NZ615293B2 - Novel octahydrothienoquinoline derivative, pharmaceutical composition comprising derivative, and use of these - Google Patents

Novel octahydrothienoquinoline derivative, pharmaceutical composition comprising derivative, and use of these Download PDF

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NZ615293B2
NZ615293B2 NZ615293A NZ61529312A NZ615293B2 NZ 615293 B2 NZ615293 B2 NZ 615293B2 NZ 615293 A NZ615293 A NZ 615293A NZ 61529312 A NZ61529312 A NZ 61529312A NZ 615293 B2 NZ615293 B2 NZ 615293B2
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NZ615293A
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Kiyoshi Kasai
Toshihiro Nishimura
Hirotaka Teranishi
Yasunori Ueno
Masako Yoshida
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Kissei Pharmaceutical Co Ltd
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Priority claimed from PCT/JP2012/056252 external-priority patent/WO2012124649A1/en
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Publication of NZ615293B2 publication Critical patent/NZ615293B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Abstract

The disclosure relates to octahydrothienoquinoline compounds of general formula (I), wherein R1 – R7 are as defined in the specification. The disclosure also relates to pharmaceutical compositions comprising the compound. Example compounds include: 1-{[(4aR*,6R*,8aR*)-2-amino-3-cyano-8-methyl-4H,4aH,5H,6H,7H,8H,8aR,9H-thieno[3,2-g]quinolin-6-yl]carbonyl}-3-[2-(dimethylarnino)ethyl]-1-(2,2-dimethylpropyl)urea; 1-{[(4aR,6R,8aR)-2-amino-3-cyano-8-methyl-4H,4aH,5H,6H,7H,8H,8aH,9H-thieno[3,2-g]quinolin-6-yl]carbonyl}-3-[(2S)-1-(dimethylarnino)propan-2-yl]-1-ethlylurea; 1-{[(4aR*,6R*,8aR*)-2-amino-3-cyano-8-methyl-4H,4aH,5H,6H,7H,8H,8aH,9H-thieno[3,2-g]quinolin-6-yl]carbonyl}-3-[2-(dimethylarnino)-2-methylpropyl]-l-propylurea; 1-{[(4aR*,6R*,8aR*)-2-amino-3-cyano-8-methyl-4H,4aH,5H,6H,7H,8H,8aH,9H-thieno[3,2-g]quinolin-6-yl]carbonyl}-3-[2-(dimethylarnino)-2-ethylbutyl]-l-ethylurea. H,5H,6H,7H,8H,8aR,9H-thieno[3,2-g]quinolin-6-yl]carbonyl}-3-[2-(dimethylarnino)ethyl]-1-(2,2-dimethylpropyl)urea; 1-{[(4aR,6R,8aR)-2-amino-3-cyano-8-methyl-4H,4aH,5H,6H,7H,8H,8aH,9H-thieno[3,2-g]quinolin-6-yl]carbonyl}-3-[(2S)-1-(dimethylarnino)propan-2-yl]-1-ethlylurea; 1-{[(4aR*,6R*,8aR*)-2-amino-3-cyano-8-methyl-4H,4aH,5H,6H,7H,8H,8aH,9H-thieno[3,2-g]quinolin-6-yl]carbonyl}-3-[2-(dimethylarnino)-2-methylpropyl]-l-propylurea; 1-{[(4aR*,6R*,8aR*)-2-amino-3-cyano-8-methyl-4H,4aH,5H,6H,7H,8H,8aH,9H-thieno[3,2-g]quinolin-6-yl]carbonyl}-3-[2-(dimethylarnino)-2-ethylbutyl]-l-ethylurea.

Description

DESCRIPTION NOVEL OCTAHYDROTHIENOQUINOLINE DERIVATIVE, PHARMACEUTICAL COMPOSITION COMPRISING DERIVATIVE, AND USE OF THESE TECHNICAL FIELD The t invention relates to novel octahydrothienoquinoline derivatives, which t dopamine D2 receptor agonistic activities, pharmaceutical compositions containing the same, and their uses.
Parkinson's disease is a progressive neurodegenerating disease which usually affects elderly patients, and the number insonian patients is growing with progressive aging of society. Parkinson's disease pathogenesis is characterized by impairment in nated motor fimction such as rest tremor, rigidity, akinesia, postural instability and the like. It is thought that Parkinson's disease results from deficiency of dopamine in the um, which is caused by degeneration of dopamine neuron in the substantia nigra. For that reasons, L-dopa or dopamine D2 receptor agonists are used for the treatment of Parkinson's disease. id="p-3" id="p-3"
[0003] L-dopa is [a precursor of dopamine, and is metabolized to dopamine which exerts its efficacy in the brain. Since L-dopa has a very short serum half—life, L-dopa is administered usually in combination with a'peripheral aromatic L—amino acid decarboxylase inhibitor and/or a catechol—O-methyltransferase inhibitor, which are the metabolizing enzyme tors of .
Dopamine D2 receptor ts exert an anti—Parkinson's effect by directly ating dopamine D2 receptors of the striatum. And,lit is known that the dopamine D2 receptor agonists are useful for ng restless legs syndrome, hyperprolactinemia or the like (for example, see Non—patent literature 1 or 2).
Various ergot or non-ergot ne D2 receptor agonists are known as dopamine D2 receptor t (for example, see Patent literature 1 to 3 about ergot dopamine D2 receptor agonist, and see Patent literature 4 to 6 about non—ergot dopamine D2 receptor agonist).
The got ne D2 receptor agonists have the disadvantage duration of action is shorter than the ergot dopamine D2 receptor agonists, since the serum half—life of them is shorter than the ergot dopamine D2 receptor agonists (for example, see Non—patent literature 3). And more, the non-ergot dopamine D2 receptor agonists have problems of side effects such as sudden onset of sleep, somnolence or the like.
The ergot dopamine D2 agonists show the long-term effectiveness compared to the non—ergot dopamine D2 receptor agonists. However, recently it has been reported that the risk of onset of cardiac valvular e increases when taken long-term high dose ofpergolide which was is a typical ergot dopamine D2 or t. So, the periodic monitoring of rdiography and the like arerequired during administering the ergot dopamine D2 or agonists. Since it is reported that cardiac valvular disease is caused by the growth stimulation ofthe cardiac valvular cells by the stimulation activity of 5-HT2B receptor as pathogenesis of cardiac valvular disease, the relevance of cardiac valvular diseases and the stimulation activity of 5-HT2B receptor is strongly suggested (for example, see Non-patent literature 4).
Accordingly, it has been expected for novel ne D2 receptor agonists exhibiting potent and lasting dopamine D2 or agonistic activities with less 5—HT2B receptorstimulating activities.
A nd represented by the formula: [Chem. 1] is known as 4,4a,5,6,7,8,8a,9-octahydrothieno[3,2g]quinoline derivative (see Non-patent literature 5). However, any pharmacological s ofthe compound are not described at all in the Non-patent literature 5.
CITATION LIST Patent literature Patent literature 1: US patent No. 4,166,182 Patent literature 2: US patent No. 3,752,814 Patent literature 3: US patent No. 4,526,892 Patent literature 4: US patent No. 4,452,808 Patent literature 5: US patent No. 849 Patent literature 6: US patent No. 4,886,812 Non-Patent literature Non-patent literature 1: Happe, S. ez‘ al, "CNS Drugs", 2004, vol.l8(l), pp.27-36 Non-patent literature 2: Crosignani, P. G. et al, "Eur. J. Obstetrics & Gynecology and Reproductive Biology", 2006, vol.125, pp.152—164 Non-patent ture 3: Prikhojan, A. et al, "J. Neural Transm.", 2000, vol'.lO7, pp.1159-1164 Non-patent literature 4: Setola, V. et al, "Mol. Pharmacol.", 2003, vol.63, pp.1223-1229 Non-patent literature 5: Bosch, J. et al, "J. Heterocyclic Chem.", 1980, , pp.745-747 SUMARY OF THE ION Object to be solved by the Invention An object of the present ion is to provide a novel compound having potent dopamine D2 receptor stimulating activities, and more preferably a compound that alleviates 5-HT2B receptor stimulating activities, or at least to provide a useful alternative to known dopamine D2 receptor stimulating compounds.
Means for g the Object The inventors of the present ion diligently worked to achieve the foregoing object and found surprisingly that compounds represented by the general formula (I) show highly potent dopamine D2 receptor simulating activities as compared to 5-HT2B receptor simulating activities. Based on these findings, the present ion has been accomplished. id="p-13" id="p-13"
[0013] That is, the present invention therefore provides a compound represented by the general formula (I): [Chem. 2] R NR2R3 or a pharmaceutically acceptable salt thereof, wherein R1 is any one of the following a) to d): a) a cyano group, b) a carbamoyl group, c) a C24 alkoxycarbonyl group, or d) a carboxy group; R2 and R3 are each independently a hydrogen atom, a C1-6 alkyl group, a C1_7 acyl group, or a C2_7 carbonyl group; R4 is a hydrogen atom, a C1-6 alkyl group, or a M alkyl group; R5is any one of the following a) to j) : a) a CM, alkyl group, b) a halo-Cm alkyl group, c) a cycloalkyl group, d) a benzo-fuzed cycloalkyl group, e) a cycloalkyl-C16 alkyl group, i) an aralkyl group, wherein the ring of the aralkyl group is unsubstituted or substituted with 1 to 5 substituents independently ed from the group consisting of a halogen atom, a C1_6 alkyl group, a halo—CM alkyl group, a C1-6 alkoxy group, and a hydroxy-C1-6 alkyl group, g) a heteroaryl-C1-6 alkyl group, n the ring of the heteroaryl-C1_6 alkyl group is tituted or substituted with 1 to 3 substituents independently selected-from the group consisting of a C1-6 alkyl group, a halo-CM alkyl group, and a C1_6 alkoxy group, h) a C2_6 alkenyl group, i) a C1_6 alkoxy-Cm alkyl group, or j) a RIORUN-C1_6 alkyl group; R6 and R7 are each independently any one of the following a) to k): a) a en atom, b) a C1_5 alkyl group, c) a halo-CH, alkyl group, (1) a heterocycloalkyl group, e) a heterocycloalkyl-C1_6 alkyl group, f) an aralkyl group, wherein the ring of the aralkyl group is tituted or substituted with l to 5 substituents independently selected from the group consisting of a halogen atom, a C1_6 alkyl group, a halo-CH, alkyl group, a C1-6 alkoxy group, and a RIORUN-C1_6 alkyl group, g) a heteroaryl-C1-6 alkyl group, wherein the ring of the heteroaryl-C1_6 alkyl group is unsubstituted or substituted with l to 3 substituents independently selected from the group consisting of a C1.6 alkyl group, a halo-CH; alkyl group, and a C1-6 alkoxy group, h) a CM alkoxy-CM alkyl group, i) a R12R13N-C1_6 alkyl group, j) a R12R13N-C1_6 alkoxy-CM alkyl group, or k) a R‘ZR‘3N-'C(0)-cl_6 alkyl grdup; R10 and R11 are each ndently a hydrogen atom, a C1-6 alkyl group or a hydroxy-C1-6 alkyl group, or R10 and R", together with the nitrogen atom to which they are bonded, form a cyclic amino group, wherein the cyclic amino group is unsubstituted or substituted with l or 2 C1_6 alkyl groups; and R12 and R13 are each independently a hydrogen atom, a C1_5 alkyl group, a hydroxy-C1-6 alkyl group or an aryl group, or R12 and R13, together with the nitrogen atom to which they are. bonded, form a cyclic amino group, wherein the cyclic amino group is unsubstituted or substituted with 1 or 2 C1-6 alkyl groups.
In another aspect, the present ion provides a pharmaceutical composition which comprises, as an active ingredient, a compound represented by the general formula (I) or a pharmaceutically able salt thereof. [00 1 5] In still another , the t invention provides a treating or preventing agent of Parkinson's e, restless legs syndrome or hyperprolactinemia which comprises a compound represented by the l formula (I) or a pharmaceutically able salt thereof. [00 1 6] In still another aspect, the present invention provides a dopamine D2 receptor agonist which comprises a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof. [001 7] In still another aspect, the present ion provides a pharmaceutical agent which comprises (1) a nd of the general formula (I) or a phannaceutically acceptable salt thereof and (2) at least one anti-Parkinson drug selected from L—dopa, dopamine D2 receptor agonists, anticholinergic agents, adenosine AZA receptor antagonists, NMDA receptor antagonists, monoamine oxidase B inhibitors, COMT inhibitors, aromatic L-amino acid decarboxylase inhibitors, droxidopa, melevodopa, threodops, zonisamide and amantadine hydrochloride.
EFFECTS OF THE INVENTION The compounds ofthe present invention t potent dopamine D2 receptor simulating activities. Moreover, compounds of the present invention have a ble safety profile since nds of the present invention have extremely slight 5-HTZB receptor stimulating activities. Accordingly, compounds of the present invention are useful as a-therapeutic or prophylactic agent for Parkinson's disease, restless legs syndrome or hyperprolactinemia.
EMBODIMENTS FOR CARRING OUT THE INVENTION id="p-19" id="p-19"
[0019] In a nd represented by the l formula (I), the following terms have the following meanings unless otherwise specified.
The term "halogen atom" refers to a fluorine, chlorine, bromine or iodine atom. id="p-21" id="p-21"
[0021] The term "C1_'6alkyl group" refers to a straight chained or ed alkyl group having 1 to 6 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a tert-pentyl group, a 1-methy1- butyl group, a 2-methylbutyl group, a 1,2-dimethylpropyl group, a hexyl group, an isohexyl group and the like. Preferred C1-6 alkyl groups for R4 are a C13 alkyl group, and more preferably a methyl group. Preferred (31-6 alkyl groups for R10, R11, R12 and R13 are a C1_3 alkyl group, and more preferably a methyl or ethyl group.
The term "halo-Cm alkyl group" refers to an alkyl group having 1 to 6 carbon atoms substituted with the same or ent 1 to 3 halogen atoms such as a fluoromethyl group, a 2-fluoroethy1 group, a difluoromethyl group, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, a 3,3,3—trifluoropropyl group, a trifluorobutyl group and the like.
The term "hydroxyl-C1_6 alkyl group" refers to an alkyl group having 1 to 6 carbon atoms substituted with a hrdroxy group such as a hydroxymethyl group, a 1-hydroxyethyl group, a 1-hydroxy-l,l-dimethylmethyl group, a 2-hydroxyethyl group, a 2-hydroxymethylpropyl group, a 3-hydroxypropy1 group and the like.
The term "CM alkoxy group" refers to a straight chained ‘or branched alkoxy group having 1 to 6 carbonatoms such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, a utoxy group, a pentyloxy group, a hexyloxy group and the like.
The term "C24 alkoxycarbonyl group" refers to a (C1_6 alkoxy)—C(O)- such as a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, an isobutoxycarbonyl group, a sec—butoxycarbonyl group, a text-butoxycarbonyl group, a oxycarbonyl group, a hexyloxycarbonyl group and the like.
The term "C14 acyl group" refers to a formyl group or a group represented by a (C1_6 alkyl)-C(O)— such as a formyl group, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a pivaloyl group, a valeryl group, an isovaleryl group and , the like.
The term "cycloalkyl group" refers to a 3- to 7-membered saturated cyclic hydrocarbon such as a ropyl group, a cyclobutyl group, a entyl group, a cyclohexyl group and a cycloheptyl group.
The term "benzo-fuzed cycloalkyl group" refers to a cycloalkyl group fuzed with a benzene ring such as an indan—l-yl group, an indanyl group, a tetrahydro- naphthalen—l -yl group and the like.
The term "heterocycloalkyl group" refers to a 4- to ered saturated heterocyclic group which contains —NH—, -O- or —S- as a member of the ring and is bondedvia a carbon atom. Examples of heterocycloalkyl groups include an azetidin-3 -yl group, a tetrahydrofuryl group, a tetrahydrothienyl group, a tetrahydro- pyranyl group, a pyrrolidinyl group, a pyrrolidin-3—yl group, a piperidiny1 group, a piperidinyl group, a piperidin—4—yl group and the like.
The heterocycloalkyl group may be optinally substituted with l or 2 C1-6 alkyl groups such as a ylazetidinyl group, a l—methylpyrrolidin—3-yl group, a 1—methylpiperidinyl group, a l-methyl-piperidin-3—yl group and the like. [003 0] The term alkyl-CM alkyl group" refers to a cyclopropylmethyl group, a cyclopentylmethyl group, a cyclohexylmethyl group and the like, preferably a ropylmethyl group. [003 1] The term "heterocycloalkyl-C1.6 alkyl group" refers to a ylazeti- din-3—y1methyl group, l-methylpiperidinylmethyl group and the like.
The term "aryl group" refers to a €6-10 aromatic hydrocarbon group such as a phenyl group, a l—naphtyl group and a 2-naphthyl group, preferably a phenyl group. id="p-33" id="p-33"
[0033] The term "heteroaryl group" refers to a 5- or 6—membered monocyclic aromatic heterocycle having 1 to 5 carbon atoms and 1 to 4 heteroatoms selected independently from the group consisting of an oxygen, nitrogen and sulfur atom, or a 8- to -membered bicyclic aromatic heterocycle having 1 to 9 carbon atoms and l to 4 heteroatoms selected ndently from the group consisting of an oxygen atom, nitrogen atom and sulfur atom, provided that said heterocycles do not include adjacent oxygen and/or sulfur atoms. Examples ofmonocyclic ic heteroaryl groups include pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,4—oxadiazolyl, 1,3,4-oxadiazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3—thiadiazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidyl, zinyl and the like, preferably thienyl, imidazolyl, thiazolyl or pyridyl. Examples of bicyclic aromatic heteroaryl groups e indazolyl, benzofilranyl, benzothienyl, benzothiazolyl, yl, isoquinolyl, phthalazinyl, benzimidazolyl, benzoxazolyl and the like. The heterocycles include all position s such as 2-pyridyl, 3-pyridyl or 4-pyridyl.
The term "aralkyl group" refers to an aryl-C1-6 alkyl group such as a benzyl group, a phenethyl group, a l—phenylethyl group, a 3-phenylpropyl group, a 4—phenyl- butyl group, a ylmethyl group and the like. Preferred aralkyl groups for R5, R6 and R7 are a phenyl-C1-6 alkyl group, and more preferably a benzyl or phenethyl group.
The term "heteroaryl—C1.6 alkyl group" refers to a 2-pyridylmethyl group, a 3—pyridylmethyl group, a 4-pyridylmethyl group, a 2-pyridylethyl group, a 3-pyridylethy1 group, a 4—pyridy1ethyl group, a 2-thienylmethyl group, an imidazol-l-ylmethyl group, an 2-imidazol-3—ylmethyl group, an 2-imidazol- l-ylethyl group, an 3-imidazolylpropyl group, a 2—thiazoly1methyl group and the like.
The term "C24; alkenyl group" refers to a ht chained or branched rated hydrocarbon group having 2 to 6 carbon atoms such as CH2=CHCH2—, CH2=CHCH2CH2—, CH3CH=CHCH2- and the like. [003 7] The term "C1_6 alkoxy—C1-6 alkyl group" includes a 2-methoxyethyl group, a 3-methoxypropyl group, an 2-ethoxyethyl group, an xypropyl group and the like. [003 8] The term "cyclic amino group" refers to a 5- to 7-membered saturated. cyclic amine which may contain —NH-, -O- or —S- as a member of the ring. Examples of cyclic amino groups include a 1-pyrrolidyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, a rpholinyl group, a [l ,4]diazepamyl group and the like. [003 9] The numbering ofthe ring atoms of the compound represented by the general formula (I) is given as follows: [Chem 3] In a chemical name in the present description, the marks "*" mean the relative configuration of the asymmetric carbon atom. For example, l—{[(4aR*, 6R*, 8aR*)— 2-amino—3-cyanomethyl-4H, 4aH, 5H, 6H, 7H, 8H, 8aH, 9H—thieno[3,2—g]quin— olin—6-yl] yl} — 1 —buty1[2-(dimethylamino)ethyl]urea (Compound 1—24) means that the asymmetric s at 4a, 6 and 8a ons are relative configurations. id="p-41" id="p-41"
[0041] In the case Where a compound represented by the general formula (I) of the present invention contains one or more asymmetric carbon atoms, all stereoisomers in the R— or S-configuration at each of asymrhetric carbons and their mixture are contemplated Within the scope of the present invention. In such cases, racemic compounds, racemic mixtures, racemic solid solutions, individual enantiomers and mixtures of diastereomers are also plated within the scope ofthe present invention. In the case Where a compound represented by the general formula (I) has the geometrical isomers, all geometrical isomers are also contemplated within the scope of the present invention. In the case Where a compOund represented by the l formula (I) has the atropisomers, all atropisomers are also contemplated-within the scope of the present invention. A compound represented by the l formula (I) or a pharmaceutically acceptable salt therof includes a solvate with a pharmaceutically acceptable solvent such as water, ethanol and the like.
Compounds ented by the general formula (I) ofthe present invention may exist in the form of salts. Examples of such salts include acid addition salts formed with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and the like; acid addition salts formed with organic acids such as formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p—toluenesulfonic acid, propionic acid, citric acid, ic acid, tartaric acid,-fumaric acid, c acid, oxalic acid, nialonic acid, maleic acid, lactic acid, malic acid, ic acid, glutamic acid, aspartic acid and the like; basic salts formed with nic bases such as lithium, sodium, potassium, calcium, magnesium and the like; basic salts formed with organic bases such as triethylamine, piperidine, morpholine, lysine and the like.
In an embodiment of a compound ented by the general formula (I) of the present invention, preferably R1 is a cyano group; R2 and R3 are preferably a hydrogen atom; R4 is preferably a en atom or a C1_6 alky group, and even more preferably a methyl group; R5 is preferably any one of the following a) to h): a) a CH, alkyl group, b) a halo-Cm alkyl group, 0) a cycloalkyl—C1_6 alkyl group, d) an aralkyl group, wherein the ring of the aralkyl group is unsubstituted or substituted with l to 5 substituents independently selected from the group consisting of a halogen atom, a C1_6 alkyl group, a halo-Cm alkyl group, a C1-6 alkoxy group and a hydroxy—C1-6 alkyl group, . e) a heteroaryl-C1_6 alkyl group, wherein the ring of the heteroaryl-C1_6 alkyl group is unsubstituted or substituted with l to 3 substituents independently selected fromthe group consisting of a C1-6 alkyl group, a halo-CM alkyl group, and a C1_6 alkoxy group, i) a C2-6 alkenyl group, g) a C1_6 alkoxy-CM alkyl group, or h) a RloR1 1N-C1_6 alkyl group; more preferably R5 is any one of the following a) to f): a) a C1-6 alkyl group, ‘ b) a cycloalkyl-C1_6 alkyl group, c) an aralkyl group, wherein the ring of the aralkyl group is unsubstituted or substituted with l to 5 substituents independently selected from the group consisting of v a n atom, a C1_6 alkyl group, a halo—Cm alkyl group, a C1_6 alkoxy group and a y-C1-6 alkyl group, (1) a heteroaryl-C1-6 alkyl group, wherein the ring of the oaryl-C1-6 alkyl group is unsubstituted or substituted with l to 3 substituents independently selected from the group consisting of a CH; alkyl group, a halo—Cm alkyl group, and a C1-6 alkoxy gr0UP: e) a C1-6 alkoxy—CM alkyl group, or f) a RIORllN-C1_5 alkyl group; even more preferably R5 is any one ofthe following a) to d): a) a CH, alkyl group, b) a lkyl-C1_6 alkyl group, 0) a C1-6 alkoxy-CM alkyl group, or d) a RIOR1 lN-C1.6 alkyl group; R6 is preferably a hydrogen atom, R7 is preferably any one of the following a) to i): a) a C1_6 alkyl group, b) a halo-CM alkyl group, c) a heterocycloalkyl-C1_6 alkyl group, d) an aralkyl group, wherein the ring of the aralkyl group is unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of a halogen atom, a C1_6 alkyl group, a halo-C145 alkyl group, a CH, alkoxy group,and a RloRllN-C1_5 alkyl group, e) a heteroaryl-C1-6 alkyl group, wherein the ring of the aryl-C1-6 alkyl group is unsubstituted or substituted with 1 to 3 substituents ndently selected from the group consisting of a C1-6 alkyl group, a halo-CM alkyl group, and a CH, alkoxy group, f) a C1-6 alkoxy-Cm alkyl group, g) a R12R13N~C1_6 alkyl group, h) a R12R13N-C1-6 alkoxy-CM alkyl group, or i) a R12R13N-C(O)-C1-6 alkyl group; more preferably R7 is any one of the following a) to f): a) a C1-6 alkyl group, b) a halo-Cm alkyl group, c) an aralkyl group, wherein the ring of the aralkyl group is unsubstituted or substituted with 1 to 5 substituents independently selectedfrom the group consisting of a halogen atom, a C1_6 alkyl group, a halo—CH,- alkyl group, a C1.6 alkoxy group, and a RIOR1 1N-C1.6 alkyl group, d) a aryl-C1_5 alkyl group, wherein the ring of the heteroaryl-C1_6 alkyl group is unsubstituted or substituted with 1 to 3 substituents independently selected from the group ting of a CH, alkyl group, a halo—CM alkyl group and a C1-6 alkoxy group, e) a C1-6 alkoxy-CH; alkyl group, or r) a R12R13N-C1-6 alkyl group; even more preferably R7 is any one of the following a) to d): a) a C1_6 alkyl group, b) an aralkyl group, wherein the ring of the aralkyl group is tituted or substituted with 1 to 5 substituents independently selected from the group consisting of a halogen atom, a C14, alkyl group, a halo—CM alkyl group, a C1-6 alkoxy group, and a RIORllN-C1-6 alkyl group, c) a heteroaryl—C1_6 alkyl group, wherein the ring of the heteroaryl-C1-5 alkyl group is unsubstituted or substituted with 1 to 3 substituents independently selected from the group ting of a CM alkyl group, a halo-CM; alkyl group and a C1_6 alkoxy group, d) a R12R13N-C1_6 alkyl group; especially preferable R7 is any one of the ing a) to b): a) a C1-6 alkyl group, or b) a R‘2R13N—C1.6 alkyl group; and preferably R10 and R11 are each independently a C1-6 alkyl group, or R10 and R11, together with the nitrogen atom to which they are bonded, form a cyclic amino group, wherein the cyclic amino group is unsubstituted or substituted with 1 or 2 C1_6 alkyl ; or preferably R12 and R13 are each independently a C14, alkyl group, or R12 and R13, together with the nitrogen atom to which they are bonded, form a cyclic amino group, n the cyclic amino group is unsubstituted or substituted with 1 or 2 C1_5 alkyl groups.
