 mg of 6-{[(1,3-dioxo-1,3-dihydro-2H-isoindo1-2-yl)oxy]methyl}nicotinamide.
Production Example 9
To a suspension of 292 mg of 6-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]methyl}nicotinamide in 4.4 ml of methanol was added 0.2 ml of a 40% methyl amine/methanol solution, followed by stirring at room temperature for 1 hour. The reaction solution was concentrated, ethyl acetate was added thereto, and the precipitated crystal was separated by filtration and then concentrated under reduced pressure to obtain 146 mg of 6-[(aminooxy)methyl]nicotinamide.
Production Example 10
To a mixture of 3.0 g of 6-chloronicotinic acid and 111 ml of THF was added 6.4 g of potassium tert-butoxide, followed by heating under reflux for 1 day. The reaction solution was poured into water, neutralized with citric acid, and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 2.16 g of 6-tert-butoxynicotinic acid.
Production Example 11
To a mixed liquid of 2163 mg of 6-tert-butoxynicotinic acid and 32 ml of acetone were added 2297 mg of potassium carbonate and 0.97 ml of methyl iodide, followed by stirring at 35° C. overnight. Ethyl acetate and water were added thereto to carry out liquid separation, and the organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 1.191 g of methyl 6-tert-butoxynicotinate.
Production Example 12
To a mixed liquid of 1191 mg of methyl 6-tert-butoxynicotinate and 35.7 ml of ethanol was slowly added 2153 mg of sodium borohydride, followed by stirring at 50° C. for 18 hours. After the addition of methanol, water and ethyl acetate were added thereto to carry out an extraction operation. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 0.949 g of (6-tert-butoxypyridin-3-yl)methanol.
Production Example 13
To a mixed liquid of 1020 mg of 5-[(aminooxy)methyl]-2-tert-butoxypyridine, which had been obtained by reacting (6-tert-butoxypyridin-3-yl)methanol and N-hydroxyphthalimide in accordance with Production Example 8, and then carrying out the removal of phthalimide in accordance with Production Example 9, and 20 ml of ethyl acetate was added 1.3 ml of concentrated hydrochloric acid under ice-cooling, followed by stirring for 30 minutes. The resulting solid was separated by filtration, concentrated hydrochloric acid was further added to the filtrate, and the precipitated solid was collected by filtration to obtain 351 mg of 5-[(aminooxy)methyl]pyridin-2(1H)-one hydrochloride as a colorless solid.
Production Example 14
To a mixture of 659 mg of 1-(chloromethyl)-4-(methylsulfonyl)benzene and 10 ml of DMSO were added 525 mg of N-hydroxyphthalimide and 445 mg of potassium carbonate, followed by stirring at 50° C. for 2 hours. The reaction solution was cooled, water was then added thereto, and the precipitated crystal was collected by filtration to obtain 685 mg of 2-{[4-(methylsulfonyl)benzyl]oxy}-1H-isoindole-1,3(2H)-dione as a white solid.
Production Example 15
To a solution of 5.08 g of tert-butyl [4-(hydroxymethyl)phenoxy]acetate and 4.6 ml of triethylamine in 30 ml of dichloromethane was added 1.98 ml of methanesulfonyl chloride under ice-cooling, followed by stirring for 1 hour under ice-cooling. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was then evaporated. To a solution of the obtained residue in 40 ml of DMF was added 4.26 g of sodium azide, followed by stirring at 60° C. for 15 hours. After leaving it to be cooled, the reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was then evaporated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-hexane) to obtain 5.16 g of tert-butyl [3-(azidomethyl)phenoxy]acetate as a pale yellow oily substance.
Production Example 16
To a mixed liquid of 5.00 g of methyl 5-formylthiophene-3-carboxylate and 50 ml of THF was added 0.67 g of sodium borohydride under ice-cooling. To the reaction solution was added dropwise 5 ml of methanol, followed by stirring for 1 hour under ice-cooling. The reaction solution was added with 1 M hydrochloric acid, extracted with ethyl acetate, and washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was then evaporated to obtain 4.86 g of methyl 5-(hydroxymethyl)thiophene-3-carboxylate as a pale yellow oily substance.
Production Example 17
To a mixed liquid of 4.86 g of methyl 5-(hydroxymethyl)thiophene-3-carboxylate and 50 ml of dichloromethane was added 4.12 ml of thionyl chloride under ice-cooling, followed by stirring at room temperature for 15 hours. The reaction solution was concentrated, added with ethyl acetate, and then washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was then evaporated to obtain 4.90 g of methyl 5-(chloromethyl)thiophene-3-carboxylate as a pale yellow oily substance.
Production Example 18
To a solution of 3.69 g of di-tert-butyl imidodicarbonate in 54 ml of DMF was added 1.91 g of potassium tert-butoxide at 0° C. under argon, followed by stirring at room temperature for 1 hour. A solution of 2.7 g of methyl 5-(chloromethyl)thiophene-3-carboxylate in 8.1 ml of DMF was slowly added thereto, followed by stirring at room temperature overnight. Water and ethyl acetate were added to the reaction solution, followed by carrying out an extraction operation, and the organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain 4.394 g of methyl 5-{[bis(tert-butoxycarbonyl)amino]methyl}thiophene-3-carboxylate.
Production Example 19
To a mixed liquid of 400 mg of ethyl difluoro(3-methylphenyl) acetate and 10 ml of carbon tetrachloride were added 349 mg of N-bromosuccinimide and 15 mg of 2,2′-azobis(isobutyronitrile), followed by heating under reflux for 2 hours. After cooling the reaction solution, the insoluble material was separated by filtration, and the filtrate was concentrated. The residue was added with hexane, washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain 458 mg of ethyl [3-(bromomethyl)phenyl](difluoro) acetate as a colorless oily substance.
Production Example 20
To a mixed liquid of 2.89 g of ethyl 2-methyl-2-(3-methylphenyl)propionate and 90 ml of carbon tetrachloride were added 4.98 g of N-bromosuccinimide and 115 mg of 2,2′-azobis(isobutyronitrile), followed by stirring at 80° C. for 2 hours, and 4.98 g of N-bromosuccinimide and 115 mg of 2,2′-azobis(isobutyronitrile) were further added thereto, followed by stirring at 80° C. for 14 hours. After cooling the reaction solution, the insoluble material was separated by filtration, and the solvent was evaporated. To the residue was added hexane and followed by washing with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was then evaporated to obtain 6.0 g of a pale yellow oily substance. The obtained oily substance was dissolved in 30 ml of THF, and 21.7 ml of diethyl phosphite and 29.3 ml of diisopropylethylamine were added thereto under ice-cooling, followed by stirring at room temperature for 13 hours. The reaction solution was poured into ice water, followed by extraction with hexane. The organic layer was washed with 1 M hydrochloric acid and a saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was evaporated, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain 2.95 g of ethyl 2-[3-(dibromomethyl)phenyl]-2-methylpropionate as a pale yellow oily substance.
Production Example 21
To a mixed liquid of 2.95 g of ethyl 2-[3-(dibromomethyl)phenyl]-2-methylpropionate and 30 ml of acetic acid was added 4.77 g of potassium acetate, followed by stirring at 100° C. for 6 hours. After cooling the reaction solution, 10 ml of 6 M hydrochloric acid was added thereto, followed by stirring at room temperature for 2 hours. The reaction solution was poured into water, followed by extraction with hexane, and the organic layer was washed with water and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was then evaporated to obtain 1.74 g of ethyl 2-(3-formylphenyl)-2-methylpropionate as a colorless oily substance.
Production Example 22
To a mixed liquid of 1.00 g of tert-butyl piperidin-4-ylcarbamate and 20 ml of pyridine was added 0.77 ml of methanesulfonyl chloride, followed by stirring at room temperature for 18 hours. After evaporating the pyridine under reduced pressure, ethyl acetate was added thereto, followed by washing with a 5% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated aqueous sodium chloride solution. After drying the organic layer over anhydrous magnesium sulfate, the solvent was evaporated, and the obtained solid was washed with diethyl ether to obtain 1.19 g of t-butyl[1-(methylsulfonyl)piperidin-4-yl]carbamate as a white solid.
Production Example 23
To a solution of 1 g of tert-butyl [3-(cyanomethyl)phenoxy]acetate in 20 ml of THF and 10 ml of methanol was added dropwise a suspension of 1.31 g of cobalt chloride and 20 ml of water, and then 459 mg of sodium borohydride was portionwise added thereto at room temperature. After stirring at room temperature for 10 minutes, the insoluble material was separated by filtration over Celite, washed with methanol, and then concentrated. The obtained residue was extracted with chloroform, and dried over anhydrous magnesium sulfate, and the solvent was then evaporated. The obtained residue was purified by silica gel column chromatography (eluent: chloroform-methanol-saturated aqueous ammonia) to obtain 632 mg of tert-butyl [3-(2-aminoethyl)phenoxy]acetate as a pale yellow oily substance.
Production Example 24
To a mixed liquid of 5.16 g of t-butyl [3-(azidomethyl)phenoxy]acetate and 50 ml of THF were added 6.17 g of triphenylphosphine and 1.04 ml of water, followed by stirring at room temperature for 4 days. The solvent was evaporated and diisopropyl ether was added thereto. The precipitated solid was separated by filtration and the solvent was evaporated again. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol-saturated aqueous ammonia) to obtain 4.10 g of t-butyl[3-(aminomethyl)phenoxy]acetate as a pale yellow oily substance.
Production Example 25
To a mixed liquid of 2.00 g of (1RS,2SR)-2-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid and 40 ml of dichloromethane were added 1.41 ml of 2-(trimethylsilyl)ethanol, 0.40 g of DMAP, and 2.21 g of WSC in this order, followed by stirring at room temperature for 60 hours. After evaporating the solvent, ethyl acetate was added thereto, followed by washing with water, a 5% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated aqueous sodium chloride solution in this order. The organic layer was dried over anhydrous magnesium sulfate and the solvent was then evaporated to obtain 2.82 g of 2-(trimethylsilyl)ethyl(1RS,2SR)-2-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylate as a colorless oily substance.
Production Example 26
To a solution of 2.82 g of 2-(trimethylsilyl)ethyl(1RS,2SR)-2-[(t-butoxycarbonyl)amino]cyclohexanecarboxylate in 10 ml of ethyl acetate, were added 20 ml of 4 M hydrogen chloride/ethyl acetate under ice-cooling, followed by stirring at room temperature for 6 hours. The reaction solution was evaporated to obtain 2.30 g of 2-(trimethylsilyl)ethyl(1RS,2SR)-2-aminocyclohexanecarboxylate as a colorless amorphous substance.
Production Example 27
To a mixed liquid of 4.40 g of N-[(benzyloxy)carbonyl]-3-[(methylsulfonyl)amino]-D-alanine methyl ester, 100 ml of THF, and 50 ml of ethanol was added 1.13 g of lithium chloride, and 1.01 g of sodium borohydride was further added thereto under ice-cooling. The reaction solution was stirred at room temperature for 14 hours, and the solvent was then evaporated under reduced pressure. After adding 150 ml of water, concentrated hydrochloric acid was added thereto until the pH reached 2 to 3. The solution was extracted with ethyl acetate, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated to obtain 3.10 g of benzyl[(1R)-2-hydroxy-1-{[(methylsulfonyl)amino]methyl}ethyl]carbamate as a white solid.
Production Example 28
To a mixed liquid of 3.10 g of benzyl[(1R)-2-hydroxy-1-{[(methylsulfonyl)amino]methyl}ethyl]carbamate and 50 ml of ethanol was added 500 mg of 5% palladium/carbon, followed by stirring at room temperature for 2 hours under a hydrogen atmosphere. The palladium/carbon was separated by filtration and the solvent was then evaporated to obtain 1.72 g of N-[(2R)-2-amino-3-hydroxypropyl]methanesulfonamide as a colorless oily substance.
Production Example 29
To 700 mg of 2-(6-methoxypyridin-2-yl)ethylamine was added 10 ml of a 47% aqueous hydrogen bromide solution, followed by stirring at 80° C. for 60 hours. After evaporating the solvent, the residue was washed with diethyl ether to obtain 1.21 g of a 6-(2-aminoethyl)pyridin-2(1H)-one hydrobromide as a pale brown solid.
Production Example 30
A mixture of 3980 mg of 2-[2-(1H-tetrazol-1-yl)ethyl]-1H-isoindole-1,3(2H)-dione, 0.90 g of hydrazine monohydrate, and 80 ml of ethanol was stirred at 70° C. for 12 hours. The reaction solution was left to be cooled and the insoluble material was then collected by filtration. The filtered material was suspended in dioxane and 3.57 g of di-tert-butyl dicarbonate was added thereto at room temperature, followed by stirring for 12 hours. The insoluble material was separated by filtration and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography using hexane/ethyl acetate as an eluent solvent to obtain 2210 mg of tert-butyl[2-(1H-tetrazol-1-yl)ethyl]carbamate as a colorless solid.
Production Example 31
To a solution of 2.62 g of tert-butyl 1H-pyrrole-3-carboxylate and 7.96 g of N-(2-bromoethyl)phthalimide in DMF (100 ml) was added 10.2 g of cesium carbonate at room temperature, followed by stirring for 12 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine and then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography using hexane/chloroform as an eluent solvent, and washed with diethyl ether to obtain 670 mg of tert-butyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindo1-2-yl)ethyl]-1H-pyrrole-3-carboxylate as a colorless solid.
Production Example 32
A mixture of 660 mg of tert-butyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1H-pyrrole-3-carboxylate, 194 mg of hydrazine monohydrate, and 19 ml of ethanol was stirred at 70° C. for 12 hours. The reaction solution was left to be cooled and the insoluble material was then separated by filtration. The filtrate was concentrated under reduced pressure to obtain 430 mg of tert-butyl 1-(2-aminoethyl)-1H-pyrrole-3-carboxylate as a yellow oily substance.
Production Example 33
To a solution of 8.75 g of 2,4-dichlorobenzaldehyde in 100 ml of chloroform were added 5.11 g of cyclopentylamine and 5 g of Molecular Sieves 4A, followed by stirring at room temperature overnight. After removing the Molecular Sieves 4A by filtration, 6.48 g of homophthalic anhydride was added thereto, followed by stirring at room temperature overnight and then reflux for 5 hours. After concentrating under reduced pressure, ethyl acetate and a 1 M aqueous sodium hydroxide solution were added thereto to carry out a liquid separation operation. The aqueous layer was acidified by the addition of 1 M hydrochloric acid, followed by extraction with chloroform-isopropyl alcohol (3:1). The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure. The obtained residue was added with ether and collected by filtration to obtain 4.48 g of 3,4-cis-2-cyclopentyl-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (Production Example 33-1) as a colorless crystal. The mother liquid was concentrated to obtain 6.46 g of 3,4-trans-2-cyclopentyl-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (Production Example 33-2) as a colorless amorphous substance.
Production Example 34
To a mixed solution of 2,4-dichlorobenzaldehyde in chloroform-methanol were added trans-2-aminocyclohexanol, triethylamine, and anhydrous sodium sulfate at room temperature, the reaction solution was stirred at 50° C. overnight, and homophthalic anhydride was then added thereto at room temperature, followed by stirring at room temperature overnight. After removing sodium sulfate by filtration, chloroform and a 1 M aqueous sodium hydroxide solution were added thereto to carry out a liquid separation operation, and the aqueous layer was stirred at room temperature for 2 hours. It was acidified by the addition of 1 M hydrochloric acid, and ethyl acetate was added thereto to carry out a liquid separation operation. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. To the residue was added diethyl ether, followed by stirring at room temperature overnight. The precipitated crystal was collected by filtration to obtain 7655 mg of 3RS,4RS-3-(2,4-dichlorophenyl)-2-(1SR,2SR-2-hydroxycyclohexyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (Production Example 34-1) as a colorless crystal. After concentrating the mother liquid, the residue was purified by silica gel column chromatography (eluent: chloroform:methanol) to obtain 6600 mg of 3SR,4SR-3-(2,4-dichlorophenyl)-2-(1RS,2RS-2-hydroxycyclohexyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (Production Example 34-2) as a colorless crystal.
Production Example 35
To 4.33 g of (3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexyl]-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid were added 50 ml of ethanol and 2 ml of concentrated sulfuric acid, followed by heating under reflux overnight. Ethyl acetate and water were added thereto to carry out a liquid separation operation, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain 2.3 g of ethyl (3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexyl]-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate as a yellow foam.
Production Example 36
To a solution of 2.25 g of ethyl (3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexyl]-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate in 30 ml of acetonitrile were added 0.75 ml of methanesulfonyl chloride and 1.6 ml of diisopropylethylamine, followed by stirring at room temperature overnight. Ethyl acetate and water were added thereto to carry out a liquid separation operation, and the organic layer was washed with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. The residue was added with diethyl ether for crystallization, and collected by filtration to obtain 2.02 g of ethyl(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate as a colorless crystal.
Production Example 37
To a solution of 1.4 g of ethyl(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate in 20 ml of DMF was added 229 mg of sodium hydride under ice-cooling, followed by stirring at the same temperature for 10 minutes, and then 0.17 ml of methyl iodide was added thereto, followed by stirring under ice-cooling for 30 minutes. Water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain 545 mg of ethyl (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[methyl(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate as a colorless amorphous substance.
Production Example 38
To a mixture of 2.0 g of ethyl(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate, 10 ml of methanol, and 10 ml of THF was added 10 ml of a 1 M aqueous sodium hydroxide solution, followed by stirring at room temperature for 1 hour. The solution was acidified by the addition of 1 M hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 1.9 g of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid as a pale yellow crystal.
Production Example 39
A mixture of 8 g of 4-(benzyloxy)-2-(carboxymethyl)benzoic acid and 30 ml of acetyl chloride was heated under reflux for 3 hours. The reaction solution was concentrated under reduced pressure, added with ether, and collected by filtration to obtain 7.50 g of 6-(benzyloxy)-1H-isochromene-1,3(4H)-dione as a dark brown solid.
Production Example 40
To 612 mg of 6-[(aminooxy)methyl]pyridin-2(1H)-one, which had been prepared by subjecting 2-[(6-oxo-1,6-dihydropyridin-2-yl)methoxy-1H-isoindole-1,3(2H)dione to removal of phthalimide in accordance with Production Example 9, was added 1.6 ml of a 4 M hydrogen chloride/ethyl acetate solution, and the precipitated solid was collected by filtration to obtain 263 mg of 6-[(aminooxy)methyl]pyridin-2(1H)-one hydrochloride as a colorless solid.
Production Example 41
To 2.04 g of (4-methyl-1H-imidazol-5-yl)methanol hydrochloride was added 20 ml of acetonitrile, and 2.1 ml of triethylamine, 3.14 g of di-tert-butyl dicarbonate, and 0.17 g of DMAP were added thereto under ice-cooling, followed by stirring at room temperature. After concentrating the reaction solution under reduced pressure, ethyl acetate and water were added thereto to carry out a liquid separation operation, and the organic layer was washed with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. The obtained residue was reacted with N-hydroxyphthalimide in accordance with Production Example 14, reacted with methylamine in accordance with Production Example 9, and then subjected to deprotection of a Boc group in accordance with Production Example 26 to obtain 0.53 g of 5-[(aminooxy)methyl]-4-methyl-1H-imidazole dihydrochloride as a colorless solid.
Production Example 42
To a solution of 529 mg of (5-fluoropyridin-2-yl)methanol and 0.64 ml of triethylamine in 8 ml of dichloromethane was added 0.35 ml of methanesulfonyl chloride under ice-cooling, followed by stirring for 1 hour under ice-cooling. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was then evaporated. The obtained residue was reacted with N-hydroxyphthalimide in accordance with Production Example 14 to obtain 522 mg of 2-[(5-fluoropyridin-2-yl)methoxy]-1H-isoindole-1,3(2H)-dione as a white solid.
Production Example 43
To a mixture of 2.97 g of 4-(hydroxymethyl)phenol, 4.90 g of tert-butyl bromoacetate, and 25 ml of DMF was added 4.96 g of potassium carbonate at room temperature, followed by stirring for 12 hours. To the reaction solution was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was then evaporated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-hexane) to obtain a pale yellow oily substance. This oily substance was subjected to methanesulfonylation in accordance with Production Example 15, and then reacted with sodium azide to obtain 4.03 g of tert-butyl[4-(azidomethyl)phenoxy]acetate as a pale yellow oily substance.
Production Example 44
To a solution of 1.63 g of ethyl(3RS,4RS)-2-[(1SR,2SR)-2-{[(3-chloropropyl)sulfonyl]amino}cyclohexyl]-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate in 20 ml of THF was added 142 mg of sodium hydride, followed by stirring at 50° C. overnight. Ethyl acetate and water were added thereto to carry out a liquid separation operation. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain 466 mg of ethyl(3RS,4RS)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-(1,1-dioxidoisothiazolidin-2-yl)cyclohexyl]-1-oxo-tetrahydroisoquinoline-4-carboxylate as a colorless crystal.
Production Example 45
A solution of 5.0 g of 4-bromothiophene-2-carbaldehyde, 11.4 ml of vinyltributyltin, and 3.6 g of tetrakistriphenylphosphine palladium in 100 ml of toluene was heated at 110° C. for 4 hours under a sealed tube condition. The organic layer was extracted with ethyl acetate and washed with water. In addition, the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain 3.4 g of 4-vinylthiophene-2-carbaldehyde as a brown liquid.
Production Example 46
A solution of 5 g of methyl 1-methyl-1H-imidazole-5-carboxylate and 22.5 g of paraformaldehyde in 50 ml of methanol was heated at 140° C. for 60 hours under a sealed tube condition. The precipitate was removed by filtration and the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain 4 g of methyl 2-(hydroxymethyl)-1-methyl-1H-imidazole-5-carboxylate as a white solid.
Production Example 47
7.4 ml of phosphorous oxychloride was added dropwise to 8.1 ml of DMF at 0° C., followed by warming to room temperature. To the solution was added ethyl 3-furanate, followed by warming to 126° C. and stirring for 1 hour. After cooling to room temperature, the reaction solution was poured into ice water. The organic layer was extracted with diethyl ether and washed with a saturated aqueous sodium carbonate solution. In addition, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain 850 mg of ethyl 5-formyl-3-furnate as a yellow solid.
Production Example 48
To a mixed liquid of 1.51 g of potassium cyanide and 70 ml of acetonitrile, 6.12 g of 1,4,7,10,13,16-hexaoxacyclooctadecane was added, followed by stirring for 2 hours. Thereafter, a solution of 5.00 g of tert-butyl 3-(chloromethyl)benzoate in 30 ml of acetonitrile was added thereto, followed by stirring at room temperature for 18 hours. The reaction solution was concentrated, diluted with diethyl ether-hexane (1:1), and then washed with water and a saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was evaporated, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain 3.86 g of tert-butyl 3-(cyanomethyl)benzoate as a colorless oily substance.
Production Example 49
A solution of 2 g of (benzyloxy)acetic acid in 30 ml of DMF was cooled to 0° C., and 2.44 g of 1-(4-aminophenyl)ethanone, 294 mg of DMAP, and 3.73 g of WSC/hydrochloride were added thereto, followed by stirring at room temperature for 3 hours. Liquid separation was carried out with ethyl acetate-1 M hydrochloric acid. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 3.12 g of N-(4-acetylphenyl)-2-(benzyloxy)acetamide.
Production Example 50
To a solution of 1.64 g of ethyl 2-(hydroxymethyl)isonicotinate in 32.8 ml of dichloromethane were added 1.24 ml of dihydropyrane and 2.32 g of pyridinium p-toluenesulfonate, followed by stirring overnight. Ethyl acetate was added thereto, followed by washing with a saturated aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 2.4 g of ethyl 2-[(tetrahydro-2H-pyran-2-yloxy)methyl]isonicotinate.
