Tetrahydroisoquinolin-1-one derivative or salt thereof

Information

  • Patent Grant
  • 10532048
  • Patent Number
    10,532,048
  • Date Filed
    Thursday, July 5, 2018
    6 years ago
  • Date Issued
    Tuesday, January 14, 2020
    4 years ago
Abstract
To provide a pharmaceutical, in particular a compound which can be used as a therapeutic agent for irritable bowel syndrome (IBS). 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.
Description
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.




embedded image


(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.




embedded image


(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.




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(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









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CAS Registry No.
RaRbN—





931939-66-1


embedded image







931315-65-0


embedded image







902607-43-6
Me2N—


902450-09-3
Ph—(CH2)2—NH—


891914-00-4
PhCH2—NH—





891913-84-1


embedded image







891913-76-1


embedded image







891913-68-1


embedded image







891913-28-3


embedded image







891913-04-5


embedded image







891912-88-2
EtNH—





891912-80-4


embedded image





















TABLE 2









891912-64-4


embedded image









891912-56-4


embedded image









891912-48-4


embedded image









891912-40-6


embedded image









891912-16-6


embedded image









891912-08-6


embedded image









891912-00-8


embedded image









891911-84-5


embedded image









891911-60-7


embedded image









891911-52-7


embedded image









891911-44-7


embedded image









891911-36-7


embedded image




















TABLE 3







891911-29-8


embedded image







891911-22-1


embedded image







891911-07-2


embedded image







891910-93-3


embedded image







891910-86-4


embedded image







891910-72-8


embedded image







891910-65-9


embedded image







891910-58-0


embedded image







891910-23-9


embedded image







891910-07-9


embedded image







891909-99-2


embedded image







891909-91-4
EtO—(CH2)3—NH—





891909-83-4


embedded image





















TABLE 4









891909-75-4


embedded image









891909-67-4


embedded image









891909-59-4
iPrO—(CH2)3—NH—







891909-51-6


embedded image









891909-27-6
PhN(Et)—(CH2)3—NH—







891909-11-8


embedded image









891909-03-8


embedded image









891908-95-5


embedded image









891908-55-7
Et2N—







891907-99-6


embedded image









891907-91-8


embedded image









891907-83-8


embedded image









891907-75-8


embedded image









891907-43-0
MeO—(CH2)3—NH—



891907-35-0
nBuNH—



891907-27-0
iPrNH—







891907-19-0


embedded image









891907-11-2
MeO—(CH2)2—NH—




















TABLE 5









891907-03-2


embedded image









891906-95-9


embedded image









891906-87-9


embedded image









891906-79-9


embedded image









891906-71-1


embedded image









891906-55-1


embedded image









891906-39-1


embedded image









891905-75-2


embedded image









891904-87-3


embedded image



















TABLE 6









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CAS Registry No.
RaRbN—







685520-62-1


embedded image









685520-61-0


embedded image









442858-62-0
EtO2C—CH2—NH—







442858-61-9


embedded image









442858-27-7
MeO2C—(CH3)2—NH—



442858-05-1
MeO2C—CH2—NH—







442858-04-0


embedded image









442857-76-3


embedded image









442857-73-0


embedded image









442856-86-2


embedded image









442856-85-1


embedded image









442856-80-6
Et2N—




















TABLE 7









442856-71-5


embedded image









442856-34-0


embedded image









442856-31-7


embedded image









442856-30-6


embedded image









442856-29-3
iPrNH—







442856-28-2


embedded image









442856-17-9


embedded image









442856-15-7
PhN(Et)—(CH2)3—NH—







442855-08-5


embedded image









442854-93-5


embedded image









442854-92-4


embedded image









442854-57-1
MeO—(CH2)2—NH—







442854-41-3


embedded image



















TABLE 8









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CAS Registry No.
RaRbN—







685520-63-2


embedded image









442859-46-3


embedded image









442859-42-9


embedded image









442859-40-7


embedded image









442859-39-4


embedded image









442859-38-3


embedded image









442859-36-1


embedded image









442859-27-0


embedded image









442859-26-9


embedded image






















TABLE 9









442859-25-8


embedded image









442859-20-3
Et2N—







442859-13-4


embedded image









442859-12-3


embedded image









442859-11-2
MeO—(CH2)3—NH—



442859-09-8
nBuN(Et)—







442859-06-5


embedded image









442859-05-4
nBuNH—







442859-03-2


embedded image









442859-02-1
EtO2C—CH2—NH—



442859-01-0
MeO—(CH2)2—NH—



442858-99-3
nBuN(Me)NH—







442858-98-2


embedded image









442858-93-7


embedded image









442858-91-5
PhCH2N(Me)—







442858-86-8


embedded image









442858-79-9


embedded image






















TABLE 10









442858-77-7


embedded image









442858-76-6


embedded image









442858-72-2


embedded image









442858-67-5


embedded image









442858-56-2
iPrNH—







442858-55-1


embedded image



















TABLE 11









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CAS Registry No.
RaRbN—







442888-72-4


embedded image









442888-70-2


embedded image









442888-60-0


embedded image









442888-49-5


embedded image









442888-41-7


embedded image









442888-39-3


embedded image









442888-37-1


embedded image









442888-35-9


embedded image












  • 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:




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[the symbols in the formula represent the following meanings:


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, 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(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(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, tetrahydrofuranyl, 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, —CO2R0, —N(R0)2, —N(R0)C(O)R0, —N(R0)C(O)-lower alkylene-OR0, or —N(R0)S(O)2-lower alkyl, and even more preferably —OR0, —N(R0)C(O)R0, or —N(R0)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-CO2R0, —N(R0)C(O)R0, —N(R0)C(O)OR0, —N(R0)C(O)-aryl, —N(R0)C(O)-lower alkylene-OR0, —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-CO2R0)—S(O)2-lower alkyl, —N(R0)S(O)2-lower alkylene-CO2R0, —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, —CO2R0, —CO2-lower alkylene-Si(lower alkyl)3, —C(O)N(R0)2, —C(O)N(R0)-lower alkylene-OR0, —C(O)N(R0)-lower alkylene-N(R0)2, —C(O)N(R0)-lower alkylene-CO2R0, —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 —CO2R0.


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(R0)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 —OR0, —N(R0)2, —N(R0)C(O)R0, —N(R0)C(O)-lower alkylene-OR0, —N(R0)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 —OR0, —N(R0)2, —N(R0)C(O)R0, —N(R0)C(O)-lower alkylene-OR0, —N(R0)S(O)2-lower alkyl and a heterocyclic group. Particularly preferably, it is cyclohexyl substituted with a group selected from the group consisting of —OR0, —N(R0)C(O)R0, and —N(R0)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)




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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)




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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)




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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)




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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 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 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 EI−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 Production 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,




embedded image



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 stirring 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-isoindol-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-isoindol-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 stirring 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 methanesulfonyl 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 stirring 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)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 stirring 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 stirring 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-[(mesyl)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 stirring 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 stirring 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