In an embodiment of a nd represented by the general formula (I), a compound represented by the general formula (I) is preferably a genral formula (II), wherein [Chem 4] R NR2R3 and the configuration at 4a, 6 and 8a positions of the quinoline ring of 4H, 4aH, 5H, 6H, 7H, 8H, 8aH, 9H-thieno[3,2-g]quinoline is represented by relative configuration, more preferably a compound represented by the general formula (I) is a genral formula (III), wherein [Chem 5] o ‘ (\ IR4 IIIIZ R7R6NA0 ‘ (III) An..— R NR2R3 and the configuration at 4a, 6 and 8a positions of the quinoline ring of 4H, 4aH, 5H, 6H, 7H, 8H, 8aH, 9H—thieno[3,2-g]quinoline is represented by absolute configuration.
In a able embodiment of the present invention, R1 is a cyano group.
In a more preferable embodiment ofthe present invention, R1 is a cyano group; and R2 and R3 are a hydrogen atom.
In an even more preferable embodiment ofthe present invention, R1 is a cyano group; R2 and R3 are a hydrogen atom; and R4 is a hydrogen atom or a C1-6 alkyl group.
In an even more able embodiment of the present invention, R1 is a cyano group; R2 and R3 are a hydrogen atom; R4 is a hydrogen atom or a C1_6 alkyl group; R6 is a hydrogen atom; and R7 is any one of the following a) to i): at) a C1.6 alkyl group, b) a halo-Cm alkyl group, c) a heterocycloalkyl-C1-6 alkyl group, d) an aralkyl group, wherein the ring of the aralkyl group is unsubstituted or , substituted with 1 to 5 substituents independently ed from the group consisting of a halogen atom, a C1_6 alkyl group, a halo—CH; alkyl group, a C1-6 alkoxy group and a RIORHN-C1_6 alkyl group, e) a heteroaryl-C1-6 alkyl group, wherein the ring of the aryl—C1-6 alkyl group is unsubstituted or substituted with l to 3 substituents independently selected from the group consisting of a C1-6 alkyl group, a halo-CM alkyl group, and a C1-6 alkoxy group, f) a C16 alkoxy—C1_6 alkyl group, g) a R12R13N—C1-6 alkyl group, h) a R12R13N-C1_6 -C1_6 alkyl group, or i) a R12R13N-C(O)¥C1_6 alkyl group.
In an even more preferable embodiment of the present invention, R1 is a cyano group; R2 and R3 are a hydrogen atom; R4 is a hydrogen atom or a C1-6 alkyl group; R5 is any one of the following a) to h): a) a CH; alkyl group, b) a halo-CM alkyl group, c) a cycloalkyl-C1-6 alkyl group, d) an aralkyl group, wherein the ring of the aralkyl group is tituted or substituted with 1 to 5 substituents independently selected from the group consisting of a halogen atom, a C1_6 alkyl group, a halo-Cm alkyl group, a C1-6 alkoxy group and a hydroxy-C1_6 alkyl group, 6) a heteroaryl-C1-6 alkyl group, wherein the ring of the aryl-C1-6 alkyl group is tituted or substituted with l to 3 substituents independently selected from the group consisting of a C1-5 alkyl group, a halo-Cm alkyl group and a C1-6 alkoxy group, i) a Cy, alkenyl group, g) a C1_6 alkoxy-CM alkyl group, or h) a RIOR1 1N-C1.5 alkyl group; R6 is a hydrogen atom; and R7 is any one of the following a) to i): a) a C14, alkyl group, b) a halo-CM alkyl group, c) a cycloalkyl—C1_6 alkyl group, d) an aralkyl group, wherein the ring of the aralkyl group is unsubstituted or substituted with l to 5 substituents independently selected from the group consisting of a halogen atom, a C1-6 alkyl group, a halo-CM alkyl group, a-C1-6 alkoxy group and a RloRllN—CM alkyl group, e) a heteroaryl—C1_6 alkyl group, n the ring of the heteroaryl-C1_5 alkyl group is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of a C1.6 alkyl group, a halo—CM alkyl group and a C1-6 alkoxy group, i) a C1.6 alkoxy-C16 alkyl group, g) a R12R13N-C1_5 alkyl group, h) a N-C1.6 alkoxy—CM alkyl group, or i) a R12R13N-C(O)-C1-6 alkyl group. id="p-50" id="p-50"
[0050] In an even more preferable embodiment of the present invention, R1 is a cyano group; R2 and R3 are a hydrogen atom; R4 is a hydrogen atom or a C1_5 alkyl group; R5is any one ofthe following a) to h): a) a C1-5 alkyl group, b) a halo-Cm alkyl group, c) a cycloalkyl-C1_6 alkyl group, (1) an aralkyl grOup, wherein the ring of the aralkyl group is unsubstituted or substituted with 1 to 5 tuents independently selected from the group consisting of a halogen atom, a CH, alkyl group, a H; alkyl group, a C1-6 alkoxy group and a y-C1-6 alkyl group, e) a heteroaryl—C1_6 alkyl group, wherein the ring of the heteroaryl—C1_5 alkyl group is unsubstituted or substituted with 1 to 3 substituents independently selected from the group ting of a C1_6 alkyl group, a halo-CM alkyl group and a C1_6 alkoxy group, i) a C2-6 alkenyl group, g) a CH, alkoxy-C1; alkyl group, or h) a R1°R"N—c1.6 alkyl group; R6 is a hydrogen atom; and R7 is any one of the ing a) to f): a) a C1-5 alkyl group, b) a halo—CM alkyl group, c) an aralkyl group, wherein the ring of the aralkyl group is unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of a halogen atom, a (31-6 alkyl group, a halo-CH; alkyl group, a C1-6 alkoxy group and a RIOR1 1N-C1.6 alkyl group, d) a heteroaryl-C1_6 alkyl group, wherein the ring of the heteroaryl-C1-6 alkyl group is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of a CM alkyl group, a halo-CH, alkyl group and a CM alkoxy group, e) a C1_6 alkoxy-CH, alkyl group, or r) a R12R13N-C1-6 alkyl group. [005 1] In an even more preferable embodiment of the present invention, R1 is a cyano group; R2 and R3 are a hydrogen atom; R4 is a methyl group; Rsis any one of the following a) to f): a) a C1_6 alkyl group, b) a cycloalkyl-C1-6 alkyl group, c) an l group, wherein the ring of the aralkyl group is unsubstituted or substituted with 1 to 5 substituents ndently selected from the group consisting of a halogen atom, a C1_6 alkyl group, a halo-CM alkyl group, a C1_6 alkoxy group and a y-C1_6 alkyl group, d) a heteroaryl-C1_6 alkyl group, wherein the ring of the 11eteroaryl-C1-6 alkyl group is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of a C1-6 alkyl group, a halo-CM alkyl group and a C14, alkoxy group, 6) a C1_6 alkoxy-CM alkyl group, or I) a RIOR1 1N-C1.6 alkyl group; R6 is a hydrogen atom; and R7 is any one of the following a) to d): a) a C1_6 alkyl group, b) an aralkyl group, wherein the ring of the aralkyl group is unsubstituted or. substituted with 1 to 5 substituents ndently ed from the group consisting of a halogen atom, a C1_6 alkyl group, a halo—CM alkyl group, a C1_6 alkoxy group and a RIORUN-C1_6 alkyl group, c) a heteroaryl-C1-6 alkyl group, wherein the ring of the heteroaryl-CM alkyl group is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of a (21-6 alkyl group, a halo-Cm alkyl group and a C1_6 alkoxy group, or d) a R12R13N—Cl_6 alkyl group. id="p-52" id="p-52"
[0052] In an even more able embodiment of the present invention, R1 is a cyano group; R2 and R3 are a hydrogen atom; R4 is a methyl group; R5is any one ofthe following a) to d): a) a C1-6 alkyl group, b) a cycloalkyl-C1_6 alkyl group, c) a CM alkoxy-C1_6 alkyl group, or d) a N-C1.6 alkyl group; R6 is a hydrogen atom, and R7 is any one ofthe following a) to b):’ a) a CH; alkyl group, or b) a R12R13N-C1-6 alkyl group.
Specific examples of preferred embodiments of the present invention are compounds selected form the group consisting of: aR, 6R, 8aR)—2-amino-3—cyano1nethyl-4H, 4aH, 5H, 6H, 7H, 8H, 8aH, 9H—thieno [3 ,2-g]quinolinyl]carbonyl} -3—[2-(dimethylamino)ethyl]— 1 lurea (Compound 1-1); ‘ 1-{[(4aR, 6R, 8aR)-2—amino-3~cyano—8—methy1-4H, 4aH, 5H, 6H, 7H, 8H, 8aH, 9H-thieno[3,2-g]quinolin-6¥yl]carbonyl}butyl-3—[2—(diethylamino)ethyl]urea (Compound 1-3); 1’-{ [(4aR, 6R, 8aR)aminocyanomethy1—4H, 4aH, 5H, 6H, 7H, 8H, 8aH, 9H—thieno[3,2—g]quinoliny1]carbonyl}-3—[3-(dimethylamino)-2,2-dimethy1pro- pyl‘]-1—ethlylurea (Compound 1—4); l-{[(4aR, 6R, 8aR)a1ninocyanomethyl-4H, 4aH, 5H, 6H, 7H, 8H, 8aH, 9H-thieno[3,2-g]quinolinyl]carbony1}ethy1-1 =[2-(pyrrolidin— 1 —y1)ethyl]urea (Compound 1—6); 1-{[(4aR*, 6R*, 8aR*)—2-amino—3-cyan078—methyl-4H, 4aH, 5H, 6H, 7H, 8H, 8aI-I, 9H-thieno[3,2-g]quinolin—6-yl]carbonyl}butyl[2-(dimethy1amino)ethy1]urea (Compound 1-24); 1-{[(4aR*, 6R*, 8aR*)—2-amino—3-cyanomethyl—4H, 4aH, 5H, 6H, 7H, 8H, 8aH, eno[3 ,2-g]quinoliny1]carbonyl} -3 - [2—(dimethylamino)ethyl]— 1 -(2-ph- enylethyl)urea und 1-30); 1-{[(4aR*, 6R*, 8aR*)—2-aminoj3-cyanomethyl-4H, 4aH, 5H, 6H, 7H, 8H, 8aH, 9H—thieno[3 ,2-g] quinolin—6-yl]carbonyl} -3 -[2-(dimethylamino)ethyl] (3—me- thylbuty1)urea (Compound 1-43); 1-{[(4aR*, 6R*, 8aR*)—2—aminocyanomcthyl-4H, 4aH', 5H, 6H, 7H, 8H, 8aH, 9H—thieno [3 uinolin—6-yl]carbonyl} -1 -buty1—3-[2-(piperidin—1-y1)ethy1]urea (Compound 1—46); 1-{[(4aR*, 6R*, 2—aminocyano-8—methyl-4H, 4aH, 5H, 6H, 7H, 8H, 2O 8aI-I, 9H—thieno[3,2-g]quinoliny1]carbonyl}[2-(dimethylamino)ethyl](2,2-di- methylpropyl)urea (Compound ; 1-{[(4aR, 6R, 8aR)—2-amino—3-cyanomethyl—4H, 4aH, 5H, 6H, 7H, 8H, 8aH, 9H—thieno[3 ,2-g]quinolin—6-yl]carbonyl } [(ZS)—1-(dimethyla1nino)propan—2—yl] ethlylurea (Compound 1-57); 1-{[(4aR*, 6R*, 8aR*)-2—aminocyano-8—methyl—4H, 4aH, 5H, 6H, 7H, 8H, 8aH, 9H—thieno[3,2-g]quinoliny1]carbonyl}[2-(dimethylamino)—2-methy1pro- py1]—1-propy1urea (Compound 1-82); 1-{[(4aR*, 6R*, 83R*)amino—3—cyano—8-methyl-4H, 4aH, 5H, 6H, 7H, 8H, 8aH, 9H—thieno[3,2—g]quinolin—6-yl]carbonyl}[2-(dimethylamino)—2-ethylbut- yl]ethylurea (Compound 1-84); l—{[(4aR, 6R, 8aR)—2-aminocyano—8-methyl-4H, 4aH, 5H, 6H, 7H, 8H, 8aH, 9H—thieno[3 ,2-g]quinolinyl]carbonyl}-l -(cyclopropylmethyl)-3 —[3-(dimethylami- no)—2,2-dimethyl-propyl]urea (Compound ; 1-{[(4aR, 6R, 8aR)-2—aminocyano-8—methy1—4H, 4aH, 5H, 6H, 7H, 8H, 8aH, 9H—thieno [3 ,2-g]quinolinyl]carbonyl}[2-(diethylamino)ethyl]-1 -ethy1urea (Compound 1-105); 1-{[(4aR, 6R, 8aR)-2—arnino—3-cyano—8-methyl—4H, 4aH, 5H, 6H, 7H, 8H, 8aH, 9H—thieno[3 ,2—g]quinolin—6-yl]carbonyl}-3 ~[1 -(dimethylamino)methylpropan—2-yl]- l-ethylurea (Compound 1-106); 1-{[(4aR, 6R, 8aR)—2-amino—3-cyano-8—methyl—4H, 4aH, 5H, 6H, 7H, 8H, 8aH, 9H—thieno [3 ,2—g] quinolin—6—yl]carbony1}[2-(dimethylamino)ethylbutyl] ethyl- urea und 1-107); 1-{[(4aR, 6R, 8aR)amino—3-cyanomethyl-4H, 4aH, 5H, 6H, 7H, 8H, 8aH, 9H—thieno [3 ,2-g]quinolin—6-yl]carbonyl } -3 —[2-(dimethy1amino)ethyl]—1 —ethylurea (Compound ; and 1-{[(4aR, 6R, 8aR)-2~amino—3-cyano—8—methyl~4H, 4aH, 5H, 6H, 7H, 8H, 8aH, 9H-thieno[3,2-g]quinolin—6-y1]carbonyI}-l~(cyclopropylmethyl)-3—[2-(dimethylami- yl]urea und 1-109), or a pharmaceutically acceptable salt therof.
Compounds represented by the general formula (I) of the t invention can" be prepared by methods as illustrated in schemes 1 and 2.
[Chem. 6] Scheme 1 ,R‘m R200 N 125.an (XI) ————-:-- Step 1-1 O 0 Ar-OC(O)C1 (XIII) Step 1-2 Step 1-4 R7-N=C=O (XVII) R5 ,R" "‘N N RS-x 'R4D A R7R6NH N N . NO 0 (XV) __'__ R7R5N’J§0 Step 1-3 Ox {0 0 0 (YIV)‘ (XU) Step 1-5 0 Add Step 1-6 ‘N ,H N o A Step 1-6 R5 4 R7R5N 0 Acid or . \N N’ ——|r- 1) R30-x R7R5N ’l‘o 0‘ 0, 2) Add own!) s RICHZCN (xm) (XX) Step 1-7 R NR2R3 In the formula, R1, R2, R3, R4, R5, R6 and R7 have the same meanings as defined above; and R20 is a C1-6 alkyl group, R30 is a halo-CM alkyl group, X ents an leaving group such as an iodine atom, a trifluoromethanesulfonyloxy group or the like, R40 is a C1-6 alkyl group or a benzyl group, Ar represents an aryl group such as a phenyl group, a 2-chlorophenyl group, a 4-nitrophenyl group or the like.
Step 1—1 A carboxylic acid derivative can be ed by alkaline hydrolysis of an ester derivative (X) in a suitable solvent. As the solvent used in the reaction, for example, methanol, ethanol, water, tetrahydrofuran, a mixed solvent thereof and the like can be illustrated. As the base, for example, sodium hydroxide, potassium hydroxide, lithium hydroxide and the like can be rated. The reaction temperature is uSually at 0°C to reflux temperature, the reaction time is usually 10 minuites to 24 hours, varying based on the starting materials employed, the solvent, the reaction temperature and the like.
An amide derivative (XII) can be prepared by condensing a carboxylic acid derivative with amine (X1) in the presence of a condensing reagent in an inert solvent.
As the inert solvent, for example, acetonitrile, ‘N,N-dimethylformamide,‘tetrahydrofuran, methylene chloride, a mixed solvent thereof and the like can be illustrated. As the condensing reagent, for example, ohexylcarbodiimide, . 1-(3 —dimethylaminopropyl)—3 -ethylcarbodiimide hydrochloride, diphenylphosphoryl azide, 4-(4,6-dimethoxy-1,3,5-triazinyl)methylmorpholinium hydrochloride and the like can be illustrated. The reaction ature is usually at ~20°C to 100°C, the reaction time is y 10 minuites to 24 hours, varying based on the starting materials employed, the solvent, the reaction ature and the like.
Alternatively, the amide derivative (XII) can be also ed by converting a carboxylic acid to its reactive derivatives (for example; an acid halide, an acid anhydride, a mixed acid anhydride, a benzotriazol-l—yl-ester, a ophenyl ester, a 2,5-diox0pyrrolidine ester and the like) according to tional methods, followed by the condensation with amine (X1) or the salt therof in a suitable solvent in the ce or absence of a base. As the solvent used in the condensation reaction, for example, acetonitrile, N,N-dimethylforamide, tetrahydrofuran, methylene chloride, a mixed solvent thereof and the like can be rated. As the base, for example, potassium carbonate, triethylamine, N,N-diisopropylethylamine, ne, N—methylmorphorine, N,N-dimethylaniline and the like can be illustrated. The reaction temperature is usually at -20°C to reflux temperature, the reaction time is usually 1 hour to 24 hours, varying based on the starting als employed, the solvent, the reaction temperature and the like.
Alternatively, the amide derivative (XII) can be also prepared by irradiating microwave to a mixture ofthe ester derivative (X) and amine (XI) in a suitable solvent.
As the solvent used in the reaction, for example, ethanol, 2-propanol, a mixed solvent thereof and the like can be illustrated. The reaction ature is usually at 100°C to 250°C, the reaction time is y 1 hour to 24 hours, varying based on the starting materials employed, the solvent, the reaction temperature and the like. [005 7] Step 1-2 An aryl carbamate derivative (XIV) can be prepared by allowing an amide derivative (XII) to react with an aryl chloroformate (XIII) in an inert solvent in the presence of a base. As the inert solvent used in the reaction, for example, tetrahydrofuran and the like can be illustrated. As the base, for example, sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium tert-butoxide and the like can be illustrated. The reaction temperature is usually at -78°C to 50°C, the reaction time is y 15 minutes to 24 hours, varying based on the ng materials employed, the solvent, the reaction temperature and the like. [005 8] Step 1-3 An acyl urea derivative (XVI) can be ed by allowing an aryl carbamate derivative (XIV) to react with amine (XV) or salt thereof in an inert solvent in the presence or absence of a base. As the inert solvent used in the reaction, for example, 2—propanol, tetrahydrofuran, methylene chloride, 1,4-dioxane, a mixed solvent thereof and the like can be rated. As the base, for example, potassium carbonate, triethylamine, N,N-diisopropylethylamine, pyridine, N-methylmorphorine, N,N—dimethylaniline and the like can be illustrated. The reaction temperature is usually at 0°C to 150°C, the reaction time is usually 15 minutes to 24 hours, varying based on the starting materials employed, the solvent, the on temperature and the like.
Step 1-4 An acyl urea derivative (XVI) can be prepared by ng an amide derivative (XII) to react with nate (XVII) in an inert solvent with metal catalyst in the ce or e of . As the inert solvent used in the reaction, for example, methylene chloride, 1,2-dichloroethane, chloroform, toluene, acetonitrile, N,N—dimethylformamide, a mixed solvent thereof and the like can be illustrated. As the metal catalyst, for example, copper(l) chloride, copper(lI) chloride, copper(I) bromide, copper(l) iodide and the like can be illustrated. As the ligand, for example, triphenylphospine, tri-para-tolylphosphine and the like can be illustrated. The reaction temperature is usually at 0°C to 120°C, the reaction time is usually 15 s to 24 hours, varying based on the starting materials employed, the solvent, the reaction temperature and the like.
Step 1-5 An octahydro-lH—quinoline derivative (XVIII) can be prepared by removing a benzyl group of an acyl urea derivative (XVI) wherein R40 is a benzyl group in a suitable solvent under an atomosphere of hydrogen in the presence of metal catalyst. As the solvent used in the on, for example, methanol, ethanol, N,N-dimethylforamide, tetrahydrofuran and the like can be illustrated. As the metal catalyst, for example, palladium-carbon, platinum dioxide and the like can be rated. The reaction temperature is usually at room temperature to 80°C, the on time is y 30 minutes to 12 hours, varying based on the starting materials employed, the solvent, the reaction temperature and the like.- I0061] Step 1—6 A 6—oxodecaquinoline derivative (XIX) wherein R4 is a C1-6 alkyl group and a 6-oxodecaquinoline derivative (XIX) n R4 is a hydrogen atom can be prepared by acid hydrolysis of a ketal derivative (XVI) wherein R40 is a C1_6 alkyl group and a ketal derivative (XVIII) in a suitable solvent. As the solvent used in the reaction, for example, tetrahydrofilran, dimethoxyethane, 1,4-dioxane, methylene chloride, 1,2-dichloroethane, form, water, a mixed solvent therof and the like can be illustrated. As the acid, for example, sulfuric acid, hydrochloric acid, oric acid, acetic acid, methane- sulfonic acid, benzenesulfonic acid and the like can be rated. The reaction temperature is usually at -50°C to 100°C, the reaction time is y 10 minuetes to 24 hours, varying based on the starting materials employed, the solvent, the reaction ‘ ature and the like.
Alternatively, a 6-oxodecaquinoline (XIX) wherein R4 is a halo-C16 alkyl group can be prepared by allowing a ketal derivative (XVIII) to react with an alkylating ’ reagent (R3o-X) in an inert solvent in the ce of a base, and then hydrolyze the ketal ring by the same method as defined above. As the inert solvent used in the alkylation reaction, for example, acetonitrile, tetrahydrofuran, N,N—dimethy1formamide, dimethoxyethane, 1,4-dioxane, methylene chloride and the like can be illustrated. As the base, for example, potassium carbonate, cesium carbonate, triethylamine, N,N-diisopropylethylamine and the like can be illustrated. The reaction temperature is usually at 0°C to reflux temperature, the reaction time is usually 1 hour to 24 hours, varying based on the starting materials employed, the solvent, the on temperature and the like.
Step 1-7 An octahydrothienoquinoline derivative (Ia) can be prepared by ng a 6-oxodecaquinoline derivative (XIX) to react with compound (XX) and sulfur in an inert solvent in the ce or absence of a base. As the inert solvent used in the on, for example, ethanol, methanol, 1,4—dioxane and the like can be illustrated. As the base, for eXample, morpholine, piperidine, triethylamine and the like can be illustrated. The reaction temperature is usually at 0°C to reflux temperature, the reaction time is usually 15 minutes to 24 hours, varying based on the starting materials ed, the solvent, the reaction temperature and the like.
Step 1-8 An acyl amide derivative (I) can be prepared by allowing an octahydrothienoquinoline derivative (Ia) to react with an acylating t in an inert solvent in the ce or e of a base. As the inert solvent used in the reaction, for example, tetrahydrofuran, 1,4—dioxane, methylene chloride, benzene and the like can be rated. As the acylating reagent, for example, an acid halide, an acid anhydride, a mixed acid anhydride and the like can be illustrated. As the base, for e, potassium carbonate, triethylamine, N,N-diisopropylethylamine, pyridine, N—methylmorphorine, N,N-dimethylaniline and the like can be illustrated. The reaction temperature is usually at 0°C to reflux temperature, the reaction time is usually 15 minutes to 24 hours, varying based on the starting materials employed, the solvent, the reaction temperature and the like.
Alternatively, an octahydrothienoquinoline derivative (1) wherein R2 is a hydrogen atom and R3 is a R24 alkoxycarbonyl group can be prepared by allowing an octahydrothienoquinoline derivative (Ia) to react with l,1'-carbonyldiimidazole in an inert solvent, and then to react with a C1_6 alcohol. As the inert solvent used in the reaction, for example, methylene chloride and the like can be rated. The reaction temperature is usually at —20°C to 60°C, the reaction time is usually 1 hour to 48 hours, varying based on the ng materials employed, the solvent, the reaction ature and the like.
[Chem 7] Scheme 2 0 R200 N’ R‘m-NHZ (XXII) NaBH3CN —_——>- _—-|s co R2" 0 0 Br/\l]/ 2 Step 2-2 O O \_l (XXIII) L] (DOG) Step 2'1 (X) 0 V k(\I 40 1;, .R ———1-— Step 2-3 0 o In the formula, R20 and R40 have the same meanings as defined above. 8th 2—1 Compound (XXIV) can be prepared by conducting coupling reaction of 1,4-cyclohexanedione monoethylene ketal (XXI), amine (XXII) and 2—(bromomethyl)- acrylic acid ester (XXIII) in an inert solvent. As the inert solvent used in the reaction, for example, toluene, benzene and the like can be illustrated. The reaction temperature is usually at -50°C to reflux temperature, the reaction time is y 1 hour to 24 hours, varying based on the starting materials employed, the solvent, the reaction temperature and the like.