Production Example 51
To a solution of 1.8 g of 1-[6-(hydroxymethyl)pyridin-2-yl]ethanone oxime in 36 ml of methanol was added 500 mg of 10% palladium-carbon (50% wet) under an argon atmosphere, followed by stifling for 7 hours under a hydrogen atmosphere. After filtration through Celite, the filtrate was evaporated under reduced pressure to obtain 1.5 g of [6-(1-aminoethyl)pyridin-2-yl]methanol.
Production Example 52
To a solution of 2.06 g of 3-amino-4-hydroxybenzoic acid in 20.6 ml of THF was added 4.81 g of CDI, followed by stirring at room temperature for 1 hour. The reaction mixture was added dropwise to a mixed liquid of 3.06 g of sodium borohydride in 20.6 ml of THF and 8.26 ml of water, cooled to 0° C., which had been separately prepared, followed by stirring overnight. 1 M hydrochloric acid was added thereto, followed by extracting with ethyl acetate, and washing with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 1.2 g of 5-(hydroxymethyl)-1,3-benzoxazol-2(3H)-one.
Production Example 53
To 5 g of diethylpyridine-2,4-dicarboxylate were added 50 ml of ethanol and 50 ml of dichloroethane, followed by ice-cooling. 932 mg of sodium borohydride was added portionwise thereto, followed by stirring for 1 hour under ice-cooling, and further at room temperature for 15 hours. After ice-cooling the reaction solution, 5 ml of 6 M hydrochloric acid was added thereto, followed by stirring for 5 minutes and concentrating. A saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extracting with chloroform-isopropanol (10:1) and drying over anhydrous magnesium sulfate. After concentrating under reduced pressure, the residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain 0.7 g of ethyl 4-(hydroxymethyl)pyridine-2-carboxylate (Production Example 53-1) and 1.6 g of ethyl 2-(hydroxymethyl)isonicotinate (Production Example 53-2), respectively.
Production Example 54
To 1.6 g of 1-(6-methoxypyridin-2-yl)ethanamine was added 23.7 ml of a 47% aqueous hydrobromic acid solution, followed by stirring at 80° C. for 60 hours. After evaporating the solvent under reduced pressure, the residue was washed with diethyl ether to obtain 2.95 g of 6-(1-aminoethyl)pyridin-2(1H)-one hydrobromide as a pale brown solid.
Production Example 55
To a solution of 2.31 g of tert-butyl 1H-pyrazole-3-carboxylate and 6.98 g of N-(2-bromoethyl)phthalimide in DMF (65 mL) was added 8.95 g of cesium carbonate at room temperature, followed by stirring for 12 hours. The reaction solution was diluted with water, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform-hexane) to obtain 1.51 g of tert-butyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1H-pyrazole-3-carboxylate as a colorless solid.
Production Example 56
To a mixture of 2.92 g of (2-hydroxyphenyl)acetonitrile, 4.71 g of tert-butyl bromoacetate and 110 mL of DMF was added 6.06 g of potassium carbonate at room temperature, followed by stirring for 12 hours. To the reaction solution was added water, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography using hexane/ethyl acetate as an eluent solvent to obtain 5.29 g of tert-butyl[2-(cyanomethyl)phenoxy]acetate as a yellow oily substance.
Production Example 57
A mixture of 1.38 g of 6-(hydroxymethyl)pyridin-2(1H)-one, 2.15 g of tert-butyl bromoacetate, 3.07 g of silver oxide, and 33 mL of DMF was stirred at room temperature for 12 hours, and then at 60° C. for 12 hours. The insoluble material was separated by filtration and the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate, followed by washing with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain 1.92 g of tert-butyl{[6-(hydroxymethyl)pyridin-2-yl]oxy}acetate as a yellow oily substance.
Production Example 58
To a mixture of 1.00 g of 3-hydroxybenzaldehyde, 1.80 g of tert-butyl(R)-lactate, 2.58 g of triphenylphosphine, and 40 mL of THF was added 1.71 g of diethyl azodicarboxylate at room temperature, followed by stirring for 12 hours. The reaction solution was diluted with ethyl acetate, followed by washing with a 5% aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain 1.49 g of tert-butyl(2S)-2-(3-formylphenoxy)propanoate as a colorless oily substance.
To a solution of 1.48 g of tert-butyl(2S)-2-(3-formylphenoxy)propanoate in methanol (30 mL) was added 0.48 g of sodium borohydride under ice-cooling, followed by stirring for 1 hour. The reaction solution was diluted with ethyl acetate, added with water, neutralized with 1 M hydrochloric acid, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 1.38 g of tert-butyl(2S)-2-[3-(hydroxymethyl)phenoxy]propanoate as a colorless oily substance.
Production Example 59
A solution of 2.90 g of 1,3-phenylene diacetic acid, 3.00 g of 4-methoxybenzylbromide, and 2.99 g of potassium hydrogen carbonate in 15 mL of DMF was stirred at room temperature for 36 hours. To the reaction solution was added water, followed by neutralization with 1 M hydrochloric acid. The product was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate. After concentrating under reduced pressure, 4.72 g of a colorless oily substance was obtained. A mixture of the obtained colorless oily substance (4.72 g), 2.42 g of HOBt, 2.78 g of WSC hydrochloride, 3.99 g of ammonium chloride, 7.55 g of triethylamine, and 18 mL of DMF was stirred at room temperature for 12 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain 4-methoxybenzyl[3-(2-amino-2-oxoethyl)phenyl]acetate as a colorless solid.
To a solution of 1.31 g of 4-methoxybenzyl [3-(2-amino-2-oxoethyl)phenyl]acetate in pyridine (20 mL) was added 718 mg of methane sulfonyl chloride under ice-cooling, followed by stirring for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with a 5% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution, and then a saturated aqueous sodium chloride solution in this order. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain 1.25 g of 4-methoxybenzyl [3-(cyanomethyl)phenyl]acetate as a yellow oily substance.
Production Example 60
A mixture of 5.05 g of 5-methyl-2-furanecarboxylic acid, 7.14 g of CDI, and 40 mL of DMF was stirred at 50° C. for 2 hours. To the reaction solution were added 6.71 g of DBU and 6.53 g of 2-methyl-2-propanol at room temperature, followed by stirring at 50° C. for 48 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was diluted with diethyl ether and washed with a 5% aqueous ammonium chloride solution, a saturated aqueous sodium hydrogen carbonate solution, and then a saturated aqueous sodium chloride solution in this order. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain 2.82 g of tert-butyl 5-methyl-2-furanecarboxylate as a yellow oily substance.
Production Example 61
To a solution of 1643 mg of 1-[6-(hydroxymethyl)pyridin-2-yl]ethanone in 25 ml of ethanol was added 0.72 ml of a 50% aqueous hydroxylamine solution, followed by stirring overnight. The reaction solution was concentrated under reduced pressure to obtain 1806 mg of 1-[6-(hydroxymethyl)pyridin-2-yl]ethanone oxime as an amorphous substance.
Production Example 62
To a mixture of 2.06 g of tert-butyl({6-[(hydroxymethyl)pyridin-2-yl]oxy}acetate, 2.60 g of triphenylphosphine, 2.70 g of phthalimide, and 40 mL of THF was added 1.73 g of diethyl azodicarboxylate at room temperature, followed by stirring for 36 hours. To the reaction solution was added ethyl acetate, followed by washing with a 5% aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 2.33 g of ({6-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]pyridin-2-yl}oxy)acetic acid as a colorless solid.
Production Example 63
To a mixture of 1266 mg of {2-[(tetrahydro-2H-pyrane-2-yloxy)methyl]pyridin-4-yl}methyl benzoate and 25 ml of methanol was added 1166 mg of pyridinium p-toluenesulfonate, followed by stirring for 2 hours. A saturated aqueous sodium hydrogen carbonate solution and chloroform were added thereto for extraction, and the organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 941 mg of [2-(hydroxymethyl)pyridin-4-yl]methyl benzoate as an amorphous substance.
Production Example Compounds 64 to 371 were prepared in the same manner as the methods of Production Examples 1 to 63 and the methods of Examples to be described later, using each of the corresponding starting materials. The structures and the physicochemical data of Production Example Compounds are shown in Tables 14 to 69.
Example 1
To a solution of 808 mg of 3,4-cis-2-cyclopentyl-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid, 0.3 ml of phenylethylamine, and 405 mg of HOBt in dichloromethane (20 ml) was added 576 mg of WSC hydrochloride at room temperature, followed by stirring for 2 hours. To the reaction solution was added chloroform, and the organic layer was washed with water and a saturated aqueous sodium chloride solution in this order, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform) to obtain 902 mg of 3,4-trans-2-cyclopentyl-3-(2,4-dichlorophenyl)-1-oxo-N-phenylethyl-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless crystal.
Example 2
To a mixture of 202 mg of 3,4-cis-2-cyclopentyl-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid and 5 ml of dichloromethane were added 0.055 ml of oxalyl chloride and one drop of DMF under ice-cooling, followed by stirring at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the obtained residue was dissolved in 5 ml of THF, and 0.13 ml of phenylethylamine and 0.07 ml of triethylamine were added thereto, followed by stirring at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, added with ethyl acetate, and washed with water and a saturated aqueous sodium chloride solution in this order. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform), and the obtained crude product was then collected by filtration using diethyl ether to obtain 127 mg of 3,4-cis-2-cyclopentyl-3-(2,4-dichlorophenyl)-1-oxo-N-phenylethyl-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless crystal.
Example 3
To a mixture of 254 mg of 3,4-trans-2-cyclopentyl-3-(2,4-dichlorophenyl)-1-oxo-N-[2-(2-pyridinyl)ethyl]-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 5 ml of dichloromethane was added 173 mg of m-chloroperbenzoic acid under ice-cooling, followed by stirring at room temperature overnight. To the reaction solution was added chloroform, washed with a 10% aqueous sodium hydrogen sulfite solution and a saturated aqueous sodium chloride solution in this order, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform-methanol) and then recrystallized from ethanol to obtain 138 mg of 3,4-trans-2-cyclopentyl-3-(2,4-dichlorophenyl)-N-[2-(1-oxidopyridin-2-yl)ethyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless crystal.
Example 4
To 654 mg of N-{[(3,4-trans-2-cyclopentyl-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}-β-alanine ethyl ester were added 5 ml of THF, 2 ml of methanol, and 5 ml of a 1 M aqueous sodium hydroxide solution at room temperature, followed by stirring at 50° C. for 3 hours. After neutralization by the addition of 1 M hydrochloric acid, ethyl acetate was added for extraction. The organic layer was washed with water and a saturated aqueous sodium chloride solution in this order, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. The obtained white solid was recrystallized from ethyl acetate to obtain 294 mg of N-{[(3,4-trans-2-cyclopentyl-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}-β-alanine as a colorless powdered crystal.
Example 5
To 410 mg of tert-butyl{2-[3-(2,4-dichlorophenyl)-1-oxo-4-[(2-phenylethyl)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl]ethyl}carbamate was added 4 ml of a 4 M hydrogen chloride/ethyl acetate solution, followed by stirring at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and chloroform and a 1 M aqueous sodium hydroxide solution were then added to carry out a liquid separation operation. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. The obtained residue was recrystallized from ethyl acetate-hexane to obtain 192 mg of 2-(2-aminoethyl)-3-(2,4-dichlorophenyl)-1-oxo-N-(2-phenylethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless powdered crystal.
Example 6
To a solution of 537 mg of 3,4-trans-2-(trans-4-aminocyclohexyl)-3-(2,4-dichlorophenyl)-1-oxo-N-(2-phenylethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in 10 ml of dichloromethane were added 0.33 ml of an aqueous formalin solution and 893 mg of sodium triacetoxyborohydride, followed by stirring at room temperature overnight. To the reaction solution was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (eluent: chloroform-methanol), and the obtained white solid was recrystallized from ethyl acetate to obtain 82 mg of 3,4-trans-3-(2,4-dichlorophenyl)-2-[trans-4-(dimethylamino)cyclohexyl]-1-oxo-N-(2-phenylethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless crystal.
Example 7
To a solution of 2.03 g of 3,4-trans-2-cyclopentyl-1-oxo-4-[(2-phenylethyl)carbamoyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid in 20 ml of THF was added 810 mg of CDI, followed by stirring under heating at 50° C. for 1 hour. After cooling to room temperature, a mixture of 200 mg of sodium borohydride and 10 ml of water was added thereto, followed by stirring at room temperature for 4 hours. Ethyl acetate and water were added thereto to carry out a liquid separation operation, and the organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform), and the obtained solid was recrystallized from ethyl acetate to obtain 255 mg of 3,4-trans-2-cyclopentyl-3-(hydroxymethyl)-1-oxo-N-(2-phenylethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless crystal.
Example 8
To 304 mg of (3RS,4RS)—N-(benzyloxy)-3-(4-methyl-3-nitrophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide were added 10 ml of acetic acid and 560 mg of reduced iron, followed by stirring at 50° C. overnight. To the reaction solution was added methanol, followed by filtration through Celite, and after concentrating the mother liquid, ethyl acetate and water were added thereto to carry out a liquid separation operation. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform:methanol). The obtained solid was made into hydrochloride using a 4 M hydrogen chloride/ethyl acetate solution, and recrystallized from isopropyl alcohol to obtain 180 mg of (3RS,4RS)-3-(3-amino-4-methylphenyl)-N-(benzyloxy)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide hydrochloride as a pale yellow powdered crystal.
Example 9
To 393 mg of 3,4-trans-2-cyclopentyl-3-(hydroxymethyl)-1-oxo-N-(2-phenylethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide were added 10 ml of THF and 44 mg of sodium hydride, followed by stirring at room temperature for 30 minutes. To the reaction mixture was added 161 mg of 4-chlorobenzylbromide, followed by stirring at room temperature overnight. To the reaction mixture were added ethyl acetate and water to carry out a liquid separation operation, and the organic layer was washed with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform) and the obtained solid was crystallized from ether-hexane, and collected by filtration to obtain 134 mg of 3,4-trans-3-{[(4-chlorobenzyl)oxy]methyl}-2-cyclopentyl-1-oxo-N-(2-phenylethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless powdered crystal.
Example 10
To a solution of 573 mg of (3RS,4RS)—N-(2-chloroethyl)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in 10 ml of DMF were added 150 mg of sodium iodide and 340 mg of 1H-pyrazole, followed by stirring at 100° C. for 24 hours. Ethyl acetate and water were added thereto to carry out a liquid separation operation, and the organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain a colorless crystal. The crystal was recrystallized from ethanol to obtain 176 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-[2-(1H-pyrazol-1-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless powdered crystal.
Example 11
To a mixture of 270 mg of (3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexyl]-3-(2,4-dichlorophenyl)-1-oxo-N-(pyridin-2-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 5 ml of pyridine was added 0.11 ml of acetic anhydride, followed by stirring at room temperature for 2 hours. Ethyl acetate and water were added thereto to carry out a liquid separation operation, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain a colorless crystal. The obtained crystal was added with diethyl ether and collected by filtration to obtain 55 mg of (3RS,4RS)-2-[(1SR,2SR)-2-acetamidecyclohexyl]-3-(2,4-dichlorophenyl)-1-oxo-N-(pyridin-2-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless powdered crystal.
Example 12
To a mixture of 538 mg of (3RS,4RS)-2-{(1SR,2SR)-2-aminocyclohexyl}-N-(benzyloxy)-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 2.5 ml of pyridine was added 0.15 ml of methanesulfonyl chloride, followed by stifling at room temperature for 6 hours. Ethyl acetate and water were added thereto to carry out a liquid separation operation, and the organic layer was washed with a 1 M aqueous hydrochloric acid solution and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform) and then recrystallized from ethyl acetate-hexane to obtain 206 mg of (3RS,4RS)-N-(benzyloxy)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino] cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless powdered crystal.
Example 13
To a mixed liquid of 200 mg of (3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexyl]-N-(benzyloxy)-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 40 ml of dimethoxyethane was added 357 mg of sulfamide, followed by stirring at 80° C. for 2 days. The reaction solution was concentrated, added with chloroform, and then washed with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then evaporated. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol), crystallized from ethyl acetate, and collected by filtration to obtain 62 mg of (3RS,4RS)-2-{(1SR,2SR)-2-[(aminosulfonyl)amino]cyclohexyl}-N-(benzyloxy)-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white crystal.
Example 14
To a mixed liquid of 269 mg of (3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexyl]-N-(benzyloxy)-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 5 ml of chloroform was added 0.21 ml of dimethylsulfamoyl chloride, followed by stirring at room temperature for 15 hours, and further at 60° C. for 24 hours. In addition, 500 mg of sodium carbonate was added thereto, followed by stirring at 60° C. for 5 hours. In addition, 0.21 ml of dimethylsulfamoyl chloride was added thereto, followed by stirring at 60° C. for 5 hours. After cooling the reaction solution, a liquid separation operation was then carried out using water and chloroform. The organic layer was washed with 1 M hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution, and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain a colorless amorphous substance. The obtained amorphous substance was crystallized with ethyl acetate to obtain 99 mg of (3RS,4RS)—N-(benzyloxy)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-{[(dimethylamino)sulfonylamino]amino}cyclohexyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white crystal.
Example 15
To a mixed liquid of 269 mg of (3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexyl]-N-(benzyloxy)-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 20 ml of ethanol was added 53 mg of nitrourea, followed by heating under reflux for 1 hour. The reaction solution was cooled and then concentrated, and the residue was purified by silica gel column chromatography (eluent: chloroform-methanol), then crystallized with acetonitrile, and collected by filtration to obtain 155 mg of (3RS,4RS)—N-(benzyloxy)-2-[(1SR,2SR)-2-(carbamoylamino)cyclohexyl]-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white crystal.
Example 16
To a mixed liquid of 269 mg of (3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexyl]-N-(benzyloxy)-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 5 ml of DMF were added 58 mg of sodium carbonate and 119 mg of methyl ethanimidothioate hydrochloride, followed by stirring at 60° C. for 1 hour. Thereafter, while stirring at 60° C., 233 mg of sodium carbonate and 478 mg of methyl ethanimidothioate hydrochloride were further added in four divided portions every 1 hour. After cooling the reaction solution, water was added thereto, followed by extraction with chloroform-isopropyl alcohol (5:1). The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol-aqueous ammonia) and then crystallized with ethyl acetate to obtain 113 mg of (3RS,4RS)—N-(benzyloxy)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-(ethanimidoylamino)cyclohexyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white crystal.
Example 17
644 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-hydroxycyclohexyl]-N-[2-(2-methoxy-6-methylpyridin-4-yl)ethyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 1.92 g of pyridine hydrochloride were mixed, followed by warming from room temperature to 200° C. over 15 minutes. The molten mixture was left to be cooled and then subjected to a liquid separation operation using water and ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain 480 mg of a low polarity product and 146 mg of a high polarity product. The low polarity product was crystallized with ethyl acetate to obtain 277 mg of (3RS,4RS)-2-[(1SR)-cyclohex-2-en-1-yl]-3-(2,4-dichlorophenyl)-N-[2-(6-methyl-2-oxo-1,2-dihydropyridin-4-yl)ethyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide (Example 17-1) as a white crystal. The high polarity product was recrystallized with ethyl acetate-ethanol to obtain 85 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-hydroxycyclohexyl]-N-[2-(6-methyl-2-oxo-1,2-dihydropyridin-4-yl)ethyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide (Example 17-2) as a white crystal.
Example 18
To a mixed liquid of 456 mg of (3RS,4RS)-N-[(3-cyanobenzyl)oxy]-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 15 ml of DMF was added 139 mg of sodium azide and subsequently 114 mg of ammonium chloride at room temperature, followed by warming to 100° C. and stirring for 12 hours. The reaction solution was cooled to room temperature, then added with water, and extracted with chloroform. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the residue was purified by silica gel column chromatography (eluent: chloroform-methanol). The crude purified product thus obtained was recrystallized with ethanol-water to obtain 171 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-{[3-(2H-tetrazol-5-yl)benzyl]oxy-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white crystal.
Example 19
A mixture of 730 mg of tert-butyl(3-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}phenoxy)acetate, 5 ml of dichloroethane, and 5 ml of trifluoroacetic acid was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: chloroform-methanol). The crude purified product thus obtained was recrystallized from ethyl acetate to obtain 184 mg of (3-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}phenoxy)acetic acid as a colorless crystal.
Example 20
To a solution of 330 mg of 3-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}benzoic acid in 5 ml of DMF was added 122 mg of CDI, followed by stirring at room temperature for 30 minutes. To the reaction solution were added 71 mg of methane sulfonamide and 0.11 ml of DBU, followed by stirring at room temperature for 3 hours. To the reaction solution was added ethyl acetate, followed by washing with 1 M hydrochloric acid and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was then evaporated. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain a crude purified product. This was recrystallized with acetonitrile-water to obtain 273 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-N-({3-[(methylsulfonyl)carbamoyl]benzyl}oxy)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white crystal.
Example 21
To a solution of 128 mg of (3RS,4RS)—N-(cyanomethoxy)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in 1.92 ml of methanol was added 0.018 ml of a hydroxylamine solution at room temperature, followed by warming to 40° C. and stirring overnight. The reaction solution was cooled to room temperature and the precipitated crystal was then collected by filtration to obtain 26 mg of (3RS,4RS)—N-[2-amino-2-(hydroxyimino)ethoxy]-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white crystal.
Example 22
To a mixed liquid of 300 mg of (3RS,4RS)—N-({3-[amino(hydroxyimino)methyl]benzyl}oxy)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 30 ml of acetonitrile were added 132 mg of 1,1′-carbonothioyl bis(1H-imidazole) and 0.27 ml of DBU under ice-cooling, followed by stirring at room temperature for 1 hour. The reaction solution was concentrated and then added with 50 ml of water, and 1 M hydrochloric acid was added thereto until the pH reached 4 to 5. After extracting with ethyl acetate, washing with a saturated aqueous sodium chloride solution and drying over anhydrous magnesium sulfate, the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol). The crude purified product thus obtained was added with ethyl acetate and collected by filtration to obtain 61 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-{[3-(5-thioxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)benzyl]oxy}-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white solid.
Example 23