embedded image


ESI+: 471






65  
P34


embedded image


ESI+: 456






34-2
P34


embedded image


ESI−: 434
racemic mixture





34-1
P34


embedded image


ESI−: 434
racemic mixture





66
P34


embedded image


ESI+: 430




















TABLE 15







67
P34


embedded image


ESI+: 462






68
P34


embedded image


ESI+: 430






69
P34


embedded image


ESI+: 456






70
P34


embedded image


ESI+: 462






33-1
P33


embedded image


ESI+: 404
racemic mixture




















TABLE 16







33-2
P33


embedded image


ESI+: 404
racemic mixture





71
P34


embedded image


ESI+: 471






72
P33


embedded image


FAB+: 532
racemic mixture





30
P30


embedded image


ESI+: 214






18
P18


embedded image


FAB+: 372






73
P31


embedded image


ESI+: 244






74
P31


embedded image


ESI+: 244




















TABLE 17







75
P31


embedded image


ESI+: 276






31
P31


embedded image


FAB+: 340






37
P37


embedded image


ESI+: 553
racemic mixture





 5
P5 


embedded image


FAB+: 244






76
P17 P14


embedded image


FAB+: 313






77
P14


embedded image


FAB+: 318






78
P42


embedded image


FAB+: 340



















TABLE 18







79
P42


embedded image


FAB+: 340





80
P14


embedded image


ESI+: 330





14
P14


embedded image


FAB+: 332





81
P14


embedded image


FAB+: 280





82
P14


embedded image


FAB+: 257





83
P14


embedded image


FAB+: 279





84
P14


embedded image


FAB+: 246





85
P14


embedded image


FAB+: 332



















TABLE 19







86
P14


embedded image


FAB+: 487





87
P14


embedded image


FAB+: 285





88
P14


embedded image


FAB+: 376





89
P42


embedded image


FAB+: 368





90
P14


embedded image


FAB+: 326





91
P14


embedded image


FAB+: 273





92
P14


embedded image


ESI+: 342



















TABLE 20







93
P14


embedded image


ESI+: 342





94
P42


embedded image


FAB+: 454





95
P14


embedded image


FAB+: 368





96
P42


embedded image


FAB+: 384





97
P42


embedded image


FAB+: 354





98
P14


embedded image


EI+: 238





99
P42


embedded image


FAB+: 326



















TABLE 21







100
P14


embedded image


EI+: 247





 42
P42


embedded image


FAB+: 273





101
P14


embedded image


FAB+: 260





102
P14


embedded image


ESI+: 330





103
P14


embedded image


ESI+: 280





104
P14


embedded image


FAB+: 298





105
P14


embedded image


FAB+: 260





106
P14


embedded image


FAB+: 260




















TABLE 22







107
P14


embedded image


FAB+: 269






108
P14


embedded image


ESI+: 318






109
P14


embedded image


ESI+: 330






 25
P25


embedded image


FAB+: 344
racemic mixture





 15
P15


embedded image


FAB+: 263






 43
P43


embedded image


FAB+: 263






110
11


embedded image


ESI+: 309




















TABLE 23







111
11


embedded image


FAB+: 503
racemic mixture





112
P34


embedded image


FAB+: 539
racemic mixture





113
P34


embedded image


ESI+: 433






114
P34


embedded image


FAB+: 463
racemic mixture





115
P34


embedded image


FAB+: 451
racemic mixture





116
P34


embedded image


FAB+: 447
racemic mixture




















TABLE 24







117
P34


embedded image


ESI+: 463
racemic mixture





118
P34


embedded image


ESI+: 463
racemic mixture





119
P34


embedded image


FAB+: 451
racemic mixture





120
P34


embedded image


ESI+: 465
racemic mixture





121
P33


embedded image


FAB+: 491






122
P33


embedded image


FAB+: 488
1′,2′-trans




















TABLE 25







123
P33


embedded image


FAB+: 562
1′,2′-trans





124
P33


embedded image


FAB+: 462
1′,2′-trans





125
P33


embedded image


FAB+: 405






126
P35


embedded image


ESI+: 491
racemic mixture





127
P34 P35


embedded image


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





35
P35


embedded image


ESI+: 461
racemic mixture




















TABLE 26







128
P35


embedded image


ESI+: 461






11
P11


embedded image


CI+: 210






17
P17


embedded image


EI+: 190






20
P20


embedded image


CI+: 365






19
P19


embedded image


EI+: 292






4
P4 


embedded image


CI+: 228






21
P21


embedded image


CI+: 221






129
P36


embedded image


FAB+: 569
racemic mixture




















TABLE 27







130
P36


embedded image


FAB+: 557
racemic mixture





131
P36


embedded image


FAB+: 557
racemic mixture





132
P34 P35 P36


embedded image


FAB+: 569
racemic mixture





133
P34 P35 P36


embedded image


FAB+: 569
racemic mixture




















TABLE 28







134
P34 P35 P36


embedded image


FAB+: 539
racemic mixture





135
P34 P35 P36


embedded image


FAB+: 539
racemic mixture





136
P36


embedded image


ESI+: 553
racemic mixture





137
P36


embedded image


FAB+: 569
racemic mixture





138
P36


embedded image


ESI+: 569
racemic mixture




















TABLE 29







139
P34 P35 P36


embedded image


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





140
P34 P35 P36


embedded image


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





141
P34 P35 P36


embedded image


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





142
P36


embedded image


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




















TABLE 30







143
P36


embedded image


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





144
P35 P36


embedded image


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





145
P34 P35 P36


embedded image


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





146
P36


embedded image


EI+: 316






147
P36


embedded image


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




















TABLE 31







148
P36


embedded image


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





149
P36


embedded image


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





150
P36


embedded image


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





36
P36


embedded image


ESI+: 539
racemic mixture




















TABLE 32







151
P36


embedded image


ESI+: 539






152
P22


embedded image


FAB+: 331






22
P22


embedded image


FAB+: 279






153
P22


embedded image


FAB−: 209






154
P22


embedded image


FAB+: 293






155
P34


embedded image


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




















TABLE 33







156
P34


embedded image


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





157
P34


embedded image


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





158
P34


embedded image


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





159
P34


embedded image


FAB+: 486






160
P34


embedded image


ESI+: 424
1′,2′-trans, 3,4-trans,





161
P34


embedded image


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




















TABLE 34







162
P34


embedded image


FAB+: 497
racemic mixture





163
P34


embedded image


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





164
P34


embedded image


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





165
P34


embedded image


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





166
P34


embedded image


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




















TABLE 35







167
P34


embedded image


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





168
P34


embedded image


FAB+: 486






169
P34


embedded image


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





170
P34


embedded image


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





171
P34


embedded image


FAB−: 531
racemic mixture




















TABLE 36







172
P34 P35 P36 P38


embedded image


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





38
P38


embedded image


ESI+: 512
racemic mixture





173
P38


embedded image


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





174
P38


embedded image


ESI+: 511




















TABLE 37







175
P38


embedded image


FAB+: 541
racemic mixture





176
P38


embedded image


FAB+: 541
racemic mixture





177
P38


embedded image


ESI+: 475
racemic mixture





178
P38


embedded image


FAB+: 541
racemic mixture




















TABLE 38







179
P38


embedded image


ESI+: 541
racemic mixture





180
P38


embedded image


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





181
P38


embedded image


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





182
P38


embedded image


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





183
P38


embedded image


FAB+: 541
racemic mixture




















TABLE 39







184
P34 P35 P36 P38


embedded image


ESI−: 617
racemic mixture





185
P38


embedded image


FAB+: 529
racemic mixture





186
P38


embedded image


FAB+: 529
racemic mixture





187
P38


embedded image


FAB+: 511






188
P38


embedded image


FAB+: 511




















TABLE 40







189
P38


embedded image


FAB+: 525
racemic mixture





 1
P1 


embedded image


ESI−: 285






 7
P7 


embedded image


CI+: 183






190
P39


embedded image


ESI+: 177






191
P39


embedded image


EI+: 180






 39
P39


embedded image


FAB+: 269






192
P23


embedded image


FAB+: 215






 23
P23


embedded image


EI+: 251



















TABLE 41







 27
P27


embedded image


FAB+: 303





 16
P16


embedded image


EI+: 172





193
P16


embedded image


EI+: 222





194
P16


embedded image


FAB+: 267





195
P16


embedded image


FAB+: 209





196
P16


embedded image


FAB−: 307





197
P16


embedded image


ESI+: 261 [M + Na]