Step 2-2 Compound (X) can be prepared by reduction of a compound (XXIV) in a suitable solvent in the presence of an acid by using a reducing t such as sodium cyanoborohydride, sodium borohydride, sodium triacetoxyborohyride or the like. As the solvent used in the reaction, for example, tetrahydrofilran, methanol, ethanol, ethyl acetate, 1,4-dioxane, a mixed solvent therof and the like can be rated. As the acid, for example, sulfuric acid, hydrochloric acid, acetic acid and the like can be illustrated.
The on temperature is usually at —50°C to 50°C, the reaction time is usually 10 minuites to 12 hours, varying based on the starting materials employed, the solvent, the reaction temperature and the like.
Step 2-3 The optical active compounds (Xa) and (Xb) can be prepared by allowing compound (X) to te by mean of optical resolution by crystallization such as ential crystallization, diastereomeric salt ion, inclusion complexation, preference enrichment and the like, enzymatic optical resolution or direct optical resolution using chiral column chromatography.
As the chiral column used in the direct optical resolution by the chiral column chromatography, for example, CHIRALPAK (registered mark of Daicel Chemical Industries) AY-H column, AD-H , IA column and the like can be illustrated. As the eluting solvent, hexane, methanol, ethanol, 2-propanol, diethylamine, a mixed solvent therof and the like can be illustrated. The eluting flow rate is 0.5 mL/min to 10 ml/min. The eluting temperature is usually at 10°C to 60°C, and the ion wavelength is 200 nm to 270 nm.
The forementioned schemes are exemplary for ing compounds ofthe present invention and synthetic intermediates thereof. Those ordinarily skilled in the art will appreciate that various changes or modifications ofthe forementioned schemes may be made without departing from the scope ofthe invention.
Compounds ented by the general formula (I) of the present invention and intermediates for preparing the compounds ofthe present invention can be isolated or purified, if required, according to conventional isolation or purification techniques well known to those in the art of the relevant field, such as solvent extraction, crystallization, recrystallization, chromatography, preparative high performance liquid chromatography or the like.
Compounds of the present ion prepared in the above-mentioned schemes exhibt excellent dopamine D2 or stimulating activitities, and are accordingly useful as a treating or prophylactic agent for the various diseases dopamine D2 receptor mediated. For example, the compounds ofthe present invention are useful as a treating or prophylactic agent such as Parkinson's disease, restless legs syndrome, hyperprolactinemia or the like, especially useful as a treating or preventing agent such as Parkinson's disease. [007 1] Compounds of the present invention can be also used, if ed, in combination with other arkinson drugs. As the other anti-Parkinson drugs include, for example, ; dopamine D2 receptor agonists such as cabergoline, bromocriptine mesylate, terguride, ’talipexole hydrochloride, ropinirole hydrochloride, ide mesylate, pramipexole hloride, rotigotine, phine and the like; anticholinergic agents such as profenarnine, yphenidyl hydrochloride, mazaticol hloride, piperiden, piroheptine hydrochloride, methixene hydrochloride and the like; adenosine A2A or nists such as istradefylline and the like; NMDA receptor antagonists such as budipine and the like; monoamine oxidase B inhibitors such as selegiline hydrochloride, rasagiline mesylate, safinamide mesylate and the like; COMT inhibitors such as entacapone and the like; aromatic L-amino acid decarboxylase inhibitors such as carbidopa, benserazide and the like; droxidopa, dopa, threodops; zonisamide; amantadine hydrochloride and the like.
Pharmaceutical compositions comprising a compound represented by the general formula (I) ofthe present invention or a pharmaceutically acceptable salt thereof as an active ingredient can be administered in various dosage forms depending on their usages. Exemplary dosage forms e powders, granules, fine granules, dry , tablets, es, injections, s, ointments, suppositories, poultices and the like, which are administered orally or parenterally.
Pharmaceutical compositions comprising a compound represented by the general formula (I) of the present ion or a pharmaceutically acceptable salt thereof can be formulated by using a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutical additive. These pharmaceutical compositions can be formulated by ng, diluting or dissolving with riate pharmaceutical additives such as excipients, egrants, binders, lubricants, diluents, buffers, tonicity agents, preservatives, wetting agents, emulsifying , dispersing agents, stabilizing agents, lizing agents and the like, according to a conventional formulation procedure depending upon their dosage forms.
The dosage of a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is appropriately determined depending on the age, sex or body weight of the individual patient, the severity of the disease, the condition to be treated and the like, which is approximately within the range of from about 0.1 mg to about 300 mg per day per adult human, ably about 0.5 mg to about 30 mg, in the case of oral stration, and approximately within the range of from about 0.01 mg to about .50 mg per day per adult human, preferably about 0.05 mg to about 10 mg, in the case of parenteral administration. The dosages may be administered in single or divided doses, for e one to several times daily.
A ceutical combination comprising a compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt f and other anti—Parkinson drugs can be administered as a single pharmaceutical composition comprising all of active ingredients, or as separately formulated pharmaceutical compositions each of which ses a single active ingredient. Where separately formulated pharmaceutical compositions are used, the compositions may be administered separately, concurrently or at different intervals. Alternatively, where separately formulated pharmaceutical compositions are used, the itions may be mixed together with an appropriate diluent, and administered simultaneously.
A pharmaceutical combination comprising a compound represented by the general formula (I) of the present invention or a phannaceutically acceptable salt therof, and any other anti—Perkinson drugs is preferably used for the treating or ting agent of Parkinson's disease, restless legs m, hyperprolactinemia or the like, especially used for the treating or preventing agent of Parkinson's disease.
In a pharmaceutical combination comprising a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof and other anti-Parkinson drugs, the compounding ratio of medicament can be appropriately determined depending on the age, sex or body weight of the individual patient, the severity of the disease, stration time, dosage form, administration method, combination of medicaments and the like.
The present invention is further rated in more detail by way of the following Reference Examples, Examples and Test Examples. However, the present invention is not limited thereto.
EXAMPLES Reference example 1-1 Ethyl hy1—2',3',4',5',7',8'-hexahydro—1'H-spiro[l,3 —dioxolane—2,6'—quinoli- ne]—3'-carboxylate To a mixture of ethyl 2-(bromomethyl)acrylate (20.42g) and toluene (320mL) was added dropwise a mixture of a 40% methylamine-methanol solution (24.1mL) and toluene(80mL) under ice cooling while stirring. The mixture was stirred for 3 minutes.
To the mixture was added a mixture of 1,4-cyclohexandione monoethylene ketal g) and toluene ) under the same conditions. The mixture was refluxed with the Dean-Stark tus for 4.5 hours. After cooling to room temperature, the mixture was passed through a layer of Celite (registered mark). The filtrate was concentrated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluent: O%-40% ethyl acetate/hexane, gradient elution) to give the title compound (22.92g). 1H—NMR ) 5 ppm: 1.20-1.35 (4H, m), 1.70-1.85 (2H, m), 1.95-2.10 (1H, m), 2.15—2.35 (4H, m), 2.60 (3H, s), 2.75-3.00 (2H, m), 3.10-3.20 (1H, m), 3.85-4.05 (4H, m), 4.15 (2H, q, J=7.1Hz) Reference examples 1-2 to 1—3 were prepared in a manner similar to those as described in reference e l-l using the corresponding amines instead of methylamine. These were illustrated in Table l.
[Table 1] Reference Reference Strucutre Strucutre example example id="p-82" id="p-82"
[0082] The physical data of reference examples 1-2 to 1-3 were shown below.
Reference example 1-2 1H-NMR(CDC13) 5 ppm: 1.15-1.35 (4H, m), 1.80-1.90 (2H, m), 1.95-2.10 (1H,1n), .50 (5H, m), 2.65—2.80 (1H, m), 2.90-3.00 (1H, m), 3.05-3.20 (1H, m), 3.90-4.20 (7H, m), 7.20-7.40 (5H, m) Reference example 1-3 1H'-NMR (CDCl3) 5 ppm: 0.86 (3H, t, J=7.4Hz), 1.26 (3H, t, J=7.1Hz), .60 (2H, 1n),'1.70-1.90 (2H, m), 1.90-2.05 (1H, m), 2.10-2.40 (5H, m), 2.65-2.90 (3H, m), 2.90—3.05 (1H, m), .25 (1H, m), 3.90-4.05 (4H, m), 4.14 (2H, q, J=7.1Hz) Reference example 2-1 Ethyl (3 'R* ,4'aR*,8‘aR*)-l'—methyloctahydro-1'H-spiro[l,3 -dioxolane-2,6'—quino- line]—3'-carboxylate To a mixture of ethyl l'-methyl-2',3',4',5',7',8'-hexahydr0-l'H-spiro[1,3—diox01— ane-2,6'—quinoline]—3'—carboxylate(reference example 1-1) (22.92g), tetrahydrofiiran (260mL) and methanol (65mL) was added a 4mol/L en chloride-dioxane on (21 .4mL), ed by sodium cyanoborohydride (6.14g) under ice bath cooling while stirring. The mixture was stirred for 10 minutes. The mixture was concentrated under reduced re, added a saturated aqueous solution of sodium bicarbonate, and ted with ethyl acetate. The separated organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was d by silica gel column chromatography (eluent: 0%-22% methanol/ethyl acetate, nt elution) to give the title compound (8.33g). The structure was illustrated in Table 2. 1H—NMR(CDC13) 5 ppm: .30 (4H, m), 1.30—1.75 (6H, m), 1.75—1.85 (1H, m), 1.85-2.00 (1H, m), 2.00—2.10 (1H, m), 2.17 (1H, t, J=11.6Hz), 2.30 (3H, s), 2.60-2.75 I(1H,m),3.05-3.15 (1H, m), 3.93 (4H, s), 4.12 (2H, q, J=7.1Hz) Reference examples 2—2 to 2-3 were prepared in a manner similar to those as described in reference example 2-1 using the corresponding enamines instead of ethyl 1'-methyl-2',3',4',5',7',8'~hexahydro-1'H—spiro[l,3-dioxolane-2,6'-quinoline]-3'—carbo- 2O xylate. These structures were illustrated in Table 2.
The physical data of reference examples 2-2 to 2-3 were shown below.
Reference example 2-2 1H—NMR (CDC13) 8 ppm: 1.15-1.30 (4H, m), 1.35-1.95 (8H, m), 2.05-2.25 (2H, m), 2.50-2.65 (1H, m), 3.00-3.10 (1H, m), 3.25 (1H, d, J=l3.9Hz), 3.95 (4H, s), 4.00-4.15 (3H, m), 7.15-7.40 (5H, m) nce example 2-3 1H—NMR (CDC13) 8 ppm: 0.85 (3H, t, z), 1.17 (1H, dd, J=24.9, 12.5Hz), 1.25 (3H, t, J=7.1Hz), 1.30-1.70 (7H, m), 1.75-1.85 (2H, m), 1.85-1.95 (1H, m), 1.95-2.10 (1H, m), 2.31 (1H, t, J=11.4Hz), 2.40-2.55 (1H, m), 2.55-2.70 (2H, m), 3.10-3.20 (1H, m), 3.93 (4H, s), 4.12 (2H, q, J=7.1Hz) Reference example 2-4 Ethyl (3 'R*,4'aR*,8'aR*)- 1 loctahydro—l 'H—spiro[1 ,3~dioxolane-2,6'—quinoli- ne] —3'-carboxy1ate To a mixture of ethyl (3'R*,4'aR*,8'aR*)-1'—benzyl-octahydro-l'H-spiro[1,3-di— oxolane-2,6'—quinoline]—3'—carboxylate (reference e 2-2) (200mg) and ethanol (4.0mL) was added 10% palladium-carbon (86mg). The mixture was stirred at room temperature for 12 hours under a hydrogen atmosphere. The mixture was passed through a layer of Celite (registered mark) and the filtrate was concentrated under reduced pressure to give ethyl (3'R*,4'aR*,8'aR*)octahydro—1'H-spiro[1,3-dioxol— ane—2i,6'-quin01ine]-3'-carboxylate (154mg). 1H-NMR(CDC13) 5 ppm : 1.25 (3H, t, J=7.1Hz), 1.25-1.55 (4H, m), 1.55-1.70 (2H, m), 1.70-1.85 (2H, m), 1.90-2.00 (1H, m), 2.10—2.20 (1H, m), 2.40-2.55 (1H, m), 2.73 (1H, t, J=12.0Hz), 3.25-3.35 (1H; m), 3.94 (4H, s), 4.12 (2H, q, J=7.1Hz) To a mixture of ethyl (3'R*,4'aR*,8'aR*)octahydro-1'H-spiro[1,3—dioxol- ane—2,6'-quinoline] —3'—carboxy1ate (154mg) and MN—dimethylformamide (2.8mL) was added potassium carbonate (184mg), followed by iodoethane (0.053mL), and the e was stirred at room temperature for 18 hours. To the reaction mixture was added brine, and extracted with ethyl acetate. After the separated c layer was dried over anhydrous sodium e, it was trated under reduced pressure to give . the title compound (157mg). The structure was illustrated in Table 2. 1H-NMR ) 8 ppm: 0.99 (3H, t, J=7.2Hz), 1.17 (1H, dd, J=24.9, 12.4Hz), 1.25 (3H, t, J=7.1Hz), 1.30-1.50 (2H, m), .75 (3H, m), 1.75-1.95 (3H, m), 2.00-2.10 (1H, m), 2.32 (1H, t, J=11.6Hz), 2.55-2.75 (2H, m), 2.75-2.90 (1H, m), 3.05-3.20 (1H, m), 3.93 (4H, s), 4.12 (2H, q, J=7.2Hz) [Table 2] . nce Reference The structures of the reference example 2-1 to 2—4 in Table 2 indicate relative configuration. id="p-93" id="p-93"
[0093] nce example 3 Ethyl (3 'R,4'aR,8'aR)-l '-methyloctahydro-l 'H-spiro [1 ,3—dioxolane-2,6'—quinoli- -carboxylate To ethyl (3 'R*,4'aR*,8'aR*)—1'—methyloctahydro—l 'H-spiro[1,3-diox0- lane-2,6'-quinoline]—3'-carb0xylate (reference example 2-1) (14.4g) was repeated chromatography using a CHIRALPAK (registered mark) AY-H (Daicel Chemical Industries) column (250mm X 20mm ID.) with the following condition: Solvent system; hexane:ethanol:diethylamine = 50:50:01 (V/V) Detection wavelength; 220nm Flow rate; 5.0mL/min Column oven temperature; 40°C.
The eluted component of the secomd peak was collected, and concentrated to give the title compound (6.9g). 1H—NMR (CDC13) 5 ppm: 1.10-1.30 (4H, m), 1.30-1.75 (6H, m), 1.75-1.85 (1H, m), .00 (1H, m), .10 (1H, m), 2.17 (1H, t, J=11.6Hz), 2.30 (3H, s), 2.60-2.75 (1H, m), 3.05-3.15 (1H, m), 3.93 (4H, s), 4.12 (2H, q, J=7.1Hz) [a]929= -11.50° (c=1.06, MeOI-I) ReferenCe example 4-1 (3 'R,4'aR,8'aR)- 1 yl-N—propyloctahydro-1 'H-spiro [1 ,3 -dioxolane-2,6'-quinoli- ne]-3'-carboxamide To a mixture of ethyl (3'R,4'aR,8'aR)—1'-methyloctahydro-1'H—spiro[1,3—dio— xolane-2,6'—quin01ine]-3'-carboxylate (reference example 3) g) and ethanol (3 SmL) was added a Smol/L aqueous solution of sodium hydroxide (7.06mL) while stirring at room temperature. The mixture was heated at 80°C and stirred for 1.5 hours.
After cooling in ice bath, it was lized by the addition of 6mol/L hydrochloric acid (5.88mL). The mixture was concentrated under reduced pressure to give (3‘R,4'aR,8'aR)-1'—methy10ctahydro-1'H—spiro[1,3~dioxolane-2,6'-quinoline]~3 '-carbo- xylic acid.
To a mixture of (3'R,4'aR,8'aR)-1'-methyloctahydro-1'H-spiro[1,3-dioxol- 6'—quinoline]-3'—carboxy1ic acid, l—propylamine (0.63 8mL), triethylamine (2.16mL) and methylene chloride (541nL) was added 1—hydroxybenzotriazole (1 .19g), followed by l-(3-dimethy1aminopropyl)—3-ethylcarbodiimide hloride (1 .49g) while stirring at room temperature. The mixture was stirred for 11 hours. The mixture was passed through a layer of Celite (registered mark) and the e was concentrated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography t: 0%-5% methanol/ethyl acetate, gradient elution) to give the title compound (1.812g). 1H—NMR (CDC13) 8 ppm: 0.91 (3H, t, J=7.4Hz), .70 (9H, m), 1.70-1.85 (2H, m), 2.00-2.10 (1H, m), 2.20-2.35 (4H, m), 2.40-2.50 (1H, m), 2.90-3.05 (1H, m), 3.15-3 .25 (2H, m), 3.85-4.00 (4H, m), 5.30-5.50 (1H, m) [aJD28= -8.00° (c=0.30, MeOH) Reference example 4-4 (3 'R,4'aR,8'aR)-N— [(1 S)—2,3 -Dihydro-lH-inden—l-yl]—l'—methyloctahydro-1'H-spiro- [1 ,3 -dioxolane—2,6'-quinoline]-3 '—carboxamide To a mixture of ethyl (3'R,4'aR,8'aR)-l'—methyl—octahydro-1'H-spiro[1,3-dioxo- lane-2,6'-quinoline]-3'-carboxylate (reference example 3) (100mg) and ethanol (35mL) was addeda lmol/L aqueous solution of sodium hydroxide (0.42mL) the mixture , and was stirred at room temperature for 2 hours. The reaction mixture was neutralized by the addition of lmol/L hydrochloric acid (0.42mL). The mixture was concentrated under reduced pressure to give (3'R,4'aR,8'aR)-l'-methyloctahydro-1'H-spiro[1,3-dioxo- lane-2,6'—quinoline]-3'-carboxylic acid.
To a mixture of (3'R,4'aR,8‘aR)-l'-methyloctahydro-1'H-spiro[1,«3-dioxo- lane-2,6‘-quinoline]—3'-carboxy1ic acid, (1S)-2,3-dihydro-1H-inden—1-amine (64mg) and methylene de (lmL) was added 1-hydroxybenzotriazole (60mg), followed by l-(3 -dimethylaminopropyl)—3-ethylcarb0diimide hydrochloride (85mg) while ng at room temperature, and the mixture was stirred for 12 hours. The mixture was passed through a layer of Celite (registered mark) and the e was trated under reduced re. The residue was purified by aminopropyl silica gel column chromatography (eluent: 0%-7% methanol/ethyl acetate, gradient elution) to give the title compound ). 1H—NMR (CDC13) 6 ppm: 1.30—1.501(3H, m), 1.50-1.85 (7H, m), 2.00-2.10 (1H, m), 2.25-2.35 (4H, m), 2.45-2.55 (1H, m), 2.55-2.70 (1H, m), 2.80-3.05 (3H, m), .00 (4H, m), 5.45—5.55 (1H, m), 5.55-5.65 (1H, m), 7.20-7.30 (4H, m) [a] 29= ° (c=0.21, MeOH) After dissolving a mixture of (3 'R,4'aR,8'aR)-N—[(1 S)—2,3-dihydro-lH-ind- en-1—yl]-1'-methyloctahydro—1'H-spiro-[l,3-dioxolane-2,6'-quinoline]-3'-carboxamide (reference example 4-4') (3mg) and acetonitrile (1 .2mL) by heating at 50°C, it was allowed to remain at room temperature for 6 days to give a single crystal. The absolute configuration of nce example 4-4 was determined by X—ray crystallographic analysis of the obtained single crystal.
By determining the absolute ration of (3'R,4'aR,8’aR)-N—[(1S)—2,3-dihy— dro— 1H—inden—l—yl]-1 '-methyloctahyd-ro-1'H-spiro[1 ,3 ~dioxolane-2,6'-quinoline] —3 '-car- boxamide (reference example 4-I4), ethyl (3'R,4'aR,8'aR)—1'—methylocta—hydro-1'H-spi— ro[1,3-dioxolane-2,6'—quinoline]~3'—carboxy1-ate(reference example 3) as its starting material, was demonstrated the same configuration.
Reference example 4-5 (3 'R*,4‘aR*,8'aR*)-1 '-Methy1-N-propyloctahydro~ l 'H-spiro- [1 ,3-dioxolane-2,6'—quin- oline]¥3'-carboxamide To a mixture of ethyl 4'aR*,8'aR*)-1'-methyl-octahydro—1'H-spiro- [1,3-dioxolane-2,6'—quinoline]-3'-carboxylate ence example 2—1) (16.67g) and ethanol (391nL) was added a Smol/L aqueous solution of sodium hydroxide (58.8mL) under water bath g, and the e was stirred at the same temperature for 1 hour.
After cooling in ice salt bath, it was neutralized by the addition of 6mol/L hydrochloric acid (49mL). The mixture .was concentrated under reduced pressure to give (3 'R* ,4'aR*,8'aR*)—1'-methyloctahydro—1'H-spiro[l ,3 -dioxo—1ane-2,6'-quinoline]-3 '—car- boxylic acid.
To a mixture of (3 'R*,4'aR*,8'aR*)-l'—methyloctahydro-l'H-spiro[1,3-dioxo- lane-2,6'—quinoline]—3'—carboxylic acid, l-propylamine (5.32mL) , triethylamine (9.01mL) and ene chloride (13 lmL) was added l-hydroxybenzotriazole , followed by l-(3-dimethy1aminopropy1)ethylcarbodiimide hloride (12.4g) while stirring at room temperature, and the mixture was stirred for 14 hours. The mixture was passed through a layer of Celite (registered mark) and the filtrate was washed with a lmol/L aqueous solution of sodium hydroxide, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluent: 0%-5% methanol/ethyl acetate, gradient elution) to give the title compound (16.18g). 1H—NMR (CDCl3) 5 ppm: 0.91 (3H, t, J=7.6Hz), .90 (11H, m), 2.00-2.15 (1H, m), . 2.20—2.35 (4H, m), 2.35—2.50 (1H, m), 2.90-3.05 (1H, m), 3.15-3.25 (2H, m), 3.85-4.00 (4H, m), 5.35-5.50 (1H, m) id="p-99" id="p-99"
[0099] Reference examples 4-2 to 4-3 and reference examples 4-6 to 4-33 were prepared in a manner similar to those as bed in reference example 4—1 or reference example 4-5 using the corresponding decahydroquinoline-3—carboxylate esters and amines instead of ethyl (3'R,4'aR,8'aR)—1'-methyloctahydro~1'H-spiro[l,3-dioxola— ne-2,6'-quinoline]-3'-carboxylate and ylamine. These were illustrated in Table 3.
[Table 3] Reference Reference ure Structure exam 1e example Table 3 (continued) Reference Reference ure Structure example example 4-28 Table 3 (continued) Ref rence6 Referen e0 Structure Structure example example The ures of the reference example 4-1 to 4—4 and 4-33 in Table 3 indicate absolute configuration, and the structures of the nce example 4-5 to 4-32 in Table 3 indicate ve configuration. [01 0 1] The physical data of reference examples 4-2 to 4-3 and reference examples 4—6 to 4—33 were shown below.