To a mixed liquid of 280 mg of (3RS,4RS)—N-({3-[amino(hydroxyimino)methyl]benzyl}oxy)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 10 ml of DMF were added 0.037 ml of pyridine and subsequently 0.084 ml of 2-ethylhexyl chloroformate under ice-cooling, followed by stirring under ice-cooling for 30 minutes. To the reaction solution was added ethyl acetate, followed by washing with water and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain 305 mg of (3RS,4RS)—N-[(3-{amino[({[(2-ethyl hexyl)oxy]carbonyl}oxy)imino]methyl}benzyl)oxy]-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white amorphous substance. To 290 mg of the present compound was added 6 ml of NMP, followed by stirring at 140° C. for 3 hours. The reaction solution was cooled, and 50 ml of water was then added thereto, followed by stirring. The precipitated solid was collected by filtration. This solid was purified by silica gel column chromatography (eluent: chloroform-methanol), then crystallized with acetonitrile-water, and collected by filtration to obtain 101 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-{[3-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)benzyl]oxy}-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white crystal.
Example 24
To a solution of 500 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-[(1-trityl-1H-1,2,4-triazol-3-yl)methoxy]-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in 7.5 ml of methanol was added dropwise 0.25 ml of concentrated hydrochloric acid under ice-cooling, followed by stirring at room temperature for 4 hours. To the reaction solution was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) and recrystallized from ethyl acetate to obtain 282 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-(1H-1,2,4-triazol-3-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless crystal.
Example 25
A solution of 400 mg of (3RS,4RS)-6-(benzyloxy)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-(pyridin-2-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 245 mg of pentamethylbenzene in 15 ml of trifluoroacetic acid was stirred at room temperature overnight. The trifluoroacetic acid was evaporated under reduced pressure, and ethyl acetate and water were added thereto to carry out a liquid separation operation. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. The residue was solidified with ethyl acetate-isopropyl alcohol and collected by filtration to obtain 350 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-6-hydroxy-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-(pyridin-2-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white solid.
Example 26
To a solution of 644 mg of (3RS,4RS)—N-[(4-tert-butoxybenzyl)oxy]-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in 8.4 ml of dichloromethane was added 0.94 ml of trifluoroacetic acid under ice-cooling, followed by stirring at room temperature for 1 hour. The solution was concentrated under reduced pressure and then recrystallized from ethyl acetate to obtain 363 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-N-hydroxy-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless crystal.
Example 27
To a mixed liquid of 350 mg of ethyl 1,2-cis-2-[3,4-trans-3-(2,4-dichlorophenyl)-1-oxo-4-[(2-phenylethyl)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl]cyclohexanecarboxylate, 25 ml of THF, and 25 ml of ethanol was added 1 ml of a 1 M aqueous sodium hydroxide solution, followed by stirring at room temperature for 60 hours, and further at 60° C. for 8 hours. After evaporating the solvent, a liquid separation operation was carried out using 1 M hydrochloric acid and chloroform. The organic layer was dried over anhydrous magnesium sulfate and the solvent was then evaporated. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol). The obtained residue was washed with diisopropyl ether-ethyl acetate to obtain 144 mg of ethyl 1,2-trans-2-[3,4-trans-3-(2,4-dichlorophenyl)-1-oxo-4-[(2-phenylethyl)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl]cyclohexanecarboxylate as a white solid.
Example 28
To a mixed liquid of 334 mg of 2-(trimethylsilylethyl) 1,2-cis-2-[3,4-trans-3-(2,4-dichlorophenyl)-1-oxo-4-[(pyridin-2-ylmethoxy)carbomoyl]carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl]cyclohexanecarboxylate and 5 ml of THF was added 0.60 ml of a 1 M solution of tetrabutylammonium fluoride in THF, followed by stirring at room temperature for 4 hours. To the reaction solution was added 20 ml of DMF, followed by stirring at room temperature for 2 hours, then evaporating the THF under reduced pressure, and stifling again at room temperature for 20 hours. The reaction solution was warmed to 60° C. and stirred for 2 hours, and then 0.30 ml of a 1 M solution of tetrabutylammonium fluoride in THF was further added thereto, followed by stirring at 60° C. for 2 hours. After evaporating the solvent under reduced pressure, 1 M hydrochloric acid was added, and a 1 M aqueous sodium hydroxide solution was added thereto until the pH reached 2. The solution was extracted with ethyl acetate and chloroform, and dried over anhydrous magnesium sulfate, and the solvent was then evaporated. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol), and the obtained residue was then washed with ethyl acetate to obtain 156 mg of 1,2-cis-2-[3,4-trans-3-(2,4-dichlorophenyl)-1-oxo-4-[(pyridin-2-ylmethoxy)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl]cyclohexanecarboxylic acid as a white solid.
Example 29
To a solution of 1000 mg of (3RS,4RS)—N-[2-amino-2-(hydroxyimino)ethoxy]-3-(2,4-dichlorophenyl)-2-(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in 26 ml of dichloroethane was added dropwise 0.4 ml of pyridine, and then 0.23 ml of methyl chloro(oxo)acetate was added dropwise thereto under ice-cooling, followed by stirring at 0° C. for 10 minutes, at room temperature for 20 minutes, and at 80° C. for 2 hours. The reaction solution was cooled to room temperature, washed with 0.1 M hydrochloric acid and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain 670 mg of methyl 3-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}-1,2,4-oxadiazole-5-carboxylate as a white amorphous substance.
Example 30
To 400 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid were added 8 ml of DMF, 243 mg of O-[3-(tetrahydro-2H-pyran-2-yl oxy)benzyl]hydroxylamine, 159 mg of HOBt, and 243 mg of WSC, followed by stifling at room temperature for 3 hours. The reaction solution was added with ethyl acetate and water to carry out a liquid separation operation, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure. To the residue was added methanol, and concentrated hydrochloric acid was added dropwise thereto under ice-cooling, followed by stirring under ice-cooling for 1 hour. The precipitated crystal was collected by filtration to obtain 275 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-N-[(3-hydroxybenzyl)oxy]-2-{(1SR,2SR)-2-Rmesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white crystal.
Example 31
To a solution of 323 mg of (3-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}-1,2,4-oxadiazol-5-yl)methyl acetate in 6.5 ml of methanol was added 66 mg of potassium carbonate, followed by stirring at room temperature for 3 hours. To the reaction solution was added ethyl acetate, followed by washing with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) and then recrystallized from ethyl acetate to obtain 157 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-N-{[5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl]methoxy}-2-{(1SR,2SR)-2-(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white crystal.
Example 32
By condensing 4-({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)butanoic acid and ethylamine using WSC and HOBt in accordance with Example 1, (3RS,4RS)-3-(2,4-dichlorophenyl)-N-[4-(ethylamino)-4-oxobutyl]-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide was obtained as a colorless crystal.
Example 33
By condensing 3,4-trans-2-cyclopentyl-1-oxo-4-[(2-phenylethyl)carbamoyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid and benzylamine using WSC and HOBt in accordance with Example 1, 3,4-trans-3-benzylcarbamoyl-2-cyclopentyl-1-oxo-N-(2-phenylethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide was obtained as a colorless crystal.
Example 34
By condensing cis-4-[3,4-trans-3-(2,4-dichlorophenyl)-1-oxo-4-[(2-phenylethyl)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl]cyclohexanecarboxylic acid and 1-methylpiperazine using WSC and HOBt in accordance with Example 1, 3,4-trans-3-(2,4-dichlorophenyl)-2-{cis-4-[(4-methylpiperazin-1-yl)carbonyl]cyclohexyl}-1-oxo-N-(2-phenylethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide was obtained as a colorless crystal.
Example 35
By condensing (3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexyl]-N-(benzyloxy)-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and hydroxyacetic acid using WSC and HOBt in accordance with Example 1, (3RS,4RS)—N-(benzyloxy)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-(glycoloylamino)cyclohexyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide was obtained as a colorless crystal.
Example 36
By treating 3,4-trans-2-cyclopentyl-3-(3-pyridinyl)-1-oxo-N-phenylethyl-1,2,3,4-tetrahydroisoquinoline-4-carboxamide with m-chloroperbenzoic acid in accordance with Example 3, 3,4-trans-2-cyclopentyl-3-(1-oxidopyridin-3-yl)-1-oxo-N-phenylethyl-1,2,3,4-tetrahydroisoquinoline-4-carboxamide was obtained as a colorless crystal.
Example 37
By treating 3,4-trans-3-(2,4-dichlorophenyl)-1-oxo-N-phenylethyl-2-[2-(3-pyridinyl)ethyl]-1,2,3,4-tetrahydroisoquinoline-4-carboxamide with m-chloroperbenzoic acid in accordance with Example 3, 3,4-trans-3-(2,4-dichlorophenyl)-1-oxo-N-phenylethyl-2-[2-(1-oxidopyridin-3-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-4-carboxamide was obtained as a colorless crystal.
Example 38
By treating methyl 4-{3,4-trans-2-cyclopentyl-1-oxo-4-[(2-phenylethyl)carbamoyl]-1,2,3,4-tetrahydroisoquinolin-3-yl}benzoate with a 1 M aqueous sodium hydroxide solution in accordance with Example 4, 4-{3,4-trans-2-cyclopentyl-1-oxo-4-[(2-phenylethyl)carbamoyl]-1,2,3,4-tetrahydroisoquinolin-3-yl}benzoic acid was obtained as a colorless crystal.
Example 39
By treating ethyl 4-{3,4-trans-3-(2,4-dichlorophenyl)-1-oxo-4-[(2-phenylethyl)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl}propanoate with a 1 M aqueous sodium hydroxide solution in accordance with Example 4, 4-{3,4-trans-3-(2,4-dichlorophenyl)-1-oxo-4-[(2-phenylethyl)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl}propanoic acid was obtained as a colorless crystal.
Example 40
By treating 4-{[({[(3RS,4RS)-trans-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-trans-2-hydroxycyclohexyl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}benzoic acid with CDI and then with sodium borohydride in accordance with Example 7, (3RS,4RS)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-1,2-trans-2-hydroxycyclohexyl]-N-{[4-(hydroxymethyl)benzyl]oxy}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide was obtained as a colorless crystal.
Example 41
To a mixed liquid of 400 mg of (3RS,4RS)—N-[2-amino-2-(hydroxyimino)ethoxy]-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 40 ml of acetonitrile were added 108 mg of CDI and 0.4 ml of DBU under ice-cooling, followed by stirring at room temperature overnight. After concentrating the reaction solution, a saturated aqueous ammonium chloride solution and ethyl acetate were added thereto, followed by extraction. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) and recrystallized from ethyl acetate to obtain 40 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-N-[(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methoxy]-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless crystal.
Example 42
To a mixture of 300 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid and 6 ml of DMF were added {5-[(aminooxy)methyl]pyrazin-2-yl}methyl acetate dihydrochloride, 0.16 ml of triethylamine, 119 mg of HOBt, and 200 mg of WSC, followed by stirring at room temperature for 3 hours. Ethyl acetate and water were added thereto to carry out a liquid separation operation. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure. To the residue were added 4.5 ml of methanol and 2.4 ml of a 1 M aqueous sodium hydroxide solution, followed by stirring at 0° C. for 2 hours, and then 1 M hydrochloric acid was added thereto for neutralization. Chloroform was added thereto for extraction, and the organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: chloroform-methanol) and then recrystallized from ethyl acetate to obtain 73 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-N-{[5-(hydroxymethyl)pyrazin-2-yl]methoxy}-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless crystal.
Example 43
To a solution of 350 mg of (3RS,4RS)—N-[2-amino-2-(hydroxyimino)ethoxy]-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in 9.2 ml of dichloroethane was added dropwise 0.15 ml of pyridine. To the reaction solution was added dropwise 0.095 ml of 2-chloro-2-oxoethyl acetate under ice-cooling, followed by stirring for 10 minutes at 0° C., 20 minutes at room temperature and then heating under reflux for 8 hours. The solution was cooled to room temperature, and ethyl acetate was added thereto, followed by washing with 0.1 M hydrochloric acid and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain 323 mg of (3-{[({[(3RS,4RS-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}-1,2,4-oxadiazol-5-yl)methyl acetate.
Example 44
To a solution of 600 mg of methyl 5-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}thiophene-3-carboxylate in 40 mL of THF was added 45 mg of lithium aluminum hydride at −78° C. The solution was warmed to 0° C., followed by stirring for 3 hours. Sodium sulfate decahydrate was added thereto, followed by stirring for 1 hour. After removing sodium sulfate by filtration, the organic layer was dried by adding anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain 162 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-N-{[4-(hydroxymethyl)-2-thienyl]methoxy}-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white solid.
Example 45
To a solution of 500 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-6-nitro-1-oxo-N-(pyridin-2-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in 10 ml of methanol-dioxane (1:1) was added 500 mg of Raney nickel, followed by stirring for 30 minutes under a hydrogen atmosphere. The catalyst was removed by filtration and the solvent was concentrated under reduced pressure to obtain 300 mg of (3RS,4RS)-6-amino-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-(pyridin-2-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a black solid.
Example 46
To a solution of 300 mg of (3RS,4RS)-6-amino-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-(pyridin-2-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, 213 mg of formaldehyde, and 11 mg of sulfuric acid in 5 ml of THF was added 125 mg of sodium borohydride at 0° C., followed by stirring for 2 hours. The reaction solution was poured into ice water and the organic layer was extracted with ethyl acetate. The solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by reverse-phase silica gel column chromatography (eluent: acetonitrile-water) to obtain 10 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-6-(dimethylamino)-2-(1R,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-(pyridin-2-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a yellow solid.
Example 47
A solution of 343 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-N-(2-hydrazino-2-oxoethoxy)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in 6.9 ml of THF was cooled to 0° C., and 116 mg of 1,1′-carbonyldiimidazole and 0.12 ml of triethylamine were added thereto, followed by stirring at 0° C. for 2 hours, and then stirring at room temperature overnight. 0.1 M hydrochloric acid was added thereto, followed by extraction with ethyl acetate. The solution was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to obtain 221 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-[(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)methoxy]-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white powder crystal.
Example 48
To a mixed liquid of 420 mg of benzyl ({6-[2-({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)ethyl]pyridin-2-yl}oxy)acetate, 5 ml of DMF, and 5 ml of ethanol was added 84 mg of 5% palladium/carbon, followed by stirring at room temperature for 15 minutes under a hydrogen atmosphere. After separating the palladium/carbon by filtration, the solvent was evaporated, and the residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain 78 mg of ({6-[2-({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)ethyl]pyridin-2-yl}oxy)acetic acid as a white solid.
Example 49
A solution of 480 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-N-{[6-(hydroxymethyl)pyridin-2-yl]methoxy}-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in 4.8 ml of dichloromethane was cooled to 0° C., 4.5 mg of DMAP and 0.13 ml of pyridine were added, and then 0.7 ml of acetic anhydride was added dropwise, followed by stirring at room temperature overnight. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain (6-{[(acetyl{[3-(2,4-dichlorophenyl)-2-{2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}pyridin-2-yl)methyl acetate.
Example 50
A solution of 714 mg of (3R,4R)-3-(2,4-dichlorophenyl)-N-{1-[6-(hydroxymethyl)pyridin-2-yl]ethyl}-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in 14.3 ml of chloroform was cooled to 0° C., and 0.23 ml of triethylamine, 0.16 ml of acetic anhydride, and 6.8 mg of DMAP were added thereto in this order, followed by stirring at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, and ethyl acetate-water was added thereto for liquid separation, followed by washing with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution. The solution was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain {6-[1-({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)ethyl]pyridin-2-yl}methyl acetate.
Example 51
To 591 mg of [({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]acetic acid were added 8 ml of DMF, 200 mg of tert-butyl hydrazinecarboxylate, 205 mg of HOBt, and 388 mg of WSC hydrochloride, followed by stirring at room temperature for 3 hours. Ethyl acetate and water were added thereto to carry out a liquid separation operation. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure. 7.7 ml of dichloromethane was added thereto, followed by cooling to 0° C., and 1.2 ml of trifluoroacetic acid was added thereto, followed by stirring at room temperature for 5 hours. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) and recrystallized from ethyl acetate to obtain 417 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-N-(2-hydrazino-2-oxoethoxy)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white powder crystal.
Example 52
A solution of 153 mg of (6-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}-1-oxidopyridin-3-yl)methyl benzoate in 3 ml of ethanol was cooled to 0° C., and 32 mg of sodium hydroxide was added thereto, followed by stirring at 0° C. for 2 hours. The solution was neutralized with 1 M hydrochloric acid, and a saturated aqueous sodium hydrogen carbonate solution and chloroform were added for liquid separation. The organic layer was dried over anhydrous magnesium sulfate and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain 24 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-N-{[5-(hydroxymethyl)-1-oxidopyridin-2-yl]methoxy}-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide.
Example 53
To a solution of 700 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid, 351 mg of 1-phenylmethanesulfonamide, and 334 mg of DMAP in 10.5 ml of DMF was added 525 mg of WSC/hydrochloride, followed by stirring at room temperature overnight. 0.1 M hydrochloric acid was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol), and ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution were then added thereto for liquid separation. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. Ethyl acetate and diisopropyl ether were added thereto, and the precipitated solid was collected by filtration to obtain 33 mg of (3RS,4RS)—N-(benzylsulfonyl)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless solid.
Example 54
To a solution of 566 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-N-[(2,2-dimethyl-4H-[1,3]dioxino[5,4-b]pyridin-6-yl)methoxy]-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in 11.3 ml of THF was added 3.2 ml of 1 M hydrochloric acid, followed by stirring at room temperature for 2 hours. 1.6 ml of 1 M hydrochloric acid was further added, followed by stirring for 2 days. The solution was neutralized with a saturated aqueous sodium hydrogen carbonate solution and then extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) and recrystallized from ethyl acetate to obtain 196 mg of rel-(3RS,4RS)-3-(2,4-dichlorophenyl)-N-{[5-hydroxy-6-(hydroxymethyl)pyridin-2-yl]methoxy}-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white crystal.
Example 55
To a solution of 433 mg of 6-{[(acetyl{[3-(2,4-dichlorophenyl)-2-{2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}-1-oxidopyridin-2-yl)methyl acetate in 8.7 ml of methanol was added 160 mg of potassium carbonate, followed by stirring. The solution was added with 1 M hydrochloric acid and then with a saturated aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol). Ethyl acetate, ethanol, and diisopropyl ether were added thereto for solidification to obtain 164 mg of 3-(2,4-dichlorophenyl)-N-{[6-(hydroxymethyl)-1-oxidopyridin-2-yl]methoxy}-2-{2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless solid.
Example 56
To a solution of 777 mg of {6-[1-({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)ethyl]-1-oxidopyridin-2-yl}methyl acetate in 17 ml of methanol was added 0.21 ml of hydrazine monohydrate, followed by stirring for one week. Ethyl acetate was added thereto, followed by stirring for a while and concentrating, and the residue was purified by silica gel column chromatography (eluent: chloroform-methanol). Ethyl acetate and diisopropyl ether were used to make a powder, thereby obtaining 501 mg of (3R,4R)-3-(2,4-dichlorophenyl)-N-{1-[6-(hydroxymethyl)-1-oxidopyridin-2-yl]ethyl}-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless solid.
Example 57
A mixture of 590 mg of 3-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}benzoic acid, 217 mg of CDI, and 9 ml of DMF was stirred at 50° C. for 1 hour, and 241 mg of guanidine carbonate was then added thereto, followed by stifling at the same temperature for 3 hours. The reaction solution was left to be cooled and the solvent was then evaporated under reduced pressure. The residue was diluted with ethyl acetate, and washed with a saturated aqueous sodium hydrogen carbonate solution and then with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform-methanol) and recrystallized from acetonitrile to obtain 348 mg of (3RS,4RS)-N-({3-[(diaminomethylene)carbamoyl]benzyl}oxy)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless solid.
Example 58
To a mixture of 990 mg of 4-methoxybenzyl (3-{2-[({(3RS,4RS)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-hydroxycyclohexyl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl}carbonyl)amino]ethyl}phenyl)acetate and 10 ml of ethylene chloride was added 10 ml of trifluoroacetic acid at room temperature, followed by stirring for 4 hours. The reaction solution was concentrated under reduced pressure. The residue was dissolved in 20 mL of methanol, and 20 mL of a saturated aqueous sodium hydrogen carbonate solution was added thereto at room temperature, followed by stirring for 30 minutes. The organic solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate and neutralized with 1 M hydrochloric acid. The product was extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain 339 mg of (3-{2-[({(3RS,4RS)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-hydroxycyclohexyl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl}carbonyl)amino]ethyl}phenyl)acetic acid as a colorless solid.
Example 59
To a mixture of 980 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2[(1SR,2SR)-2-hydroxycyclohexyl]-N-[2-(3-hydroxyphenyl)ethyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, 1160 mg of triphenylphosphine, 1080 mg of tert-butyl (2R)-2-hydroxypropanate, and 30 mL of THF was added 770 mg of diethyl azodicarboxylate at room temperature, followed by stifling for 12 hours. The reaction solution was diluted with ethyl acetate and washed with a saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain 1460 mg of tert-butyl (2S)-2-(3-{2-[({(3RS,4RS)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-hydroxycyclohexyl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl}carbonyl)amino]ethyl}phenoxy)propanate as a yellow solid.
The compounds of Examples 60 to 899 as shown in Tables below were prepared in the same manner as the methods of Examples 1 to 59, using each of the corresponding starting materials. The structures of each Example Compound are shown in Tables 70 to 275, and the production processes and the physicochemical data of each Example Compound are shown in Tables 276 to 300.
Furthermore, the structures of the other compounds of the present invention are shown in Tables 301 to 302. These can be easily synthesized by using the production processes as described above, the methods described in Examples, methods obvious to a skilled person in the art, or modified methods thereof.