198
P16


embedded image


ESI+: 239



















TABLE 42







 24
P24


embedded image


EI+: 237





199
P24


embedded image


EI+: 237





 2
P2 


embedded image


ESI+: 225





 12
P12


embedded image


EI+: 181





200
P8 


embedded image


FAB+: 342





 8
P8 


embedded image


FAB+: 298





201
P8 


embedded image


FAB+: 271





202
P8 


embedded image


APCI+: 384



















TABLE 43







203
P8


embedded image


ESI+: 384





204
P8


embedded image


ESI+: 412





205
P8


embedded image


FAB+: 356





206
P8


embedded image


ESI−: 368





207
P56 P8


embedded image


FAB+: 383





208
P8


embedded image


ESI+: 370





209
P40


embedded image


CI+: 139



















TABLE 44







210
P40


embedded image


FAB+: 210





211
P8 P40


embedded image


CI+: 140





212
P8 P40


embedded image


FAB+: 198





 40
P40


embedded image


FAB+: 141





213
P8 P40


embedded image


FAB+: 259





214
P40


embedded image


FAB+: 196





215
P40


embedded image


FAB+: 155





216
P8 P40


embedded image


FAB+: 164





217
P40


embedded image


FAB+: 210





218
P8 P40


embedded image


FAB+: 126




















TABLE 45







 26
P26


embedded image


FAB+: 244
racemic mixture





219
P25 P26


embedded image


FAB+: 244
racemic mixture





220
P26


embedded image


ESI+: 179






221
P26


embedded image


FAB+: 172






222
P26


embedded image


FAB+: 193






 41
P41


embedded image


FAB+: 128






 28
P28


embedded image


FAB+: 169






 3
P3


embedded image


CI+: 265






223
P40


embedded image


FAB+: 202



















TABLE 46







224
P40


embedded image


FAB+: 183





225
P40


embedded image


EI+: 148





226
P14 P9


embedded image


FAB+: 155





227
P9


embedded image


CI+: 212





 9
P9


embedded image


CI+: 168





228
P40


embedded image


ESI+: 168





229
P40


embedded image


FAB+: 150





230
P9


embedded image


EI+: 126





231
28 P9


embedded image


CI+: 130





232
P8 P9


embedded image


CI+: 145





233
P8 P9


embedded image


EI+: 138



















TABLE 47







234
P9


embedded image


EI+: 253





235
P9


embedded image


CI+: 238





236
P9


embedded image


EI+: 223





237
P9


embedded image


FAB+: 324





238
P9


embedded image


CI+: 196





239
P9


embedded image


CI+: 212





240
P9


embedded image


FAB+: 357





241
P9


embedded image


CI+: 143



















TABLE 48







242
P9


embedded image


FAB+: 202





243
P9


embedded image


CI+: 130





244
P9


embedded image


CI+: 143





245
P9


embedded image


FAB+: 238





246
P14 P40


embedded image


FAB+: 196





247
P9


embedded image


CI+: 231





248
P8 P9


embedded image


CI+: 180





249
P9


embedded image


CI+: 212





250
P9


embedded image


CI+: 130





251
P9


embedded image


CI+: 130





252
P9


embedded image


EI+: 115



















TABLE 49







253
P40


embedded image


FAB+: 188





254
P9


embedded image


ESI+: 254





255
P9


embedded image


ESI+: 254





256
P9


embedded image


ESI+: 282





257
P9


embedded image


CI+: 226





258
P9


embedded image


ESI+: 254





259
P9


embedded image


ESI+: 240





260
P9


embedded image


ESI+: 200



















TABLE 50







261
P9


embedded image


ESI+: 200













262
P9


embedded image


ESI+: 200





263
P9


embedded image


ESI+: 150





264
P9


embedded image


ESI+: 240





265
P32


embedded image


EI+: 152





266
P32


embedded image


ESI+: 114





267
P32


embedded image


ESI+: 146





 32
P32


embedded image


ESI+: 211





 13
P13


embedded image


FAB+: 141





 29
P29


embedded image


FAB+: 139




















TABLE 51







 10
P10


embedded image


FAB+: 196






 6
P6


embedded image


ESI−: 242






268
P33


embedded image


ESI+: 478
racemic mixture





269
P35 P36


embedded image


ESI+: 584
racemic mixture





270
P42


embedded image


FAB+: 454






271
P38


embedded image


ESI+: 556
racemic mixture



















TABLE 52







272
P33


embedded image


ESI+: 464





273
P42


embedded image


FAB+: 261





274
P9


embedded image


FAB+: 324





275
P35 P36


embedded image


ESI+: 569





 55
P55


embedded image


ESI+: 342



















TABLE 53







276
P8 


embedded image


ESI+: 342





277
P9  P40


embedded image


FAB+: 131





278
P9 


embedded image


ESI+: 254





279
P32


embedded image


ESI+: 212





280
P51 P40


embedded image


ESI+: 123





281
P14


embedded image


ESI+: 303





282
P8 


embedded image


ESI+: 333



















TABLE 54







 57
P57


embedded image


FAB+: 240





283
P9 


embedded image


ESI+: 173





284
P38


embedded image


EI+: 186





 52
P52


embedded image


EI+: 165





285
P60


embedded image


CI+: 243





286
P9 


embedded image


FAB+: 203





62
P62


embedded image


ESI+: 369





287
P32


embedded image


ESI+: 212



















TABLE 55







288
20


embedded image


ESI−: 327





289
P8  P9 


embedded image


FAB+: 203





290
P8  P9 


embedded image


FAB+: 181





291
P19


embedded image


CI+: 321





292
P8 


embedded image


ESI+: 310





293
P26


embedded image


FAB+: 229





294
P14


embedded image


ESI+: 402





295
P9 


embedded image


CI+: 274





296
P9 


embedded image


FAB+: 180




















TABLE 56







297
20


embedded image


FAB−: 341






298
P26


embedded image


ESI+: 243






299
P16


embedded image


ESI+: 170






300
P8  P9 


embedded image


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


embedded image


ESI+: 269






302
12


embedded image


ESI+: 603
racemic mixture




















TABLE 57







 44
P44


embedded image


ESI+: 565
racemic mixture





 58
P58


embedded image


EI+: 252






303
P32


embedded image


ESI+: 239






304
P62


embedded image


FAB+: 381






305
P8 


embedded image


FAB+: 341






306
P9 


embedded image


CI+: 211



















TABLE 58







307
P32


embedded image


ESI+: 252





308
P4 


embedded image


FAB+: 245





309
P8 


embedded image


FAB+: 390





310
P9 


embedded image


FAB+: 260





53-1
P53


embedded image


CI+: 182





53-2
P53


embedded image


EI+: 180





311
P14


embedded image


ESI+: 316



















TABLE 59







312
P48


embedded image


CI+: 268





313
P23


embedded image


FAB+: 272





 50
P50


embedded image


FAB+: 266





314
P12


embedded image


FAB+: 244





315
P4 


embedded image


FAB+: 328





 63
P63


embedded image


FAB+: 244





316
P14


embedded image


ESI+: 332



















TABLE 60







317
P8  P9  P40


embedded image


ESI+: 259





318
P14


embedded image


FAB+: 420





319
P9 


embedded image


CI+: 290





320
P48


embedded image


FAB+: 268





321
P14 P9 


embedded image


CI+: 274





322
P23


embedded image


EI+: 271





 61
P61


embedded image


FAB+: 167





323
P19


embedded image


CI+: 275, 277



















TABLE 61







324
P16 P8  P9 


embedded image


ESI+: 216





 46
P46


embedded image


ESI+: 171





 51
P51


embedded image


CI+: 153





325
P48


embedded image


ESI−: 222





326
P55


embedded image


ESI−: 222





327
P32


embedded image


APCI+: 213





328
P8 


embedded image


ESI+: 316





 47
P47


embedded image


APCI+: 169





329
P9 


embedded image


ESI+: 186



















TABLE 62







330
P19


embedded image


APCI+: 279





331
P30


embedded image


FAB+: 239





332
P55


embedded image


FAB+: 343





333
P23


embedded image


ESI+: 228





334
P57


embedded image


ESI+: 387





335
P16


embedded image


FAB+: 171





336
P32


embedded image


ESI+: 214





337
P61 P51


embedded image


EI+: 152



















TABLE 63







338
P61


embedded image


EI+: 249





339
P26


embedded image


ESI+: 287





340
P48


embedded image


ESI+: 214





341
P8 


embedded image


APCI−: 314





342
P51


embedded image


FAB+: 236





343
P16


embedded image


FAB−: 199





344
P56


embedded image


FAB+: 386



















TABLE 64







345
P26


embedded image


ESI+: 286





346
P61 P51


embedded image


CI+: 222





 54
P54


embedded image


FAB+: 139





347
P8 


embedded image


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 = 4.21 Hz), 7.82-7.93 (4H, m)