Reference example 4-2 1H-NMR (CDC13) 5 ppm: 0.92 (3H, t, J=8Hz), 1.20-1.90 (11H, m), 2.00-2.15 (1H, m), 2.20-2.50 (6H, m), 2.90—3.05 (1H, m), 3.15-3.35 (3H, m), 3.85-4.00 (4H, m), 5.30-5.50 (1H, m) Reference example 4-3 1H—NMR (CDC13) 5 ppm: 1.13. (3H, t, J=7.2Hz), 1.25-1.90 (9H, m), 2.00—2.10 (1H, m), 2.20—2.35 (4H, m), 2.35-2.50 (1H,~ m), .10 (1H, m), 3.20-3.40 (2H, m), 3.85-4.00 (4H, m), 5.39 (1H, brs) [a]D27= —20.25° (c=0.32, MeOH) Reference example 4—6 1H-NMR (CDC13) 5 ppm: 1.05.3117 (3H, m), 1.20—1.90 (9H, m), .10 (1H, m), 2.20-2.35 (4H, m), 2.38—2.50 (1H, m), 2.90—3.10 (1H, m), 3.20-3.41 (2H, m), 3.93 (4H, s), 5.38 (1H, b'r's) Reference example 4-7 1H—NMR (CDC13) 5 ppm: 0.92 (3H, t, , 1.20-1.90 (11H, m), 2.00-2.15 (1H, m), 2.20—2.50 (6H, m), 2.90-3.05 (1H, m), 3.15-3.35 (3H, m), 3.85-4.00 (4H, m), 5.30-5.50 (1H, m) nce example 4—8 MS(ESI, m/z):295(M+H)+ Reference example 4-9 1H-NMR (CDC13) 5 ppm: 1.21-1.87 (11H, m), 2.01-2.10 (1H, m), 2.19-2.33 (4H, m), 2.39-2.51 (1H, m), 2.92-3.04 (1H, m), .40 (5H, m), 3.44-3.51 (2H, m), 3.93 (4H, s), 6.14 (1H, brs) nce example 4—10 1H-NMR (CDC13) 5 ppm: 1.30-1.90 (8H, m), 2.00-2.10 (1H, m), 2.25-2.40 (4H, m), 2.40-2.60 (1H, m), 2.95-3.10 (1H, m), 3.10-3.30 (1H, m), 3.85-4.00 (4H, m), 4.30—4.55 (2H, m), 5.65—5.80 (1H, m), 7.20-7.40 (5H, m) Reference example 4-11 MS(ESI, m/z):359(M+H)+ Reference example 4-12 lH—NMR (CDC13) 5 ppm: 0.90 (6H, d, J=6.8Hz), 1.25—1.46 (3H, m), 1.48—1.85 (7H, m), 2.00—2.15 (1H, m), 2.20-2.35 (4H, m), .54 (1H, m), 2.90-3.03 (1H, m), .12 (2H, m), 3.90-3.98 (4H, m), 5.35-5.55 (1H, m) Reference example 4-13 lH—NMR(CDC13) 5 ppm: 0.10-0.25 (2H, m), 0.40-0.60 (2H, m), 0.85—1.00 (1H, m), 1.20—1.90 (9H, m), 1.95-2.15 (1H, m), 2.20-2.35 (4H, m), 2.40—2.55 (1H, m), 2.90-3.05 (1H, m), 3.05-3.20 (2H, m), .00 (4H, m), 5.40—5.60 (1H, m) Reference e 4—14_ V(CDC13) 5 ppm: 1.25-1.45 (3H, m), 1.45—1.70 (4H, m), 1.70—1.85 (2H, m), 2.00-2.10 (1H, m), 2.25-2.35 (4H, m), 2.40-2.55 (1H, m), .05 (1H, m), 3.90-4.00 (4H, m), .70 (2H, m), 5.75-5.90 (1H, m), 6.90-7.00 (2H, m), 7.20—7.25 (1H, m) Reference example 4-15 1H—NMR (CDC13) 5 ppm: 1.30-1.50 (3H, m), 1.50—1.70 (4H, m), 1.75-1.85 (2H, m), 2.00-2.10 (1H, In), 2.25-2.35 (4H, m), 2.50-2.65 (1H, m), 3.00-3.10 (1H, m), 3.90-4.00 (4H, m), 4.75 (2H, ddd, J=18.4, 16.3, 5.6Hz), 6.25-6.35 (1H, m), 7.30 (1H, d, J=3.3Hz), 7.71 (1H, d, J=3.3Hz) Reference example 4-16 1H—NMR (CDC13) 5 ppm: 1.20-1.90 (9H, m), 2.00—2.10 (1H, m), 2.20-2.40 (4H, m), 2.40—2.60 (1H, m), 2.90—3.10 (1H, m), 3.80—4.00 (6H, m), 5.00-5.30 (2H, m), 5.40—5.60 (1H, brs), 5.70-6.00 (1H, m) Reference e 4-17 1H—NMR (CDC13) 6 ppm: 0.89 (3H, t, J=7.0Hz), .70 (12H, m), 1.70-1.85 (3H, m), 2.00—2.10 (1H, m), 2.20-2.35 (4H, m), .50 (1H, m), 2.90—3.05 (1H, m), 3.15-3.30 (2H, m), 3.85-4.00 (4H, m), 5.35-5.50 (1H, m) Reference example 4-18 1H-NMR (CDC13) 8 ppm: 0.80 (2H, m), 1.05-1.90 (18H ,m), 2.00-2.10 (1H, m), .35 (4H, m), .55 (1H, m), 2.90-3.15 (3H, m), 3.85—4.00 (4H, m), 5.35-5.55 (1H, m) Reference example 4-19 1H-NMR (CDC13) 8 ppm: 1.20-1.90 (9H, m), 2.00-2.10 (1H, m), 2.20-2.40 (7H, m), 2.40-2.60 (1H, m), 2.90-3.10 (1H, m), 3.80-4.00 (4H, m), 4.30-4.50 (2H, m), 5.40-5.60 (1H, m), 7.10-7.30 (4H, m) Reference example 4—20 1H—NMR(CDC13) 5 ppm: 0.91 (6H, d, J=6.6Hz), 1.20-1.70 (10H, m), 1.70-1.85 (2H, m), 2.00—2.15 (1H, m), 2.20-2.35 (4H, m), 2.35-2.55 (1H, m), 2.90-3.05 (1H, m), 3.20-3.30 (2H, m), 3.85-4.00 (4H, m), 5.30-5.45 (1H, m) Reference example 4-21 1H-NMR (CDC13) 8 ppm: 1.20 (3H, t, J=7.0Hz), 1.25—1.90 (9H, m), 2.00-2.10 (1H, m), 2.20-2.35 (4H, m), .55 (1H, m), 2.95-3.05 (1H, m), 3.35-3.55 (6H, m), 3.85-4.00 (4H, m), 5.75-5.95 (1H, m) - Reference example 4-22 1H—NMR (CDC13) 6 ppm: 1.20—1.46 (3H, m), 1.46-1.90 (6H, m), 2.00-2.15 (1H, m), 2.15-2.55 (7H, m), 2.90-3.05 (1H, m), 3.50 (2H, q, J=6.4Hz), 3.85-4.00 (4H, m), .65—5.80 (1H, m) Reference example 4-23 lH—NMR (CDC13) 8 ppm: 1.15-1.90 (11H, m), 2.00-2.10 (1H, m), 2.22 (1H, t, J=11.2Hz), 2.28 (3H, s), 2.33-2.46 (1H, m), 2.64 (2H, t, J=7.2Hz), 2.85-3.00 (1H, m), 3.28 (2H, q, J=6.8Hz), 3.85-4.05 (4H, m), 5.30-5.50 (1H, m), 7.14-7.24 (3H, m), 7.24-7.34 (2H, m) .
Reference example 4-24 1H—NMR (CDC13) 5 ppm: 0.89 (9H, s), 1.25—1.85 (9H, m), 2.00-2.15 (1H, m), 2.20235 (4H, m), 2.40—2.55 (1H, m), 2.90—3.05 (1H, m). 3.05 (2H, d, z), 3.94 (4H, s), .35-5.50 (1H, m) id="p-123" id="p-123"
[0123] Reference example 4-25 1H—NMR ) 5 ppm: 1.25-1.47 (3H, m), 1.47—1.70 (4H, m), 1.70—1.90 (4H, m), 2.00-2.20 (3H, m), 2.20-2.35 (4H, m), 2.40-2.55 (1H, m), 2.90—3.05 (1H, m), 3.25-3.40 (2H, m), 3.85-4.00 (4H, m), .75 (1H, m) id="p-124" id="p-124"
[0124] nce example 4—26 MS(ESI, m/z):313(M+H)+ Reference example 4-27 , 1H-NMR(CDC13) 5 ppm: 1.25—1.70 (7H, m), 1.70—1.85 (2H, m), .10 (1H, m), 2.20-2.35 (4H, m), 2.40-2.55 (1H, m), 2.80 (3H, d, J=4.8Hz), 2.90—3.05 (1H, m), 3.90-4.00 (4H, m), 5.35-5.50 (1H, m) Reference example 4—28 1H-NMR (CDC13) 5 ppm: 0.89 (3H, t, J=7.3Hz), 1.19-1.77 (11H, m), 1.78-1.93 (2H, m), 2.13—2.24 (2H, m), 2.27-2.39 (1H, m), 2.87-2.97 (1H, m), .25 (3H, m), 3.88-4.01 (4H, m), 4.04-4.13 (1H, m), 5.20-5.36 (1H, m), .36 (5H, m) Reference example 4—29 MS(ESI, m/z):311(M+H)+ Reference example 4-30 1H—NMR (CDC13) 5 ppm: 0.90-1.05 (3H, m), .20 (3H, m), 1.25-1.50 (3H, m), 1.50—1.90 (6H, m), 2.00-2.10 (1H, m), 2.30—2.50 (2H, m), 2.60—2.90 (2H, m), 2.95-3.05 (1H, m), 3.20-3.35 (2H, m), 3.85-4.00 (4H, m), 5.41 (1H, brs) Reference example 4-31 1H—NMR(CDC13) 5 ppm: H, t, J=7.4Hz), .95 (11H, m), 2.10-2.25 (2H, m), 2.25—2.40 (1H, m), 2.90-3.00 (1H, m), 3.05-3.25 (3H, m), 3.90-4.00 (4H, m), 4.10 (1H, d, J=13.8Hz), 5.25-5.40 (1H, m), 7.15-7.35 (5H, m) Reference example 4-32 le-NMR (CDC13) 5 ppm: 1.07 (3H, t, J=7.3Hz), 1.25-1.78 (7H, m), 1.79—1.93 (2H, m), 2.13—2.25 (2H, m), .39 (1H, m), 2.88-2.99 (1H, m), 3.10-3.31 (3H, m), 3.87-4.00 (4H, m), 4.05-4.15 (1H, m), 5.17—5.39 (1H, m), 7.16-7.36 (5H, m) Reference example 4-33 1H-NMR (CDC13) 5 ppm: 0.10-0.25 (2H, m), 0.40-0.60 (2H, m), 0.80-1.00 (1H, m), 1.20—1.48 (3H, m), 1.48-1.70 (4H, m), 1.70-1.90 (2H, m), .15 (1H, m), 2.20-2.35 (4H, m), 2.40-2.55 (1H, m), 2.90—3.05 (1H, m), 3.05-3.14 (2H, m), 3.90-4.00 (4H, m), .49 (1H, brs) [a] 27: -18.52° (c=0.30, MeOH) [0 1 32] Reference example 5-1 (3 'R,4'aR,8‘aR)- l '—Methyl-N-[2-(pyrrolidin—1—yl)ethy1]octa-hydro-l 'H-spiro [1 ,3 -dioxo- lane-2,6'-quinoline]-3'-carb0xamide A mixture of ethyl (3'R,4'aR,8'aR)-l'~methyloctahydro-l'H-spiro[1,3-dioxo- lane-2,6'-quinoline]-3’-carboxylate (reference example 3) (100mg) and mino- ethyl)pyrrolidine (0.22mL) was stirred under microwave irradiation to 210°C for 12 hours. The e was purified by aminopropyl silica gel column chromatography (eluent: 0%-10% methanol/ethyl acetate, gradient elution) to give the title compound (73mg). 1H—NMR(CDC13) 6 ppm: 1.24-1.46 (3H, m), 1.48-1.70 (4H, m), 1.70-1.86 (6H, m), 2.01-2.11 (1H, m), 2.23-2.33 (1H, m), 2.29 (3H, s), 2.43-2.53 (5H, m), 2.53-2.60 (2H, m), 2.94-3.01 (1H, m),‘3.28—3.37 (2H, m), 3.90-3.97 (4H, m), 6.05-6.18 (1H, m) [0 1 3 3] Reference example 5-2 (3 aR*,8'aR*)-N- [3 thylamino)propyl]-1'-rnethy1-octahydro-l 'H-spiro- ’20 [1,3 -dioxolane—2,6'-quinoline]-3'-carboxamide A mixture of ethyl (3 'R*,4'aR*,8'aR*)~ 1 '-methyloctahydro-1'H-spiro[l,3-di- oxolane-2,_6'-quinoline]-3'—carboxylate ence example 2-1) (2.053 g) and (3-aminopropyl)dimethylamine (4.44mL) was stirred under microwave irradiation to 210°C for 10 hours. The mixture was purified by aminopropyl silica gel column chromatography t: 0%-10% methanol/ethyl acetate, gradient elution) to give the title compound (2.557g). 1H-NMR ) 6 ppm: .90 (11H, m), 2.00-2.15 (1H, m), 2.15-2.55 (13H, m), 2.95-3.05 (1H, m), 3.25-3.40 (2H, m), 3.85-4.00 (4H, m), 7.35-7.50 (1H, m) Reference examples 5-3 to 5-8 were ed in a manner similar to those as described in reference example 5-2 using the corresponding decahydroquinoline-3 -carb- oxylate esters and amines instead of ethyl (3'R*,4'aR*,8'aR*)-1'-methyloctahy- dro-l'H—spiro[1,3-dioxolane—2;6'-quinoline]-3'-carboxylate (reference example 2-1) and (3-aminopropyl)dimethylamine. These were illustrated in Table 4.
[Table 4] R f R f example e The structure of the reference example 5—1 in Table 4 indicates absolute configuration, and the structures of the nce example 5-2 to 5—8 in Table 4 indicate relative configuration.
The physical data ofreference examples 5—3 to 5-8 were shown below.
Reference example 5-3 MS(ESI, m/z):368(M+H)+ Reference example 5—4 lH—NMR (CDC13) 5 ppm: 1.20-1.90 (8H, m), 2.00-2.10 (1H, m), .35 (11H, m), 2.38 (2H, t, z), 2.42-2.55 (1H, m), 2.90-3.05 (1H, m), 3.20—3.35 (2H, m), 3.90-4.01 (4H, m), 6.00-6.15 (1H, m) Reference example 5—5 MS(ESI, m/z):354(M+H)+ Reference e 5-6 lH—NMR(CDC13) 8 ppm: 1.24-1.87 (13H, m), 2.01-2.11 (1H, m), 2.22-2.35 (1H, m), 2.29 (3H, s), 2.41-2.62 (7H, m), 2.94-3.02 (1H, m),>3.27-3.37 (2H, m), 3.89-3.98 (4H, m), 6.05—6.18 (1H, m) Reference example 5-7 1H—NMR (CDC13) 8 ppm: 0.84 (3H, t, J=7.3Hz), .70 (9H, m), 1.70-1.90 (3H, m), .10 (1H, m), 2.20-2.25 (7H, m), 2.30-2.55 (5H, m), 2.55-2.70 (1H, m), 3.00-3.10 (1H, m), 3.25-3.40 (2H, m), 3.85-4.00 (4H, m), 7.35-7.45 (1H, m) Reference example 5-8 lH-NMR(CDC13) 5 ppm: 0.98 (3H, t, J=7.1Hz), 1.20-1.50 (3H, m), 1.50-1.70 (4H, m). 1.70-1.90 (3H, m), 2.00-2.10 (1H, m), 215-230 (7H, m), 2.30—2.50 (4H, m), 2.60-2.75 (1H, m), 2.75-2.90 (1H, m), .10 (1H, m), 3.25-3.40 (2H, m), 3.85-4.00 (4H, m), 7.30—7.45 (1H, In) [0 143] Reference example 6-1 Phenyl N—{ [(3 'R,4'aR,8_'aR)-1 '-methyloctahydro- 1 'H—spiro[1,3 -dioxolane-2,6’-quino— lin] —3'-yl]carbonyl}-N-propylcarbamate To a mixture of (3'R,4'aR,8'aR)-l'-methyl-N-propyloctahydro-1'H-spiro- [1,3 -dioxolane-2,6'-quinoline]-3'-carboxamide (reference example 4-1) (1 .816g) and tetrahydrofuran (31mL) was added a lmol/L sodium hexamethyldisilazide-tetra— hydrofuran solution (7.97mL) at -42°C. After stirring at the same temperature for 20 minutes, phenyl chloroformate (0.999mL) was added to the mixture, and then stirred for 1.5 hours. After warming to room temperature, water and ethyl acetate were added. The separated oraganic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 0%-15% ol/ethyl acetate, gradient elution) to give the title compound 1H—NMR(CDC13) 5 ppm: 0.95 (3H, t, J=7.5Hz), 1.15—1.50 (3H, m), 1.50-1.85 (7H, m), 1.90-2.10 (2H, .m), 2.29 (3H, s), 2.38 (1H, t, J=ll.3Hz), 2.95-3.05 (1H, m), 3.65-3.80 (1H, m), 3.80-3.95 (6H, m), 7.10-7.20 (2H, m), 7.25-7.35 (1H, m), 7.35—7.50 (2H, m) id="p-144" id="p-144"
[0144] nce e 6-5 Phenyl N—{ [(3 'R*,4'aR*,8'aR*)- 1 '-methyloctahydro— l 'H-spiro—[l ,3-dioxolane-2,6'—quin— olin] -3'-yl]carbony1}-N-propylcarbamate To a mixture of (3 'R*,4'aR*,8'aR*)—l '—methy1~N-propyloctahydro-l'H-spiro- [l,3~dioxolane-2,6'—quinoline]-3'—carboxamide (reference example 4-5) (539mg) and ydrofuran ) was added a lmol/L sodium hexamethyldisilazide—tetra— hydrofuran solution (2.4mL) at -20°C. After stirring at the same temperature for 20 minutes, phenyl chloroforrnate (0.298mL) was added to the mixture, and then stirred for 1 hour. After warming to room temperature, water and ethyl acetate were added. The separated oraganic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 0%-9% methanol/ethyl acetate, gradient elution) to give the title compound (622mg). 1H-NMR(CDC13) 5 ppm: 0.95 (3H, t, J=7.6Hz), 1.10-1.50 (3H, m), 1.50—1.85 (7H, m), 1.85-2.10 (2H, m), 2.28 (3H, s), 2.38 (1H, t, J=10.8Hz), 2.90-3.10 (1H, m), .00 (7H, m), 7.10-7.20 (2H, m), 7.20—7.35 (1H, m), 7.35—7.50 (2H, m) id="p-145" id="p-145"
[0145] Reference examples 6—2 to 6-4 and nce es 6-6 to 6-40 were ed in a manner similar to those as described in reference example 6-1 or reference e 6-5 using the corresponding amides and aryl chloroformates instead of (3 ’R,4'aR,8'aR)- 1 ’-methy1-N—propyloctahydro-1 'H-Spiro [l ,3 -dioxolane-2,6'—quino- line] -3'-carboxamide and phenyl chloroformate. These were illustrated in Table 5.
[Table 5] Reference we."am80.mh8 ure Structure example Table 5 (continued) Reference Reference SW.uame ure example exam I 1e Table 5 (continued) 8 erence 6 erence Structure Structure example e The structures ofthe reference example 6-1 to 6-4 and 6-39 to 6-40 in Table 5 indicate absolute configuration, and the structures of the reference example 6-5 to 6-38 in Table 5 indicate relative configuration.
The physical data of reference examples 6-2 to 6-4 and reference examples 6-6 to 6-40 were shown below.
Reference example 6-2 lH-NMR(CDC13) 5 ppm: 0.96 (3H, t, J=7.2Hz), 1.20—1.90 (11H, m), 2.00-2.15 (2H, m), 2.20-2.40 (4H, m), 2.95-3.10 (1H, m), .80 ('1H, m), 3.80-4.00 (6H, m), 7.30-7.40 (2H,m), 8.25-8.35 (2H,m) Reference example 6-3 , m/z):448(M+H)+ Reference example 6-4 MS(ESI, m/z):536(M+H)+ Reference example 6—6 MS(ESl, 62(M+H)+ Reference example 6-7 1H-NMR(CDC13) 6 ppm: .50 (6H, m), 1.50-1.85 (5H, m), 1.85-2.10 (2H, m), 2.29 (3H, s), 2.38 (1H, t, J=11.2Hz), 2.90—3.05 (1H, m), 3.65—3.85 (1H, m), 3.85-4.00 (6H, m), 7.12—7.20 (2H, m), 7.25-7.32 (1H, m), 7.38-7.46 (2H, m) Reference example 6-8 (CDC13) 8 ppm: 1.20-1.75 (10H, m), 1.75-1.85 (1H, m), 1.85-1.95 (1H, m), 1.95—2.10(1H, m), 2.30 (3H, s), 2.37 (1H, t, J=11.2Hz), 2.95-3.05 (1H, m), 3.65-3.80 (1H, m), 3.85-4.00 (6H, m), 7.30-7.40 (2H, m), 8.25-8.35 (2H, m) Reference example 6-9 1H—NMR (CDC13) 5 ppm: 1.15-1.50 (6H, m), .85 (5H, m), 1.90—2.10 (2H, m), 2.29 (3H, s), 2.38 (1H, t, J=11.3Hz), 2.85-3.10 (1H, m), 3.70-3.85 (1H, m), 3.85-3.95 (4H, m), 3.97 (2H, q, J=7.1Hz), 7.20-7.30 (2H, m), 7.30-7.40 (1H, m), 7,45-7.50 (1H, Reference example 6—10 1H—NMR (CDC13) 5 ppm: 0.95 (3H, t, J=7.2Hz), .50 (6H, m), 1.50-1.88 (6H, m), 1.88-2.10 (2H, m), 2.29 (3H, s), 2.38 (1H, t, J=11.2Hz), 2.95-3.05 (1H, m), 3.65-3.80 (1H, m), 3.80-4.00 (6H, m), 7.12-7.18 (2H, m), 7.26-7.32 (1H, m), 7.38—7.46 (2H, m) nce example 6-11 lH—NMR (CDC13) 5 ppm: 0.96 (3H, t, J=7.3Hz), 1.20-1.50 (6H, m), .75 (5H, m), 1.75-1.85 (1H, m), .95 (1H, m), 1.95-2.10 (1H, m), 2.30 (3H, s), 2.37 (1H, t, J=11.2Hz), 2.95-3.10 (1H, m), 3.65-3.80 (1H, m), 3.80-3.95 (6H, m), 7.30-7.40 (2H, m), 8.25-8.35 (2H, m) Reference example 6-12 MS(ESI, m/z):415(M+H)+ Reference example 6-13 MS(ESI, m/z):447(M+H)+ id="p-159" id="p-159"
[0159] Reference example 6-14 MS(ESI, m/z):465(M+H)+ Reference example 6-15 1H—NMR (CDC13) 5 ppm: 1.20-1.50 (4H, m), 1.50-1.70 (2H, m), 1.75-1.85 (1H, m), 1.95-2.10 (1H, m), 2.20—2.40 (4H, m), 2.80-3.20 (6H, m), 3.75—4.00 (6H, m), .05. (2H, m), 7.15-7.35 (6H, m), 7.35-7.45 (2H, m) Reference example 6-16 MS(ESI, m/z):431(M+H)+ Reference example 6-17 1H—NMR (CDC13) 8 ppm: .40 (2H, m), 0.45-0.60 (2H, m), 1.15-1.50 (4H, m), 1.50-1.85 (5H, m), 1.90-2.10 (2H, m), 2.29(3H, s), 2.38 (1H, t, J%11.2Hz), 2.95—3.10 (1H, m), 3.70-3.85 (3H, m), 3.85—3.95 (4H, m), .20 (2H, m), 7.25-7.35 (1H, m), 7.35-7.50 (2H, m) id="p-163" id="p-163"
[0163] Reference e 6-18 MS(ESI, m/z):471(M+H)+ Reference example 6-19 lH—NMR (CDC13) 6 ppm: 1.20—1.50 (3H, m), 1.50-1.85 (5H, m), 1.95-2.10 (2H, m), 2.30 (3H, s), 2.42 (1H, t, J=11.2Hz), 3.00-3.15 (1H, m), 3.80-4.00 (5H, m), 5.41 (2H, dd, 3, 16.0Hz), 7.05—7.10 (2H, m), 7.20—7.30 (1H, m), 7.31 (1H, d, J=3.3Hz), 7.35—7.45 (2H, m), 7.75 (1H, 'd, J=3.3Hz) Reference example 6-20 MS(ESI, m/z):415(M+H)+ Reference example 6-21 MS(ESI, m/z):445(M+H)+ Reference example 6-22 MS(ESI, m/z):47l(M+H)+ Reference e 6-23 MS(ESI, m/z):479(M+H)+ Reference example 6-2'4 MS(ESI, m/z):445(M+H)+ Reference example 6-25 , m/z):447(M+H)+ Reference example 6-26 1H—NMR (CDC13) 5 ppm: 1.16 (3H, t, J=7.0Hz), 1.20-1.50 (3H, m), 1.50-1.75 (4H, m), 1.75-1.85 (1H, m), 1.85-2.10 (2H, m), 2.30 (3H, s), 2.37 (1H, t, J=11.2Hz), 3.00—3.10 (1H, m), 3.45—3.55 (2H, m), 3.55—3.75 (3H, m), 3.85—3.95 (4H, m), 4.05-4.15 (2H, m), 7.30-7.40 (2H, m), .35 (2H, m) Reference e 6-27 1H-NMR ) 5 ppm: 1.10-1.50 (3H, m), 1.50-1.85 (5H, m), 1.85-2.10 (2H, m), 2.29 (3H, s), 2.33-2.42 (1H, m), 2.42—2.55 (2H, m), 2.95-3.05 (1H, m), 3.70-3.85 (1H, m), 3.85-4.00 (4H, m), 4.10-4.25 (2H, m), 7.10—7.20 (2H, m), 7.25-7.35 (1H, m), 7.40-7.50 (2H, m) Reference example 6-28 1H—NMR (CDC13) 8 ppm: .50 (3H, m), 1.50-1.85 (5H, m), 1.85-2.10 (4H, m), 2.28 (3H, s), 2.37 (1H, t, J=9.2Hz), 2.68 (2H, t, J=6.4Hz), 2.95-3.05 (1H, m), 3.70-3.80 (1H, m), 3.85—3.95 (6H, m), 7.08—7.14 (2H, m), 7.14-7.22 (3H, m), 7.24-7.32 (3H, m), 7.3 8-7.46 (2H, m) Reference example 6—29 MS(ESI, m/z):490(M+I-I)+ Reference example 6—30 MS(ESI, 85(M+H)+ Reference example 6-31 MS(ESI, m/z):433(M+H)+ nce example 6-32 1H-NMR (CDC13) 5 ppm: 1.20-1.50 (3H, m), 1.50—1.75 (4H, m), 1.75-1.85 (1H, m), 1.85—2.10 (2H, m), 2.30 (3H, s), 2.37 (1H, t, J=11.3Hz), 3.00-3.10 (1H, m), 3.35 (3H, s), 3.58 (2H, t, J=5.4Hz), 3.60-3.75 (1H, m), 3.85-3.95 (4H, m), 4.05-4.15 (2H, m), 7.30—7.40 (2H, m), 8.25-8.35 (2H, m) Reference example 6—33 1H—NMR (CDC13) 5 ppm: 1.20-1.75 (7H, m), 1.75—1.85 (1H, m), 1.85—2.10 (2H, m), 2.30 (3H, s), 2.38 (1H, t, J=11.2Hz), 2.95-3.10 (1H, m), H, s), .85 (1H, m), 3.85-3.95 (4H, m), 7.30-7.40 (2H, m), 8.25—8.35 (2H, m) Reference example 6-34 MS(ESI, m/z):389(M+H)+ Reference example 6-35 1H-NMR (CDC13) 8 ppm: 0.92 (3H, t, J=7.4Hz), 1.20-2.00 (13H, m), 2.10-2.20 (1H, m), 2.24 (1H, t, J=11.2Hz), 2.95—3.05 (1H, m), 3.18 (1H, d, J=13.8Hz), 3.55-3.70 (1H, m), .85 (2H, m), 3.85-4.00 (4H, m), 4.05-4.20 (1H, m), 7.15-7.35 (7H, m), 8.25-8.35 (2H, m) Reference example 6-36 MS(ESI, 1n/z):431(M+H)+ Reference example 6-37 MS(ESI, m/z):417(M+H)+ Reference example 6—38 1H-NMR (CDC13) 5 ppm: 0.90 (3H, t, J=7.4Hz), 1.20-1.35 (1H, m), 1.37 (1H, t, J=12.8Hz), 1.40-1.85 (7H, m), .00 (2H, m), .20 (1H, m), 2.28 (1H, t, J=11.1Hz), 2.90-3.05 (1H, m), 3.21 (1H, d, J=13.9Hz), 3.65—3.80 (3H, m), 3.85-3.95 (4H, m), 4.08 (1H, d, J=13.9Hz), 7.00-7.10 (2H, m), 7.15-7.35 (6H, m), 7.35-7.45 (2H,. m) nce example 6—39 MS(ESI, m/z):474(M+H)+ Reference example 6-40 , m/z):403(M+H)+ Reference example 7-1 l-{ [(3 'R,4'aR,8 'aR)-1 '-Methyloctahydro—l ro [1 ,3 -dioxolane-2,6'-quinolin]-3 '—y1]- carbonyl} -3 -ethyl[2—(pyrrolidin-1 -y1)ethyl]urea To a mixture of 'aR,8‘aR)-1'-methy1—N—[2-(pyrrolidin—l-yl)ethyl]octa— hydro-1'H—spiro[1,3-dioxolane-2,6'—quinoline]-3'-carboxamide (reference e 5-1) (73mg) and 1,2-dichloroethane (lmL) was added copper(I) chloride (21mg) and ethyl isocyanate (0.049mL) at room temperature, and the mixture was stirred for 2.5 hours.