TABLE 14





PEx
Syn
Structure
Data
Note







64
P34




ESI+: 471



 


65
P34




ESI+: 456


 


34-2
P34




ESI−: 434
racemic mixture


 


34-1
P34




ESI−: 434
racemic mixture


 


66
P34




ESI+: 430




















TABLE 15







67
P34




ESI+: 462



 


68
P34




ESI+: 430


 


69
P34




ESI+: 456


 


70
P34




ESI+: 462


 


33-1
P33




ESI+: 404
racemic mixture




















TABLE 16







33-2
P33




ESI+: 404
racemic mixture


 


71
P34




ESI+: 471


 


72
P33




FAB+: 532
racemic mixture


 


30
P30




ESI+: 214


 


18
P18




FAB+: 372


 


73
P31




ESI+: 244


 


74
P31




ESI+: 244




















TABLE 17







75
P31




ESI+: 276



 


31
P31




FAB+: 340


 


37
P37




ESI+: 553
racemic mixture


 


 5
P5




FAB+: 244


 


76
P17 P14




FAB+: 313


 


77
P14




FAB+: 318


 


78
P42




FAB+: 340



















TABLE 18







79
P42




FAB+: 340


 


80
P14




ESI+: 330


 


14
P14




FAB+: 332


 


81
P14




FAB+: 280


 


82
P14




FAB+: 257


 


83
P14




FAB+: 279


 


84
P14




FAB+: 246


 


85
P14




FAB+: 332



















TABLE 19







86
P14




FAB+: 487


 


87
P14




FAB+: 285


 


88
P14




FAB+: 376


 


89
P42




FAB+: 368


 


90
P14




FAB+: 326


 


91
P14




FAB+: 273


 


92
P14




ESI+: 342



















TABLE 20







93
P14




ESI+: 342


 


94
P42




FAB+: 454


 


95
P14




FAB+: 368


 


96
P42




FAB+: 384


 


97
P42




FAB+: 354


 


98
P14




EI+: 238


 


99
P42




FAB+: 326



















TABLE 21







100
P14




EI+: 247


 


 42
P42




FAB+: 273


 


101
P14




FAB+: 260


 


102
P14




ESI+: 330


 


103
P14




ESI+: 280


 


104
P14




FAB+: 298


 


105
P14




FAB+: 260


 


106
P14




FAB+: 260




















TABLE 22







107
P14




FAB+: 269



 


108
P14




ESI+: 318


 


109
P14




ESI+: 330


 


 25
P25




FAB+: 344
racemic mixture


 


 15
P15




FAB+: 263


 


 43
P43




FAB+: 263


 


110
11




ESI+: 309




















TABLE 23







111
11




FAB+: 503
racemic mixture


 


112
P34




FAB+: 539
racemic mixture


 


113
P34




ESI+: 433


 


114
P34




FAB+: 463
racemic mixture


 


115
P34




FAB+: 451
racemic mixture


 


116
P34




FAB+: 447
racemic mixture




















TABLE 24







117
P34




ESI+: 463
racemic mixture


 


118
P34




ESI+: 463
racemic mixture


 


119
P34




FAB+: 451
racemic mixture


 


120
P34




ESI+: 465
racemic mixture


 


121
P33




FAB+: 491


 


122
P33




FAB+: 488
1′,2′-trans




















TABLE 25







123
P33




FAB+: 562
1′,2′-trans


 


124
P33




FAB+: 462
1′,2′-trans


 


125
P33




FAB+: 405


 


126
P35




ESI+: 491
racemic mixture


 


127
P34 P35




ESI+: 445
1′-2′-trans, 3,4-trans, diastereo mixture


 


 35
P35




ESI+: 461
racemic mixture




















TABLE 26







128
P35




ESI+: 461



 


 11
P11




CI+: 210


 


 17
P17




EI+: 190


 


 20
P20




CI+: 365


 


 19
P19




EI+: 292


 


 4
P4




CI+: 228


 


 21
P21




CI+: 221


 


129
P36




FAB+: 569
racemic mixture




















TABLE 27







130
P36




FAB+: 557
racemic mixture


 


131
P36




FAB+: 557
racemic mixture


 


132
P34 P35 P36




FAB+: 569
racemic mixture


 


133
P34 P35 P36




FAB+: 569
racemic mixture




















TABLE 28







134
P34 P35 P36




FAB+: 539
racemic mixture


 


135
P34 P35 P36




FAB+: 539
racemic mixture


 


136
P36




ESI+: 553
racemic mixture


 


137
P36




FAB+: 569
racemic mixture


 


138
P36




ESI+: 569
racemic mixture




















TABLE 29







139
P34 P35 P36




ESI+: 535
1′,2′-trans, 3,4-trans, racemic mixture


 


140
P34 P35 P36




FAB+: 529
1′,2′-trans, 3,4-trans, racemic mixture


 


141
P34 P35 P36




FAB+: 513
1′,2′-trans, 3,4-trans, racemic mixture


 


142
P36




ESI+: 523
1′,2′-trans, 3,4-trans, racemic mixture




















TABLE 30







143
P36




ESI+: 523
1′,2′-trans, 3,4-trans, racemic mixture


 


144
P35 P36




ESI+: 530
1′,2′-trans, 3,4-trans, racemic mixture


 


145
P34 P35 P36




FAB+: 507
1′,2′-trans, 3,4-trans, racemic mixture


 


146
P36




EI+: 316


 


147
P36




ESI+: 519
1′,2′-trans, 3,4-trans, racemic mixture, less polar




















TABLE 31







148
P36




ESI+: 519
1′,2′-trans, 3,4-trans, racemic mixture, more polar


 


149
P36




ESI+: 499
1′,2′-trans, 3,4-trans, racemic mixture, less polar


 


150
P36




ESI+: 499
1′,2′-trans, 3,4-trans, racemic mixture, more polar


 


 36
P36




ESI+: 539
racemic mixture




















TABLE 32







151
P36




ESI+: 539



 


152
P22




FAB+: 331


 


 22
P22




FAB+: 279


 


153
P22




FAB−: 209


 


154
P22




FAB+: 293


 


155
P34




FAB+: 426
1′,2′-trans, 3,4-trans, racemic mixture, less polar




















TABLE 33







156
P34




FAB+: 426
1′,2′-trans, 3,4-trans, racemic mixture, more polar


 


157
P34




FAB+: 434
1′,2′-trans, 3,4-trans, racemic mixture, less polar


 


158
P34




FAB+: 434
1′,2′-trans, 3,4-trans, racemic mixture, more polar


 


159
P34




FAB+: 486


 


160
P34




ESI+: 424
1′,2′-trans, 3,4-trans,


 


161
P34




ESI+: 511
3,4-trans, diastereo mixture




















TABLE 34







162
P34




FAB+: 497
racemic mixture


 


163
P34




ESI−: 485
3,4-trans, diastereo mixture


 


164
P34




ESI−: 485
3,4-trans, diastereo mixture


 


165
P34




FAB+: 533
3,4-trans, diastereo mixture


 


166
P34




ESI+: 422
1′,2′-trans, 3,4-trans, racemic mixture, more polar




















TABLE 35







167
P34




ESI+: 422
1′,2′-trans, 3,4-trans, racemic mixture, less polar


 


168
P34




FAB+: 486


 


169
P34




FAB+: 394
1′,2′-trans, 3,4-trans, racemic mixture, less polar


 


170
P34




FAB+: 394
1′,2′-trans, 3,4-trans, racemic mixture, more polar


 


171
P34




FAB+: 531
racemic mixture




















TABLE 36







172
P34 P35 P36 P38




ESI+: 461
1′,2′- trans, 3,4- trans, racemic mixture


 


 38
P38




ESI+: 512
racemic mixture


 


173
P38




ESI+: 502
1′,2′- trans, 3,4- trans, racemic mixture


 


174
P38




ESI+: 511




















TABLE 37







175
P38




FAB+: 541
racemic mixture


 


176
P38




FAB+: 541
racemic mixture


 


177
P38




ESI+: 475
racemic mixture


 


178
P38




FAB+: 541
racemic mixture




















TABLE 38







179
P38




ESI+: 541
racemic mixture


 


180
P38




ESI+: 485
1′,2′-trans, 3,4-trans, racemic mixture


 


181
P38




ESI+: 501
1′,2′-trans, 3,4-trans, racemic mixture


 


182
P38




ESI+: 479
1′,2′-trans, 3,4-trans, racemic mixture


 


183
P38




FAB+: 541
racemic mixture




















TABLE 39







184
P34 P35 P36 P38




ESI−: 617
racemic mixture


 


185
P38




FAB+: 529
racemic mixture


 


186
P38




FAB+: 529
racemic mixture


 


187
P38




FAB+: 511


 


188
P38




FAB+: 511




















TABLE 40







189
P38




FAB+: 525
racemic mixture


 


 1
P1




ESI−: 285


 


 7
P7




CI+: 183


 


190
P39




ESI+: 177


 


191
P39




EI+: 180


 


 39
P39




FAB+: 269


 


192
P23




FAB+: 215


 


 23
P23




EI+: 251



















TABLE 41







 27
P27




FAB+: 303


 


 16
P16




EI+: 172


 


193
P16




EI+: 222


 


194
P16




FAB+: 267


 


195
P16




FAB+: 209


 


196
P16




FAB−: 307


 


197
P16




ESI+: 261 [M + Na]


 


198
P16




ESI+: 239



















TABLE 42







 24
P24




EI+: 237


 


199
P24




EI+: 237


 


 2
P2




ESI+: 225


 


 12
P12




EI+: 181


 


200
P8




FAB+: 342


 


 8
P8




FAB+: 298


 


201
P8




FAB+: 271


 


202
P8




APCI+: 384



















TABLE 43







203
P8




ESI+: 384


 


204
P8




ESI+: 412


 


205
P8




FAB+: 356


 


206
P8




ESI−: 368


 


207
P56 P8




FAB+: 383


 


208
P8




ESI+: 370


 


209
P40




CI+: 139



















TABLE 44







210
P40




FAB+: 210


 


211
P8 P40




CI+: 140


 


212
P8 P40




FAB+: 198


 


 40
P40




FAB+: 141


 


213
P8 P40




FAB+: 259


 


214
P40




FAB+: 196


 


215
P40




FAB+: 155


 


216
P40




FAB+: 164


 


217
P40




FAB+: 210


 


218
P8 P40




FAB+: 126




















TABLE 45







 26
P26




FAB+: 244
racemic mixture


 


219
P25 P26




FAB+: 244
racemic mixture


 


220
P26




ESI+: 179


 


221
P26




FAB+: 172


 


222
P26




FAB+: 193


 


 41
P41




FAB+: 128


 


 28
P28




FAB+: 169


 


 3
P3




CI+: 265


 


223
P40




FAB+: 202



















TABLE 46







224
P40




FAB+: 183


 


225
P40




EI+: 148


 


226
P14 P9




FAB+: 155


 


227
P9




CI+: 212


 


 9
P9




CI+: 168


 


228
P40




ESI+: 168


 


229
P40




FAB+: 150


 


230
P9




EI+: 126


 


231
28 P9




CI+: 130


 


232
P8 P9




CI+: 145


 


233
P8 P9




EI+: 138



















TABLE 47







234
P9




EI+: 253


 


235
P9




CI+: 238


 


236
P9




EI+: 223


 


237
P9




FAB+: 324


 


238
P9




CI+: 196


 


239
P9




CI+: 212


 


240
P9




FAB+: 357


 


241
P9




CI+: 143



















TABLE 48







242
P9




FAB+: 202


 


243
P9




CI+: 130


 


244
P9




CI+: 143


 


245
P9




FAB+: 238


 


246
P14 P40




FAB+: 196


 


247
P9




CI+: 231


 


248
P8 P9




CI+: 180


 


249
P9




CI+: 212


 


250
P9




CI+: 130


 


251
P9




CI+: 130


 


252
P9




EI+: 115



















TABLE 49







253
P40




FAB+: 188


 


254
P9




ESI+: 254


 


255
P9




ESI+: 254


 


256
P9




ESI+: 282


 


257
P9




CI+: 226


 


258
P9




ESI+: 254


 


259
P9




ESI+: 240


 


260
P9




ESI+: 200



















TABLE 50







261
P9




ESI+: 200


 


262
P9




ESI+: 200


 


263
P9




ESI+: 150


 


264
P9




ESI+: 240


 


265
P32




EI+: 152


 


266
P32




ESI+: 114


 


267
P32




ESI+: 146


 


 32
P32




ESI+: 211


 


 13
P13




FAB+: 141


 


 29
P29




FAB+: 139




















TABLE 51







 10
P10




FAB+: 196



 


 6
P6




ESI−: 242


 