 48
P48


embedded image


CI+: 218





348
P23


embedded image


EI+: 221




















TABLE 65







349
P61 P51


embedded image


FAB+: 252






350
P36


embedded image


ESI+: 506
racemic mixture





351
P38


embedded image


ESI+: 478
racemic mixture





 49
P49


embedded image


CI+: 184






352
P61 P51


embedded image


FAB+: 195



















TABLE 66







 56
P56


embedded image


ESI+: 248





 59
P59


embedded image


ESI+: 300





353
P56


embedded image


EI+: 264





354
P61 P51


embedded image


CI+: 266





355
P23


embedded image


ESI+: 296





 45
P45


embedded image


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 


embedded image


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






357
P16 P8 


embedded image


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


embedded image


ESI+: 450
racemic mixture





359
P9 


embedded image


ESI+: 152






360
P48


embedded image


ESI+: 224




















TABLE 68







361
P8  P9 


embedded image


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


embedded image


ESI+: 228






363
P33 P34


embedded image


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





364
P33 P34


embedded image


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





365
P33 P34


embedded image


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




















TABLE 69







366
P33 P34


embedded image


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





367
P33 P34


embedded image


ESI+: 486






368
P33 P34


embedded image


ESI+: 511
racemic mixture





 60
P60


embedded image


EI+: 182






369
P19


embedded image


EI+: 260, 262






370
P48


embedded image


ESI−: 206






371
P23


embedded image


ESI+: 212


















TABLE 70





Ex
Structure
Note







60


embedded image








61


embedded image








62


embedded image








63


embedded image


racemic mixture





64


embedded image




















TABLE 71







65


embedded image








66


embedded image


racemic mixture





67


embedded image


racemic mixture





68


embedded image








69


embedded image


racemic mixture


















TABLE 72







70


embedded image


racemic mixture





71


embedded image








72


embedded image


racemic mixture





73


embedded image


racemic mixture





74


embedded image


racemic mixture


















TABLE 73







75


embedded image


racemic mixture





 1


embedded image


racemic mixture





76


embedded image


racemic mixture





77


embedded image


racemic mixture





78


embedded image




















TABLE 74







 3


embedded image


racemic mixture





79


embedded image


racemic mixture





80


embedded image


racemic mixture





81


embedded image








82


embedded image


racemic mixture


















TABLE 75







83


embedded image


racemic mixture





84


embedded image


racemic mixture





85


embedded image


racemic mixture





86


embedded image


racemic mixture





37


embedded image


racemic mixture


















TABLE 76







87


embedded image








88


embedded image


racemic mixture





89


embedded image


racemic mixture





90


embedded image








91


embedded image


racemic mixture


















TABLE 77







92


embedded image


racemic mixture





93


embedded image


racemic mixture





94


embedded image








95


embedded image


racemic mixture





96


embedded image


racemic mixture





97


embedded image


racemic mixture


















TABLE 78







 98


embedded image


racemic mixture





 99


embedded image


racemic mixture





100


embedded image


racemic mixture





101


embedded image


racemic mixture





102


embedded image








103


embedded image


racemic mixture


















TABLE 79







104


embedded image


racemic mixture





105


embedded image


racemic mixture





106


embedded image


racemic mixture





107


embedded image


racemic mixture





108


embedded image








 2


embedded image


racemic mixture


















TABLE 80







109


embedded image


racemic mixture





 39


embedded image


racemic mixture





110


embedded image


racemic mixture





111


embedded image


racemic mixture





 4


embedded image


racemic mixture


















TABLE 81







112


embedded image








113


embedded image


racemic mixture





114


embedded image


racemic mixture





115


embedded image


racemic mixture





116


embedded image


racemic mixture





117


embedded image


racemic mixture


















TABLE 82







118


embedded image








119


embedded image


racemic mixture





120


embedded image


racemic mixture





121


embedded image


racemic mixture





122


embedded image


racemic mixture





123


embedded image


racemic mixture


















TABLE 83







124


embedded image


racemic mixture





36


embedded image


racemic mixture





125


embedded image


racemic mixture





126


embedded image


racemic mixture





127


embedded image


racemic mixture





38


embedded image


racemic mixture


















TABLE 84







128


embedded image


racemic mixture





7


embedded image


racemic mixture





129


embedded image


racemic mixture





130


embedded image


racemic mixture





10


embedded image


racemic mixture


















TABLE 85







131


embedded image


racemic mixture





132


embedded image


racemic mixture





133


embedded image


racemic mixture





134


embedded image


racemic mixture


















TABLE 86







135


embedded image


racemic mixture





136


embedded image


racemic mixture





137


embedded image


racemic mixture





138


embedded image


racemic mixture


















TABLE 87







139


embedded image


racemic mixture





140


embedded image


racemic mixture





141


embedded image


racemic mixture





142


embedded image


racemic mixture


















TABLE 88







143


embedded image


racemic mixture





144


embedded image


racemic mixture





145


embedded image


3,4-trans, diastereo mixture





146


embedded image


racemic mixture


















TABLE 89







147


embedded image








9


embedded image


racemic mixture





148


embedded image


1′,2′- 3,4-trans, diastereomer of Ex 149, more polar





149


embedded image


1′,2′- 3,4-trans, diastereomer of Ex 148, more polar


















TABLE 90







11


embedded image


racemic mixture





150


embedded image


racemic mixture





151


embedded image








152


embedded image


racemic mixture





153


embedded image


racemic mixture


















TABLE 91







154


embedded image








155


embedded image








156


embedded image








157


embedded image








158


embedded image


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


















TABLE 92







159


embedded image


1′,2′-trans, 3,4-trans, diastereomer of Ex 160, less polar





160


embedded image


1′,2′-trans, 3,4-trans, diastereomer of Ex 159, more polar





161


embedded image


racemic mixture





162


embedded image


racemic mixture





163


embedded image


racemic mixture


















TABLE 93







164


embedded image


racemic mixture





165


embedded image


racemic mixture





166


embedded image


racemic mixture





167


embedded image


racemic mixture





168


embedded image


1′,2′-cis, 3,4-trans, racemic mixture


















TABLE 94







169


embedded image


racemic mixture





170


embedded image


racemic mixture





171


embedded image


racemic mixture





172


embedded image


racemic mixture





173


embedded image


racemic mixture


















TABLE 95







174


embedded image


racemic mixture





175


embedded image


racemic mixture





176


embedded image


racemic mixture





177


embedded image


racemic mixture





178


embedded image


racemic mixture


















TABLE 96







34


embedded image


racemic mixture





179


embedded image


racemic mixture





180


embedded image


racemic mixture





181


embedded image


racemic mixture





182


embedded image


racemic mixture


















TABLE 97







183


embedded image


racemic mixture





184


embedded image








185


embedded image


1′,2′-trans, 3,4-trans, diastereomer of Ex 186, less polar





186


embedded image


1′,2′-trans, 3,4-trans, diastereomer of Ex 185,





187


embedded image


racemic mixture


















TABLE 98







188


embedded image








189


embedded image


1′,2′- trans, 3,4- trans, dia- stereo- mer of Ex190, less polar





190


embedded image


1′,2′- trans, 3,4- trans, dia- stereo- mer of Ex189, more polar





191


embedded image


3,4- trans, dia- stereo- mer of Ex192, less polar





192


embedded image


3,4- trans, dia- stereo- mer of Ex191, more polar


















TABLE 99







193


embedded image


racemic mixture





194


embedded image








195


embedded image








196


embedded image


3,4-trans, dia- stereo- mer of Ex197, less polar





197


embedded image


3,4-trans, dia- stereo- mer of Ex196, more polar


















TABLE 100







198


embedded image


1′,2′- trans, 3,4- trans, dia- stereo- mer of Ex199, less polar





199


embedded image


1′,2′- trans, 3,4- trans, dia- stereo- mer of Ex198, more polar





200


embedded image


1′,2′- trans, 3,4- trans, dia- stereo- mer of Ex201, less polar





201


embedded image


1′,2′- trans, 3,4- trans, dia- stereo- mer of Ex200, more polar





202


embedded image


3,4-trans


















TABLE 101







203


embedded image


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





204


embedded image


racemic mixture





205


embedded image


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





206


embedded image


3,4-trans, distereo mixture





207


embedded image


3,4-trans distereo mixture


















TABLE 102







208


embedded image


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





209


embedded image


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





210


embedded image


racemic mixture





211


embedded image


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





212


embedded image


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


















TABLE 103







213


embedded image


race- mic mix- ture





214


embedded image








215


embedded image








216


embedded image


race- mic mix- ture





217


embedded image


race- mic mix- ture


















TABLE 104







218


embedded image








219


embedded image








220


embedded image


3,4-trans





221


embedded image


racemic mixture





222


embedded image


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


















TABLE 105







223


embedded image


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





224


embedded image


1′,2′-trans, 3,4-trans





225


embedded image


1′,2′-trans, 3,4-trans





226


embedded image


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





227


embedded image


racemic mixture


















TABLE 106







228


embedded image


racemic mixture





229


embedded image


racemic mixture





230


embedded image


racemic mixture





231


embedded image


racemic mixture


















TABLE 107







232


embedded image


racemic mixture





233


embedded image


racemic mixture





234


embedded image


racemic mixture





235


embedded image




















TABLE 108







236


embedded image








237


embedded image








238


embedded image


racemic mixture





239


embedded image


racemic mixture


















TABLE 109







240


embedded image


racemic mixture





241


embedded image


racemic mixture





242


embedded image


racemic mixture





243


embedded image


racemic mixture


















TABLE 110







244


embedded image


racemic mixture





245


embedded image


racemic mixture





246


embedded image


racemic mixture





247


embedded image


racemic mixture


















TABLE 111







248


embedded image


racemic mixture





249


embedded image


racemic mixture





250


embedded image


racemic mixture