The mixture was purified by aminopropyl silica gel column chromatography (eluent: 0%—5% methanol/ethyl acetate, gradient elution) to give the title nd (46mg). 1H-NMR(CDC13) 6 ppm: 1.16 (3H, t, z), 1.28—1.48 (3H, m), 1.51-1.73 (4H, 1n), 1.74—1.91 (6H, m), 2.00-2.10 (1H, m), 2.29 (3H, s), 2.30-2.39 (1H, m), 2.52—2.75 (6H, m), 2.90-3.01 (1H, m), 3.14-3.33 (3H, m), 3.55—4.00 (6H, m), 9.28—9.65 (1H, m) [0 1 87] Reference example 7—2 l—{[(3'R*,4'aR*,8'aR*)—1'-Methyloctahydro-1'H-spiro[1 ,3 -dioxolane-2,6'—quinolin] -3 '- yl] carbonyl} - l - [3-(dimethylamino)propyl]ethylurea To a mixture of (3'R*,4'aR*,8'aR*)-N—[3-(dimethylamino)propyl]-1 '-methyl- octahydro—l'H—spiro[1,3-dioxolane-2,6'-quinoline]-3'-carboxamide (reference e -2) (2.512g) and 1,2-dichloroethane (25mL) were added copper(I) chloride (732mg) and ethyl isocyanate (1.75mL) at room temperature, and the mixture was stirred for 1 hour. The mixture was purified by aminopropyl silica gel column chromatography (eluent: 2% methanol/ethyl acetate) to give the title compound (2.3 09g). 1H-NMR ) 6 ppm: 1.16 (3H, t, J=7.4Hz), 1.30—1.50 (3H, m), 1.50-1.90 (8H, m), 200-215 (111, m), 2.15-2.40 (12H, m), .00 (1H, m), 3.05-3.35 (3H, m), 3.55-3.90 (2H, m), 3.90—4.00 (4H, m), 9.37 (1H, br) [0 1 8 8] Reference examples 7-3 to 7—9 were prepared in a manner similar to those as described in reference example 7-2 using the corresponding amides and isocyanates instead of (3'R,4'aR,8'aR)—1'-methyl-N-[2-(pyrroli’din-l-yl)ethyl]-octahydro-1'H—spiro- [1,3-dioxolane-2,6'-quinoline]-3'—carboxamide and ethyl isocyanate. These were illustrated in Table 6. id="p-189" id="p-189"
[0189] [Table 6] nce ~ Reference The structure ofthe reference example 7-1 in Table 6 indicates absolute configuration, and the structures of the reference e 7-2 to 7-9 in Table 6 indicate relative configuration.
The physical data of reference examples 7-3 to 7-9 were shown below.
Reference example 7-3 lH—NMR ) 5 ppm: 1.01 (6H, t, J=7.2Hz), 1.10-1.30 (6H, m), 1.30-1.50 (3H, m), 1.50-1.90 (5H, m), 2.00-2.10 (1H, m), 2.29 (3H, s), 2.34 (1H, t, J=11.2Hz), 2.40-2.65 (5H, m), .00 (1H, m), 3.10-3.35 (4H, m), 3.65—3.85 (2H, m), 3.90-4.00 (4H, m), 9.33 (1H, brs) Reference example 7—4 1H-NMR(CDC13) 5 ppm: 1.10—1.25 (7H, m), 1.25-1.50 (3H, m), 1.50—1.90 (7H, m), 2.00-2.10 (1H, m), 2.15-2.40 (12H, m), .00 (1H, m), 3.05-3.25 (1H, m), 3.50-4.05 (7H, m), 9.33 (1H, brs) Reference example 7-5 MS(ESI, m/z):397(M+H)+ Reference example 7-6 IH-NMR (CD013) 5 ppm: 1.02 (6H, t, J=7.2Hz), 1.16 (3H, t, J=7.3Hz), 1.23—1.49 (3H, m), 1.50-1.74 (4H, m), 1.75—1.95 (2H, m), 1.99-2.09 (1H, m), 2.29 (3H, s), 2.31-2.41 (1H, m), 2.44—2.65 (6H, m), 2.88-3.00 (1H, m), 3.16-3.39 (3H, m), 3.42-3.66 (1H,1n), 3.68-3.84 (1H, m), 3.87-4.00 (4H, m), .96 (1H, m) I V Reference example 7-7 1H-NMR (CDC13) 5 ppm: 1.16 (3H, t, J=7.3Hz), .49 (3H, m), .91 (10H, m), 2.00-2.10 (1H, m), 2.29 (3H, s), 2.29-2.40.(1H, m), 2.50—2.78 (6H, m), 2.90-3.00 (1H, m), 3.11-3.34 (3H, m), 3.56—4.02 (6H, m), 9.33—9.64 (1H, m) [01 96] Reference example 7-8 1H-NMR (CDC13) 6 ppm: 0.84 (3H, t, J=7.4Hz), 1.16 (3H, t, J=7.3Hz), 1.25-1.85 (12H, m), 1.85—1.95 (1H, m), 1.95-2.10 (1H, m), 2.22 (6H, s), 2.25—2.40 (2H, m), 2.40-2.55 (2H, m), 2.55-2.70 (1H, m), 2.95-3.05 (1H, m), 3.05-3.20 (1H, m), 3.20—3.35 (2H, m), 3.60—3.90 (2H, m), 3.94 (4H, s), 9.36 (1H, brs) [01 97] Reference example 7-9 1H—NMR ) 6 ppm: 0.98 (3H, t, J=7.1Hz), 1.16 (3H, t, J=7.3Hz), .50 (3H, m), 1.50-1.70 (3H, m), .85 (4H, m), 1.85-1.95 (1H, m), 2.00—2.10(1H, m), 2.22 (6H, s), 2.25-2.40 (2H, m), 2.49 (1H, t, J=ll.2Hz), 2.65—2.85 (2H, m), 2.90-3.00 (1H, m), 3.05-3.20 (1H, m), 3.20-3.35 (2H, m), 3.60-3.90 (2H, m), 3.94 (4H, s), 9.37 (1H, brs) Reference example 8-1 1 - { [(3 'R,4'aR,8'aR)- 1 '-Methyloctahydro- l ro[1 ,3—dioxolane-2,6'—quinolin]-3'-yl]- yl} —3 -[2;(dimethy1amino)ethyl]-1 -propylurea To a mixture ofphenyl N—{[(3'R,4'aR,8'aR)—1'—methyloctahydro-1'H-spiro- [1,3~dioxolane—2,6'~quinolin]-3'-yl]carbonyl}«N-propylcarbamate (reference example 6-1) (2.401 g) and 2-propanol (3 OmL) was added N,N—dimethy1 ethylenediamine (1.26mL) While stirring at room temperature. The mixture was heated at 53°C and stirred for 13 hours. After oooling to room temperature, the on mixture was trated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluent: 0%-100% ethyl acetate/hexane, gradient elution) to give the title compound (2.3 83 g). 1H-NMR (CDC13) 6 ppm: 0.92 (3H, t, J=7.4Hz), 1.35-1.50 (3H, m), 1.50-1.90 (8H, m), 2.00-2.15 (1H, m), 2.26 (6H, s), 2.31 (3H, s), 2.37 (1H, t, J=ll.2Hz), 2.46 (2H, t, z), 2.85-3.10 (2H. m), 3.35-3.45 (2H, m), .70 (1H, m), 3.70-3.80 (1H, m), 3.90—4.00 (4H, m), 9.33 (1H, br) [a] 28= -6.62° (c=0.3l, MeOH) [0 1 99] Reference example 8-6 1-{ [(3 'R*,4‘aR*,8'aR*)- l '-Methyloctahydro-1 'Hespiro[l ,3 -dioxolane-2,6'—quinolin] -3 '- yl] carbonyl}—3-[2-(dimethylamino)ethyl]propylurea To a mixture ofphenyl 'R*,4'aR*,8'aR*)-1'-methyloctahydro-l'H-spiro- [l ,3-dioxolane-2,6'—quinolin]-3'-yl]carbonyl}-N-propylcarbarnate (reference example 6—5) (2.025g) and 2—propanol (26mL) was added N,N—dimethyl nediamine (1.06mL) while stirring at room temperature, and the mixture was heated at 50°C and stirred for 12 hours. After cooling to room temperature, the reaction mixture was trated under d pressure. The residue was purified by aminopropyl silica gel column chromatography (eluent: 0%-75% ethyl acetate/hexane, gradient elution) to give the title compound (1 .984g).
(CDC13) 6 ppm: 0.80-1.00 (3H, m), 1.30-1.90 (11H, m), 2.00-2.20 (1H, m), 2.25 (6H, s), 2.31 (3H, s), 2.32-2.50 (3H, m), 2.80-3.10 (2H, m), 3.30-3.50 (2H, m), 3.60-3.85 (2H, m), 3.90-4.00 (4H, m), 9.32 (1H, brs) Reference examples 8—2 to 8-5, reference examples 8—7 to 8-83, reference examples 8-85 to 8—89, and reference examples 8—91 to 8-96 were ed in a manner similar to those as described in reference example 8-1 or reference example 8—6 using the corresponding phenyl carbamates and amines instead of phenyl N—{ [(3 'R,4'aR,8'aR)- l '-methyloctahydro—l 'H—spiro[1,3-dioxolane-2,6'—quinolin]-3'-yl]- carbonyl}-N-propylcarbamate and N,N-dimethy1 ethylenediamine. These were illustrated in Table 7.
Reference example 8-84 l-{ [(3'R*,4'aR*,8'aR*)— l '-Methyloctahydro- l ro[l ,3 -dioxolane-2,6'—quinolin]-3 '- yl]carbonyl} —1 - [3 thylamino)propyl]-3—(2—fluoroethy1)urea To a mixture of (3'R*,4'aR*,8'aR*)-N-[3-(dimethylamino)propyl]-l '-methyl- octahydro-l'H—spiro[1,3-dioxolane-2,6'-quinoline]—3'-carboxarnide ence example -2) (300mg) and tetrahydrofiiran (IOmL) was added a lmol/L sodium hexamethyldisilazide-tetrahydrofuran solution (1 .2mL) at —40°C. After stirring at the same temperature for 35 s, a mixture of 4-nitrophenyl chloroformate (232mg) and tetrahydrofuran (lmL) was added to the mixture, and then stirred for 1.5 hours.
After warming to room temperature and stirring for 20 minutes, 2-fluoroethylamine hydrochloride (176mg) and triethylamine (0.246mL) were added to the reaction mixture, and then d at the same temperature for 4 hours. A saturated s solution of sodium bicarbonate was added to the reaction mixture, and extracted with ethyl acetate.
After the separated organic layer was dried over anhydrous sodium sulfate, the residue was purified by aminopropyl silica gel column chromatography (eluent: 0%—10% methanol/ethyl e, gradient elution) to give the title compound (195mg). The structure was illustrated in Table 7. 1H—NMR (CDC13) 8 ppm: 1.30-1.90 (11H, m), 2.00-2.10 (1H, m), 2.16-2.39 (3H, m), 2.22 (6H, s), 2.30 (3H, s), 2.88-2.99 (1H, m), 3.12-3.32 (1H, m), 3.44-3.86 (4H, m), 3.88—3.97 (4H, m), 4.46 (1H, t, J=4.8Hz), 4.58 (1H, t, J=4.8Hz), 0.09 (1H, m) Reference example 8-90 was ed in a manner similar to those as described in reference example 8-84 using the corresponding nitrophenyl carbamate and amine instead of (3 'R*,4'aR*,8'aR*)-N— [3 -(dimethylamino)propyl]-l'-methyloctahy- dro—l'H-spiro[l ,3—dioxolane-2,6'—quinoline]-3'-carboxamide and 2-fluoroethylamine hydrochloride. This was illustrated in Table 7.
Reference example 8-97 1-{ [(3'R*,4'aR*,8'aR*)-1'-(2-Fluoroethy1)octahydro-l'H—spiro[l ,3 -dioxolane-2,6'—qui- nolin]-3 '-yl]carbonyl } -3 — [2—(dimethylamino)ethyl] -1 ~propylurea To a mixture of 1—{[(3'R*,4'aR*,8'aR*)octahydro-1'H—spiro[l,3-dioxo- ,6'-quinolin]~3 '—yl] carbonyl} —3 -[2-(dimethylamino)ethyl] propylurea (reference example 9-4) (111mg) and methylformamide (1.0mL) was added potassium carbonate (85mg), followed by 1-fluoroiodoethane (124mg), and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction e, and extracted with ethyl acetate. After the ted organic layer was dried over anhydrous sodium sulfate, it was concentrated under reduced re. The residue was purified by aminopropyl silica gel column chromatography (eluent: 10%-100% ethyl acetate/hexane, gradient elution) to give the title compound (23mg). 1H-NMR (CDC13) 6 ppm: 0.94 (3H, t, J=7.2Hz), 1.30-1.90 (10H, m), 1.90-2.10 (2H, m), 2.25 (6H, s), 2.45 (2H, t, J=6.4Hz), 2.66 (1H, t, J=10.8Hz), 2.75-3.15 (4H, m), 3.3-3.45 (2H, m), 3.60-3.80 (2H, m), 3.85-4.00 (4H, m), 4.40-4.53 (1H, m), 4.53-4.65 (1H, m), 9.28 (1H, brs) Reference es 8-98 to 8-100 were prepared in a manner similar to those as described in reference example 8-97 using the corresponding decahydroquinolines, and alkyl halides or alkyl es instead of l-{[(3'R*,4'aR*,8'aR*)octahydro-l'H-spiro— [1,3 -dioxolane—2,6'—quinolin]-3'—yl]carbonyl}-3—[2-(dimethylamino)ethyl]propylurea and 1-fluoroiodoethane. These were illustrated in Table 7.
[Table 7] Re erencef _ Re erencef ure Structure example example Table 7 (continued) nce Reference Struc ure1: tmCtm9 example example Table ’7 nued) Reference Structure exam . 1e ma.Mmepmk8 Table 7 nued) Reference Reference Stmm6 Structure Table ’7 nued) Reference Structure Re"axam6pmk Structure example acmmbe.I.emm7 /w0n.tm{as\l/tmCmre 6pmm8 Structure Table 7(continued) Reference nce StmCwe Structure example exam - le Table 7 (continued) Reference Reference The structures of the reference example 8-1 to 8-5, 8-48 and 8—91 to 8-96 in Table 7 indicate te configuration, and the structures of the reference example 8-6 to 8-47, 8-49 to 8-90 and 8-97 to 8—100 in Table 7 indicate relative configuration.
The al data of reference examples 8-2 to 8-5, nce examples 8-7 to 8—83, reference examples 8-85 to 8-96 and reference examples 8-98 to 8-100 were shown below.
Reference example 8-2 , m/z):497(M+H)+ Reference example 8-3 1H-NMR (CDC13) 5 ppm: 0.94 (3H, t, J=7.4Hz), 1.02 (6H, t, J=7.2Hz), .48 (5H, m), 1.51-1.88 (8H, m), 2.02—2.13 (1H, m), 2.31 (3H, s), 2.33-2.41 (1H, m), 2.49—2.60 (6H, m), 2.87-3.07 (2H, m), 3.30—3.39 (2H, m), 3.61-3.86 (2H, m), 3.90—4.01 (4H, m), 9.15-9.38 (1H, m) Reference example 8—4 2O 1H-NMR(CDC13) 5 ppm: 0.91 (6H, s), 1.22 (3H, t, J=7.2Hz), 1.35-1.50 (3H, m), 1.50—1.90 (6H, m), 2.00-2.20 (3H, m), 2.25-2.45 (10H, m), 2.90—3.15 (2H, m), 3.15-3.25 (2H, m), 3.75—4.00 (6H, m), 9.30-9.50 (1H, m) Reference example 8-5 1H—NMR (CDClg) 5 ppm: 1.30-1.75 (7H, m), 1.75-1.85 (1H, m), 2.00-2.10 (7H, m), 2.10-2.25 (3H, m), 2.29 (3H, s), 2.30—2.45 (1H, m), 2.45—2.60 (1H, m), 2.85—3.00 (1H, m), 3.00-3.20 (5H, m), 3.90-3.95 (4H, m), .20 (1H, m) 7.10-7.25 (4H, m) nce example 8—7 1H--NMR(CDC13) 5 ppm: 1.17-1.27 (3H, m), 1.34-1.49 (3H, m), 1.51-1.87 (8H, m), 2.03-2.13 (1H, m), 2.21 (6H, s), 2.27—2.41 (6H, m), 2.89-3.10 (2H, m), 3.27—3.36 (2H, m), .90 (2H, m), 3.91—4.00 (4H, m), 9.28 (1H, brs) Reference example 8—8 MS(ESI, m/z):397(M+H)+ nce example 8-9 1H—NMR(CDC13) 6 ppm: 1.02 (6H, t, J=7.2Hz), 1.22 (3H, t, J=7.1Hz), 1.35-1.50 (3H, m), 1.50-1.90 (6H, m), 2.00-2.15 (1H, m), 2.32 (3H, s), 2.37 (1H, t, J=11.3Hz), 2.50-2.65 (6H, m), 2.85-3.10 (2H, m), 3.30-3.40 (2H, m), 3.70-4.00 (6H, m), 9.29 (1H, brs) ‘20 [0214] Reference example 8-10 1H-NMR (CDC13) 6 ppm: 0.94 (3H, t, z), 1.15-1.30 (4H, m), .50 (3H, m), 1.50-1.90 (7H, m), 2.00—2.15 (1H, m), 2.32 (3H, s), 2.36 (1H, t, J=11.3Hz), 2.90-3.10 (2H, m), 3.15—3.30 (2H, m), 3.75—4.00 (6H, m), 9.15-9.35 (1H, m) id="p-215" id="p-215"
[0215] Reference example 8-11 lH—NMR (CDC13) 5 ppm: 1.23 (3H, t, J;6.9Hz), 1.32—1.49 (3H, m), 1.51-1.88 (6H, m), 2.02-2.12 (1H, m), 2.27-2.40 (1H, m), 2.32 (3H, s), 2.79-3.09 (4H, m), 3.46-3.58 (2H, m), 3.75-3.90 (2H,-m), .98 (4H, m), 7.16-7.35 (5H, m), 9.24-9.39 (1H, m) Reference example 8-12 1H—NMR(CDC13) 8 ppm: 1.22 (3H, t, J=7.0Hz), 1.35-1.50 (3H, m), 1.50—1.90 (8H, m), .15 (1H, m), 2.25-2.45 (4H, m), 2.90-3.10 (2H, m), .40 (5H, m), 3.44 (2H, t, J=6.2Hz), 3.75—4.00 (6H, m), 9.32 (1H, brs) Reference example 8-13 1H-NMR ) 6 ppm: 1.24 (3H, t, J=7.0Hz), 1.33—1.88 (9H, m), 2.01-2.13 (1H, m), 2.32 (3H, s), 2.33-2.43 (1H, m), 2.87-3.10 (2H, m), 3.37 (3H, s), 3.43-3.54 (4H, m), 3.75-4.00 (6H, m), 9.33-9.48 (1H, m) Reference example 8-14 1H-NMR(CDC13) 5 ppm: 1.24 (3H, t, J=7.0Hz), 1.33-1.88 (9H, m), 2.03-2.14 (1H, m), 2.28-2.41 (1H, m), 2.32 (3H, s), 2.85 (3H, d, J=4.8Hz), 2.88-3.11 (2H, m), 3.74—4.02 (6H, m), 9.06-9.26 (1H, m) [0219j Reference e 8-15 .20 MS(ESI, m/z):425(M+H)+ Reference example 8—16 1H-NMR(CDC13) 6 ppm: 1.26 (3H, t, J=7.0Hz), 1.35-1.90 (9H, m), 2.00-2.15 (1H, m), 2.32 (3H, s), 2.41 (1H, t, J=11.4Hz), .00 (1H, m), 3.00—3.15 (1H, m), 3.80-4.00 (6H, m), 4.63 (2H, d, J=5.0Hz), 7.15-7.25 (1H, m), 7.25-7.30 (1H, m), 7.60-7.70 (1H, m), 8.55-8.65 (1H, m), 9.98 (1H, brs) Reference example 8-17 , m/z)’:409(M+H)+ Reference example 8-18 MS(ESI, m/z):441(M+H)+ Reference example 8—19 MS(ESI, In/z):459(M+H)+ Reference example 8-20 , m/z):398(M+H‘)+ Reference example 8—21 1H—NMR (CDC13) 8 ppm: 1.20-1.65 (8H, m), 1.75-1.85 (1H, m), 2.00-2.10 (1H, m), 2.20-2.35 (10H, m), 2.46 (2H, t, J=6.5Hz), .85 (1H, m), 2.85-3.00 (3H, m), 3.35—3.45 (2H, m), 3.85-4.05 (6H, m), 7207.40 (5H, m), 9.31 (1H, br) Reference example 8-22 1H-NMR (CDC13) 6 ppm: 1.22 .(3H, t, J=7.0Hz), 1.31—1.48 (3H, m), 1.51—1.88 (6H, m), .14 (1H, m), 2.28-2.39 (1H, m), 2.31 (3H, s), 2.81-3.07 (4H, m'), 3.47-3.58 (2H, m), 3.74—4.01 (6H, m), 7.19—7.29 (1H, m), 7.51-7.58 (1H, m), 8.43-8.52 (2H, m), 9.34-9.44 (1H, m) nce example 8-23 1H—NMR (CDC13) 5 ppm: 1.23 (3H, t, J=7.1Hz), 1.33—1.48 (5H, m), 1.50-1.87 (10H, m), 2.01-2.13 (1H, m), 2.28-2.52 (7H, m), 2.32 (3H, s), 2.88-3.09 (2H, m), 3.33—3.45 (2H, m), 3.73-4.00 (6H, m), 9.16-9.40 (1H, m) Reference example 8-24 1H—NMR (CDC13) 5 ppm: 1.26 (3H, t, J=7.1Hz), 1.35-1.49 (3H, m), 1.50-1.91 (6H, m), 2.00-2.14 (lH, m), 2.29-2.42 (1H, m), 2.32 (3H, s), 2.90-3.13 (2H, m), 3.78-4.05 (6H, m), 4.48 (2H, d, J=5.8Hz), 7.10-7.32 (2H, m), 8.48-8.64 (2H, m), 9.69-9.88 (1H, m) Reference example 8-25 lH—NMR (CDC13) 6 ppm: 1.23 (3H, t, J=7.1Hz), 1.33—1.89 (13H, m), 2.02-2.12 (1H, m), 2.20 (6H, s), 2.23—2.29 (2H, m), 2.29—2.39 (1H, m), 2.32 (3H, s), 2.88—3.08 (2H, m), 3.22-3.33 (2H, m), 3.75-4.01 (6H, m), 9.19—9.35 (1H, m) Reference e 8-26 1H—NMR (CDC13) 8 ppm: 0.90 (6H, d, J=6.4Hz), 1.30-1.95 (10nH, m), 2.00—2.15 (1H, m), 2.20—2.40 (10H, m), 2.40—2.55 (2H, m), .95 (1H, m), 3.00—3.15 (1H, m), 3.30-3.45 (2H, m), .75 (2H, m), 3.90-4.00 (4H, m), 9.32 (1H, brs) Reference example 8-27 MS(ESI, m/z):423(M+H)+ Reference example 8-28 1H—NMR (CDC13) 5 ppm: .50 (3H, m), 1.50-1.65 (5H, m), 1.75-1.90 (1H, m), 2.00-2.10 (1H, m), 2.25 (_6H, s), 2.27 (3H, s), 2.35 (1H> t, J=11.3Hz), 2.45 (2H, t, J=6.3Hz), 2.80—2.95 (1H, m), 3.15-3.30 (1H, m), 3.35-3.50 (2H, m), .00 (4H, m), .19 (2H, dd, J=34.2, 16.4Hz), 6.90-7.05 (2H, m), 7.15—7.25 (1H, m), 9.24 (1H, br) id="p-233" id="p-233"