268
P33




ESI+: 478
racemic mixture


 


269
P35 P36




ESI+: 584
racemic mixture


 


270
P42




FAB+: 454


 


271
P38




ESI+: 556
racemic mixture



















TABLE 52







272
P33




ESI+: 464


 


273
P42




FAB+: 261


 


274
P9




FAB+: 324


 


275
P35 P36




ESI+: 569


 


 55
P55




ESI+: 342



















TABLE 53







276
P8




ESI+: 342


 


277
P9 P40




FAB+: 131


 


278
P9




ESI+: 254


 


279
P32




ESI+: 212


 


280
P51 P40




ESI+: 123


 


281
P14




ESI+: 303


 


282
P8




ESI+: 333



















TABLE 54







 57
P57




FAB+: 240


 


283
P9




ESI+: 173


 


284
P38




EI+: 186


 


 52
P52




EI+: 165


 


285
P60




CI+: 243


 


286
P9




FAB+: 203


 


 62
P62




ESI+: 369


 


287
P32




ESI+: 212



















TABLE 55







288
20




ESI−: 327


 


289
P8 P9




FAB+: 203


 


290
P8 P9




FAB+: 181


 


291
P19




CI+: 321


 


292
P8




ESI+: 310


 


293
P26




FAB+: 229


 


294
P14




ESI+: 402


 


295
P9




CI+: 274


 


296
P9




FAB+: 180




















TABLE 56







297
20




FAB−: 341



 


298
P26




FAB+: 243



 


299
P16




ESI+: 170



 


300
P8 P9




NMR1: 2.50 (2H, s), 4.50 (3H, s), 6.00 (2H, s), 6.13-6.16 (1H, m), 6.71-6.73 (1H, m), 11.84 (1H, s)



 


301
P62




ESI+: 269



 


302
12




ESI+: 603
racemic mixture




















TABLE 57







 44
P44




ESI+: 565
racemic mixture


 


 58
P58




EI+: 252



 


303
P32




ESI+: 239



 


304
P62




FAB+: 381



 


305
P8




FAB+: 341



 


306
P9




CI+: 211



















TABLE 58







307
P32




ESI+: 252


 


308
P4




FAB+: 245


 


309
P8




FAB+: 390


 


310
P9




FAB+: 260


 


53-1
P53




CI+: 182


 


53-2
P53




EI+: 180


 


311
P14




ESI+: 316



















TABLE 59







312
P48




CI+: 268


 


313
P23




FAB+: 272


 


 50
P50




FAB+: 266


 


314
P12




FAB+: 244


 


315
P4




FAB+: 328


 


 63
P63




FAB+: 244


 


316
P14




ESI+: 332



















TABLE 60







317
P8 P9 P40




ESI+: 259


 


318
P14




FAB+: 420


 


319
P9




CI+: 290


 


320
P48




FAB+: 268


 


321
P14 P9




CI+: 274


 


322
P23




EI+: 271


 


 61
P61




FAB+: 167


 


323
P19




CI+: 275, 277



















TABLE 61







324
P16 P8 P9




ESI+: 216


 


 46
P46




ESI+: 171


 


 51
P51




CI+: 153


 


325
P48




ESI−: 222


 


326
P55




ESI−: 222


 


327
P32




APCI+: 213


 


328
P8




ESI+: 316


 


 47
P47




APCI+: 169


 


329
P9




ESI+: 186



















TABLE 62







330
P19




APCI+: 279


 


331
P30




FAB+: 239


 


332
P55




FAB+: 343


 


333
P23




ESI+: 228


 


334
P57




ESI+: 387


 


335
P16




FAB+: 171


 


336
P32




ESI+: 214


 


337
P61 P51




EI+: 152



















TABLE 63







338
P61




EI+: 249


 


339
P26




ESI+: 287


 


340
P48




ESI+: 214


 


341
P8




APCI−: 314


 


342
P51




FAB+: 236


 


343
P16




FAB−: 199


 


344
P56




FAB+: 386



















TABLE 64







345
P26




ESI+: 286


 


346
P61 P51




CI+: 222


 


 54
P54




FAB+: 139


 


347
P8




NMR1: 1.19 (3H, t, J = 9.0 Hz), 3.90 (2H, s), 4.10 (2H, q, J = 9.0 Hz), 5.27 (2H, s), 6.87 (1H, d, J = 4.2 Hz), 7.10 (1H, d, J = 4.2 Hz), 7.82-7.93 (4H, m)


 


 48
P48




CI+: 218


 


348
P23




EI+: 221




















TABLE 65







349
P61 P51




FAB+: 252



 


350
P36




ESI+: 506
racemic mixture


 


351
P38




ESI+: 478
racemic mixture


 


 49
P49




CI+: 184



 


352
P61 P51




FAB+: 195



















TABLE 66







 56
P56




ESI+: 248


 


 59
P59




ESI+: 300


 


353
P56




EI+: 264


 


354
P61 P51




CI+: 266


 


355
P23




ESI+: 296


 


 45
P45




NMR1: 5.31 (1H, d, J = 8.2 Hz), 5.79 (1H, d, J = 13.3 Hz), 6.75 (1H, dd, J = 13.3, 8.2 Hz), 8.07 (1H, s), 8.25 (1H, s), 9.92 (1H, s)




















TABLE 67







356
P8




NMR1: 3.92 (3H, s), 5.22 (2H, s), 6.35 (1H, d, J = 3.0 Hz), 6.85 (1H, d, J = 3.0 Hz), 7.82-7.88 (4H, m)



 


357
P16 P8




NMR1: 5.17 (1H, d, J = 8.1 Hz), 5.62 (2H, d, J = 13.2 Hz), 6.66 (1H, dd, J = 13.2, 8.1 Hz), 7.50 (1H, s), 7.58 (1H, s), 7.83-7.89 (4H, m)



 


358
P33 P34




ESI+: 450
racemic mixture


 


359
P9




ESI+: 152



 


360
P48




ESI+: 224




















TABLE 68







361
P8 P9




NMR1: 3.38-3.52 (2H, m), 4.48-4.55 (1H, m), 4.65 (2H, s), 4.66-4.71 (1H, s), 5.15 (1H, d, J = 3.9 Hz), 6.08 (2H, s), 6.98 (1H, s), 7.22 (1H, s)


 


362
P23




ESI+: 228


 


363
P33 P34




ESI−: 480
diastereomer of PEx364, racemic mixture, 1′,2′-trans, 3,4-trans


 


364
P33 P34




ESI+: 482
diastereomer of PEx363, racemic mixture, 1′,2′-trans, 3,4-trans


 


365
P33 P34




ESI−: 480
diastereomer of PEx366, racemic mixture, 1′,2′-trans, 3,4-trans




















TABLE 69







366
P33 P34




ESI+: 482
diastereomer of PEx365, racemic mixture, 1′,2′-trans, 3,4-trans


 


367
P33 P34




ESI+: 486


 


368
P33 P34




ESI+: 511
racemic mixture


 


 60
P60




EI+: 182


 


369
P19




EI+: 260, 262


 


370
P48




ESI−: 206


 


371
P23




ESI+: 212


















TABLE 70





Ex
Structure
Note







60






 


61






 


62






 


63




racemic mixture


 


64






















TABLE 71







65






 


66




racemic mixture


 


67




racemic mixture


 


68






 


69




racemic mixture


















TABLE 72







70




racemic mixture


 


71






 


72




racemic mixture


 


73




racemic mixture


 


74




racemic mixture


















TABLE 73







75




racemic mixture


 


 1




racemic mixture


 


76




racemic mixture


 


77




racemic mixture


 


78






















TABLE 74







 3




racemic mixture


 


79




racemic mixture


 


80




racemic mixture


 


81






 


82




racemic mixture


















TABLE 75







83




racemic mixture


 


84




racemic mixture


 


85




racemic mixture


 


86




racemic mixture


 


37




racemic mixture


















TABLE 76







87






 


88




racemic mixture


 


89




racemic mixture


 


90






 


91




racemic mixture


















TABLE 77







92




racemic mixture


 


93




racemic mixture


 


94






 


95




racemic mixture


 


96




racemic mixture


 


97




racemic mixture


















TABLE 78







 98




racemic mixture


 


 99




racemic mixture


 


100




racemic mixture


 


101




racemic mixture


 


102






 


103




racemic mixture


















TABLE 79







104




racemic mixture


 


105




racemic mixture


 


106




racemic mixture


 


107




racemic mixture


 


108






 


 2




racemic mixture


















TABLE 80







109




racemic mixture


 


 39




racemic mixture


 


110




racemic mixture


 


111




racemic mixture


 


 4




racemic mixture


















TABLE 81







112






 


113




racemic mixture


 


114




racemic mixture


 


115




racemic mixture


 


116




racemic mixture


 


117




racemic mixture


















TABLE 82







118






 


119




racemic mixture


 


120




racemic mixture


 


121




racemic mixture


 


122




racemic mixture


 


123




racemic mixture


















TABLE 83







124




racemic mixture


 


 36




racemic mixture


 


125




racemic mixture


 


126




racemic mixture


 


127




racemic mixture


 


 38




racemic mixture


















TABLE 84







128




racemic mixture


 


 7




racemic mixture


 


129




racemic mixture


 


130




racemic mixture


 


 10




racemic mixture


















TABLE 85







131




racemic mixture


 


132




racemic mixture


 


133




racemic mixture


 


134




racemic mixture


















TABLE 86







135




racemic mixture


 


136




racemic mixture


 


137




racemic mixture


 


138




racemic mixture


















TABLE 87







139




racemic mixture


 


140




racemic mixture


 


141




racemic mixture


 


142




racemic mixture


















TABLE 88







143




racemic mixture


 


144




racemic mixture


 


145




3,4-trans, diastereo mixture


 


146




racemic mixture


















TABLE 89







147






 


 9




racemic mixture


 


148




1′,2′-trans, 3,4-trans, diastereomer of Ex149, more polar


 


149




1′,2′-trans, 3,4-trans, diastereomer of Ex148, more polar


















TABLE 90







 11




racemic mixture


 


150




racemic mixture


 


151






 


152




racemic mixture


 


153




racemic mixture


















TABLE 91







154






 


155






 


156






 


157






 


158




1′,2′-trans, 3,4-trans, diastereo mixture


















TABLE 92







159




1′,2′-trans, 3,4-trans, diastereomer of Ex160, less polar


 


160




1′,2′-trans, 3,4-trans, diastereomer of Ex159, more polar


 


161




racemic mixture


 


162




racemic mixture


 


163




racemic mixture


















TABLE 93







164




racemic mixture


 


165




racemic mixture


 


166




racemic mixture


 


167




racemic mixture


 


168




1′,2′-cis, 3,4-trans, racemic mixture


















TABLE 94







169




racemic mixture


 


170




racemic mixture


 


171




racemic mixture


 


172




racemic mixture


 


173




racemic mixture


















TABLE 95







174




racemic mixture


 


175




racemic mixture


 


176




racemic mixture


 


177




racemic mixture


 


178




racemic mixture


















TABLE 96







 34




racemic mixture


 


179




racemic mixture


 


180




racemic mixture


 


181




racemic mixture


 


182




racemic mixture


















TABLE 97







183




racemic mixture


 


184






 


185




1′,2′-trans, 3,4-trans, diastereomer of Ex186, less polar


 


186




1′,2′-trans, 3,4-trans, diastereomer of Ex185


 


187




racemic mixture


















TABLE 98







188






 


189




1′,2′-trans, 3,4-trans, diastereomer of Ex190, less polar


 


190




1′,2′-trans, 3,4-trans, diastereomer of Ex189, more polar


 


191




3,4-trans, distereomer of Ex192, less polar


 


192




3,4-trans, distereomer of Ex191, more polar


















TABLE 99







193




racemic mixture


 


194






 


195






 


196




3,4-trans, diastereomer of Ex197, less polar


 


197




3,4-trans, diastereomer of Ex196, more polar


















TABLE 100







198




1′,2′-trans, 3,4-trans, diastereomer of Ex199, less polar


 


199




1′,2′-trans, 3,4-trans, diastereomer of Ex198, more polar


 


200




1′,2′-trans, 3,4-trans, diastereomer of Ex201, less polar


 


201




1′,2′-trans, 3,4-trans, diastereomer of Ex200, more polar


 


202




3,4-trans


















TABLE 101







203




1′,2′-trans, 3,4-trans, diastereomer of Ex409


 


204




racemic mixture


 


205




1′,2′-trans, 3,4-trans, distereo mixture


 


206




3,4-trans, distereo mixture


 


207




3,4-trans, distereo mixture


















TABLE 102







208




1′,2′-trans, 3,4-trans, distereomer of Ex209


 


209




1′,2′-trans, 3,4-trans, distereomer of Ex208


 


210




racemic mixture


 


211




3,4-trans, diastereomer of Ex212, less polar


 


212




3,4-trans, diastereomer of Ex211, more polar


















TABLE 103







213




racemic mixture


 


214






 


215






 


216




racemic mixture


 


217




racemic mixture


















TABLE 104







218






 


219






 


220




3,4-trans


 


221




racemic mixture


 


222




3,4-trans, diastereomer of Ex223, less polar


















TABLE 105







223




3,4-trans, diastereomer of Ex222, more polar


 


224




1′,2′-trans, 3,4-trans


 


225




1′,2′-trans, 3,4-trans


 


226




racemic mixture, 1′,2′-cis, 3,4-trans


 


227




racemic mixture


















TABLE 106







228




racemic mixture


 


229




racemic mixture


 


230




racemic mixture


 


231




racemic mixture


















TABLE 107







232




racemic mixture


 


233




racemic mixture


 


234




racemic mixture


 


235






















TABLE 108







236






 


237






 


238




racemic mixture


 


239




racemic mixture


















TABLE 109







240




racemic mixture


 


241




racemic mixture


 


242




racemic mixture


 


243




racemic mixture


















TABLE 110







244




racemic mixture


 


245




racemic mixture


 


246




racemic mixture


 


247




racemic mixture


















TABLE 111







248




racemic mixture


 


249




racemic mixture


 


250




racemic mixture


 


251




racemic mixture


















TABLE 112







252




racemic mixture


 


253




racemic mixture


 


254




racemic mixture


 


255




racemic mixture


















TABLE 113







256




racemic mixture


 


257






 


258




racemic mixture


 


259




racemic mixture


















TABLE 114







260




3,4-trans, diatereo mixture


 


261




racemic mixture


 


262




racemic mixture


 


263




racemic mixture


















TABLE 115







264




racemic mixture


 


265




3,4-trans, diastereomer of Ex266, less polar


 


266




3,4-trans, diastereomer of Ex265, more polar


 


267




racemic mixture


 


268




racemic mixture


















TABLE 116







269




racemic mixture


 


270




3,4-trans


 


271




diastereomer of Ex275, more polar


 


272




racemic mixture


















TABLE 117







273




racemic mixture


 


274




racemic mixture


 


275




diastereomer of Ex271, less polar


 


276




racemic mixture


 


277






















TABLE 118







278






 


279




racemic mixture


 


280




racemic mixture


 


281




racemic mixture


















TABLE 119







282




racemic mixture


 


283




racemic mixture


 


284




3,4-trans, diatereo mixture


 


285




3,4-trans, diatereo mixture


















TABLE 120







286




3,4-trans, diatereo mixture


 


287




3,4-trans, diastereo mixture


 


288




1′,2′-trans, 3,4-trans, diastereo mixture


 


289




1′,2′-trans, 3,4-trans, diastereomer of Ex290, more polar


 


290




racemic mixture, diastereomer of Ex289, less polar


















TABLE 121







291




racemic mixture


 


292




racemic mixture


 


293




3,4-trans, diastereomer of Ex294, less polar


 


294




3,4-trans, diastereomer of Ex293, more polar


















TABLE 122







295




racemic mixture


 


296




3,4-trans


 


297




racemic mixture


 


298




racemic mixture


















TABLE 123







299




racemic mixture


 


300




racemic mixture


 


301




racemic mixture


 


302




racemic mixture, diastereomer of Ex306, less polar


















TABLE 124







303




racemic mixture


 


304




racemic mixture


 


305




racemic mixture


 


306




racemic mixture, diastereomer of Ex302, more polar


















TABLE 125







307




racemic mixture


 


308




racemic mixture


 


309




racemic mixture


 


310




racemic mixture


















TABLE 126







311




racemic mixture


 


312




racemic mixture


 


313




racemic mixture


 


314




racemic mixture


















TABLE 127







315




racemic mixture


 


316




racemic mixture


 


317




racemic mixture


 


318




racemic mixture


















TABLE 128







319




racemic mixture


 


320




racemic mixture


 


321




racemic mixture


 


322




racemic mixture


















TABLE 129







323




racemic mixture


 


324




racemic mixture


 


325




racemic mixture


 


326




racemic mixture


















TABLE 130







327




racemic mixture


 


328






 


329






 


330






















TABLE 131







331




racemic mixture


 


332






 


333






 


334




racemic mixture


















TABLE 132







335




racemic mixture


 


336




racemic mixture


 


337




racemic mixture


 


338




racemic mixture


















TABLE 133







339




racemic mixture


 


340




racemic mixture


 


341




racemic mixture


 


342




chiral compound, diastereomer of Ex343, less polar


















TABLE 134







343




chiral compound, diastereomer of Ex342, more polar


 


344




racemic mixture


 


345




racemic mixture


 


346




racemic mixture


















TABLE 135







347




racemic mixture


 


348




racemic mixture


 


349




racemic mixture


 


350




racemic mixture


















TABLE 136







351




racemic mixture


 


352




racemic mixture


 


353




racemic mixture


 


354




racemic mixture


















TABLE 137







355




racemic mixture


 


356




racemic mixture


 


357




racemic mixture


 


358




diastereo mixture


















TABLE 138







359






 


360




racemic mixture


 


361




racemic mixture


 


362




racemic mixture


















TABLE 139







363




racemic mixture


 


364




racemic mixture


 


365




racemic mixture


 


366




diastereo mixture


















TABLE 140







367




racemic mixture


 


368




racemic mixture


 


369




racemic mixture


 


370




racemic mixture


















TABLE 141







371




racemic mixture


 


372




racemic mixture


 


373




racemic mixture


 


374




racemic mixture


















TABLE 142







375




racemic mixture, diastereomer of Ex377, more polar


 


376




racemic mixture


 


377




racemic mixture, diastereomer of Ex375, less polar


 


378




racemic mixture


















TABLE 143







379




racemic mixture


 


380




racemic mixture


 


381




racemic mixture


 


382






















TABLE 144







383




racemic mixture


 


384






 


385






 


386




chiral compound, diastereomer of Ex387, less polar


















TABLE 145







387




chiral compound, diastereomer of Ex386, more polar


 


388




racemic mixture


 


389




racemic mixture


 


390




racemic mixture


















TABLE 146







391




racemic mixture


 


392




racemic mixture


 


393




racemic mixture


 


394




racemic mixture


















TABLE 147







395




racemic mixture


 


396




racemic mixture


 


397




racemic mixture


 


398




racemic mixture


















TABLE 148







399




racemic mixture


 


400






 


401






 


402




1′,2′-trans, 3,4-trans, diastereomer of Ex404


 


403




racemic mixture


















TABLE 149







404




1′,2′-trans, 3,4-trans, diastereomer of Ex402


 


405




racemic mixture


 


406




racemic mixture


 


407






 


408






















TABLE 150







409




1′,2′-trans, 3,4-trans, diastereomer of Ex203


 


410




1′,2′-trans, 3,4-trans, diastereomer of Ex411, less polar


 


411




1′,2′-trans, 3,4-trans, diastereomer of Ex410, more polar


 


412




racemic mixture, 1′,2′-cis, 3,4-trans, diastereomer of Ex28


 


413






















TABLE 151







414




1′,2′-trans, 3,4-trans


 


415






 


416






 


417






 


418






















TABLE 152







419






 


420




1′,2′-cis, 3,4-trans, racemic mixture less polar


 


421




1′,2′-cis, 3,4-trans, racemic mixture more polar


 


422




racemic mixture


 


423




racemic mixture


















TABLE 153







424




racemic mixture


 


425






 


426






 


427




racemic mixture


 