251


embedded image


racemic mixture


















TABLE 112







252


embedded image


racemic mixture





253


embedded image


racemic mixture





254


embedded image


racemic mixture





255


embedded image


racemic mixture


















TABLE 113







256


embedded image


racemic mixture





257


embedded image








258


embedded image


racemic mixture





259


embedded image


racemic mixture


















TABLE 114







260


embedded image


3,4-trans, diatereo mixture





261


embedded image


racemic mixture





262


embedded image


racemic mixture





263


embedded image


racemic mixture


















TABLE 115







264


embedded image


racemic mixture





265


embedded image


3,4-trans, diastereomer of Ex 266, less polar





266


embedded image


3,4-trans, diastereomer of Ex 265, more polar





267


embedded image


racemic mixture





268


embedded image


racemic mixture


















TABLE 116







269


embedded image


racemic mixture





270


embedded image


3,4-trans





271


embedded image


diastereomer of Ex 275, more polar





272


embedded image


racemic mixture


















TABLE 117







273


embedded image


racemic mixture





274


embedded image


racemic mixture





275


embedded image


diastereomer of Ex 271, less polar





276


embedded image


racemic mixture





277


embedded image




















TABLE 118







278


embedded image








279


embedded image


racemic mixture





280


embedded image


racemic mixture





281


embedded image


racemic mixture


















TABLE 119







282


embedded image


racemic mixture





283


embedded image


racemic mixture





284


embedded image


3,4- trans, diatereo mixture





285


embedded image


3,4- trans, diatereo mixture


















TABLE 120







286


embedded image


3,4-trans, diatereo mixture





287


embedded image


3,4-trans, diastereo mixture





288


embedded image


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





289


embedded image


1′,2′-trans, 3,4-trans, diaste- reomer of Ex 290, more polar





290


embedded image


racemic mixture, diaste- reomer of Ex 289, less polar


















TABLE 121







291


embedded image


racemic mixture





292


embedded image


racemic mixture





293


embedded image


3,4-trans, diastereomer of Ex 294, less polar





294


embedded image


3,4-trans, diastereomer of Ex 293, more polar


















TABLE 122







295


embedded image


racemic mixture





296


embedded image


3,4-trans





297


embedded image


racemic mixture





298


embedded image


racemic mixture


















TABLE 123







299


embedded image


racemic mixture





300


embedded image


racemic mixture





301


embedded image


racemic mixture





302


embedded image


racemic mixture, diastereomer of Ex 306, less polar


















TABLE 124







303


embedded image


racemic mixture





304


embedded image


racemic mixture





305


embedded image


racemic mixture





306


embedded image


racemic mixture, diastereomer of Ex 302, more polar


















TABLE 125







307


embedded image


racemic mixture





308


embedded image


racemic mixture





309


embedded image


racemic mixture





310


embedded image


racemic mixture


















TABLE 126







311


embedded image


racemic mixture





312


embedded image


racemic mixture





313


embedded image


racemic mixture





314


embedded image


racemic mixture


















TABLE 127







315


embedded image


racemic mixture





316


embedded image


racemic mixture





317


embedded image


racemic mixture





318


embedded image


racemic mixture


















TABLE 128







319


embedded image


racemic mixture





320


embedded image


racemic mixture





321


embedded image


racemic mixture





322


embedded image


racemic mixture


















TABLE 129







323


embedded image


racemic mixture





324


embedded image


racemic mixture





325


embedded image


racemic mixture





326


embedded image


racemic mixture


















TABLE 130







327


embedded image


racemic mixture





328


embedded image








329


embedded image








330


embedded image




















TABLE 131







331


embedded image


racemic mixture





332


embedded image








333


embedded image








334


embedded image


racemic mixture


















TABLE 132







335


embedded image


racemic mixture





336


embedded image


racemic mixture





337


embedded image


racemic mixture





338


embedded image


racemic mixture


















TABLE 133







339


embedded image


racemic mixture





340


embedded image


racemic mixture





341


embedded image


racemic mixture





342


embedded image


chiral compound, diastereomer of Ex 143, less polar


















TABLE 134







343


embedded image


chiral compound diastereomer of Ex 342, more polar





344


embedded image


racemic mixture





345


embedded image


racemic mixture





346


embedded image


racemic mixture


















TABLE 135







347


embedded image


racemic mixture





348


embedded image


racemic mixture





349


embedded image


racemic mixture





350


embedded image


racemic mixture


















TABLE 136







351


embedded image


racemic mixture





352


embedded image


racemic mixture





353


embedded image


racemic mixture





354


embedded image


racemic mixture


















TABLE 137







355


embedded image


racemic mixture





356


embedded image


racemic mixture





357


embedded image


racemic mixture





358


embedded image


diastereo mixture


















TABLE 138







359


embedded image








360


embedded image


racemic mixture





361


embedded image


racemic mixture





362


embedded image


racemic mixture


















TABLE 139







363


embedded image


racemic mixture





364


embedded image


racemic mixture





365


embedded image


racemic mixture





366


embedded image


diastereo mixture


















TABLE 140







367


embedded image


racemic mixture





368


embedded image


racemic mixture





369


embedded image


racemic mixture





370


embedded image


racemic mixture


















TABLE 141







371


embedded image


racemic mixture





372


embedded image


racemic mixture





373


embedded image


racemic mixture





374


embedded image


racemic mixture


















TABLE 142







375


embedded image


racemic mixture, diastereomer of Ex 377, more polar





376


embedded image


racemic mixture





377


embedded image


racemic mixture, diastereomer of Ex 377, less polar





378


embedded image


racemic mixture


















TABLE 143







379


embedded image


racemic mixture





380


embedded image


racemic mixture





381


embedded image


racemic mixture





382


embedded image




















TABLE 144







383


embedded image


racemic mixture





384


embedded image








385


embedded image








386


embedded image


chiral compound, diastereomer of Ex387, less polar


















TABLE 145







387


embedded image


chiral compound, diastereomer of Ex386, more polar





388


embedded image


racemic mixture





389


embedded image


racemic mixture





390


embedded image


racemic mixture


















TABLE 146







391


embedded image


racemic Mixture





392


embedded image


racemic mixture





393


embedded image


racemic mixture





394


embedded image


racemic mixture


















TABLE 147







395


embedded image


racemic mixture





396


embedded image


racemic mixture





397


embedded image


racemic mixture





398


embedded image


racemic mixture


















TABLE 148







399


embedded image


racemic mixture





400


embedded image








401


embedded image








402


embedded image


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





403


embedded image


racemic mixture


















TABLE 149







404


embedded image


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





405


embedded image


racemic mixture





406


embedded image


racemic mixture





407


embedded image








408


embedded image




















TABLE 150







409


embedded image


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





410


embedded image


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





411


embedded image


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





412


embedded image


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





413


embedded image




















TABLE 151







414


embedded image


1′,2′-trans, 3,4-trans





415


embedded image








416


embedded image








417


embedded image








418


embedded image




















TABLE 152







419


embedded image








420


embedded image


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





421


embedded image


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





422


embedded image


racemic mixture





423


embedded image


racemic mixture


















TABLE 153







424


embedded image


racemic mixture





425


embedded image








426


embedded image








427


embedded image


racemic mixture





428


embedded image


racemic mixture


















TABLE 154







429


embedded image


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





430


embedded image


racemic mixture





431


embedded image








432


embedded image


racemic mixture





433


embedded image


3,4-trans, diastereo mixture





434


embedded image


3,4-trans, diastereo mixture


















TABLE 155







435


embedded image


racemic mixture





436


embedded image


3,4-trans





437


embedded image


racemic mixture





438


embedded image


1′,2′-trans, 3,4-trans





439


embedded image


racemic mixture


















TABLE 156







440


embedded image


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





441


embedded image


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





442


embedded image


1′,2′-trans, 3,4-trans





443


embedded image


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





444


embedded image


racemic mixture


















TABLE 157







445


embedded image








446


embedded image








447


embedded image








448


embedded image








449


embedded image


1′,2′-trans, 3,4-trans


















TABLE 158







450


embedded image


racemic mixture





451


embedded image


racemic mixture





452


embedded image


racemic mixture





453


embedded image


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





454


embedded image


1′,2′-cis, 3,4- trans, diastere- omer of Ex455


















TABLE 159







455


embedded image


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





456


embedded image


1′,2′- trans, 3,4- trans





457


embedded image


1′,2′- trans, 3,4- trans, diastere- omer of Ex456





458


embedded image


3,4-trans





459


embedded image


chiral com- pound, 3,4-trans


















TABLE 160







460


embedded image


race- mic mix- ture





461


embedded image


race- mic mix- ture





462


embedded image


race- mic mix- ture





463


embedded image


race- mic mix- ture


















TABLE 161







464


embedded image


racemic mixture





465


embedded image


racemic mixture





466


embedded image


racemic mixture





467


embedded image




















TABLE 162







468


embedded image


racemic mixture





469


embedded image


racemic mixture





470


embedded image


racemic mixture





471


embedded image


racemic mixture


















TABLE 163







472


embedded image


racemic mixture





473


embedded image


racemic mixture





474


embedded image


racemic mixture





475


embedded image


racemic mixture


















TABLE 164







476


embedded image


racemic mixture





477


embedded image


racemic mixture





478


embedded image


racemic mixture





479


embedded image


racemic mixture


















TABLE 165







480


embedded image


racemic mixture





481