[0233] Reference e 8-29 MS(ESI, m/z):466(M+H)+ Reference example 8—30 MS(ESI, m/z):409(M+H)+ Reference example 8-31 MS(ESI, m/z):439(M+H)+ Reference example 8-32 1H-NMR ) 5 ppm: 0.85-1.30 (5H, m), 1.30—1.50 (3H, m), 1.50-1.90 (12H, m), 2.00-2.15 (1H, m), 2.25 (6H, s), 2.25-2.40 (4H, m), 2.44 (2H, t, J=6.4Hz), 2.85-2.95 (1H, m), 3.00—3.15 (1H, m), 3.30-3.45 (2H, m), .65 (1H, m), 3.65-3.80 (1H, m), 3.90-4.05 (4H, m), 9.30 (1H, br) Reference example 8-33 1H—NMR ) 8 ppm: 1.20-1.70 (6H, m), 1.70-1.85 (1H, m), 1.90-2.05 (1H, m), 2.10-2.55 (16H, m), 2.75—2.95 (2H, m), 3.35-3.50 (2H, m), 3.80-4.00 (4H, m), 5.01 (2H, s), 6.85—6.95 (1H, m), 7.10—7.25 (3H, m) Reference example 834 1H—NMR (CDC13) 6 ppm: 0.93 (6H, d, J=6.6Hz), 1.30-1.90 (12H, m), 2.00-2.15 (1H, m), 2.26 (6H, s), 2.31 (3H, s), 2.38 (1H, t, J=11.3Hz), 2.47 (2H, t, z), 2.85-2.95 (1H, m), 2.95-3.10 (1H, m), 3.35-3.45 (2H, m), 3.60-3.75 (1H, m), 3.75—3.85 (1H, m), .00 (4H, m), 9.33 (1H, brs) Reference example 8—35 1H—NMR (CDC13) 5 ppm: 1.23 (3H, t, J=7.0Hz), 1.33-1.49 (3H, m), 1.52-1.88 (6H, m), 2.01-2.14 (1H, m), 2.25—2.39 (1H, m), 2.32 (6H, s), 2.32 (3H, s), 2.43-2.52 (2H, m), 2.77-3.09 (6H, m), 3.43—3.54 (2H, m), 3.77-3.99 (6H, m), .22 (4H, m), 9.28-9.42 (1H, m) Reference example 8—36 1H—NMR (CDC13) 5 ppm: 0.94 (3H, t, J=7.4Hz), 1.02 (6H, t, J=7.2Hz), 1.26-1.48 (5H, m), 1.51-1.88 (8H, m), 2.02—2.13 (1H, m), 2.31 (3H, s), 2.33—2.41 (1H, m), 2.49-2.60 (6H, m), 2.87-3.07 (2H, m), 3.30-3.39 (2H, m), 3.61-3.86 (2H, m), 3.90-4.01 (4H, m), 9.15-9.38 (1H, m) Reference e 8-37 1H-NMR (CDC13) 5 ppm: 0.94 (3H, t, J=7.3Hz), 1.28-1.48 (7H, m), 1.50—1.88 (12H, m), 2.01-2.13 (1H, m), 2.28-2.51 (7H, m), 2.31 (3H, s), 2.87—3.09 (2H, m), 3.32—3.45 (2H, m), 3.61-3.86 (2H, m), 3.89-4.02 (4H, m), 9.13-9.37 (1H, m) Reference example 8 1H-NMR (CDCI3) 5 ppm: 0.94 (3H, t, J=7.3Hz), 1.28-1.48 (5H, m), 1.50-1.88 (12H, m), 2.01-2.12 (1H, m), 2.31 (3H, s), .42 (1H, m), 2.47-2.58 (4H, m), 2.58-2.67 (2H, m), 2.88-3.08 (2H, m), 3.36-3.47 (2H, m), .86 (2H, m), 3.90-4.00 (4H, m), 9.17-9.42 (1H, m) id="p-243" id="p-243"
[0243] Reference example 8—39 1H—NMR (CDC13) 5 ppm: 0.92 (3H, t, J=7.2Hz), 1.02 (6H, t, z), 1.30-1.50 (3H, m), 1.50-1.90 (8H, m), 2.00-2.15 (1H, m), 2.31 (3H, s), .41 (1H, m), 2.45-2.65 (6H, m), 2.85—3.10 (2H, m), 3.25—3.40 (2H, m), 3.55-3.85 (2H, m), 3.88-4.02 (4H, m), 9.27 (1H, brs) Reference example 8—40 MS(ESI, m/z):451(M+H)+ Reference example 8-41 1H—NMR (CDCl3) 5 ppm: 1.16 (3H, t,0J=7.0Hz), 1.25-1.50 (3H, m), 1.50-1.90 (6H, m), 2.00-2.10 (1H, m), 2.20—2.40 (10H, m), 2.45 (2H, t, J=6.5Hz), 2.90-3.00 (1H, m), 3.30—3.60 (7H, m), 3.80—4.05 (6H, m), 9.14 (1H, br) Reference example 8-42 1H—NMR (CDC13) 5 ppm: 1.23 (3H, t, J=7.1Hz), .48 (3H, m), 1.51-1.87 (6H, m), 2.02-2.12 (1H, m), 2.28-2.42 (1H, m), 2.31 (3H, s), 2.75-2.83 (2H, m), 2.89-3.07 (2H, m), 3.51—3.59 (2H, m), 3.63 (3H, s), 3.75-3.99 (6H, m), 6.65-6.70 (1H, m), 7.30-7.35 (1H, m), 9.17-9.41 (1H, m) Reference example 8-43 ’15 , m/z):465(M+H)+ Reference example 8-44 1H—NMR (CDC13) 8 ppm: 1.23 (3H, t, J=7.1Hz), 1.33-1.48 (3H, m), 1.51—1.88 (6H, m), .12 (1H, m), 2.27-2.39 (1H, In); 2.31 (3H, s), 2.88—3.07 (2H, m), 3.55-3.64 (2H, m), 3.74—4.01 (6H, m), 4.08-4.17 (2H, m), 6.91—6.96 (1H, m), 7.04-7.11 (1H, m), .50 (1H, m), 9.38—9.50 (1H, m) Reference example 8-45 MS(ESI, m/z):487(M+H)+ id="p-250" id="p-250"
[0250] nce example 8-46 IH—NMR (CDC13) 5 ppm: 0.96 (3H, d, J=6.8Hz), 1.23 (3H, t, J=6.9Hz), 1.33—1.90 (9H, m), 2.01-2.13 (1H, m), 2.25 (6H, s), 2.26-2.43 (1H, m), 2.31 (3H, s), 2.62-2.75 (1H, m), 2.87-3.08 (2H, m), 3.14-3.24 (1H, m), 3.27-3.39 (1H, m), 3.74-4.02 (6H, m), 9.18-9.43 (1H, m) Reference example 8-47 1H—NMR ) 5 ppm: 0.91 (9H, s), 1.30-1.50 (3H, m), .90 (6H, m), 2.00-2.10 (1H, m), 2.20-2.35 (10H, m), 2.44 (2H, t, J=6.4Hz), 2.85—2.95 (1H, m), 3.10-3.25 (1H, m), 3.30-3.40 (2H, m), 3.78 (2H, brs), 3.90-4.00 (4H, m), 8.89 (1H, br) Reference example 8-48 1H-NMR (CDC13) 5 ppm: 1.19 (3H, d, J=6.6Hz), 1.23 (3H, t, J=7.0Hz), 1.33—1.49 (3H, m), .94 (6H, m), 2.03-2.12 (1H, m), .20 (1H, m), 2.24 (6H, s), 2.29—2.43 (2H, m), 2.31 (3H, s), 2.89—3.08 (2H, m), 3.67-4.03 (7H, m), 9.13-9.27 (1H, m) Reference example 8-49 1H—NMR (CDC13) 5 ppm: 0.94 (3H, t, J=7.3Hz), 1.29-1.49 (5H, m), 1.49-1.88 (10H, m), 2.01-2.12 (1H, m), 2.21 (6H, s), 2.25-2.41 (3H, m), 2.31 (3H, s), 2.87-3.09 (2H, m), 3.25-3.36 (2H, m), 3.60-3.85 (2H, m), 3.89-4.01 (4H, m), 9.20-9.38 (1H, m) Reference example 8—50 1H—NMR (CDC13) 5 ppm: 0.94 (3H, t, J=7.3Hz), 1.26-1.90 (17H, m), 2.01—2.13 (1H, m), 2.20 (6H, s), 2.22—2.39 (3H, m), 2.31 (3H, s), 2.87-3.07 (2H, m), 3.22—3.33 (2H, m), 3.61-3.86 (2H, m), 3.90-4.01 (4H, m), 9.21-9.36 (1H, m) Reference e 8-51 1H—NMR (CDC13) 6 ppm: 0.94 (3H, t, J=7.3Hz), 1.00 (12H, d, J=6.5Hz), 1.24-1.88 (13H, m), .14 (1H, m), 2.30-2.42 (1H, m), 2.31 (3H, s), 2.50-2.61 (2H, m), 2.86-3.08 (4H, m), 3.21-3.31 (2H, m),_3.61—3.86 (2H, m), 3.88-4.00 (4H, m), .37 (1H, m) Reference example 8-52 , m/z):479(M+H)+ Reference example 8-53 1H-NMR (CDC13) 6 ppm: 0.93 (3H, t, J=7.4Hz), 1.30-1.50 (3H, m), 1.50-1.90 (10H, m), 2.00—2.15 (1H, m), 2.21 (6H, s), 2.25—2.40 (6H, m), 2.85-3.10 (2H, m), 3.25-3.35 (2H, m), 3.60-3.85 (2H, m), 3.90—4.00 (4H, m), 9.30 (1H, s) Reference example 8-54 1H—NMR(CDC13) 5 ppm: 0.93 (3H, t, J=7.4Hz), 1.30-1.90 (15H, m), 2.00-2.15 (1H, m), 2.15-2.40 (12H, m), 2.85-3.10 (2H, m), 3.20-3.35 (2H, m), 3.60-3.85 (2H, m), 3.90—4.00 (4H, m), 9.20-9.35 (1H, m) Reference example 8-55 1H-NMR(CDC13) 5 ppm: 0.93 (3H, t, J=7.3Hz), 1.29-1.88 (13H, m), 2.01-2.12 (1H, m), 2.30 (6H, s), 2.34—2.47 (5H, m), 2.88-3.08 (2H, m), 3.35-3.47 (2H, m), .86 (4H, m), 3.89-4.00 (4H, m), 4.07—4.15 (2H, 111), 973-1002 (1H, m) Reference example 8-56 1H-NMR(CDC13) 5 ppm: 1.02 (6H, s), 1.24 (3H, t, J=6.9Hz), 1.35-1.89 (9H, m), 2.01-2.12 (1H, m), 2.22 (6H; s), 2.31 (3H, s), 2.35-2.46 (1H, m), 2.90-3.10 (2H, m), 3.26 (2H, d, J=4.8Hz), 3.75-4.01 (6H, m), .46 (1H, m) nce example 8-57 1H-NMR (CDC13) 5 ppm: 0.94 (3H, t, J=7.3Hz), 1.28-1.89 (14H, m), .12 (1H, m), 2.22-2.74 (10H, m), 2.29 (3H, s), 2.31 (3H, s), 2.85-3.10 (2H, m), 3.33-3.46 (2H, m), 3.60-3.87 (2H, m), 3.88-4.02 (4H, m), 9.13-9.42 (1H, m) nce example 8—58 MS(ESI, m/z):455(M+H)+ Reference example 8—59 MS(ESI, m/z):467(M+H)+ id="p-264" id="p-264"
[0264] Reference example 8—60 MS(ESI, m/z):441(M+H)+ Reference example 8-61 , m/z):455(M+H)+ Reference e 8-62 1H—NMR (CDC13) 5 ppm: 1.02 (6H, t, J=7.2Hz), 1.29-1.48 (3H, m), 1.51-1.87 (6H, m), 2.02-2.12 (1H, m), 2.26-2.38 (1H, m), 2.31 (3H, s), 2.49-2.63 (6H, m), 2.89-2.98 (1H, m), 3.03-3.16(1H,1n), 3.31-3.40 (2H, m), 3.34 (3H, s), 3.86-4.02 (4H, m), 9.16-9.36 (1H, 1n) Reference example 8-63 1H-NMR (CDC13) 5 ppm: 1.23 (3H, t, J=6.9Hz), .49 (3H, m), 1.51-1.88 (6H, m), 2.01-2.13 (1H, m), 2.26 (6H, s), 2.30-2.41 (1H, m), 2.31 (3H, s), 2.48—2.55 (2H, m), 2.88-3.08 (2H, m), 3.44-3.51 (2H, m), 3.52—3.61 (4H, m), 3.75-4.02 (6H, m), 9.30-9;45 (1H, m) Reference example 8—64 1H—NMR (CDC13) 5 ppm: 1.23 (3H, t, J==6.9Hz), .49 (3H, m), 1.49-1.88 (6H, m), 2.01-2.13 (1H, m), 2.28 (3H, s), .40 (1H, m), 2.31 (3H, s), .68 (1H, m), 2.84-3.09 (4H, m), 3.30-3.38 (2H, m), 3.41-3.49 (2H, m), 3.75—4.01 (6H, m), 9.27-9.38 (1H, m) Reference example 8-65 1H—NMR(CDC13) 5 ppm: 1.30-1.87 (15H, m), 2.03-2.12 (1H, m), 2.28-2.52 (7H, m), 2.3 1 (3H, s), 2.89-2.99 (1H, m), .16 (1H, m), 3.34 (3H, s), 3.36-3.45 (2H, m), 3.88—4.00 (4H, m), 9.18—9.33 (1H, m) Reference example 8-66 MS(ESI, m/z):482(M+H)+ id="p-271" id="p-271"
[0271] Reference example 8-67 MS(ESI, m/z):453(M+H)+ Reference example 8-68 IH-NMR (CDC13) 5 ppm: 0.91 (6H, s), 1.29-1.89 (8H, m), 2.03—2.12 (1H, m), 2.15 (2H, s), 2.24—2.40 (2H, m), 2.28 (6H, s), 2.32 (3H, s), 2.91-3.01 (1H, m), 3.07-3.20 (1H, m), 3.19 (2H, d, J=5.5Hz), 3.33 (3H, s), 3.88-4.00 (4H, m), 9.39-9.51 (1H, m) Reference example 8-69 1H-NMR (CDC13) 6 ppm: 1.17 (3H, t, J=7.0Hz), .88 (11H, m), 1.99-2.11 (1H, m), 2.22 (6H, s), 2.25—2.36 (3H, m), 2.29 (3H, s), 2.91-3.01 (1H, m), 3.23-3.62 (7H, m), 3.77-4.06 (6H, m), 8.28-9.94 (1H, m) Reference example 8-70 1H—NMR (CDC13) 5 ppm: 1.17 (3H, t, J=7.0Hz), 1.25-1.88 (13H, m), 2.00-2.10 (1H, m), 2.21 (6H, s), 2.23-2.38 (3H, m), 2.29 (3H, s), 2.89-3.00 (1H, m), 3.20-3.62 (7H, m), 3.75-4.10 (6H, m), 8.55-9.77 (1H, m) Reference example 8-71 ‘ MR (CDC13) 5 ppm: 0.30-0.55 (4H, m), 0.90-1.05 (1H, m), 1.35-1.90 (11H, m), 2.00-2.15 (1H, m), 2.24 (6H, s), 2.30-2.45 (6H, m), 2.90-3.00 (1H, m), 3.10-3.25 (1H, m), 3.25—3.35 (2H, m), 3.75.(2H, d, J=6.7Hz), 3.90-4.00 (4H, m), 9.32 (1H, brs) Reference example 8—72 1H-NMR ) 5 ppm: 1.02 (6H, s), 1.29—1.49 (3H, m), 1.50-1.88 (6H, m), 1.98-2.10 (1H, m), 2.22 (6H, s), .40 (1H, m), 2.30 (3H, s), 2.91-3.02 (1H, m), 3.16-3.39 (3H, m), 3.33 (3H, s), 3.46-3.58 (2H, m), 3.76—4.07 (6H, m), 8.26-9.55 (1H, m) nce example 8—73 1H-NMR (CDC13) 5 ppm: 0.93 (3H, t, J=7.4Hz), 1.02. (6H, s), 1.33-1.87 (11H, m), .12 (1H, m), 2.23 (6H, s), 2.31 (3H, s), 2.35-2.45 (1H, m), 2.85-3.10 (2H, m), 3.25 (2H, d, J=4.8Hz), 3.60-3.84 (2H, m), 3.88-4.01 (4H, m), 9.09-9.47 (1H, m) nce example 8-74 1H—NMR (CDC13) 8 ppm: 0.86-0.97 (3H, m), 0.91 (6H, s), 1.34-1.50 (3H, m), 1.51-1.88 (8H, m), 2.02—2.12 (1H, m), 2.14 (2H, s), 2.28 (6H, s), 2.31 (3H, s), 2.33-2.42 (1H, m), 2.88-3.11 (2H, m), 3.19 (2H, d, J=5.5Hz), 3.59—3.83 (2H, m), 3.88-4.02 (4H, m), 9.29-9.52 (1H, m) Reference example 8—75 1H-NMR (CDC13) 8 ppm: 0.87 (6H, t, J=7.4Hz), 1.23 (3H, t, J=7.0Hz), 1.34-1.88 (13H, m), 2.01-2.13 (1H, m), 2.31 (3H, s), 2.32 (6H, s), 2.35-2.43 (1H, m), 2.90-3.10 (2H, m), 3.30 (2H, d, J=5.0Hz), 3.75-4.01 (6H,'m), 9.10-9.45 (1H, m) Reference example 8-76 lH-NMR ) 5 ppm: 0.91 (6H, s), 1.22 (3H, t, J=7.1Hz), 1.34-1.50 (3H, m), .89 (6H, m), 2.01-2.12 (1H, m), 2.14 (2H, s), 2.28 (6H, s), 2.32 (3H, s), 2.33-2.42 (1H, m), .12 (2H,'m), 3.19 (2H, d, J=5.8Hz), 3.75—4.00 (6H, m), 9.33-9.47 (1H, m) Reference example 8-77 1H-NMR (CDC13) 6 ppm: 1.22 (3H, t, J=7.1Hz), 1.30-1.47 (3H, m), 1.51-1.75 (5H, m), 1.79-1.88 (1H, m), 2.00-2.12 (1H, m), 2.24—2.37 (1H, m), 2.31 (3H, s), 2.85-2.93 (1H, m), .05 (1H, m), 2.96 (3H, s), 3.41-3.56 (4H, m), 3.73-4.00 (6H, m), 6.63-6.78 (3H, m), 7.17-7.25 (2H, m), 9.30-9.41 (1H, m) Reference example 8-78 1I-I-NMR(CDC13) 5 ppm: 0.93 (3H, t, J=7.3Hz), 1.28-1.89 (13H, m), 2.02-2.13 (1H, m), ' 2.27 (3H, s), 2.31 (3H, s), 2.33-2.43 (1H, m), 2.52-2.63 (4H, m), 2.86—3.08 (2H, m), 3.34-3.45 (2H, m), 3.55-3.87 (4H, m), 3.89—4.01 (4H, m), 9.45-9.69 (1H, m) Reference example 8-79 1H-NMR(CDC13) 5 ppm: 0.92 (3H, t, J=7.3Hz), 0.99 (6H, t, z), 1.22-1.36 (2H, m), 1.38-2.02 (11H, m), 2.12-2.26 (2H, m), 2.46-2.59 (6H, m), 2.82-2.95 (2H, m), 3.14-3.22 (1H, m), 3.25-3.34 (2H, m), 3.48-3.66 (2H, m), 3.91-4.03 (4H, m), 4.07-4.19 (1H, m), .35 (5H,1n), 9.10—9.34 (1H, m) Reference example 8—80 1H—NMR(CDC13) 6 ppm: 0.92 (3H, t, J=7.3Hz), .01 (19H, m), 2.12-2.26 (2H, m), .49 (6H, m), 2.81-2.94 (2H, m), 3.14-3.22 (1H, m), 3.28-3.40 (2H, m), 3.47-3.65 (2H, m), 3.90—4.03 (4H, m), 4.08-4.19 (1H, m), 7.16—7.34 (5H, m), 9.07-9.34 (1H, m) nce example 8-81 1H-NMR(CDC13) 8 ppm: 0.92 (3H, t, J=7.4Hz), 1.21-1.36 (2H, m), 1.39-2.01 (11H, m), 2.12-2.26 (2H, m), 2.22 (6H, s), 2.36-2.44 (2H, m), 2.80-2.95 (2H, m), .22 (1H, In), 3.29-3.38 (2H, m), 3.48—3.66 (2H, m), 3.90-4.03 (4H, m), 4.08—4.19 (1H, m), 7.17—7.35 (5H, m), 9.18-9.36 (1H, m) Reference e 8-82 MS(ESI, 25(M+H)+ id="p-287" id="p-287"
[0287] Reference example 8-83 MS(ESI, m/z):411(M+H)+ Reference example 8-85 1H—NMR (CDC13) 6 ppm: 1.23 (3H, t, J=7.0Hz), 1.33—1.87 (11H, m), 1.90-2.00 (2H, m), 2.03—2.20 (3H, m), 2.27 (3H, s), 2.31—2.41 (1H, m), 2.32 (3H, s), 2.60—2.82 (2H, m), 2.91-3.10 (2H, m), 3.59-4.02 (7H, m), 9.16-9.40 (1H, m) Reference example 8-86 1H—NMR (CDC13) 5 ppm: 0.94 (3H, t, J=7.4Hz), 1.28-1.49 (8H, m), 1.45 (9H, s), 1.51-1.96 (9H, m), 2.02-2.12 (1H, m), 2.27-2.40 (1H, m), 2.31 (3H, s), 2.86-3.08 (4H, m), 3.61-4.05 (9H, m), 9.30-9.45 (1H, m) Reference example 8-87 1H—NMR (CDC13) 5 ppm: 1.15-1.30 (3H, m), 1.33-1.50 (3H, m), .95 (6H, m), 2.00-2.13 (1H, m), 2.25-2.40 (7H, m), 2.80—2.91 (2H, m), 2.91-2.98 (1H, m), 2.98—3.08 (1H, m), 3.65-3.75 (2H, m), 3.75-3.90 (2H, m), 3.90-4.00 (4H, m), 4.35-4.50 (1H, m), 9.59 (1H, d, J=6.4Hz) Reference example 8-88 IH—NMR ) 8 ppm: 0.92 (3H, t, J=7.2Hz), 1.30-1.50 (3H, m), 1.50-1.95 (8H, m), 2.00—2.15 (1H, m), 2.25—2.45 (7H, m), 2.80-2.96 (3H, m), 2.97—3.10 (1H, m), 3.50-3.80 (4H, m), 3.90-4.00 (4H, m), 4.30-4.50 (1H, m), 9.59 (1H, d, J=6.4Hz) Reference example 8-89 1H-NMR (CDC13) 5 ppm: 0.87 (3H, t, J=7.4Hz), 1.35—1.90 (10H, m), 1.90-2.00 (1H, m), 2.10-2.30 (8H, m), 2.44 (2H, t, J=6.5Hz), 2.80-2.95 (2H, m), 3.21 (1H, d, J=13.5Hz), 3.30—3.40 (2H, m), .60 (2H, m), 3.90-4.05 (4H, m), 4.13 (1H, d, J=13.5Hz), 7.15-7.35 (5H, m), 9.30 (1H, br) Reference example 8-90 (CDC13) 8 ppm: 0.85-0.90 (6H, m), 1.12 (3H, t, J=7.0Hz), 1.35—2.05 (10H, m), 2.11 (2H, s), 2.15-2.35 (7H, m), 2.85—3.00 (2H, m), 3.05-3.20 (2H, m), 3.21 (1H, d, J=13.7Hz), 3.60-3.75 (2H, m), 3.90—4.00 (4H, m), 4.14 (1H, d, J=13.7Hz), 7.15—7.35 (5H, m), 9.34 (1H, br) nce example 8-91 1H—NMR ) 8 ppm: 0.35-0.42 (2H, m), .52 (2H, m), 0.91 (6H, s), 0.93-1.05 (1H, m), 1.35-1.50 (3H, m), 1.50-1.73 (4H, m), 1.74—1.88 (2H, m), 2.00—2.11 (1H, m), 2.15 (2H, s), 2.20-2.44 (10H, m), 2.90-3.00 (1H, m), 3.10-3.30 (3H, m), 3.76 (2H, d, J=6.4Hz), 3.90-4.00 (4H, m), 9.42 (1H, brs) [<1]ng = —10.39° (c=0.28, MeOH) Reference example 8-92 1H—NMR (CDC13) 5 ppm: 1.20 (6H, t, z), 1.22 (3H, t, z), 1.34-1.90 (8H, m), 2.00-2.15 (1H, m), .45 (4H, m), 2.45-2.65 (7H, m), 2.85-3.10 (2H, m), 3.30-3.40 (2H, m), 3.70-3.91 (2H, m), 3.91-4.00 (4H, m), 9.27 (1H, brs) Reference example 8-93 1H—NMR (CDCl3) 8 ppm: 1.21 (3H, t, J=7,2Hz), 1.34 (6H, s), 1.35-1.90 (9H, m), .15 (1H, m),2.20-2.45 (10H, m), 2.49 (2H, s), 2.90-3.10 (2H, m), 3.70—3.88 (2H, m), 3.88-4.00 (4H, m), 9.35 (1H, brs) Reference example 8-94 lH—NMR (CDC13) 5 ppm: 0.87 (6H, t, J=7.6Hz), 1.23 (3H, t, J=7.0Hz), 1.30-1.90 (13H, m), .15 (1H, m), 2.20-2.45 (10H, m), 2.90—3.10 (2H, m), 3.30 (2H, d), 3.75—4.00 (6H, m), 9.15-9.45 (1H, m) Reference example 8-95 1H-NMR(CDC13) 5 ppm: 1.24 (3H, t), 1.35-1.50 (3H, m), 1.50—1.90 (6H, m), 2.00—2.15 (1H, m), 2.20—2.50 (l2H, m), 2.85-3.10 (2H, 111), 3303.45 (2H, m), .00 (6H, m), 9.20-9.40 (1H, m) ,)": -12.97° (c=0.33, MeOH) id="p-299" id="p-299"
[0299] Reference example 8—96 1H:NMR(CDC13) 5 ppm: 0.35—0.45 (2H, m), 0.45—0.55 (2H, m), 0.90—1.05 (1H, m), 1.30-1.90 (9H, m), 2.00—2.15 (1H, m), 2.25 (6H, s), 2.31 (3H, s), 2.38 (1H, t, J=11.2Hz), 2.44 (2H, t, J=6.8Hz), 2.90-3.00 (1H, m), 3.10-3.25 (1H, m), 3.33-3.45 (2H, m), 3.76 (2H, d, J=6.8Hz), 3.90—4.00 (4H, m), 9.29 (1H, brs) Reference example 8—98 1H—NMR (CDC13) 6 ppm: 0.95 (3H, t, J=7.2Hz), 1.30—1.90 (8H, m), 1.90-2.02 (1H, m), 2.10-2.22 (1H, m), 2.25 (6H, s), 2.44 (2H, t, J=7.2Hz), .32 (6H, m), 3.33-3.45 (2H, m), 3.60-3.80 (2H, m), 3.90-4.00 (5H, m), 9.23 (1H, brs) [03 01] Reference example 8-99 1H—NMR (CDC13) 5 ppm: 0.91 (6H, s), 1.23 (3H, t, J=7.0Hz), 1.35-1.50 (3H, m), 1.50-1.90 (6H, m), 1.95-2.10 (2H, m), 2.15 (2H, 3), 2,28 (6H, s), 2.60-2.70 (1H, m), 2.75-3.15 (3H, m), 3.19 (2H, d, J=5.6Hz), 3.70-4.00 (6H, m), 4.40-4.65 (2H, m), 9.38 (1H, brs) id="p-302" id="p-302"
[0302] Reference example 8-100 MS(ESI, 07(M+H)+ Reference example 9-1 l-{ ,4'aR*,8'aR*)Octahydro-1'H-spiro[1,3 lane-2,6'-quinolin] -3 '-yl]carbon- y1}— l -butyl-3 -[2-(diethylamino)ethyl]urea To a mixture of l-{[(3'R*,4’aR*,8'aR*)-l'-benzyloctahydro-1'H-spiro[l,3-dio- xolane-2,6'—quinolin] -3 '—yl] carbonyl}- 1 —butyl-3 — ethylamino)ethyl]urea ence example 8-79) (177mg) and ethanol (6.0mL) was added 10% palladium-carbon (70mg), and-the mixture was stirred at room ature for 2 hours under a hydrogen atmosphere. The mixture was passed through a layer of Celite (registered mark) and the filtrate was concentrated under reduced pressure to give the title compound (142mg). 1H-NMR(CDC13) 8 ppm: 0.95 (3H, t, J=7.5Hz), 1.02 (6H, t, J=7.2Hz), 1.29-1.86 (13H, m), 2.18-2.30 (1H, m), 2.48—2.62 (6H, m), .95 (2H, m), 3.13-3.22 (1H,lm), 3.28-3.38 (2H, m), 3.62-3.83 (2H, m), 3.90—4.01 (4H, m), .40 (1H, m) Reference examples 9—2 to 9-5 were prepared in a manner similar to those as described in reference example 9-ll using the corresponding amines instead of 1—{ [(3'R*,4'aR*,8'aR*)—1'-benzyloctahydro-1'H-spiro[1,3 —dioxolane-2,6'—quinolin]-3 '- y1]carbonyl}butyl[2-(diethylamino)ethyl]urea. These were illustrated in Table 8.