428




racemic mixture


















TABLE 154







429




1′,2′-trans, 3,4-trans, diastereomer of Ex443, more polar


 


430




racemic mixture


 


431






 


432




racemic mixture


 


433




3,4-trans, diastereo mixture


 


434




3,4-trans, diastereo mixture


















TABLE 155







435




racemic mixture


 


436




3,4-trans


 


437




racemic mixture


 


438




1′,2′-trans, 3,4-trans


 


439




racemic mixture


















TABLE 156







440




1′,2′-cis, 3,4-trans, racemic mixture


 


441




1′,2′-trans, 3,4-trans, racemic mixture


 


442




1′,2′-trans, 3,4-trans


 


443




1′,2′-trans, 3,4-trans, diastereomer of Ex429, less polar


 


444




racemic mixture


















TABLE 157







445






 


446






 


447






 


448






 


449




1′,2′-trans, 3,4-trans


















TABLE 158







450




racemic mixture


 


451




racemic mixture


 


452




racemic mixture


 


453




1′,2′-cis, 3,4-trans, racemic mixture


 


454




1′,2′-cis, 3,4-trans, diastereomer of Ex455


















TABLE 159







455




1′,2′-cis, 3,4-trans, racemic mixture


 


456




1′,2′-trans, 3,4-trans


 


457




1′,2′-trans, 3,4-trans, diastereomer of Ex456


 


458




3,4-trans


 


459




chiral compound, 3,4-trans


















TABLE 160







460




racemic mixture


 


461




racemic mixture


 


462




racemic mixture


 









 


463




racemic mixture


















TABLE 161







464




racemic mixture


 


465




racemic mixture


 


466




racemic mixture


 


467






















TABLE 162







468




racemic mixture


 


469




racemic mixture


 


470




racemic mixture


 


471




racemic mixture


















TABLE 163







472




racemic mixture


 


473




racemic mixture


 


474




racemic mixture


 


475




racemic mixture


















TABLE 164







476




racemic mixture


 


477




racemic mixture


 


478




racemic mixture


 


479




racemic mixture


















TABLE 165







480




racemic mixture


 


481




racemic mixture


 


482




racemic mixture


 


483




racemic mixture


 


484




racemic mixture


















TABLE 166







485




racemic mixture


 


486




racemic mixture


 


487




racemic mixture


 


488




racemic mixture


 


489




racemic mixture


















TABLE 167







490




racemic mixture


 


491




racemic mixture


 


492




racemic mixture


 


493




racemic mixture


 


494




racemic mixture


















TABLE 168







495




racemic mixture


 


496




racemic mixture


 


497




racemic mixture


 


498




racemic mixture


 


499




racemic mixture


















TABLE 169







500




racemic mixture


 


501




racemic mixture


 


502




racemic mixture


 


503




racemic mixture


 


504




racemic mixture


















TABLE 170







505




racemic mixture


 


506




racemic mixture


 


507




racemic mixture


 


 32




racemic mixture


















TABLE 171







508




racemic mixture


 


509




racemic mixture


 


510




racemic mixture


 


511




racemic mixture


 


512




racemic mixture


















TABLE 172







513




racemic mixture


 


514




racemic mixture


 


515




racemic mixture


 


 33




racemic mixture


 


516




1′,2′-trans, 3,4-trans


















TABLE 173







517




1′,2′-trans, 3,4-trans


 


518




1′,2′-trans, 3,4-trans, diastereomer of Ex519


 


519




1′,2′-trans, 3,4-trans, diastereomer of Ex518


 


520




1′,2′-trans, 3,4-trans


















TABLE 174







521




1′,2′-trans, 3,4-trans


 


522




1′,2′-trans, 3,4-trans


 


523




1′,2′-trans, 3,4-trans


 


524




3,4-trans, racemic mixture


















TABLE 175







525




3,4-trans


 


526




3,4-trans


 


 35




racemic mixture


 


527




racemic mixture


















TABLE 176







528




racemic mixture


 


529






 


530




racemic mixture


 


531






















TABLE 177







532




racemic mixture


 


533




racemic mixture


 


534




racemic mixture


 


535




racemic mixture


















TABLE 178







536




racemic mixture


 


537




racemic mixture


 


538




racemic mixture


 


539




racemic mixture


















TABLE 179







540




racemic mixture


 


541






 


542






 


543




racemic mixture


















TABLE 180







544




racemic mixture


 


545




racemic mixture


 


546




racemic mixture


 


547




racemic mixture


















TABLE 181







548




racemic mixture


 


549




racemic mixture


 


550




racemic mixture


 


551




racemic mixture


















TABLE 182







552




racemic mixture


 


553




racemic mixture


 


554




racemic mixture


 


555






















TABLE 183







556






 


557






 


558




racemic mixture


 


559




racemic mixture


















TABLE 184







560






 


561




racemic mixture


 


562




racemic mixture


 


563




racemic mixture


















TABLE 185







564




racemic mixture


 


565




racemic mixture


 


566




racemic mixture


 


567




racemic mixture


















TABLE 186







568




racemic mixture


 


569




racemic mixture


 


570






 


571




racemic mixture


















TABLE 187







572




racemic mixture


 


573




3,4-trans racemic mixture


 


574




racemic mixture


 


575




racemic mixture


















TABLE 188







576




racemic mixture


 


577




racemic mixture


 


578




3,4-trans


 


 16




racemic mixture


 


 15




racemic mixture


















TABLE 189







22




racemic mixture


 


43




racemic mixture


 


29




racemic mixture


















TABLE 190







 23




racemic mixture


 


 41




racemic mixture


 


579




racemic mixture


 


 13




racemic mixture


















TABLE 191







580




racemic mixture


 


581




racemic mixture, diastereomer of Ex582, less polar


 


582




racemic mixture, diastereomer of Ex581, more polar


 


583




racemic mixture


















TABLE 192







 14




racemic mixture


 


584




racemic mixture


 


 12




racemic mixture


 


585




racemic mixture


















TABLE 193







586






 


587




diastereomer of Ex594, less polar


 


588




racemic mixture


 


589






















TABLE 194







590




racemic mixture


 


591




racemic mixture


 


592




racemic mixture


 


593




racemic mixture


















TABLE 195







594




diastereomer of Ex587, more polar


 


595




racemic mixture


 


596




racemic mixture


 


 18




racemic mixture


















TABLE 196







597




racemic mixture


 


598




chiral compound, diastereomer of Ex599


 


599




chiral compound, diastereomer of Ex598


 


600




racemic mixture


















TABLE 197







 21




racemic mixture


 


601




racemic mixture


 


 20




racemic mixture


 


 27




1′,2′-trans, 3,4-trans


















TABLE 198







 40




racemic mixture


 


602




racemic mixture


 


 8




racemic mixture


 


603




racemic mixture


 


604




1′,2′-trans, 3,4-trans, diastereomer of Ex605


















TABLE 199







605




1′,2′-trans, 3,4-trans, diastereomer of Ex604


 


606






 


 6




racemic mixture


 


607






 


 42




racemic mixture


















TABLE 200







 31




racemic mixture


 


608




1′,2′-trans, 3,4-trans, diastereo mixture


 


609




racemic mixture


 


610




racemic mixture


 


611




1′,2′-trans, 3,4-trans, diastereomer of Ex616


















TABLE 201







612






 


613






 


614






 


615






 


616




1′,2′-trans, 3,4-trans, diastereomer of Ex611


 


617






















TABLE 202







618






 


619




racemic mixture


 


620




racemic mixture


 


 5




racemic mixture


 


621




racemic mixture


















TABLE 203







 30




racemic mixture


 


622




racemic mixture


 


623




1′,2′-trans, 3,4-trans, diastereomer of Ex 624


 


 28




1′,2′-cis, 3,4-trans


 


624




1′,2′-trans, 3,4-trans, diastereomer of Ex 623


















TABLE 204







 24




racemic mixture


 


625




racemic mixture


 


626




racemic mixture


 


627




racemic mixture


















TABLE 205







628




racemic mixture


 


629




racemic mixture


 


630




racemic mixture


 


631






















TABLE 206







632




racemic mixture


 


633




racemic mixture


 


 19




racemic mixture


 


634




racemic mixture


















TABLE 207







635




racemic mixture


 


636




racemic mixture


 


 25




racemic mixture


 


637




racemic mixture


















TABLE 208







 26




racemic mixture


 


 17-2




racemic mixture


 


 17-1




3,4-trans


 


638






















TABLE 209







639






 


640




racemic mixture


 


 53




racemic mixture


 


641




racemic mixture


















TABLE 210







642




racemic mixture


 


 45




racemic mixture


 


643




racemic mixture


















TABLE 211







644




racemic mixture


 


645




racemic mixture


 


646




racemic mixture


 


647






















TABLE 212







648






 


649






 


650




racemic mixture


 


651




racemic mixture


















TABLE 213







 52




racemic mixture


 


652




racemic mixture


 


653




racemic mixture


 


654






















TABLE 214







655






 


656




chiral compound, diastereomer of Ex 657, more polar


 


657




chiral compound, diastereomer of Ex 656, less polar


 


 51




racemic mixture


















TABLE 215







658




racemic mixture


 


659




chiral compound, diastereomer of Ex 667, more polar


 


660




racemic mixture


 


661






















TABLE 216







662






 


663






 


664




racemic mixture


 


665




racemic mixture


















TABLE 217







666




racemic mixture


 


667




chiral compound, diastereomer of Ex 659, less more


 


668




racemic mixture


 


 46




racemic mixture


















TABLE 218







669




racemic mixture


 


670




racemic mixture


 


 47




racemic mixture


















TABLE 219







671




racemic mixture


 


672




racemic mixture


 


673




racemic mixture


















TABLE 220







674




racemic mixture


 


675




racemic mixture


 


676




racemic mixture


 


677




racemic mixture


















TABLE 221







678




racemic mixture


 


679






 


680






 


681




racemic mixture


















TABLE 222







682




racemic mixture


 


683




racemic mixture


 


684




racemic mixture


 


 49




racemic mixture


















TABLE 223







685




racemic mixture


 


686




racemic mixture


 


687




racemic mixture


 


688




racemic mixture


















TABLE 224







 55




racemic mixture


 


689




racemic mixture


 


690




racemic mixture


 


691




racemic mixture


















TABLE 225







692




diastereo mixure, 1′,2′-trans, 3,4-trans


 


693




diastereo mixture, 1′,2′-trans, 3,4-trans


 


 54




racemic mixture


 


694




racemic mixture


















TABLE 226







695




racemic mixture


 


696




racemic mixture


 


697




racemic mixture


 


698






















TABLE 227







699




racemic mixture


 


700






 


701






 


702




racemic mixture


 


703




racemic mixture


















TABLE 228







704




racemic mixture


 


705




racemic mixture


 


706






 


707




racemic mixture


 


708




racemic mixture


















TABLE 229







 44




racemic mixture


 


709






 


710






 


711




racemic mixture


















TABLE 230







712






 


713




racemic mixture


 


714




racemic mixture


 


715






















TABLE 231







 57




racemic mixture


 


716




racemic mixture


 


717




racemic mixture


 


718






















TABLE 232







719




racemic mixture


 


720




racemic mixture


 


721






 


722






 


723




chiral compound, diastereomer of Ex724, more polar


















TABLE 233







724




chiral compound, diastereomer of Ex723, less polar


 


725




racemic mixture


 


726




chiral compound, diastereomer of Ex727, less polar


















TABLE 234







727




chiral compound, diastereomer of Ex726, more polar


 


728




racemic mixture


 


729




chiral compound, diastereomer of Ex733, more polar


 


730




racemic mixture


















TABLE 235







731




racemic mixture


 


732




racemic mixture


 


733




chiral compound, diastereomer of Ex729, less polar


















TABLE 236







734




chiral compound, diastereomer of Ex735, more polar


 


735




chiral compound, diastereomer of Ex734, less polar


 


736




chiral compound, diastereomer of Ex738, more polar


















TABLE 237







737




chiral compound


 


738




chiral compound, diastereomer of Ex736, less polar


 


739




racemic mixture


 


740




racemic mixture


















TABLE 238







741




racemic mixture


 


742




racemic mixture, diastereomer of Ex743, less polar


 


743




racemic mixture, diastereomer of Ex742, more polar


 


744




racemic mixture, diastereomer of Ex749, less polar


 


745




racemic mixture


















TABLE 239







746




racemic mixture


 


747




racemic mixture


 


748




racemic mixture


 


 59






















TABLE 240







749




racemic mixture, diastereomer of Ex744, more polar


 


750




racemic mixture


 


751




diastero mixture, 1′,2′-trans, 3,4-trans


 


752






 


753




racemic mixture


















TABLE 241







754






 


755




racemic mixture


 


756




chiral compound, diastereomer of Ex757, less polar


 


757




chiral compound, diastereomer of Ex756, more polar


















TABLE 242







758




racemic mixture


 


 50




chiral compound


 


759






 


760






















TABLE 243







761






 


762






 


763






 


764




racemic mixture


















TABLE 244







765






 


766




racemic mixture


 


767




racemic mixture


 


768




racemic mixture


















TABLE 245







769




racemic mixture


 


770






 


771




racemic mixture


 


772




racemic mixture


















TABLE 246







773






 


774




racemic mixture


 


775






 


776




racemic mixture


















TABLE 247







777




racemic mixture


 


 48




racemic mixture


 


778






 


779






















TABLE 248







780






 


781






 


782




racemic mixture


 


783




chiral compound, diastereomer of Ex784, less polar


















TABLE 249







784




chiral compound, diastereomer of Ex783, more polar


 


785






 


786






 


787




chiral compound


















TABLE 250







788




racemic mixture


 


789




racemic mixture


 


790






 


791






 


792






















TABLE 251







793




racemic mixture


 


794




diastereo mixure


 


795




chiral compound, diastereomer of Ex796, less polar


















TABLE 252







796




chiral compound, diastereomer of Ex795, more polar


 


797




racemic mixture


 


798




chiral compound, diastereomer of Ex799, less polar


 


799




chiral compound, diastereomer of Ex798, more polar


















TABLE 253







800




diastereo mixture


 


801




chiral compound


 


802




diastereo mixture


 


803




chiral compound


















TABLE 254







804




racemic mixture


 


805




chiral compound


 


 56




chiral compound


 


806




racemic mixture


















TABLE 255







807




racemic mixture


 


808




racemic mixture


 


809




racemic mixture


 


810




chiral compound, diastereomer of Ex811, less polar


















TABLE 256







811




chiral compound, diastereomer of Ex810, more polar


 


812






 


813




racemic mixture


 


814




chiral compound, diastereomer of Ex815, less polar


















TABLE 257







815




chiral compound, diastereomer of Ex814, more polar


 


816




racemic mixture


 


817






 


818






















TABLE 258







819




racemic mixture


 


820




racemic mixture


 


821






 


822




racemic mixture


















TABLE 259







823




racemic mixture


 


824




racemic mixture


 


825




racemic mixture


 


826




racemic mixture


















TABLE 260







827




racemic mixture


 


828






 


829




racemic mixture


 


 58






















TABLE 261







830




racemic mixuture, 1′,2′-trans, 3,4-trans, diastereomer of Ex831, more polar


 


831




racemic mixuture, 1′,2′-trans, 3,4-trans


 


832




chiral compound, diastereomer of Ex833, less polar


 


833




chiral compound, diastereomer of Ex832, more polar


 


834




racemic mixture


















TABLE 262







835




diastereo mixture


 


836




racemic mixture


 


837




racemic mixture


 


838




racemic mixture


 


839




racemic mixture


















TABLE 263







840




racemic mixture


 


841




diastereo mixture


 


842




diastereo mixture


 


843






















TABLE 264







844




racemic mixture


 


845






 


846




racemic mixture


 


847




chiral compound, 3,4-trans


 


848




racemic mixture, diastereomer of Ex849, less polar


















TABLE 265







849




racemic mixture, diastereomer of Ex848, more polar


 


850




racemic mixture, diastereomer of Ex851, less polar


 


851




racemic mixture, diastereomer of Ex850, more polar


 


852






 


853




racemic mixture


















TABLE 266







854




chiral compound, diastereomer of Ex855, less polar


 


855




chiral compound, diastereomer of Ex854, more polar


 


856






 


857




racemic mixture


 


858




racemic mixture


















TABLE 267







859




racemic mixture


 


860




racemic mixture, 1′,2′-trans, 3,4-trans


 


861




racemic mixure, 1′,2′-trans, 3,4-trans


 


862




racemic mixture


 


863




racemic mixture, 1′,2′-trans, 3,4-trans


 


864




racemic mixture


















TABLE 268







865




racemic mixture, 1′,2′-trans, 3,4-trans


 


866




racemic mixture, diastereomer of Ex872, 1′,2′-trans, 3,4-trans


 


867




racemic mixture, 1′,2′-trans, 3,4-trans


 


868




racemic mixture


 


869




racemic mixture, 1′,2′-trans, 3,4-trans


















TABLE 269







870




racemic mixture, 1′,2′-trans, 3,4-trans


 


871




racemic mixture, diastereomer of Ex863, 1′,2′-trans, 3,4-trans


 


872




racemic mixture, diastereomer of Ex866, 1′,2′-trans, 3,4-trans


 


873




racemic mixture, 1′,2′-trans, 3,4-trans


 


874




1′,2′-trans, 3,4-trans


















TABLE 270







875




1′,2′-trans, 3,4-trans


 


876






 


877






 


878




racemic mixture


















TABLE 271







879




racemic mixture


 


880






 


881




racemic mixture


 


882




racemic mixture


 


883




racemic mixture


















TABLE 272







884






 


885




racemic mixture


 


886






 


887




racemic mixture


 


888






















TABLE 273







889




racemic mixture


 


890






 


891






 


892






















TABLE 274







893




racemic mixture


 


894




racemic mixture


 


895




less polar, diastereomer of Ex896


 


896




more polar, diastereomer of Ex895


















TABLE 275







897




racemic mixture


 


898




racemic mixture


 


899




racemic mixture




















TABLE 276







Ex
Syn
Data




















60
1
FAB+: 573



61
1
FAB+: 574



62
1
FAB+: 559



63
1
FAB+: 537



64
3
FAB+: 590



65
1
FAB+: 548



66
1
ESI+: 537



67
1
FAB+: 537



68
1
FAB+: 573



69
1
FAB+: 544



70
1
FAB+: 519



71
1
FAB+: 533



72
1
FAB+: 508



73
1
FAB+: 523



74
5
FAB+: 536



75
6
FAB+: 564



1
1
FAB+: 507



76
1
FAB+: 508



77
1
FAB+: 521



78
1
FAB+: 525



3
3
ESI+: 524



79
1
FAB+: 525



80
1
FAB+: 503



81
1
FAB+: 565



82
1
FAB+: 511



83
1
FAB+: 467



84
1
ESI+: 499



85
1
FAB+: 491



86
1
FAB+: 539



37
37
FAB+: 560



87
1
FAB+: 533



88
1
FAB+: 503



89
1
FAB+: 511



90
1
FAB+: 525



91
1
FAB+: 483





















TABLE 277









92
1
FAB+: 513



93
1
FAB+: 483



94
1
FAB+: 548



95
5
FAB+: 522



96
1
FAB+: 567



97
1
FAB+: 538



98
1
FAB+: 475



99
1
FAB+: 499



100
1
FAB+: 491



101
1
FAB+: 499



102
1
FAB+: 559



103
6
FAB+: 550



104
3
FAB+: 524



105
1
FAB+: 503



106
1
FAB+: 499



107
1
FAB+: 497



108
1
FAB+: 565



2
2
FAB+: 507



109
39
FAB+: 497



39
39
FAB+: 511



110
1
FAB+: 391



111
1
FAB+: 431



4
4
FAB+: 475



112
1
FAB+: 573



113
32
FAB+: 488



114
32
FAB+: 474



115
38
FAB+: 407



116
33
FAB+: 420



117
33
FAB+: 434



118
1
FAB+: 573



119
1
FAB+: 514



120
1
FAB+: 516



121
1
FAB+: 529



122
1
FAB+: 440



123
1
FAB+: 440



124
1
FAB+: 440



















TABLE 278







36
36
FAB+: 456


125
36
FAB+: 456


126
36
FAB+: 456


127
1
FAB+: 497


38
38
FAB+: 483


128
38
FAB+: 483


7
7
FAB+: 393


129
1
FAB+: 467


130
10
FAB+: 498


10
10
FAB+: 604


131
10
FAB+: 527


132
3
ESI+: 633


133
3
ESI+: 617


134
3
ESI+: 617


135
3
ESI+: 645


136
3
ESI+: 617


137
3
FAB+: 647


138
3
ESI+: 663


139
3
ESI+: 647


140
3
ESI+: 651


141
3
ESI+: 633


142
3
ESI+: 633


143
3
ESI+: 667


144
3
FAB+: 647


145
3
ESI+: 655


146
3
ESI+: 631


147
3
ESI+: 633




NMR1: 1.00-1.90 (7H, m), 2.06-2.23 (1H, m), 2.92 (3H, s),




3.25-3.45 (1H, m), 3.60 (1H, s), 4.12 (1H, brs), 4.90-5.06




(2H, m), 5.21 (1H, s), 6.39 (1H, brs), 6.89 (1H, d, J =




8.4 Hz), 7.04-7.20 (2H, m), 7.27-7.69 (6H, m), 7.87-7.97




(1H, m), 8.29 (1H, d, J = 6.4 Hz), 11.64 (1H, brs)