embedded image


racemic mixture





482


embedded image


racemic mixture





483


embedded image


racemic mixture





484


embedded image


racemic mixture


















TABLE 166







485


embedded image


racemic mixture





486


embedded image


racemic mixture





487


embedded image


racemic mixture





488


embedded image


racemic mixture





489


embedded image


racemic mixture


















TABLE 167







490


embedded image


racemic mixture





491


embedded image


racemic mixture





492


embedded image


racemic mixture





493


embedded image


racemic mixture





494


embedded image


racemic mixture


















TABLE 168







495


embedded image


racemic mixture





496


embedded image


racemic mixture





497


embedded image


racemic mixture





498


embedded image


racemic mixture





499


embedded image


racemic mixture


















TABLE 169







500


embedded image


racemic mixture





501


embedded image


racemic mixture





502


embedded image


racemic mixture





503


embedded image


racemic mixture





504


embedded image


racemic mixture


















TABLE 170







505


embedded image


racemic mixture





506


embedded image


racemic mixture





507


embedded image


racemic mixture





32


embedded image


racemic mixture


















TABLE 171







508


embedded image


racemic mixture





509


embedded image


racemic mixture





510


embedded image


racemic mixture





511


embedded image


racemic mixture





512


embedded image


racemic mixture


















TABLE 172







513


embedded image


racemic mixture





514


embedded image


racemic mixture





515


embedded image


racemic mixture





 33


embedded image


racemic mixture





516


embedded image


1′,2′-trans, 3,4-trans


















TABLE 173







517


embedded image


1′,2′-trans, 3,4-trans





518


embedded image


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





519


embedded image


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





520


embedded image


1′,2′-trans, 3,4-trans


















TABLE 174







521


embedded image


1′,2′-trans, 3,4-trans





522


embedded image


1′,2′-trans, 3,4-trans





523


embedded image


1′,2′-trans, 3,4-trans





524


embedded image


3,4-trans, racemic mixture


















TABLE 175







525


embedded image


3,4-trans





526


embedded image


3,4-trans





 35


embedded image


racemic mixture





527


embedded image


racemic mixture


















TABLE 176







528


embedded image


racemic mixture





529


embedded image








530


embedded image


racemic mixture





531


embedded image




















TABLE 177







532


embedded image


racemic mixture





533


embedded image


racemic mixture





534


embedded image


racemic mixture





535


embedded image


racemic mixture


















TABLE 178







536


embedded image


racemic mixture





537


embedded image


racemic mixture





538


embedded image


racemic mixture





539


embedded image


racemic mixture


















TABLE 179







540


embedded image


racemic mixture





541


embedded image








542


embedded image








543


embedded image


racemic mixture


















TABLE 180







544


embedded image


racemic mixture





545


embedded image


racemic mixture





546


embedded image


racemic mixture





547


embedded image


racemic mixture


















TABLE 181







548


embedded image


racemic mixture





549


embedded image


racemic mixture





550


embedded image


racemic mixture





551


embedded image


racemic mixture


















TABLE 182







552


embedded image


racemic mixture





553


embedded image


racemic mixture





554


embedded image


racemic mixture





555


embedded image





















TABLE 183







556


embedded image








557


embedded image








558


embedded image


racemic mixture





559


embedded image


racemic mixture


















TABLE 184







560


embedded image








561


embedded image


racemic mixture





562


embedded image


racemic mixture





563


embedded image


racemic mixture


















TABLE 185







564


embedded image


racemic mixture





565


embedded image


racemic mixture





566


embedded image


racemic mixture





567


embedded image


racemic mixture


















TABLE 186







568


embedded image


racemic mixture





569


embedded image


racemic mixture





570


embedded image








571


embedded image


racemic mixture


















TABLE 187







572


embedded image


racemic mixture





573


embedded image


3,4-trans racemic mixture





574


embedded image


racemic mixture





575


embedded image


racemic mixture


















TABLE 188







576


embedded image


racemic mixture





577


embedded image


racemic mixture





578


embedded image


3,4-trans





 16


embedded image


racemic mixture





 15


embedded image


racemic mixture


















TABLE 189







22


embedded image


racemic mixture





43


embedded image


racemic mixture





29


embedded image


racemic mixture


















TABLE 190







 23


embedded image


racemic mixture





 41


embedded image


racemic mixture





579


embedded image


racemic mixture





 13


embedded image


racemic mixture


















TABLE 191







580


embedded image


racemic mixture





581


embedded image


racemic mixture, diastereomer of Ex582, less polar





582


embedded image


racemic mixture, diastereomer of Ex581, more polar





583


embedded image


racemic mixture


















TABLE 192







 14


embedded image


racemic mixture





584


embedded image


racemic mixture





 12


embedded image


racemic mixture





585


embedded image


racemic mixture


















TABLE 193







586


embedded image








587


embedded image


diastere- omer of Ex594, less polar





588


embedded image


racemic mixture





589


embedded image




















TABLE 194







590


embedded image


racemic mixture





591


embedded image


racemic mixture





592


embedded image


racemic mixture





593


embedded image


racemic mixture


















TABLE 195







594


embedded image


diastere- omer of Ex587, more polar





595


embedded image


racemic mixture





596


embedded image


racemic mixture





 18


embedded image


racemic mixture


















TABLE 196







597


embedded image


racemic mixture





598


embedded image


chiral com- pound, diaste- reomer of Ex599





599


embedded image


chiral com- pound, diaste- reomer of Ex598





600


embedded image


racemic mixture


















TABLE 197







 21


embedded image


racemic mixture





601


embedded image


racemic mixture





 20


embedded image


racemic mixture





 27


embedded image


1′,2′-trans, 3,4-trans


















TABLE 198







 40


embedded image


racemic mixture





602


embedded image


racemic mixture





 8


embedded image


racemic mixture





603


embedded image


racemic mixture





604


embedded image


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


















TABLE 199







605


embedded image


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





606


embedded image








 6


embedded image


racemic mixture





607


embedded image








 42


embedded image


racemic mixture


















TABLE 200







 31


embedded image


racemic mixture





608


embedded image


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





609


embedded image


racemic mixture





610


embedded image


racemic mixture





611


embedded image


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


















TABLE 201







612


embedded image








613


embedded image








614


embedded image








615


embedded image








616


embedded image


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





617


embedded image




















TABLE 202







618


embedded image








619


embedded image


racemic mixture





620


embedded image


racemic mixture





 5


embedded image


racemic mixture





621


embedded image


racemic mixture


















TABLE 203







 30


embedded image


racemic mixture





622


embedded image


racemic mixture





623


embedded image


1′,2′-trans, 3,4-trans, diastere- omer of Ex624





 28


embedded image


1′,2′-cis, 3,4- trans





624


embedded image


1′,2′-trans, 3,4-trans, diastere- omer of Ex623


















TABLE 204







 24


embedded image


racemic mixture





625


embedded image


racemic mixture





626


embedded image


racemic mixture





627


embedded image


racemic mixture


















TABLE 205







628


embedded image


racemic mixture





629


embedded image


racemic mixture





630


embedded image


racemic mixture





631


embedded image




















TABLE 206







632


embedded image


racemic mixture





633


embedded image


racemic mixture





 19


embedded image


racemic mixture





634


embedded image


racemic mixture


















TABLE 207







635


embedded image


racemic mixture





636


embedded image


racemic mixture





 25


embedded image


racemic mixture





637


embedded image


racemic mixture


















TABLE 208







 26


embedded image


racemic mixture





 17-2


embedded image


racemic mixture





 17-1


embedded image


3,4-trans





638


embedded image




















TABLE 209







639


embedded image








640


embedded image


racemic mixture





 53


embedded image


racemic mixture





641


embedded image


racemic mixture


















TABLE 210







642


embedded image


racemic mixture





 45


embedded image


racemic mixture





643


embedded image


racemic mixture


















TABLE 211







644


embedded image


racemic mixture





645


embedded image


racemic mixture





646


embedded image


racemic mixture





647


embedded image




















TABLE 212







648


embedded image








649


embedded image








650


embedded image


racemic mixture





651


embedded image


racemic mixture


















TABLE 213







 52


embedded image


racemic mixture





652


embedded image


racemic mixture





653


embedded image


racemic mixture





654


embedded image


racemic mixture


















TABLE 214







655


embedded image








656


embedded image


chiral compound, diastereomer of Ex657, more polar





657


embedded image


chiral compound, diastereomer of Ex656, less polar





 51


embedded image


racemic mixture


















TABLE 215







658


embedded image


racemic mixture





659


embedded image


chiral compound, diastereomer of Ex667, more polar





660


embedded image


racemic mixture





661


embedded image




















TABLE 216







662


embedded image








663


embedded image








664


embedded image


racemic mixture





665


embedded image


racemic mixture


















TABLE 217







666


embedded image


racemic mixture





667


embedded image


chiral compound, diastereomer of Ex659, less more





668


embedded image


racemic mixture





 46


embedded image


racemic mixture


















TABLE 218







669


embedded image


racemic mixture





670


embedded image


racemic mixture





47


embedded image


racemic mixture


















TABLE 219







671


embedded image


racemic mixture





672


embedded image


racemic mixture





673


embedded image


racemic mixture


















TABLE 220







674


embedded image


racemic mixture





675


embedded image


racemic mixture





676


embedded image


racemic mixture





677


embedded image


racemic mixture


















TABLE 221







678


embedded image


racemic mixture





679


embedded image








680


embedded image








681


embedded image


racemic mixture


















TABLE 222







982


embedded image


racemic mixture





683


embedded image


racemic mixture





684


embedded image


racemic mixture





49


embedded image


racemic mixture


















TABLE 223







685