[Table 8] Reference Reference Structure Structure exam-1e example The structures of the reference example 9-1 to 9-5 in Table 8 indicate relative configuration.
The physical data of reference examples 9—2 to 9-5 were shown below. id="p-307" id="p-307"
[0307] Reference example 9-2 1H—NMR (CDC13) 5 ppm: 0.95 (3H, t, J=7.3Hz), 1.29-1.87 (19H, m), 2.17-2.53 (7H, m), 2.74—2.95 (2H, m), 3.12-3 .22 (1H, m), 3.33-3.44 (2H, m), .83 (2H, m), 3.90-4.01 (4H, m), 8.98-9.47 (1H, m) [03 08] Reference example 9-3 1H—NMR(CDC13) 5 ppm: 0.95 (3H, t, J=7.3Hz), 1.27-1.87 (13H, m), 2.17-2.29 (1H, m), 2.25 (6H, s), 2.39-2.48 (2H, m), 2.73-2.97 (2H, m), 3.12-3.23 (1H, m), 3.31-3.42 (2H, m), .84 (2H, m), 3.91—4.02 (4H, m), .46 (1H, m) [03 09] Reference example 9-4 MS(ESI, m/z):397(M+H)+ [03 10] Reference e 9-5 MS(ESI, m/z):425(M+H)+ [03 11] Reference example 10-1 1 -{ [(3 R,4aR,8aR)Methyloxodecahydroquinolin—3 -yl]carbonyl} -3—[2-(dimethy1- amino)ethyl]—1 -propy1urea To 1-{[(3'R,4'aR,8'aR)-1'-methyloctahydro-1'H-spiro[l,3-dioxolane-2,6'-quino~ lin] -3'-yl]carb0nyl}[2-(dimethylamino)ethyl]propy1urea (reference example 8—1) (2.3 66g) was added 2mol/L hydrochloric acid (3OmL) and the e was stirred at - room temperature for 2 hours. After l ether was added to the reaction mixture and washed, the aqueous layer was made alkaline with potassium carbonate. The mixture was extracted with methylene chloride/methanol mixed solvent lene chloride:methanol=9: 1). After the organic layer was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure to give the title compound (1 .605g). 1H—NMR (CDC13) 8 ppm: 0.94 (3H, t, z), 1.45-1.90 (6H, m), 1.95-2.05i(1H, m), 2.10-2.55 (17H, m), 2.90-3.10 (2H, m), 3.30-3.45 (2H, m), 3.60-3.80 (2H, m), 9.22 (1H, brs) [a]D28= -37;56° (c=0.38, MeOH) [03 1 2] Reference example 10-7 1—{ [(3R*,4aR*,8aR*)—1-Methyloxodecahydroquinolin-3~yl]carbonyl}-1—[3—(dimeth— ylamino)propyl]ethylurea To 1 —{ [(3 'R* ,4'aR*,8'aR*)— l '-methyloctahydro- 1 'H—spiro[1 ,3 —dioxolane-2,6'—qu- inolin]—3'-yl]carbonyl}-l-[3—(dimethylamino)propy1]ethylurea (reference example 7-2) g) was added 2mol/L hydrochloric acid (103mL) and the mixture was stirred at room temperature for 2 hours. The reaction e was made alkaline with potassium carbonate. The mixture was extracted with methylene chloride/methanol mixed solvent lene dezmethanol=9:1). After the organic layer was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure to give the title compound (2.084g).
MS(ESI, m/z):3 67(M+H)+ [03 13] Reference examples 10-2 to 10-6 and reference examples 10-8 to 10-108 were ed in a manner similar to those as described in reference example 10-1 or reference example 10-7 using the corresponding ketals instead of 1—{ [(3'R,4'aR,8'aR)—1'-methyloctahydro-l'H-spiro[l,3 —dioxolane—2,6'—quinolin] -3 '-yl] - carbonyl}[2-(dimethylamino)ethyl]-l-pr0pylurea. These were illustrated in Table 9. [03 14] [Table 9] Re erencef R f6 erence Structure Structure e example Table 9 nued) Reference Reference Structure Structure example exam - le -15 10-22 -23 -24 -25 Table 9 (continued) nce Reference ‘ -41 Table 9 nued) Reference Reference Structure Structure example example Table 9 nued) Reference Reference example Table 9 (continued) Reference example mapmarmePmm Table 9 (continued) nce weam9D,.mm6 Structure example Table 9 (continued) Reference nce The structures of the reference example 10-1 to 10—6, 10-57 and 10—102 to -107 in Table 9 indicate absolute configuration, and the ures of the reference examplel 0—7 to 10-56, 10—58 to 10-101 and 10-108 in Table 9 indicate relative configuration.
The physical data of reference examples 10-2 to 10-6 and reference examples -8 to 10-108 were shown below.
Reference example 10-2 MS(ESI, 53(M+H)+ [03 17] Reference example 10-3 , 09(M+H)+ [03 18] Reference e 10—4 1H—NMR (CDC13) 6 ppm: 0.91 (6H, s), 1.23 (3H, t, J=7.2Hz), 1.50-1.65 (2H, m), 1.70-1.90 (2H, m), 1.95-2.10 (1H, m), 2.10-2.60 (17H, m), 2.95—3.15 (2H, m), 3.20 (2H, d, J=5.6Hz), 3.75—3.90 (2H, m), 9.35 (1H, hrs) [03 19] Reference example 10-5 MS(ESI, m/z):441(M+H)+ Reference example 10-6 MS(ESI, m/z):379(M+H)+ Reference example 10—8 MS(ESI, m/z):395(M+H)+ id="p-322" id="p-322"
[0322] Reference example 10-9 MS(ESI, m/z):381(M+H)+ Reference example 10—10 MS(ESI, m/z):353(M+H)+ Reference example 10-1 1 MS(ESI, m/z):381(M+H)+ Reference example 10-12 MS(ESI, m/z):379(M+H)+ Reference example 10-13 1H—NMR(CDC13) 6 ppm: 0.86 (3H, t, J=7.3Hz), 1.16 (3H, t, J=7.3Hz), 1.40-1.65 (4H, m), 1.65-1.95 (4H, m), 2.10-2.25 (7H, m), 2.25-2.60 (9H, m), 2.60-2.75 (1H, m)‘, 3.00-3.10 (1H, m), 3.10-3.35 (3H, m), 3.60-3.85 (2H, m), 9.40 (1H, brs) id="p-327" id="p-327"
[0327] Reference e 10-14 (CDC13) 5 ppm: 1.03 (3H, t, J=7.1Hz), 1.17 (3H, t, J=7.3Hz), 1.40-1.65 (2H, m), 1.65-1.95 (4H, m), 2.10-2.25 (7H, m), 2.25-2.50 (7H, m), 2.55 (1H, t, J=1l.1Hz), 2.70—2.90 (2H, m), 2.95-3.10 (1H, m), 3.10-3.35 (3H, m), 3.60-3.85 (2H, m), 9.41 (1H, brs) nce example 10-15 1H—NMR(CDC13) 8 ppm: 0.94 (3H, t, J=7.6Hz), 1.40-1.70 (4H, m), 1.70-1.90 (2H, m), 1.90—2.10 (1H, m), 2.10-2.60 (17H, m), 2.90—3.10 (2H, m), .50 (2H, m), 3.60-3.80 (2H, m), 9.22 (1H, brs) Reference example 10-16 MS(ESI, 67(M+H)+ "[0330] Reference example 10-17 MS(ESI, m/z):353(M+H)+ [033 1] Reference example 1 0-1 8 MS(ESI, m/z):381(M+H)+ ‘ [0332] Reference example 10—19 MS(ESI, m/z):324(M+H)+ Reference example 10-20 MS(ESI, m/z):386(M+H)+ Reference example 10-21' MS(ESI, m/z):354(M+H)+ Reference example 10-22 MS(ESI, m/z):340(M+H)+ [033 6] Reference example 10-23 MS(ESI, 96(M+H)+ [033 7] v Reference example 10-24 MS(ESI, m/z):381(M+H)+ [033 8] Reference e 10-25 MS(ESI, m/z):373(M+H)+ [033 9] Reference example 10-26 , m/z):365(M+H)+ Reference example 10-27 MS(ESI, m/z):397(M+H)+ Reference example 10-28 MS(ESI, 15(M+H)+ Reference e 10-29 MS(ESI, m/z):354(M+H)+ Reference example 10-30 MS(ESI, m/z):429(M+H)+ Reference example 10-31 MS(ESI, m/z):387(M+H)+ id="p-345" id="p-345"
[0345] Reference example 10-32 MS(ESI, m/z):393(M+H)+ Reference example 10-33 MS(ESI, m/z):373(M+H)+ nce example 10-34 MS(ESI, m/z):381(M+H)+ Reference example 10-35 MS(ESI, m/z):381(M+H)+ Reference example 10-36 MS(ESI, m/z):379(M+H)+ [03 50] Reference example 10-37 MS(ESI, m/z):421(M+H)+ Reference example 10-38 MS(ESI, m/z):422(M+H)+ [03 52] Reference example 10—39 MS(ESI, m/z):365(M+H)+ Reference example 10-40 , m/z):395(M+H)+ [03 54] Reference example 10-41 MS(ESI, m/z):421(M+H)+ Reference example 10-42 MS(ESI, 29(M+H)+ Reference example 10—43 MS(ESI, m/z):395(M+H)+ Reference example 10-44 , m/z):457(M+H)+ Reference example 10-45 MS(ESI, 09(M+H)+ [03 59] Reference example 10-46 MS(ESI, m/z):421(M+H)+ Reference example 10-47 MS(ESI, m/z):407(M+H)+ Reference e 10-48 lH—NMR (CDC13) 5 ppm: 0.94 (3H, t, J=6.0Hz), 1.02 (6H, t, J=5.6Hz), 1.45-1.90 (6H, m), 1.95-2.10 (1H, m), 2.15-2.25 (1H, m), 2.30—2.65 (14H, m), 2.90-3.10 (2H, m), 3.30-3.40 (2H, m), 3.60-3.80 (2H, m), 9.17 (1H, brs) Reference example 10—49 1H-NMR (CDC13) 8 ppm: 0.94 (3H, t, z), 1.29-1.90 (12H, m), 1.95-2.05 (1H, m), 2.10-2.25 (1H, m), 2.25—2.55 (14H, m), 2.90-3.10 (2H, m), 3.30—3.45 (2H, m), 3.60-3.80 (2H, m), 9.14 (1H, brs) Reference example 10-50 (CDC13) 8 ppm: 1.16 (3H, t, Jé7.0Hz), 1.40-1.65 (2H, m), 1.65-2.05 (4H, m), 2.10-2.55 (16H, m), 2.95-3.10 (1H, m), 3.30-3.65 (7H, m), 3.85—4.10(2H, m), 9.09 (1H, Reference example 10-51 MS(ESI, m/z):390(M+H)+ Reference example 10-52 MS(ESI, m/z):421(M+H)+ [03 66] Reference example 10-53 MS(ESI, m/z):376(M+H)+ [03 67] Reference example 10-54 MS(ESI, m/z):443(M+H)+ [03 68] Reference example 10-55 MS(ESI, m/z):3 67(M+H)+ nce example 10-56 MS(ESI, m/z):395(M+H)+ * [0370] Reference example 10-57 MS(ESI, 67(M+H)+ [a]D28= -8.96° (c=0.43, MeOH) Reference example 10—58 MS(ESI, m/z):395(M+H)+ Reference example 10-59 MS(ESI, m/z):409(M+H)+ id="p-373" id="p-373"
[0373] Reference example 10-60 MS(ESI, m/z):437(M+H)+ [03 74] Reference example 10-61 MS(ESI, m/z):435(M+H)+ Reference example 10-62 MS(ESI, m/z):381(M+H)+ Reference example 10-63 MS(ESI, m/z):395(M+H)+ id="p-377" id="p-377"
[0377] nce example 10-64 MS(ESI, m/z):450(M+H)+ Reference example 10-65 MS(ESI, m/z):381(M+H)+ Reference example 10-66 MS(ESI, m/z):436(M+H)+ Reference example 10-67 MS(ESI, m/z):411(M+H)+ [03 8 1] nce example 10-68 MS(ESI, m/z):423(M+H)+ [03 82] Reference e 10-69 MS(ESI, m/z):397(M+H)+ [03 83] Reference example 10-70 , m/z):411(M+H)+ [03 84] Reference example 10-71 MS(ESI, m/z):367(M+H)+ [03 85] Reference example 10—72 MS(ESI, m/z):397(M+H)+ [03 86] Reference example 10-73 MS(ESI, m/z):365(M+H)+ [03 87] Reference example 10—74 MS(ESI, m/z):379(M+H)+ [O3 88] Reference example 10-75 MS(ESI, m/z):438(M+H)+ nce example 10-76 MS(ESI, m/z):409(M+H)+ Reference example 10-77 1H—NMR(CDC13)5 ppm: 0.92 (6H, s), 1.45-1.65 (2H, m), 1.70—1.95 (2H, m), .10 (1H, m), 2.10-2.55 (17H, m),’2.95-3.05 (1H, m), 3.10—3.25 (3H, m), 3.34 (3H, s), 9.30-9.50 (1H, m) Reference example 10-78 MS(ESI, m/z):411(M+H)+ [03 92] Reference example 10—79 MS(ESI, m/z):425(M+H)+ [03 93] Reference example 10—80 lH—NMR (CDC13) 5 ppm: 0.35-0.45 (2H, m), 0.45-0.55 (2H, m), 0.90-1.05 (1H, m), - 1.45-1.65 (2H, m), 1.65-1.90 (4H, m), .10 (1H, m), .30 (7H, m), 2.30-2.55 (10H, m), 2.95-3.05 (1H, m), 3.15—3.40 (3H, m), 3.65-3.85 (2H, m), 9.25 (1H, hrs) [03 94] Reference example 10—81 MS(ESI, m/z):4l 1(M+H)+ Reference example 10-82 MS(ESI, m/z):395(M+H)+ Reference example 10-83 , m/z):409(M+H)+ id="p-397" id="p-397"
[0397] Reference example 10-84 MS(ESI, m/z):409(M+H)+ Reference example "10—85 , m/z):395(M+H)+ Reference example 10-86 MS(ESI, m/z):415(M+H)+ Reference example 10-87 MS(ESI, m/z):411(M+H)+ Reference example 10-88 MS(ESI, m/z):395(M+H)+ nce example 10-89 MS(ESI, m/z):407(M+H)+ Reference example 10-90 MS(ESI, m/z):367(M+H)+ Reference example 10-91 MS(ESI, m/z):38l(M+H)+ Reference example 10-92 , m/z):367(M+H)+ id="p-406" id="p-406"
[0406] Reference e 10-93 MS(ESI, m/z):385(M+H)+ Reference example 10-94 MS(ESI, m/z):379(M+H)+ Reference example 10—95 MS(ESI, m/z):393(M+H)+ nce example 10—96 MS(ESI, m/z):351(M+H)+ Reference example 10-97 , m/z):365(M+H)+ Reference example 10-98 1H—NMR (CDC13) 8 ppm: 0.95 (3H, t, J=7.6Hz), 1.40-1.90 (6H, m), 2.10-2.60 (14H, m), 2.60-2.80 (1H, m), 2.80—3.15 (4H, m), 3.30-3.45 (2H, m), 3.60-3.80 (2H, m), 4.40-4.80 (2H, m), 9.19 (1H, brs) Reference example 10—99 lH-NMR ) 5 ppm: 0.95 (3H, t, J=7.2Hz), 1.40—1.90 (4H, m), 2.10-2.27 (7H, m), 2.27—2.70 (8H, m), 2.80-3.05 (2H, m), 3.05-3.34 (4H, m), .45 (2H, m), 3.60-3.80 (2H, m), 9.14 (1H, brs) nce example 10-100 lH—NMR (CDC13) 5 ppm: 0.92 (6H, s), 1.24 (3H, t, Jm7.0Hz), 1.45—1.70 (2H, m), 1.70-1.90 (2H, m), 2.10—2.55 (14H, m), 2.65-2.80 (1H, m), 2.85-3.15 (4H, m), 3.20 (2H, d, J=5.5Hz), 3.75—3.90 (2H, m), 4.40—4.75 (2H, m), 9.31 (1H, brs) Reference example 1 0-101 MS(ESI, m/z):463(M+H)+ Reference example 10—102 lH-NMR ) 5 ppm: 0.30-0.45 (2H, 111), 045—055 (2H, m), 0.70—1.10 (7H, m), 1.45—1.65 (3H, m), 1.70-1.95 (2H, m), 1.95-2.10 (1H, m), 2.10—2.55 (16H, m), 2.90—3.10 (1H, m), 3.10—3.30 (3H, m), 3.60-3.85 (2H, m), 9.35 (1H, brs) [001328 = -21.70° (c=0.39, MeOH) id="p-416" id="p-416"
[0416] Reference e 10—103 1H-NMR (CDC13) 5 ppm: 1.02 (6H, t, J=7.2Hz), 1.24 (3H, t, J=7.2Hz), 1.45-1.65 (2H, m), 1.70-1.90 (2H, m), 1.95-2.10 (1H, m), 2.10-2.25 (1H, m), 2.28-2.65 (14H, m), 2.90—3.10 (2H, m), 3.30-3.40 (2H, m), 3.80-3.90 (2H, m), 9.18 (1H, hrs) MD" = ° (c=0.28, MeOH) Reference example 10-104 1H—NMR(CDC13) 5 ppm: 1.22 (3H, t, J=7.2Hz), 1.34 (6H, s), 1.45—1.70 (2H, m), 1.70—1.90 (2H, m), 1.95—2.10 (1H, m), 2.10-2.26 (1H, m), 2.27—2.55 (16H, m), 2.90-3.10 (2H, m), .90 (2H, m), 9.27 (1H, brs) [a]D28= ° (c=0.29, MeOH) Reference example 10-105 IH—NMR (CD013) 6 ppm: 0.87 (6H, t, J=7.5Hz), 1.24 (3H, t, J=7.0Hz), 1.35-2.55 (24H, m), 2.95-3.15 (2H, m), 3.29 (2H, d, J=4.8Hz), 3.75—3.90 (2H, m), 9.00—9.50 (1H, m) [001328 = 21.470 4, MeOH) Reference example 10-106 lH—NMR (CDC13) 5 ppm: 1.25 (3H, t, J=7.1Hz), 1.40—2.55 (22H, m), 2.90—3.10 (2H, m), 3.30-3.45 (2H, m), 3.80-3.90 (2H, m), 9.00-9.45 (1H, m) MD" = —35.33° (c=0.42, MeOH) Reference example 10-107 1H-NMR (CDC13) 5 ppm: 0.30-0.45 (2H, m), 0.45—0.60 (2H, m), 0.90-1.05 (1H, m), 1.45-1.65 (2H, m), 1.70-1.90 (3H, m), 1.95—2.10 (1H, m), 2.10-2.55 (16H, m), 2.90-3.05 (1H, m), 3.10-3.25 (1H, m), 3.30-3.45 (2H, m), 3.65-3.85 (2H, m), 9.19 (1H, brs) [a1D28= —20.70° (c=0.28, MeOH) Reference example 10-108 MS(ESI, m/z):353(M+H)+ Example 1-1 1- { [(4aR,6R,8aR)—2-Aminocyanomethyl—4H,4aH,5H,6H,7H,8H,8aH,9H—thieno- [3 ,2—g]quinolin—6-yl]carbonyl}-3 -[2-(dimethylamino)ethyl]— l -propylurea und 1-1) To a e of R,4aR,8aR)methyloxodecahydroquinolin—3 -yl]- carbonyl}-3—[2—(dimethylamino)ethyl]—l-propylurea (reference example 10-1) (1.602g) and ethanol (44mL) were added malononitrile (435mg), morpholine (0.572mL), followed by elemental sulfer (282mg) while stirring at room temperature. The mixture was heated at 55°C and stirred for 1.5 hours. After cooling to room ature, the reaction mixture was concentrated under reduced pressure. The e was purified by aminopropyl silica gel column chromatography (eluent: O%—5% methanol/ethyl acetate, gradient elution) to give the title compound (1.479g) as a solid. 1H—NMR ) 5 ppm: 0.94 (3H, t, J=7.4Hz), 1.45-1.85 (4H, m), 1.95-2.15 (2H, m), 2.15-2.30 (7H, m), 2.30—2.55 (7H, m), 2.60-2.75 (1H, m), .00 (2H, m), 3.00—3.10 (1H, m), 3.35-3.45 (2H, m), 3.60-3.85 (2H, m), 4.65 (2H, s), 9.27 (1H, br) MD": -105.54° (0:030, MeOH) I Example 1-7 1-{ [(4aR*,6R*,8aR*)Aminocyano—8—methyl-4H,4aH,5H,6H,7H,8H,8aH,9H—thi— eno [3,2-g] quinolin—6—yl]carbonyl} — l - [3-(dimethylamino)propyl]-3 —ethylurea (compound 1-7) To a e of 1-{[(3R*,4aR*,8aR*)-1—methyloxodecahydroquinolin-3 -yl]- carbonyl}[3—(dimethylamino)propyl]-3—ethylurea (reference example 10-7) (216mg) and ethanol (6mL) were added malononitrile (71mg), morpholine (0.077mL), followed by elemental sulfer (39mg) while stirring at room temperature, and the mixture was heated at 55°C and stirred for 2 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by ropyl silica gel column chromatography (eluent: 0%-5% methanol/ethyl acetate, gradient elution) to give the title compound (201mg) as a solid. 1H—NMR (CDC13) 5 ppm: 1.17 (3H, t, J=7.3Hz), 1.40—1.55 (1H, m), 1.65—1.90 (3H, m), 1.95-2.15 (2H, m), 2.15-2.25 (7H, m), 2.25—2.45 (7H, m), 2.60-2.70 (1H, m), .05 (2H, m), 3.20-3.40 (3H, m), 3.65-3.85 (2H, m), 4.64 (2H, s), 9.44 (1H, brs) ' ' id="p-424" id="p-424"
[0424] Compounds 1-2 to 1-6 and compounds 1-8 to 1-110 were prepared in a manner similar to those as bed in example 1-1 or example 1—7 using the corresponding octahydroquinolines and methyl oacetate or 2—cyanoacetamide instead of 1-{ aR,8aR)methy1oxodecahydroquinolin—3~yl]carb-only} -3 -[2-(dimethy1- amino)ethyl]-l-propy1urea and malononitrile. These were illustrated in Table 10.