9
9
FAB+: 517


148
11
FAB+: 580


149
11
FAB+: 580


11
11
FAB+: 581


150
1
ESI−: 635


151
1
FAB+: 550


152
1
FAB+: 589


153
1
FAB+: 582


154
1
FAB+: 561


















TABLE 279







155
1
FAB+: 561


156
1
FAB+: 563


157
1
FAB+: 563




NMR1: 1.19 (3H, d, J = 6.0 Hz), 3.10-3.40 (2H, m), 3.54




(1H, s), 3.99-4.12 (1H, m), 4.34 (1H, brs), 4.46-4.58 (1H, m),




4.80 (2H, brs), 4.90 (1H, brs), 5.75 (1H, s), 6.79 (1H, d, J =




8.4 Hz), 6.99-7.08 (1H, m), 7.17 (1H, d, J = 8.4 Hz),




7.31-7.51 (6H, m), 7.61 (1H, s), 7.96-8.09 (1H, m),




11.63 (1H, brs)


158
1
FAB+: 523


159
1
FAB+: 498


160
1
FAB+: 498


161
1
FAB+: 555


162
1
FAB+: 551


163
1
FAB+: 552


164
1
FAB+: 538


165
1
FAB+: 636


166
1
FAB+: 579


167
1
FAB+: 482


168
1
FAB+: 536


169
1
FAB+: 510


170
1
FAB+: 540


171
1
FAB+: 553


172
1
FAB+: 578


173
1
FAB+: 552


174
1
FAB+: 583


175
1
FAB+: 565


176
1
FAB+: 579


177
1
FAB+: 549


178
1
FAB+: 538


34
34
FAB+: 647


179
1
FAB+: 551


180
1
FAB+: 664


181
1
FAB+: 555


182
1
FAB+: 539


183
1
FAB+: 555


184
1
FAB+: 540


185
1
FAB+: 668


186
1
FAB+: 668


187
1
FAB+: 547


188
1
FAB+: 540


189
1
FAB+: 505


















TABLE 280







190
1
FAB+: 505


191
1
FAB+: 499


192
1
FAB+: 499


193
1
FAB+: 533


194
1
FAB+: 528


195
1
ESI+: 528


196
1
ESI+: 561


197
1
ESI+: 559


198
1
FAB+: 505


199
1
FAB+: 505


200
1
FAB+: 594


201
1
FAB+: 594


202
1
FAB+: 597


203
1
FAB+: 527


204
1
ESI+: 534


205
1
FAB+: 626


206
1
FAB+: 610


207
1
FAB+: 610


208
1
FAB+: 682


209
1
FAB+: 682


210
1
FAB+: 539


211
1
ESI+: 515


212
1
ESI+: 515


213
1
FAB+: 533


214
1
ESI−: 541


215
1
ESI−: 541




NMR1: 1.16 (3H, d, J = 6.0 Hz), 2.54-2.64 (2H, m),




3.09-3.38 (4H, m), 3.77 (1H, s), 3.99-4.11 (1H, m), 4.27-4.37




(1H, m), 4.52 (1H, brs), 5.13 (1H, d, J = 4.4 Hz), 5.70




(1H, s), 6.65 (2H, d, J = 8.4 Hz), 6.81 (1H, d, J =




8.4 Hz), 6.94 (2H, d, J = 8.4 Hz), 7.11-7.24 (2H, m),




7.36-7.49 (2H, m), 7.60 (1H, d, J = 2.0 Hz), 7.95-8.08




(1H, m), 8.35-8.50 (1H, m), 9.17 (1H, s)


216
1
FAB+: 632


217
1
FAB+: 533


218
1
FAB+: 538


219
1
FAB+: 538




NMR1: 1.54-1.71 (1H, m), 1.76-1.90 (1H, m), 1.96-2.21




(2H, m), 3.01-3.24 (2H, m), 3.27-3.40 (1H, m), 3.55 (1H,




brs), 3.70 (1H, s), 4.70-4.80 (2H, m), 5.25 (1H, s), 7.10-7.18




(1H, m), 7.22 (1H, dd, J = 2.4, 8.4 Hz), 7.30-7.47 (7H,




m), 7.52 (1H, d, J = 8.4 Hz), 7.62 (1H, d, J = 2.0 Hz),




7.82-7.90 (1H, m), 11.34 (1H, s)




















TABLE 281









220
1
FAB+: 610



221
1
FAB+: 573



222
1
FAB+: 529



223
1
ESI−: 527



224
1
ESI+: 541



225
1
FAB+: 561



226
1
FAB+: 616



227
1
FAB+: 549



228
1
FAB+: 664



229
1
FAB+: 679



230
1
FAB+: 679



231
1
FAB+: 602



232
1
ESI+: 680



233
1
ESI+: 694



234
1
FAB+: 678



235
1
ESI+: 674



236
1
FAB+: 614



237
1
FAB+: 614



238
1
FAB+: 693



239
1
FAB+: 659



240
1
FAB+: 587



241
1
FAB+: 694



242
1
FAB+: 587



243
1
ESI+: 675



244
1
FAB+: 670



245
1
ESI+: 602



246
1
ESI+: 607



247
1
ESI+: 672



248
R381
ESI+: 574



249
R381
FAB+: 573



250
1
FAB+: 567



251
1
FAB+: 566



252
1
ESI+: 658



253
1
ESI+: 658



254
1
FAB+: 632



255
1
FAB+: 585



256
1
FAB+: 584



257
1
FAB+: 674



258
1
ESI+: 658





















TABLE 282









259
1
FAB+: 630



260
1
FAB+: 639



261
1
ESI+: 603



262
1
FAB+: 600



263
1
FAB+: 607



264
1
FAB+: 628



265
1
FAB+: 616



266
1
FAB+: 616



267
1
ESI+: 603



268
1
ESI+: 631



269
1
FAB+: 629



270
1
FAB+: 617



271
1
FAB+: 577



272
1
FAB+: 554



273
1
ESI+: 601



274
1
FAB+: 601



275
1
FAB+: 577



276
1
ESI+: 602



277
1
ESI+: 539



278
1
ESI+: 539



279
1
FAB+: 601



280
1
ESI+: 554



281
1
FAB+: 624



282
1
ESI−: 626



283
1
FAB+: 582



284
1
ESI+: 593



285
1
ESI+: 593



286
1
FAB+: 592



287
1
FAB+: 592



288
1
FAB+: 498



289
1
FAB+: 530



290
1
FAB+: 530



291
1
FAB+: 704



292
1
FAB+: 502



293
1
FAB+: 529



294
1
ESI−: 527



295
1
FAB+: 638



296
1
FAB+: 630



297
1
FAB+: 633



298
1
FAB+: 744



299
1
FAB+: 746





















TABLE 283









300
1
ESI+: 718



301
1
FAB+: 730



302
1
FAB+: 647



303
1
ESI+: 633



304
1
FAB+: 751



305
1
ESI+: 688



306
1
ESI+: 647



307
1
ESI+: 723



308
1
FAB+: 730



309
1
FAB+: 652



310
1
FAB+: 638



311
1
FAB+: 710



312
1
ESI+: 849



313
1
ESI+: 660



314
1
ESI+: 673



315
1
FAB+: 647



316
1
FAB+: 647



317
1
ESI+: 730



318
1
ESI+: 656



319
1
FAB+: 730



320
1
ESI+: 728



321
1
ESI+: 618



322
1
FAB+: 688



323
1
FAB+: 692



324
1
FAB+: 704



325
1
FAB+: 704



326
1
FAB+: 634



327
1
FAB+: 702



328
1
FAB+: 617



329
1
ESI+: 674



330
1
FAB+: 680



331
1
FAB+: 635



332
1
FAB+: 608



333
1
ESI+: 688



334
1
FAB+: 622



335
1
ESI+: 631



336
1
FAB+: 617



337
1
FAB+: 617



338
1
ESI+: 660



339
1
FAB+: 635



340
1
ESI+: 622





















TABLE 284









341
1
FAB+: 647



342
1
FAB+: 563



343
1
FAB+: 563



344
1
FAB+: 635



345
1
ESI+: 660



346
1
FAB+: 631



347
1
ESI+: 622



348
1
ESI+: 647



349
1
ESI+: 673



350
1
ESI+: 606



351
1
FAB+: 620



352
1
ESI+: 632



353
1
FAB+: 619



354
1
ESI−: 568



355
1
FAB+: 620



356
1
FAB+: 642



357
1
FAB+: 622



358
1
ESI+: 631



359
1
ESI+: 680



360
1
ESI+: 565



361
1
FAB+: 607



362
1
ESI+: 591



363
1
ESI+: 642



364
1
FAB+: 613



365
1
ESI+: 651



366
1
FAB+: 657



367
1
FAB+: 637



368
1
FAB+: 631



369
1
ESI+: 637



370
1
FAB+: 623



371
1
FAB+: 631



372
1
ESI+: 618



373
1
ESI+: 688



374
1
FAB+: 631



375
1
FAB+: 601



376
1
FAB+: 702



377
1
FAB+: 601



378
1
ESI+: 647



379
1
ESI+: 643



380
1
FAB+: 654



381
1
ESI+: 602



















TABLE 285







382
1
FAB+: 630


383
1
FAB+: 657


384
1
FAB+: 587


385
1
FAB+: 587


386
1
FAB+: 630


387
1
FAB+: 630


388
1
FAB+: 631


389
1
FAB+: 671


390
1
ESI+: 679


391
1
FAB+: 640


392
1
ESI+: 647


393
1
FAB+: 608


394
1
ESI+: 643


395
1
FAB+: 660


396
1
ESI+: 602


397
1
ESI+: 602


398
1
ESI+: 640


399
1
ESI+: 641


400
1
FAB+: 538


401
1
FAB+: 538




NMR1: 1.54-1.71 (1H, m), 1.75-1.89 (1H, m), 1.97-2.21




(2H, m), 2.99-3.25 (2H, m), 3.26-3.41 (1H, m), 3.55




(1H, brs), 3.70 (1H, s), 4.67-4.82 (2H, m), 5.25 (1H, s),




7.10-7.18 (1H, m), 7.22 (1H, dd, J = 2.4, 8.4 Hz),




7.27-7.40 (7H, m), 7.52 (1H, d, J = 8.4 Hz), 7.62




(1H, d, J = 2.0 Hz), 7.80-7.90 (1H, m),




11.34 (1H, s)


402
1
ESI+: 528


403
1
FAB+: 547


404
1
ESI+: 528


405
1
FAB+: 569


406
1
FAB+: 582


407
1
FAB+: 529


408
1
FAB+: 529


409
1
FAB+: 527


410
1
FAB+: 539


411
1
FAB+: 539


412
1
ESI−: 593


413
1
FAB+: 540


414
1
FAB+: 668


415
1
FAB+: 540


416
1
FAB+: 592


417
1
FAB+: 592




















TABLE 286









418
1
FAB+: 592



419
1
FAB+: 592



420
1
FAB+: 537



421
1
FAB+: 537



422
1
FAB+: 551



423
1
FAB+: 540



424
1
FAB+: 539



425
1
FAB+: 587



426
1
FAB+: 575



427
1
FAB+: 566



428
1
FAB+: 551



429
1
FAB+: 530



430
1
FAB+: 510



431
1
FAB+: 538



432
1
FAB+: 508



433
1
FAB+: 608



434
1
FAB+: 538



435
1
FAB+: 601



436
1
FAB+: 587



437
1
FAB+: 613



438
1
FAB+: 674



439
1
FAB+: 539



440
1
FAB+: 593



441
1
FAB+: 500



442
1
FAB+: 499



443
1
FAB+: 530



444
1
FAB+: 540



445
1
FAB+: 530



446
1
FAB+: 530



447
1
FAB+: 530



448
1
FAB+: 530



449
1
FAB+: 596



450
1
FAB+: 540



451
1
ESI+: 515



452
1
FAB+: 540



453
1
FAB+: 596



454
1
ESI+: 595



455
1
ESI+: 595



456
1
ESI+: 595



457
1
ESI+: 595



458
1
FAB+: 571





















TABLE 287









459
1
FAB+: 571



460
1
FAB+: 538



461
1
FAB+: 605



462
1
ESI+: 618



463
1
ESI+: 606



464
1
ESI+: 746



465
1
ESI+: 690



466
1
ESI+: 703



467
1
ESI+: 692



468
1
ESI+: 746



469
1
ESI+: 732



470
1
ESI+: 718



471
1
ESI+: 692



472
1
ESI+: 692



473
1
FAB+: 642



474
1
ESI+: 732



475
1
ESI+: 606



476
1
ESI+: 746



477
1
FAB+: 618



478
1
ESI+: 638



479
1
ESI+: 692



480
1
ESI+: 605



481
1
FAB+: 543



482
1
ESI+: 557



483
1
FAB+: 571



484
1
FAB+: 674



485
1
ESI+: 674



486
1
FAB+: 597



487
1
FAB+: 553



488
1
FAB+: 597



489
1
FAB+: 589



490
1
FAB+: 576



491
1
FAB+: 567



492
1
FAB+: 545



493
1
FAB+: 546



494
1
ESI−: 567



495
1
FAB+: 567



496
1
FAB+: 567



497
1
FAB+: 607



498
1
FAB+: 553



499
1
ESI+: 573



















TABLE 288







500
1
FAB+: 573


501
1
ESI+: 592


502
1
FAB+: 603


503
1
ESI+: 565


504
1
FAB+: 565


505
1
FAB+: 573


506
1
FAB+: 505


507
1
ESI+: 557


32
32
FAB+: 623


508
32
FAB+: 595


509
32
ESI+: 659


510
32
FAB+: 610


511
32
ESI+: 582


512
32
ESI+: 596


513
32
FAB+: 610


514
32
FAB+: 582


515
32
FAB+: 596


33
33
FAB+: 496


516
34
FAB+: 581


517
34
FAB+: 567


518
34
FAB+: 595


519
34
FAB+: 595


520
34
FAB+: 611


521
34
FAB+: 637


522
34
FAB+: 638


523
34
FAB+: 650


524
34
FAB+: 596


525
34
FAB+: 609


526
34
ESI−: 627


35
35
FAB+: 596


527
35
FAB+: 623


528
4
ESI+: 674


529
4
ESI−: 571




NMR1: 1.19 (3H, d, J = 6.0 Hz), 3.12-3.48 (2H, m), 3.55




(1H, s), 4.01-4.13 (1H, m), 4.28-4.38 (1H, m), 4.47-4.60 (1H,




m), 4.80-4.97 (3H, m), 5.73 (1H, s), 6.79 (1H, d, J = 8.4




Hz), 7.01-7.09 (1H, m), 7.17 (1H, dd, J = 2.0, 8.4 Hz),




7.39-7.69 (5H, m), 7.91-8.08 (3H, m), 11.67 (1H, s), 13.04




(1H, brs)


530
4
ESI+: 661


531
4
ESI−: 571


532
4
FAB+: 644


















TABLE 289







533
4
ESI+: 666


534
4
ESI+: 666


535
4
ESI+: 665


536
4
ESI+: 645


537
4
FAB+: 688


538
4
ESI+: 688


539
4
ESI+: 690


540
4
ESI+: 674


541
4
ESI+: 674




NMR1: 1.00-2.30 (8H, m), 2.94 (3H, s), 3.58 (3H, s), 4.07




(1H, brs), 4.74 (1H, d, J = 11.0 Hz), 4.77 (1H, d,




J = 11.0 Hz), 5.18 (1H, s), 6.36 (1H, d, J = 6.9




Hz), 6.88 (1H, d, J = 8.4 Hz), 7.08-7.11 (1H, m),




7.16 (1H, d, J = 2.0 Hz), 7.18 (1H, d, J = 2.0




Hz), 7.26 (2H, d, J = 8.0 Hz), 7.30 (2H, d, J =




8.0 Hz), 7.43-7.48 (2H, m), 7.64 (1H, d, J = 2.0 Hz)




7.93-7.96 (1H, m), 11.42 (1H, s), 12.34 (1H, brs)