embedded image


racemic mixture





686


embedded image


racemic mixture





687


embedded image


racemic mixture





688


embedded image


racemic mixture


















TABLE 224







55


embedded image


racemic mixture





689


embedded image


racemic mixture





690


embedded image


racemic mixture





691


embedded image


racemic mixture


















TABLE 225







692


embedded image


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





693


embedded image


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





54


embedded image


racemic mixture





694


embedded image


racemic mixture


















TABLE 226







695


embedded image


racemic mixture





696


embedded image


racemic mixture





697


embedded image


racemic mixture





698


embedded image




















TABLE 227







699


embedded image


racemic mixture





700


embedded image








701


embedded image








702


embedded image


racemic mixture





703


embedded image


racemic mixture


















TABLE 228







704


embedded image


racemic mixture





705


embedded image


racemic mixture





706


embedded image








707


embedded image


racemic mixture





708


embedded image


racemic mixture


















TABLE 229







44


embedded image


racemic mixture





709


embedded image








710


embedded image








711


embedded image


racemic mixture


















TABLE 230







712


embedded image








713


embedded image


racemic mixture





714


embedded image


racemic mixture





715


embedded image




















TABLE 231







57


embedded image


racemic mixture





716


embedded image


racemic mixture





717


embedded image


racemic mixture





718


embedded image




















TABLE 232







719


embedded image


racemic mixture





720


embedded image


racemic mixture





721


embedded image








722


embedded image








723


embedded image


chiral compound, diastereomer of Ex724, more polar


















TABLE 233







724


embedded image


chiral compound, diastereomer of Ex 723, less polar





725


embedded image


racemic mixture





726


embedded image


chiral compound, diastereomer of Ex 727, less polar


















TABLE 234







727


embedded image


chiral compound, diastereomer of Ex 726, more polar





728


embedded image


racemic mixture





729


embedded image


chiral compound, diastereomer of Ex 733, more polar





730


embedded image


racemic mixture


















TABLE 235







731


embedded image


racemic mixture





732


embedded image


racemic mixture





733


embedded image


chiral compound, diastereomer of Ex 729, less polar


















TABLE 236







734


embedded image


chiral compound, diastereomer of Ex 735, more polar





735


embedded image


chiral compound, diastereomer of Ex 734, less polar





736


embedded image


chiral compound, diastereomer of Ex 738, more polar


















TABLE 237







737


embedded image


chiral compound





738


embedded image


chiral compound, diastereomer of Ex 736, less polar





739


embedded image


racemic mixture





740


embedded image


racemic mixture


















TABLE 238







741


embedded image


racemic mixture





742


embedded image


racemic mixture, diastereomer of Ex 743, less polar





743


embedded image


racemic mixture, diastereomer of Ex 742, more polar





744


embedded image


racemic mixture, diastereomer of Ex 749, less polar





745


embedded image


racemic mixture


















TABLE 239







746


embedded image


racemic mixture





747


embedded image


racemic mixture





748


embedded image


racemic mixture





 59


embedded image




















TABLE 240







749


embedded image


racemic mixture, diastereomer of Ex 744, more polar





750


embedded image


racemic mixture





751


embedded image


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





752


embedded image








753


embedded image


racemic mixture


















TABLE 241







754


embedded image








755


embedded image


racemic mixture





756


embedded image


chiral compound, diastereomer of Ex 757, less polar





757


embedded image


chiral compound, diastereomer of Ex 756, more polar


















TABLE 242







758


embedded image


racemic mixture





 50


embedded image


chiral compound





759


embedded image








760


embedded image




















TABLE 243







761


embedded image








762


embedded image








763


embedded image








764


embedded image


racemic mixture


















TABLE 244







765


embedded image








766


embedded image


racemic mixture





767


embedded image


racemic mixture





768


embedded image


racemic mixture


















TABLE 245







769


embedded image


racemic mixture





770


embedded image








771


embedded image


racemic mixture





772


embedded image


racemic mixture


















TABLE 246







773


embedded image








774


embedded image


racemic mixture





775


embedded image








776


embedded image


racemic mixture


















TABLE 247







777


embedded image


racemic mixture





 48


embedded image


racemic mixture





778


embedded image








779


embedded image




















TABLE 248







780


embedded image








781


embedded image








782


embedded image


racemic mixture





783


embedded image


chiral compound, diastereomer of Ex784, less polar


















TABLE 249







784


embedded image


chiral compound, diastereomer of Ex783, more polar





785


embedded image








786


embedded image








787


embedded image


chiral compound


















TABLE 250







788


embedded image


racemic mixture





789


embedded image


racemic mixture





790


embedded image








791


embedded image








792


embedded image




















TABLE 251







793


embedded image


racemic mixture





794


embedded image


diastereo mixure





795


embedded image


chiral compound, diastereomer of Ex796, less polar


















TABLE 252







796


embedded image


chiral compound, diastereomer of Ex795, more polar





797


embedded image


racemic mixture





798


embedded image


chiral compound, diastereomer of Ex799, less polar





799


embedded image


chiral compound, diastereomer of Ex798, more polar


















TABLE 253







800


embedded image


diastereo mixure





801


embedded image


chiral compound





802


embedded image


diastereo mixure





803


embedded image


chiral compound


















TABLE 254







804


embedded image


racemic mixture





805


embedded image


chiral compound





 56


embedded image


chiral compound





806


embedded image


racemic mixture


















TABLE 255







807


embedded image


racemic mixture





808


embedded image


racemic mixture





809


embedded image


racemic mixture





810


embedded image


chiral compound, diastereomer of Ex811, less polar


















TABLE 256







811


embedded image


chiral compound, diastereomer of Ex810, more polar





812


embedded image








813


embedded image


racemic mixture





814


embedded image


chiral compound, diastereomer of Ex815, less polar


















TABLE 257







815


embedded image


chiral compound, diastereomer of Ex814, more polar





816


embedded image


racemic mixture





817


embedded image








818


embedded image




















TABLE 258







819


embedded image


racemic mixture





820


embedded image


racemic mixture





821


embedded image








822


embedded image


racemic mixture


















TABLE 259







823


embedded image


racemic mixture





824


embedded image


racemic mixture





825


embedded image


racemic mixture





826


embedded image


racemic mixture


















TABLE 260







827


embedded image


racemic mixture





828


embedded image








829


embedded image


racemic mixture





 58


embedded image




















TABLE 261







830


embedded image


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





831


embedded image


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





832


embedded image


chiral compound, diastereomer of Ex833, less polar





833


embedded image


chiral compound, diastereomer of Ex832, more polar





834


embedded image


racemic mixture


















TABLE 262







835


embedded image


diastereo mixture





836


embedded image


racemic mixture





837


embedded image


racemic mixture





838


embedded image


racemic mixture





839


embedded image


racemic mixture


















TABLE 263







840


embedded image


racemic mixture





841


embedded image


diastereo mixture





842


embedded image


diastereo mixture





843


embedded image




















TABLE 264







844


embedded image


racemic mixture





845


embedded image








846


embedded image


racemic mixture





847


embedded image


chiral com- pound, 3,4-trans





848


embedded image


racemic mixture, dia- stereomer of Ex849, less polar


















TABLE 265







849


embedded image


racemic mixture, diastereomer of Ex848, more polar





850


embedded image


racemic mixture, diastereomer of Ex851, less polar





851


embedded image


racemic mixture, diastereomer of Ex850, more polar





852


embedded image








853


embedded image


racemic mixture


















TABLE 266







854


embedded image


chiral compound, diastereomer of Ex855, less polar





855


embedded image


chiral compound, diastereomer of Ex854, more polar





856


embedded image








857


embedded image


racemic mixture





858


embedded image


racemic mixture


















TABLE 267







859


embedded image


racemic mixture





860


embedded image


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





861


embedded image


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





862


embedded image


racemic mixture





863


embedded image


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





864


embedded image


racemic mixture


















TABLE 268







865


embedded image


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





866


embedded image


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





867


embedded image


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





868


embedded image


racemic mixture





869


embedded image


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


















TABLE 269







870


embedded image


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





871


embedded image


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





872


embedded image


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





873


embedded image


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





874


embedded image


1′,2′-trans, 3,4-trans


















TABLE 270







875


embedded image


1′,2′-trans, 3,4-trans





876


embedded image








877


embedded image








878


embedded image


racemic mixture


















TABLE 271







879


embedded image


racemic mixture





880


embedded image








881


embedded image


racemic mixture





882


embedded image


racemic mixture





883


embedded image


racemic mixture


















TABLE 272







884


embedded image








885


embedded image


racemic mixture





886


embedded image








887


embedded image


racemic mixture





888


embedded image




















TABLE 273







889


embedded image


racemic mixture





890


embedded image








891


embedded image








892


embedded image




















TABLE 274







893


embedded image


racemic mixture





894


embedded image


racemic mixture





895


embedded image


less polar, diastereomer of Ex896





896


embedded image


more polar, diastereomer of Ex895


















TABLE 275







897


embedded image


racemic mixture





898


embedded image


racemic mixture





899


embedded image


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 (7 H, m), 2.06-2.23 (1 H, m), 2.92 (3 H, s),




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




(2 H, m), 5.21 (1 H, s), 6.39 (1 H, brs), 6.89 (1 H, d, J = 8.4




Hz), 7.04-7.20 (2 H, m), 7.27-7.69 (6 H, m), 7.87-7.97 (1 H,




m), 8.29 (1 H, d, J = 6.4 Hz), 11.64 (1 H, 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 (3 H, d, J = 6.0 Hz), 3.10-3.40 (2 H, m), 3.54




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




m), 4.80 (2 H, brs), 4.90 (1 H, brs), 5.75 (1 H, s), 6.79 (1 H,




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




7.31-7.51 (6 H, m), 7.61 (1 H, s), 7.96-8.09 (1 H, m), 11.63




(1 H, 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 (3 H, d, J = 6.0 Hz), 2.54-2.64 (2 H, m), 3.09-3.38




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




4.52 (1 H, brs), 5.13 (1 H, d, J = 4.4 Hz), 5.70 (1 H, s), 6.65




(2 H, d, J = 8.4 Hz), 6.81 (1 H, d, J = 8.4 Hz), 6.94 (2 H, d, J =




8.4 Hz), 7.11-7.24 (2 H, m) 7.36-7.49 (2 H, m), 7.60 (1 H, d,




J = 2.0 Hz), 7.95-8.08 (1 H, m), 8.35-8.50 (1 H, m), 9.17 (1 H,




s)


216
1
FAB+: 632


217
1
FAB+: 533


218
1
FAB+: 538


219
1
FAB+: 538




NMR1: 1.54-1.71 (1 H, m), 1.76-1.90 (1 H, m), 1.96-2.21 (2 H,




m), 3.01-3.24 (2 H, m), 3.27-3.40 (1 H, m), 3.55 (1 H, brs), 3.70




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




7.22 (1 H, dd, J = 2.4, 8.4 Hz), 7.30-7.47 (7 H, m), 7.52 (1 H, d,




J = 8.4 Hz), 7.62 (1 H, d, J = 2.0 Hz), 7.82-7.90 (1 H, m), 11.34




(1 H, 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 (1 H, m), 1.75-1.89 (1 H, m), 1.97-2.21




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




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




7.10-7.18 (1 H, m), 7.22 (1 H, dd, J = 2.4, 8.4 Hz), 7.27-7.40




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




7.80-7.90 (1 H, m), 11.34 (1 H, 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 (3 H, d, J = 6.0 Hz),





3.12-3.48 (2 H, m), 3.55 (1 H, s),





4.01-4.13 (1 H, m), 4.28-4.38 (1 H, m),





4.47-4.60 (1 H, m), 4.80-4.97 (3 H, m),





5.73 (1 H, s), 6.79 (1 H, d, J = 8.4 Hz),





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





8.4 Hz), 7.39-7.69 (5 H, m), 7.91-8.08





(3 H, m), 11.67 (1 H, s), 13.04 (1 H, 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 (8 H, m), 2.94 (3 H, s),





3.58 (3 H, s), 4.07 (1 H, brs), 4.74 (1 H, d,





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





5.18 (1 H, s), 6.36 (1 H, d, J = 6.9 Hz), 6.88





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





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





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





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





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





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



542
4
FAB+: 710





NMR1: 0.48-0.71(1 H, m), 1.01-1.37





(4 H, m), 1.40-1.65 (2 H, m), 2.46-





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





(2 H, m), 4.66-4.84 (3 H, m), 5.17





(1 H, s),6.68 (1 H, d, J = 8.4 Hz),





7.02-7.09 (1 H, m), 7.12-7.20 (3 H, m),





7.27-7.40 (2 H, m), 7.46 (1 H, d,





J = 0.8 Hz), 7.64 (1 H, d, J = 8.0 Hz),





8.57 (1 H, 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 (8 H, m), 2.10-2.24





(1 H, m), 2.69-2.83 (2 H, m), 2.92





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





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





(1 H, m), 6.85 (1 H, d, J = 8.0 Hz),





7.11-7.22 (2 H, m), 7.35-7.48 (4 H, m),





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





(2 H, m), 7.88-7.96 (1 H, m), 8.07





(1 H, brs), 12.08 (1 H, brs)



701
 19
ESI+: 672





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





(1 H, m), 2.59-2.74 (2 H, m), 2.91





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





(2 H, s), 3.75 (1 H, s), 3.93 (1 H, brs), 5.24





(1 H, s), 6.41-6.54 (1 H, m), 6.85





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





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





2.0 Hz), 7.89-7.98 (1 H, m), 8.08 (1 H,





brs), 12.28 (1 H, 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 (2 H, t, J = 6.9 Hz),




1.00-2.00 (5 H, m), 2.10-2.25 (1 H, m),




2.40 (2 H, t, J = 7.2 Hz), 2.94 (3 H, s),




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




3.98 (1 H, t, J = 6.3 Hz), 4.73 (1 H, d,




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




Hz), 5.16 (1 H, s), 6.32-6.38 (1 H, m),




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




m), 7.39-7.48 (2 H, m), 7.63 (1 H, d,




J = 2.0 Hz), 7.89-7.98 (1 H, m), 11.39




(1 H, brs)


710
 1
ESI+: 751


711
 19
ESI+: 708


712
 19
ESI+: 708




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




(1 H, m), 2.59-2.74 (2 H, m), 2.91




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




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




(1 H, s), 6.41-6.54 (1 H, m), 6.85 (1 H, d,




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




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




7.89-7.98 (1 H, m), 8.08 (1 H,




brs), 12.28 (1 H, 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 (8 H, m), 2.94 (3 H, s),





3.58 (3 H, s), 4.07 (1 H, brs), 4.74





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





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





J = 6.9 Hz), 6.88 (1 H, d, J = 8.4 Hz),





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





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





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





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





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





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


embedded image







2


embedded image







3


embedded image







4


embedded image





















TABLE 302









5


embedded image












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 pharmaceutical composition comprising a compound of formula (I) a pharmaceutically acceptable salt, solvate, or hydrate thereof and a pharmaceutically acceptable excipient, wherein formula (I) is represented by:
  • 2. The pharmaceutical composition of claim 1, 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).
  • 3. The pharmaceutical composition of claim 2, wherein R2 is phenyl which may be substituted with halogen, lower alkyl, or —OR0.
  • 4. The pharmaceutical composition of claim 2, wherein R3 is —H.
  • 5. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is a solid composition.
  • 6. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is a liquid composition.
  • 7. The pharmaceutical composition of claim 6, wherein the liquid composition is for parenteral administration.
  • 8. The pharmaceutical composition of claim 6, wherein the liquid composition is for oral administration.
  • 9. A compound of formula (I) a pharmaceutically acceptable salt, solvate, or hydrate thereof and a pharmaceutically acceptable excipient, wherein formula (I) is represented by:
  • 10. The compound of claim 9, 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).
  • 11. The compound of claim 10, 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)C(O)R0, —N(R0)—C(O)-lower alkylene-OR0, —N(R0)S(O)2-lower alkyl and heterocyclic group.
  • 12. The compound of claim 11, wherein R2 is phenyl which may be substituted with halogen, lower alkyl, or —OR0.
  • 13. The compound of claim 9, wherein R3 is —H.
  • 14. The compound of claim 9, wherein the compound of formula (I) is
Priority Claims (1)
Number Date Country Kind
2007-140097 May 2007 JP national
Parent Case Info

This application is a Continuation of U.S. patent application Ser. No. 15/350,427, filed Nov. 14, 2016, which is a Continuation of U.S. patent application Ser. No. 14/836,228, filed Aug. 26, 2015, which is a Divisional of U.S. patent application Ser. No. 13/942,158, filed Jul. 15, 2013, which is a Divisional of U.S. patent application Ser. No. 12/600,894, filed Nov. 19, 2009, which is the U.S. National Phase of PCT/JP2008/059621, filed Mar. 26, 2008, which claims priority from Japanese Patent Application No. P2007-140097, filed May 28, 2007, all of which are incorporated herein by reference in entirety.

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Related Publications (1)
Number Date Country
20190000832 A1 Jan 2019 US
Divisions (2)
Number Date Country
Parent 13942158 Jul 2013 US
Child 14836228 US
Parent 12600894 US
Child 13942158 US
Continuations (2)
Number Date Country
Parent 15350427 Nov 2016 US
Child 16027988 US
Parent 14836228 Aug 2015 US
Child 15350427 US