542
4
FAB+: 710




NMR1: 0.48-0.71 (1H, m), 1.01-1.37 (4H, m), 1.40-1.65 (2H,




m), 2.46-2.59 (1H, m), 2.78 (3H, s), 3.15-3.50 (2H, m),




4.66-4.84 (3H, m), 5.17 (1H, s), 6.68 (1H, d, J = 8.4




Hz), 7.02-7.09 (1H, m), 7.12-7.20 (3H, m), 7.27-7.40 (2H,




m), 7.46 (1H, d, J = 0.8 Hz), 7.64 (1H, d, J =




8.0 Hz), 8.57 (1H, brs)


543
4
ESI+: 718


544
4
ESI+: 702


545
4
ESI−: 702


546
4
FAB+: 638


547
4
FAB+: 624


548
4
ESI+: 702


549
4
ESI+: 676


550
4
ESI+: 674


551
4
ESI+: 640


552
4
ESI+: 678


553
4
ESI−: 688


554
4
ESI+: 690


555
4
FAB+: 660


556
4
ESI+: 660


557
4
ESI+: 666


558
4
FAB+: 620


559
4
ESI+: 596


560
4
ESI+: 660


561
4
FAB+: 583


562
4
ESI+: 583




















TABLE 290









563
4
ESI+: 660



564
4
ESI+: 660



565
4
ESI+: 678



566
4
FAB+: 678



567
4
ESI+: 690



568
4
FAB+: 718



569
4
ESI+: 647



570
4
ESI+: 678



571
4
FAB+: 678



572
38
FAB+: 592



573
39
ESI+: 569



574
39
ESI+: 582



575
39
ESI+: 602



576
39
FAB+: 565



577
39
FAB+: 636



578
39
FAB+: 573



16
16
FAB+: 579



15
15
ESI−: 579



22
22
ESI+: 716



43
43
FAB+: 680



29
29
ESI+: 666



23
23
ESI+: 700



41
41
FAB+: 624



579
23
ESI+: 830



13
13
FAB+: 617



580
13
FAB+: 609



581
13
FAB+: 577



582
13
FAB+: 577



583
13
FAB+: 618



14
14
FAB+: 645



584
12
FAB+: 576



12
12
FAB+: 616



585
12
FAB+: 617



586
12
ESI+: 617



587
12
FAB+: 608



588
12
FAB+: 678



589
12
ESI+: 617



590
12
FAB+: 615



591
12
FAB+: 562



592
12
FAB+: 630



593
12
FAB+: 616





















TABLE 291









594
12
FAB+: 608



595
12
FAB+: 580



596
12
FAB+: 610



18
18
ESI+: 684



597
18
FAB+: 592



598
18
ESI+: 606



599
18
ESI+: 606



600
18
ESI+: 608



21
21
ESI+: 598



601
21
ESI+: 674



20
20
ESI+: 737



27
27
FAB+: 593



40
40
ESI−: 568



602
40
FAB+: 569



8
8
FAB+: 577



603
6
FAB+: 566



604
6
FAB+: 540



605
6
FAB+: 540



606
6
FAB+: 524



6
6
FAB+: 564



607
6
FAB+: 524



42
42
ESI+: 648



31
31
FAB+: 638



608
5
ESI+: 526



609
5
ESI+: 484



610
5
FAB+: 538



611
5
FAB+: 582



612
5
ESI+: 510



613
5
ESI+: 510



614
5
ESI+: 510



615
5
ESI+: 510



616
5
FAB+: 582



617
5
FAB+: 508



618
5
FAB+: 508



619
5
FAB+: 536



620
5
FAB+: 536



5
5
FAB+: 482



621
5
FAB+: 538



30
30
FAB+: 632



622
30
ESI+: 648



623
28
FAB+: 568





















TABLE 292









28
28
FAB+: 568



624
28
FAB+: 568



24
24
ESI+: 607



625
19
ESI+: 632



626
19
FAB+: 674



627
19
ESI+: 672



628
19
ESI+: 688



629
19
FAB+: 654



630
19
FAB+: 674



631
19
ESI+: 690



632
19
ESI+: 584



633
19
ESI+: 613



19
19
ESI+: 690



634
19
ESI+: 647



635
19
ESI+: 632



636
19
FAB+: 690



25
25
ESI+: 633



637
25
FAB+: 690



26
26
FAB+: 526



17-2
17
FAB+: 568



17-1
17
FAB+: 550



638
1
ESI+: 724



639
1
ESI+: 780



640
53
ESI+: 650



53
53
ESI+: 664



641
30
ESI+: 648



642
1
ESI+: 662



45
45
ESI+: 632



643
4
ESI+: 676



644
1
ESI+: 623



645
1
ESI+: 748



646
1
ESI+: 704



647
1
ESI+: 688



648
1
FAB+: 676




4



649
1
ESI+: 690




4



650
4
FAB+: 718



651
3
FAB+: 767



52
52
ESI+: 663





















TABLE 293









652
19
ESI+: 648



653
1
FAB+: 611




19



654
4
ESI+: 674



655
1
ESI+: 674




4



656
1
FAB+: 615



657
1
FAB+: 615



51
51
ESI+: 598



658
1
FAB+: 665



659
3
ESI+: 631



660
1
ESI+: 695



661
43
ESI+: 624



662
41
ESI+: 680



663
55
ESI+: 638



664
20
ESI+: 767



665
6
ESI+: 703




12



666
4
ESI+: 651



667
3
ESI+: 631



668
39
ESI+: 675



46
46
FAB+: 660



669
1
FAB+: 673



670
1
ESI+: 721



47
47
ESI+: 624



671
1
ESI+: 704



672
1
FAB+: 672



673
1
ESI+: 731



674
1
ESI+: 710




19



675
19
ESI+: 648



676
19
FAB+: 675



677
1
ESI+: 695



678
1
ESI+: 735



679
1
ESI+: 710




19



680
1
ESI+: 688




19



681
P8
ESI−: 675




P9




1



















TABLE 294







682
1
FAB+: 658


683
4
ESI+: 663


684
1
FAB+: 611


49
49
FAB+: 689


685
3
FAB+: 705


686
4
FAB+: 597


687
1
FAB+: 633


688
1
ESI+: 731


55
55
FAB+: 663


689
1
FAB+: 703


690
20
FAB+: 674


691
19
ESI+: 675


692
1
ESI+: 744


693
19
ESI+: 688


54
54
ESI+: 663


694
3
FAB+: 719


695
1
FAB+: 752


696
P38
ESI+: 714



1


697
54
FAB+: 679


698
52
ESI+: 648


699
4
FAB+: 700


700
1
ESI+: 735




NMR1: 0.99-1.85 (8H, m), 2.10-2.24 (1H, m), 2.69-2.83




(2H, m), 2.92 (3H, s), 3.25-3.45 (5H, m), 3.73 (1H, s),




3.95 (1H, brs), 5.21 (1H, s), 6.41-6.51 (1H, m), 6.85




(1H, d, J = 8.0 Hz), 7.11-7.22 (2H, m), 7.35-7.48




(4H, m), 7.64 (1H, d, J = 2.0 Hz), 7.73-7.81 (2H,




m), 7.88-7.96 (1H, m), 8.07 (1H, brs), 12.08 (1H, brs)


701
19
ESI+: 672




NMR1: 0.99-1.87 (8H, m), 2.11-2.26 (1H, m), 2.59-2.74




(2H, m), 2.91 (3H, s), 3.18-3.40 (2H, m), 3.51 (2H, s),




3.75 (1H, s), 3.93 (1H, brs), 5.24 (1H, s), 6.41-6.54




(1H, m), 6.85 (1H, d, J = 8.0 Hz), 7.01-7.23 (6H, m),




7.39-7.48 (2H, m), 7.65 (1H, d, J = 2.0 Hz), 7.89-




7.98 (1H, m), 8.08 (1H, brs), 12.28 (1H, brs)


702
19
FAB+: 595


703
4
FAB+: 589


704
1
ESI+: 669


705
1
FAB+: 555


706
1
ESI+: 746


707
1
FAB+: 531


708
1
ESI+: 678


















TABLE 295







44
44
ESI−: 650


709
4
FAB+: 718




NMR1: 1.09 (2H, t, J = 6.9 Hz), 1.00-2.00 (5H, m),




2.10-2.25 (1H, m), 2.40 (2H, t, J = 7.2 Hz), 2.94




(3H, s), 3.18-3.50 (3H, m), 3.57 (1H, s), 3.98 (1H, t,




J = 6.3 Hz), 4.73 (1H, d, J = 11.3 Hz), 4.78




(1H, d J = 11.3 Hz), 5.16 (1H, s), 6.32-6.38 (1H,




m), 6.85-6.95 (3H, m), 7.05-7.50 (3H, m), 7.39-7.48




(2H, m), 7.63 (1H, d, J = 2.0 Hz), 7.89-7.98 (1H,




m), 11.39 (1H, brs)


710
1
ESI+: 751


711
19
ESI+: 708


712
19
ESI+: 708




NMR1: 0.99-1.87 (8H, m), 2.11-2.26 (1H, m), 2.59-2.74




(2H, m), 2.91 (3H, s), 3.18-3.40 (2H, m), 3.51 (2H,




s), 3.75 (1H, s), 3.93 (1H, brs), 5.24 (1H, s), 6.41-




6.54 (1H, m), 6.85 (1H, d, J = 8.0 Hz), 7.01-7.23




(6H, m), 7.39-7.48 (2H, m), 7.65 (1H, d, J = 2.0




Hz), 7.89-7.98 (1H, m), 8.08 (1H, brs), 12.28 (1H, brs)


713
19
ESI+: 631


714
19
ESI+: 633


715
3
ESI+: 767


57
57
ESI+: 701


716
4
FAB+: 650


717
32
ESI+: 596


718
52
ESI+: 663


719
1
FAB+: 596


720
1
ESI+: 572


721
4
ESI+: 641


722
32
FAB+: 610


723
21
ESI+: 596


724
21
FAB+: 596


725
1
FAB+: 751


726
1
ESI+: 639


727
1
ESI+: 639


728
P9 
ESI+: 617



P40



1


729
41
ESI+: 622


730
52
ESI+: 647


731
3
FAB+: 767


732
52
FAB+: 663


733
41
ESI+: 622


734
18
ESI+: 682


735
18
ESI+: 682




















TABLE 296









736
21
ESI+: 672



737
41
ESI+: 698



738
21
ESI+: 672



739
4
ESI+: 589



740
44
ESI−: 650



741
1
ESI+: 782



742
1
ESI+: 538



743
1
ESI+: 538



744
3
ESI+: 554



745
44
ESI−: 573



746
1
ESI+: 555



747
1
ESI+: 563



748
21
ESI+: 596



59
59
ESI+: 681



749
3
ESI+: 554



750
41
ESI+: 622



751
19
ESI−: 623



752
19
FAB+: 710



753
19
ESI+: 633



754
19
ESI+: 708



755
19
ESI+: 631



756
1
ESI+: 645



757
1
ESI+: 645



758
1
ESI+: 644



50
50
ESI+: 687



759
1
ESI+: 731



760
1
ESI+: 706



761
19
ESI−: 609



762
19
FAB+: 675



763
19
ESI+: 650



764
1
ESI+: 709



765
1
ESI−: 656



766
1
ESI+: 678



767
44
ESI+: 667



768
4
FAB+: 664



769
44
ESI+: 650



770
1
ESI+: 720



771
1
ESI+: 643



772
19
ESI+: 587



773
19
ESI+: 664



774
1
ESI+: 779





















TABLE 297









775
1
ESI+: 706



776
P8
ESI+: 633




P9




1



777
35
ESI+: 597



48
48
ESI+: 689



778
19
ESI+: 650



779
1
FAB+: 633



780
1
ESI+: 661



781
4
ESI+: 619



782
1
ESI−: 577



783
1
ESI+: 631



784
1
ESI+: 631



785
48
ESI+: 601



786
48
ESI+: 601



787
1
ESI+: 672




19



788
21
ESI+: 612



789
3
ESI+: 613



790
4
ESI+: 647



791
19
ESI+: 617



792
19
ESI+: 617



793
P9
ESI+: 678




1



794
1
ESI+: 714



795
19
ESI+: 658



796
19
ESI+: 658



797
41
ESI+: 638



798
1
ESI+: 562



799
1
ESI+: 562



800
1
FAB+: 744



801
19
ESI+: 688



802
1
ESI+: 667



803
19
ESI+: 611



804
44
ESI−: 634



805
3
ESI+: 703



56
56
ESI: 661



806
4
ESI+: 650



807
44
ESI+: 636



808
19
ESI+: 658



809
19
ESI+: 581





















TABLE 298









810
1
ESI+: 671



811
1
ESI+: 671



812
1
ESI−: 718



813
P23
ESI−: 641




1



814
1
ESI+: 687



815
1
ESI+: 687



816
19
ESI+: 587



817
19
ESI+: 664



818
P23
ESI+: 744




1



819
1
ESI+: 667



820
19
ESI+: 611



821
19
ESI+: 688



822
P9 
ESI+: 681




1




4



823
1
FAB+: 666




44



824
1
ESI+: 655



825
4
ESI+: 641



826
1
ESI+: 513



827
36
ESI+: 599



828
1
ESI+: 792



829
1
ESI+: 715



58
58
ESI+: 672



830
1
ESI+: 526



831
1
ESI+: 526



832
19
ESI+: 702



833
19
ESI+: 702



834
1
ESI+: 556



835
P33
ESI−: 601




1



836
1
ESI+: 644



837
1
ESI+: 567



838
58
ESI+: 595



839
11
ESI+: 580



840
35
ESI+: 596



841
1
ESI−: 680



842
1
FAB+: 605



843
1
ESI+: 721



















TABLE 299







844
1
ESI+: 643


845
19
ESI+: 664


846
19
ESI+: 587


847
P33
FAB+: 541



1


848
1
FAB+: 587


849
1
FAB+: 587


850
1
FAB+: 587


851
1
FAB+: 587


852
1
ESI+: 701


853
58
ESI+: 581


854
1
FAB+: 591


855
1
FAB+: 591


856
4
ESI+: 674




NMR1: 1.00-2.30 (8H, m), 2.94 (3H, s), 3.58 (3H, s), 4.07




(1H, brs), 4.74 (1H, d, J = 11.0 Hz), 4.77 (1H, d,




J = 11.0 Hz), 5.18 (1H, s), 6.36 (1H, d, J = 6.9




Hz), 6.88 (1H, d, J = 8.4 Hz), 7.08-7.11 (1H, m), 7.16




(1H, d, J = 2.0 Hz), 7.18 (1H, d, J = 2.0 Hz), 7.26




(2H, d, J = 8.0 Hz), 7.30 (2H, d, J = 8.0 Hz), 7.43-




7.48 (2H, m), 7.64 (1H, d, J = 2.0 Hz) 7.93-7.96 (1H,




m), 11.42 (1H, s), 12.34 (1H, brs)


857
1
FAB+: 616


858
1
ESI+: 627


859
19
ESI+: 571


860
1
ESI+: 540


861
1
ESI+: 513


862
1
ESI+: 545


863
1
ESI+: 564


864
1
ESI+: 589


865
1
ESI+: 537


866
1
ESI+: 532


867
1
ESI+: 505


868
1
ESI+: 616


869
1
ESI+: 548


870
1
ESI+: 574


871
1
FAB+: 564


872
1
FAB+: 532


873
1
ESI+: 542


874
1
ESI+: 573


875
1
ESI+: 608


876
21
ESI+: 598


877
1
FAB+: 728




















TABLE 300









878
1
FAB+: 651



879
1
FAB+: 603



880
1
FAB+: 764



881
1
FAB+: 687



882
1
FAB+: 764



883
1
FAB+: 689



884
1
ESI+: 766



885
1
ESI+: 689



886
1
ESI+: 764



887
1
ESI+: 687



888
1
ESI−: 665



889
1
FAB+: 601



890
1
ESI+: 691



891
1
ESI+: 691



892
P9 
ESI+: 678




1



893
1
ESI+: 714



894
1
FAB+: 637



895
1
FAB+: 758



896
1
ESI+: 758



897
1
FAB+: 636



898
P33
ESI+: 622




1



899
P33
APCI+: 435




1


















TABLE 301





No
Structure







1






 


2






 


3






 


4























TABLE 302









5














INDUSTRIAL APPLICABILITY
The compound (I) of the present invention as described above is useful as a therapeutic agent for the diseases in which BB2 receptors are related, in particular, for IBS since it has an excellent BB2 receptor antagonistic activity, and further, it exhibits excellent efficacy regarding bowel movement disorders.

## Claims

1. A tetrahydroisoquinolin-1-one derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof:



in which groups R1-R5 and m are as follows
R1: lower alkylene-OH, lower)alkylene-N(R0)(R6), lower alkylene-CO2R0, cycloalkyl, cycloalkenyl, aryl, heterocyclic group, -(lower alkylene substituted with —OR0)-aryl or lower alkylene-heterocyclic group, wherein the lower alkylene, cycloalkyl, cycloalkenyl, aryl and heterocyclic group in R1 may each be substituted,
R0: the same as or different from each other, each representing —H or lower alkyl,
R6: R0, —C(O)—R0, —CO2-lower alkyl or —S(O)2-lower alkyl,
R2: lower alkyl, lower alkylene-OR0, lower alkylene-aryl, lower alkylene-heterocyclic group, lower)alkylene-N(R0)CO-aryl, lower alkylene-O-lower alkylene-aryl, —CO2R0, —C(O)N(R0)2, —C(O)N(R0)-aryl, —C(O)N(R0)-lower alkylene-aryl, or aryl, wherein the aryl and heterocyclic group in R2 may each be substituted,
R3: —H or lower alkyl, or R2 and R3 may be combined to form C2-6 alkylene,
R4: —N(R7)(R8), —N(R0)—OH, —N(R10)—OR7, —N(R0)—N(R0)(R7), —N(R0)—S(O)2-aryl, or —N(R0)—S(O)2—R7, wherein the aryl in R4 may be substituted,
R7: lower alkyl, halogeno-lower alkyl, lower alkylene-CN, lower alkylene-OR0, lower alkylene-CO2R0, lower)alkylene-C(O)N(R0)2, lower))alkylene-C(O)N(R0)N(R0)2, lower alkylene-C(═NH)NH2, lower alkylene-C(═NOH)NH2, heteroaryl, lower alkylene-X-aryl, or lower alkylene-X-heterocyclic group, wherein the lower alkylene, aryl, heteroaryl, and heterocyclic group in R7 may each be substituted,
X: single bond, —O—, —C(O)—, —N(R0), —S(Op)—, or *—C(O)N(R0)—, wherein * in X represents a bond to lower alkylene,
m: an integer of 0 to 3,
p: an integer of 0 to 2,
R8: —H or lower alkyl, or R7 and R8 may be combined to form lower alkylene-N(R9)-lower alkylene, lower alkylene-CH(R9)-lower alkylene, lower alkylene-arylene-lower alkylene, or lower alkylene-arylene-C(O)—,
R9: aryl and heteroaryl which may each be substituted,
R10: —H lower alkyl, or —C(O)R0,
R5: lower alkyl, halogeno-lower alkyl, halogen, nitro, —OR0, —O-halogeno-lower alkyl, —N(R0)2, —O-lower alkylene-CO2R0, or —O-lower alkylene-aryl, wherein the aryl in R5 may be substituted,
provided that, when R4 is —N(R7)(R8),
(1) a compound wherein R1 is unsubstituted cyclopentyl and R2 is unsubstituted 2-thienyl;
(2) a compound wherein R1 is unsubstituted cyclohexyl and R2 is 4-methoxyphenyl;
(3) a compound wherein R1 is 4-methoxyphenyl and R2 is 4-methoxyphenyl; and
(4) a compound wherein R1 is (morpholin-4-yl)ethyl and R2 is 4-ethoxyphenyl are excluded, and

further provided that, 2,3-bis(4-chlorophenyl)-N-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
3-(4-chlorobenzyl)-2-(4-chlorophenyl)-N-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
3-[3,5-bis(trifluoromethyl)phenyl]-2-cyclopropyl-N-(2-furylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
3-[3,5-bis(trifluoromethyl)phenyl]-2-cyclopropyl-N-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
ethyl 3-{3-[3,5-bis(trifluoromethyl)phenyl]-4-{[2-(4-methoxyphenyl)ethyl]carbamoyl}-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl}propanoate,
N-benzyl-3-[3,5-bis(trifluoromethyl)phenyl]-1-oxo-2-(tetrahydrofuran-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
3-[3,5-bis(trifluoromethyl)phenyl]-N-(2-methoxyethyl)-2-(2-morpholin-4-ylethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
3-[3,5-bis(trifluoromethyl)phenyl]-2-(2-furylmethyl)-N-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
3-[3,5-bis(trifluoromethyl)phenyl]-N-(2-furylmethyl)-2-(2-morpholin-4-ylethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, and
(4-chlorophenyl)[3-(4-chlorophenyl)-4-[(2-methoxyethyl)carbamoyl]-1-oxo-3-,4-dihydroisoquinolin-2(1H)-yl]acetic acid are excluded.

2. The compound as described in claim 1 or a pharmaceutically acceptable salt thereof, wherein R3 is —H.

3. The compound as described in claim 2 or a pharmaceutically acceptable salt thereof, wherein R2 is phenyl which may be substituted with halogen, lower alkyl, or —OR0.

4. The compound as described in claim 3 or a pharmaceutically acceptable salt thereof, wherein R4 is —N(R0)-lower alkylene-(aryl or heteroaryl, which may each be substituted), or)-N(R0)—O-lower alkylene-(aryl or heteroaryl, which may each be substituted).

5. The compound as described in claim 4 or a pharmaceutically acceptable salt thereof, wherein R1 is (lower alkylene)-OH or substituted cycloalkyl {wherein said lower alkylene may be substituted with a member selected from the group consisting of —OH and phenyl (which may be substituted with halogen, lower alkyl, or —OR0), and said substituted cycloalkyl is substituted with a member selected from the group consisting of —OR0, —N(R0)2, —N(R0)C(O)R0, —N(R0)C(O)-lower alkylene-OR0, —N(R0)S(O)2-lower alkyl and heterocyclic group}.

6. The compound as described in claim 1, which is selected from the group consisting of:
(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-(pyridin-2-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-N-[(1-oxidopyridin-2-yl)methoxy]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
3-{[({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl} benzoic acid,
(4-{[({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}phenyl)acetic acid,
(3-{[({[(3R,4R)-3-(2,4-dichlorophenyl-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}phenoxy)acetic acid,
{3-[2-({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)ethyl]phenyl}(difluoro)acetic acid,
(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-N-(2-{3-[(methylsulfonyl)carbamoyl]phenyl}ethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,
{4-[2-({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)ethyl]phenyl}acetic acid, and
4-(3-{[({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl} amino)oxy]methyl}phenoxy)butanoic acid;

or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition comprising the compound as described in claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

8. The compound
(4-{[({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl} amino)oxy]methyl}phenyl)acetic acid,

or a pharmaceutically acceptable salt thereof.