[Tabel 10] Table 10 (continued) ure SHuCtmmu Table 10 (continued) nd CO d Structure Structure No. mN00.m Table 10 (continued) nd Compound SHuam9 No. No.
Table 10 (continued) Compound CmPmo.d ure Structure No. N Table 10 (continued) Compound Compound 9 Structure No. No Table 10 (continued) nd Cm50.m Structure Structure Table 10 (continued) 1-100 1-101 1-102 1-103 1-104 The structures of compound 1—1 to 1-6, 1-57 and 1-104 to 1-109 in Table 10 indicate absolute configuration, and the ures of compound 1-7 to 1-56, 1-58 to 1— 1 O3 and 1-1 10 in Table 10 indicate relative configuration. id="p-426" id="p-426"
[0426] The physical data of compounds 1-2 to 1-6 and compounds 1—8 to 1-110 were shown below.
Compound 1-2 1H—NMR ) 6 ppm: 0.95 (3H, t, J=7.5Hz)., 1.40-1.90 (4H, m),'1.95-2.15 (2H, m), 2.15-2.30 (1H, m), 2.30-2.55 (8H, m), 2.60-2.75 (1H, m), 2.77 (2H, t, z), 2.90—3.15 (3H, m), 3.41 (2H, q, J=5.8Hz), 3.60-3.85 (2H, m), 4.60-4.70 (2H, m), 9.37 (1H, brs) [aJD26= —1o3.02° 4, MeOH) id="p-428" id="p-428"
[0428] Compound 1—3 1H-NMR (CDC13) 5 ppm: 0.94 (3H, t, J=7.3Hz), 1.02 (6H, t, J=7.2Hz), 1.27-1.43 (2H, m), 1.46—1.64 (3H, m), 1.68-1.86 (1H, m), .11 (2H, m), 2.16-2.28 (1H, m), 2.31-2.72 (9H, m), 2.34 (3H, s), 2.87-3.12 (3H, m), 3.28-3.41 (2H, m), 3.63-3.89 (2H, m), 4.64 (2H, s), 9.01-9.42 (1H, m) Compound 1—4 1H-NMR (CDC13) 6 ppm: 0.92 (6H, s), 1.25 (3H, t, J=7.2Hz), 1.50—1.65 C(lH, m), .90 (1H, m), 1.95-2.55 (16H, m), 2.60-2.75 (1H, m), 2.90-3.17 (3H, m), 3.21 (2H, d,’ J=5.2Hz), 3.75-3.95 (2H, m), 4.65 (2H, s), 9.38 (1H, brs) [a]D28= -88.997° (c=0.33, MeOH) Compound 1—5 1H-NMR (CDC13) 8 ppm: .85 (4H, m), 1.95-2.25 (11H, m), 2.25-2.40 (4H, m),2.40-2.45 (1H,m), 2.50-2.65 (2H, m), 2.85-3.00 (2H, m), 3.00-3.25 (5H, m), 4.60-4.75 (2H, m),6.15-6.35 (1H,m) 7.10—7.30 (4H, m) [a]D28= 423.090 (c=0.45, MeOH) Compound 1—6 1H—NMR(CDC13) 6 ppm: 1.17 (3H, t, J=7.3Hz), 1.37-1.51 (1H, m), 1.65—1.89 (5H, m), 1.93-2.23 (3H, m), 2.25-2.47 (2H, m), 2.31 (3H, s), 2.54-2.78 (7H, m), 2.84-2.97 (1H, m), 2.97-3.08 (1H, m), 3.16-3.43 (3H, m), 3.53-3.96 (2H, m), 4.90 (2H, s), 9.36-9.79 (1H, m) [a1D29= —112.38° 5, MeOH) Compound 1-8 1H—NMR (CDC13) 5 ppm: 1.02 (6H, t, J=7.2Hz), 1.17 (3H, t, J=7.3Hz), 1.40-1.55 (1H, m), .90 (3H, m), 1.95—2.10 (2H, m), 2.15—2.25 (1H, m), .50 (7H, m), 2.54 (4H, q, J=7.2Hz), 2.60—2.70 (1H, m), 2.85—3.05 (2H, m), .35 (3H, m), 3.60-3.85 (2H, m), 4.60-4.70 (2H, m), 9.39 (1H, br) Compound 1—9 1H-NMR (CDC13) 6 ppm: 1.18 (6H, d, J=6.6Hz), 1.35-1.55 (1H, m), 1.70-1.90 (3H, m), 1.95-2.25 (9H, m), .45 (7H, m), 2.55-2.70 (1H, m), 2.85-3.05 (2H, m), 3.15—3.45 (1H, m), 3.55-3.85 (2H, 1n), 3.85-4.00 (1H, m), 4.60-4.75 (2H, m), 9.38 (1H, brs) Compound 1,-10 1H—NMR (DMSO-d6) 6 ppm: 1.20-1.90 (8H, m), 2.00-2.10 (1H, m), 2.15-2.35 (11H, m), 2.38 (2H, t, J=6.4Hz), 2.42-2.55 (1H, m), 2.90-3.05 (1H, m), 3.20-3.35 (2H, m), 3.90—4.01 (4H, m), 6.00-6.15 (1H, m) Compound 1-11 1H—NMR (CDC13) 5 ppm: 1.03 (6H, t, J=7.2Hz), 1.17 (3H, t, J=7.3Hz), .50 (1H, m), 1.69—1.87 (1H, m), 1.92—2.25 (3H, m), 2.27-2.45 (2H, m), 2.31 (3H, s), 2.46—2.72 (7H, m), 2.86-3.08 (2H, m), 3.16-3.88 (5H, m), 4.63 (2H, 5), 959-1000 (1H, m) Compound 1-12 1H-NMR (CDC13) 5 ppm: 1.17 (3H, t, J=7.3Hz), 1.36-1.51 (1H, m), 1.51-1.90 (5H, m), 1.93-2.13 (2H, m), 2.13-2.25 (1H, m), 2.25-2.48 (2H, m), 2.31 (3H, s), 2.49-2.81 (7H, m), 2.83-3.11 (2H, m), 3.18-3.45 (3H, m), 3.57-3.93 (2H, m), 4.65 (2H, s), 9.31-9.79 (1H, m) Compound 1—13 1H-NMR ) 6 ppm: 0.87 (3H, t, J=7.3Hz), 1.17 (3H, t, J=7.3Hz), 1.40-1.55 (3H, m), 1.65-1.90 (3H, m), 200-210 (1H, m), 2.15-2.55 (13H, m), 2.55-2.70 (2H, m), 2.85-3.00 (1H, m), 3.00-3.10 (1H, m), 3.10-3.35 (3H, m), 3.65—3.85 (2H, m), 4.68 (2H, brs), 9.42 (1H, br) Compound 1—14 (CDC13) 5 ppm: 1.01 (3H, t, J=7.1Hz), 1.17 (3H, t, J=7.3Hz), 1.35-1.55 (1H, m), 1.65-190 (3H, m), 2.00-2.10 (1H, m), 2.15-2.45 (11H, m), 2.53 (1H, 1:, J=11.1Hz), 2.60-2.75 (2H, m), 2.75-3.10 (3H, m), 3.15-3.35 (3H, m), 3.65-3.85 (2H, m), 4.60-4.70 (2H, m), 9.42 (1H, brs) id="p-439" id="p-439"
[0439] nd 1-15 1H-NMR (DMSO-ds) 5 ppm: 0.75-0.90 (3H, m), 1.20-1.40 (1H, m), .70 (3H, m), 1.80-2.25 (14H, m), 2.25-2.50 (3H, m), 2.80-2.95 (2H, m), .10 (1H, m), 3.15-3.30 (2H, m), 3.45-3.65 (2H, m), 7.01 (2H, s), 8.67 (1H, brs) id="p-440" id="p-440"
[0440] Compound 1-16 1H-NMR (CD013) 6 ppm: 1.18-1.35 (5H, m), 1.45-1.88 (3H, m), 1.95-2.12 (2H, m), 2.14-2.29 (7H, m), 2.29—2.50 (6H, m), 2.60—2.72 (1H, m), 2.90—3.16 (3H, m), 3.27-3.38 (2H, m), 3.77—3.92 (2H, m), 4.67 (2H, s), 9.25 (1H, brs) Compound 1—17 1H—NMR (CDC13) 8 ppm: 1.26 (3H, t, J=7.1Hz), 1.50-1.65 (1H, m), 1.65-1.90 (1H, m), 1.95—2.15 (2H, m), 2.15-2.55 (14H, m), 2.60-2.75 (1H, m), 2.90-3.15 (3H, m), 3.35—3.45 (2H, m), 3.75-4.00 (2H, m), .75 (2H, m), 9.28 (1H, brs) Compound 1—18 1H—NMR (CDC13) 5 ppm: 1.03 (6H, t, J=7.2Hz), 1.26 (3H, t, J=7.1Hz), 1.56 (1H, q, J=12.3Hz), 1.70-1.85 (1H, m), 1.95-2.15 (2H, m), .30 (1H, m), .45 (4H, m), 2.46 (1H, t, J=11.2Hz), .75 (7H, m), 2.90-3.15 (3H, m), 3.30—3.40 (2H, m), 3.75—3.95 (2H, m), 4.60-4.70 (2H, m), 9.24 (1H, brs) Compound 1-19 1H—NMR (CDC13) 8 ppm: 0.95 (3H, t, J=7.4Hz), 1.26 (3H, t, J=7.1Hz), 1.45-1.65 (3H, m), 1.70—1.90 (1H, m), 1.95-2.15 (2H, m), 2.15-2.30 (1H, m), 2.30-2.50 (5H, m), 2.60—2.75 (1H, m), 2.90-3.15 (3H, m), 3.20-3.30 (2H, m), 3.80-4.00 (2H, m), 4.60-4.75 (2H, m), 9.25 (1H, brs) id="p-444" id="p-444"
[0444] Compound 1—20 1H-NMR (CDC13) 5 ppm: 1.25 (3H, t, z), 1.45-1.63 (1H, m), 1.68-1.86 (1H, m), 1.92—2.12 (2H, m), 2.15-2.29 (1H, m), 2.31-2.48 (2H, m), 2.34 (3H, s), 2.61-2.74 (1H, m), 2.80-3.13 (5H, m), 3.48—3.60 (2H, m), .95 (2H, m), 4.65 (2H, s), 7.16-7.36 (5H, m), 9.18-9.41 (1H, m) Compound 1-21 1H—NMR (CDC13) 5 ppm: 1.26 (3H, t, J=7.0Hz), 1.47-1.65 (1H, m), 1.70-1.87 (3H, m), 1.96-2.13 (2H, m), 2.17-2.29 (1H, m), 2.32-2.50 (2H, m), 2.35 (3H, s), 2.62-2.73 (1H, m), 2.91-3.15 (3H, m), 3.31-3.48 (4H, m), 3.35 (3H, s), .95 (2H, m), 4.65 (2H, s), 9.17-9.36 (1H, m) Compound 1-22 1H—NMR(CDC13) 5 ppm: 1.26 (3H, t, J=6.9Hz), 1.48-1.64 (1H, m), 1.70-1.87 (1H, m), 1.94-2.12 (2H, m), 2.17-2.28 (1H, m), 2.30-2.52 (2H, m), 2.34 (3H, s), 2.61-2.73 (1H, m), 2.90-3.15 (3H, m), 3.38 (3H, s), 3.44—3.56 (4H, m), 3.79—3.95 (2H, m), 4.65 (2H, s), .45 (1H, m) Compound 1-23 1H-NMR (CDC13) 8 ppm: 1.27 (3H, t, J=7.0Hz), .64 (1H, m), 1.70-1.86 (1H, m), 1.95-2.13 (2H, m), 2.15-2.29 (1H, m), 2.30-2.49 (2H, m), 2.35 (3H, s), 2.61-2.73 (1H, m), 2.87 (3H, d, J=4.8Hz), 2.91-3.17 (3H, m), 3.81-3.97 (2H, m), 4.65 (2H, s), 9.02-9.26 (1H, m) nd 1-24 lH—NMR (DMSO-d6) 6 ppm: 0.80-0.95 (3H, m), 1.20-1.37 (3H, m), 1.38-1.54 (2H, m), 1.54-1.70 (1H, m), 1.80-2.25 (14H, m), 2.26—2.37 (2H, m), 2.37—2.47 (1H, m), 2.80-2.95 (2H, m), 2.95-3.10 (1H, m), 3.15-3.30 (2H, m), 3.45-3.70 (2H, m), 7.02 (2H, s), 8.20-9.00 (1H, m) Compound 1-25 lH-NMR ) 5 ppm: 1.29 (3H, t, J=7.0Hz), 1.50-1.70 (1H, m), .90 (1H, m), 1.95-2.15 (2H, m), 2.15—2.30 (1H, m), 2.30-2.45 (4H, m), 2.49 (1H, t, J=11.3Hz), 2.60-2.75 (1H, m), 2.90—3.05 (2H, m), 3.05-3.15 (1H, m), 3.80—4.00 (2H, m), 4.60-4.70 (4H, m), 7.15-7.25 (1H, m), 7.25-7.35 (1H, m), 7.60—7.70 (1H, m), 8.55—8.65 (1H, m), 9.97 (1H, brs) Compound 1-26 1H-NMR ) 5 ppm: 0.64-0.77 (2H, m), 1.08—1.34 (4H, m), 1.41—1.56 (1H, m), 1.70-1.86 (1H, m), 1.98—2.11 (2H, m), 2.16-2.49 (12H, m), 2.60-2.73 (1H, m), 2.76-2.85 (1H, m), 2.90-3.05 (1H, m), 3.30—3.43 (2H, m), 3.61—3.78 (1H, m), 4.64 (2H, brs), 8.48 (1H, brs) Compound 1-27 1H-NMR (DMSO-d6) 5 ppm: 1.21-1.40 (1H, m), .78 (3H, m), 1.83-2.25 (14H, m), 2.29-2.48 (3H, m), 2.80-2.94 (2H, m), 3.00-3.13 (1H, m), 3.17-3.48 (7H, m), 3.53-3.75 (2H, m), 7.02 (2H, s), 8.71 (1H, brs) Compound 1-28 1H-NMR (DMSO-d6) 5 ppm: 1.16-1.34 (1H, m), 1.39-1.57 (1H, m), 1.70-1.92 (2H, m), 1.95-2.23 (11H, m), 2.26-2.42 (3H, m), 2.70-2.88 (2H, m), 2.93-3.11 (1H, m), 3.15-3.53 (3H, m), 4.77-5.09 (2H, m), 7.02 (2H, s), .30 (3H, m), 7.31-7.39 (2H, m), 8.88 (1H, brs) id="p-453" id="p-453"
[0453] nd 1-29 1H-NMR (CDC13) 5 ppm: 1.10-1.22 (3H, m), 1.40—1.60 (1H, m), 1.70-2.10 (5H, m), 2.15-2.50 (6H, m), 2.60-2.75 (1H, m), 2.90-3.00 (2H, m), 3.10—3.50 (8H, m), 3.75-4.00 (2H, m), 4.67 (2H, brs), 9.08 (1H, brs) id="p-454" id="p-454"
[0454] Compound 1-30 1H—NMR ) 5 ppm: 1.30-1.45 (1H, m), 1.50-1.65 (2H, m), 1.90-2.05 (1H, m), 2.05—2.20 (1H, m), 2.20-2.45 (11H, m), 2.47 (2H, t, J=6.2Hz), .60 (1H, m), 2.75-3.05 (5H, m), 3.35-3.50 (2H, m), 3.90—4.20 (2H, m), 4.60-4.75 (2H, m), 7.15-7.40 (5H, m), 9.29 (1H, brs) Compound 1-31 1H—NMR (CDC13) 5 ppm: 1.25 (3H, t, J=6.9Hz), 1.44-1.62 (1H, m), 1.69-1.87 (1H, m), 1.94-2.12 (2H, m), 2.16-2.28 (1H, m), 2.31-2.48 (2H, m), 2.34 (3H, s), .74 (1H, m), 2.81-3.12 (5H, m), 3.48-3.58 (2H, m), 3.76-3.96 (2H, m), 4.66 (2H, s), .30 (1H, m), 7.51-7.60 (1H, m), 8.44—8.52 (2H, m), .45 (1H, m) id="p-456" id="p-456"
[0456] Compound 1-32 1H—NMR (CDC13) 6 ppm: 1.26 (3H, t, J=7.1Hz), 13891.48 (2H, m), 1.51-1.64 (5H, m), 1.72-1.85 (1H, m), 1.96-2.11 (2H, m), 2.17-2.28 (1H, m), 2.34 (3H, s), 2.36—2.52 (8H, m), 2.62-2.71 (1H, m), 2.90-3.12 (3H, m), 3.37-3.45 (2H, m), 3.79-3.93 (2H, m), 4.65 (2H, s), 9.09-9.32 (1H, m) Compound 1-33 lH-NMR (DMSO‘dfi) 8 ppm: 1.10 (3H, t, J=7.1Hz), 2.19 (3H, s), 3.58-3.78 (2H, m), 4.39 (2H, d, J=5.7Hz), 7.02 (2H, s), 7.22-7.33 1(2H, In), .54 (2H, m), 9.04-9.21 (1H, m) Compound 1-34 1H—NMR (CDC13) 6 ppm: 1.26 (3H, t, J=7.1Hz), 1.44-1.66 (5H, m), 1.68—1.87 (1H, m), 1.95—2.12 (2H, m), 2.17-2.30 4(3H, m), 2.21 (6H, s), .49 (2H, m), 2.35 (3H, s), 2.61—2.73 (1H, m), 2.90-3.13 (3H, m), 3.24-3.35 (2H, m), 3.79—3.93 (2H, m), 4.65 (2H, s), 9.19-9.32 (1H, m) Compound 1—35 1H-NMR (CDC13) 5 ppm: 0.85-1.00 (6H, In), 1.40-1.65 (1H, m), 1.65-2.10 (4H, m), 2.15-2.50 (14H, m), 2.60-2.75 (1H, m), .00 (2H, m), 3.05-3.20 (1H, m), 3.30-3.45 (2H, m), 3.60-3.80 (2H, m), 4.60-4.70 (2H, m), 9.22 (1H, brs)‘ Compound 1-36 1H—NMR (CDC13) 5 ppm: 0.30-0.45 (2H, m), 0.45-0.60 (2H, m), 0.80-1.10 (1H, m), 1.50-1.65 (1H, m), 1.65-1.90 (1H, m), 1.95-2.15 (2H, m), .55 (14H, m), 2.60-2.75 (1H, m), .05 (2H, m), 3.15-3.30 (1H, m), 3.35-3.45 (2H, m), 3.70-3.85 (2H, m), 4.65—4.75 (2H, m), 9.26 (1H, brs) Compound 1-37 1H-NMR (CDC13) 5 ppm: 1.35—1.55 (1H, m), .80 (2H, m), 1.95-2.10 (1H, m), 2.10-2.20 (1H, m), 2.20-2.50 (13H, m), 2.50-2.60 (1H, m), 2.85-3.00 (2H, m), 3.20-3.35 (1H, m), 3.35-3.50 (2H, m), 4.60—4.70 (2H, m), 5.10 (1H, d, J=16.5Hz), 5.35 (1H, d, J=16.5Hz), 6.90-7.05 (2H, m), 7.20-7.30 (1H, m), 9.20 (1H, br) Compound 1-38 1H-NMR (CDC13) 5 ppm: 1.46 (1H, q, J=12.3Hz), 1.65~1.80 (1H, m), 1.80-1.95 (1H, m), 1.95—2.10 (1H, m), 2.10-2.25 (1H, m), 2.26 (6H, s), 2.30(3H, s), 2.30—2.65 (5H, m), 2.85—3.05 (2H, m), 3.35-3.50 (3H, m), 4.60-4.70 (2H, m), 5.15-5.50 (2H, m), 7,32 (1H, d, J=3.3Hz), 7.72 (1H, d, z), 9.24 (1H, br) Compound 1-39 1H-NMR(CDC13) 5 ppm: 1.40-1.80 (1H, m), 1.90-2.10 (2H, m), 2.15—2.50 (13H, m), 2.55—2.70 (1H, m), 2.85—3.15 (3H, m), 3.30-3.50 (2H, m), 3.65-3.80 (2H, m), .60 (2H, m), .75 (2H, m), 5.05—5.30 (2H, m), 5.80-6.05 (1H, m), 9.28 (1H,1n) Compound 1-40 1H—NMR (CDC13) 5 ppm: 0.90 (3H, t, J=7.0Hz), 1.20-1.45 (4H, m), 1.45-1.85 (4H, m), .15 (2H, m), 2.15—2.30 (7H, m), 2.30-2.55 (7H, m), 2.60-2.75 (1H, m), .00 (2H, m), 3.00-3.10 (1H, m), 3.35-3.45 (2H, m), 3.65-3.90 (2H, m), 4.65-4.75 (2H, m), 9.28 (1H, br) Compound 1-41 1H—NMR (CDC13) 5 ppm: 0.90-1.10 (2H, m), .30 (3H, m), 1.45-1.85 (8H, m), 1.95-2.10 (2H, m), 2.15-2.30 (7H, m), 2.30—2.50 (7H, m), 2.60-2.75 (1H, m), 2.90-3.00 (2H, m), 3.05-3.20 (1H, m), 3.35-3.45 (2H, m), 3.55-3.80 (2H, m), 4.65—4.75 (2H, m), 9.26 (1H, br) Compound 1-42 1H—NMR (CDC13) 5 ppm: 1.40—1.65 (2H, m), 1.75—1.90 (1H, m), 1.90-2.20 (1H, m), 2.20—2.35 (14H, m), 2.40-2.60 (4H, m), 2.80-2.95 (3H, m), 3.35-3.50 (2H, m), 4.55—4.70 (2H, m), 4.90-5.15 (2H, m), 6.85-7.00 (1H, m), 7.10—7.25 (3H, m), 9.36 (1H, brs) Compound 1—43 1H-NMR (CDC13) 8 ppm: 0.95 (6H, d, J=6.6Hz), 1.45-1.85 (5H, m), 1.95-2.15 (2H, m), 2.15—2.30 (7H, m), 2.30-2.55 (7H, m), 2.60—2.75 (1H, m), .10 (3H, m), 3.35-3.45. (2H, m), 3.65-3.90 (2H, m), 4.60-4.80 (2H, m), 9.27 (1H, brs) Compound 1-44 1H—NMR (CDC13) 6 ppm: 1.26 (3H, t, J=7.0Hz), 1.47—1.63 (1H, m), .86 (1H, m), 1.94—2.12 (2H, m), 2.16-2.54 (5H, m), 2.32 (6H, s), 2.35 (3H, s), 2.62-2.72 (1H, m), 2.77-3.16 (7H, m), 3.43-3.55 (2H, m), 3.78-3.96 (2H, m), 4.65 (2H, s), 7.10—7.23 (4H, m), 9.23-9.42 (1H, m) Compound 1-45 1H-NMR (CDC13) 5 ppm: 0.94 (3H, t, J=7.3Hz), 1.02 (6H, t, J=7.2Hz), 1.27-1.43 (2H, m), 1.46-1.64 (3H, m), .86 (1H, m), 1.95-2.11 (2H, m), 2.16-2.28 (1H, m), 2.31—2.72 (9H, m), 2.34 (3H, s), 2.87-3.12 (3H, m), 3.28-3.41 (2H, m), 3.63-3.89 (2H, m), 4.64 (2H, s), 9.01-9.42 (1H, m) Compound 1-46 1H—NMR (CDC13) 5 ppm: 0.94 (3H, t, J=7.5Hz), 1.29-1.85 (12H, m), 1.96-2.12 (2H, m), 2.16-2.28 (1H, m), 2.30-2.54 (8H, m), 2.34 (3H, s), 2.60-2.74 (1H, m), 2.88-3.14 (3H, ‘ m), 3.34-3.47 (2H, m), 3.62-3.89 (2H, m), 4.66 (2H, s), 8.96-9.43 (1H, m) Compound 1—47 1H-NMR (CDC13) 6 ppm: 0.94 (3H, t, J=7.5Hz), 1.28—1.43 (2H, m), 1.46-1.66 (3H, m), 1.69-1.87 (5H, m), 1.95-2.13 (2H, 1n), 2.16-2.28 (1H, m), 2.30-2.74 (9H, m), 2.34 (3H, s), 2.87-3.13 (3H, m), 3.37-3.48 (2H, m), 3.63-3.89 (2H, m), 4.64 (2H, s), 9.10-9.39 (1H, Compound 1-48 1H—NMR (DMSO—d5) 8 ppm: 0.84 (3H, t, z), 0.94 (6H, t, J=7.2Hz), 1.20-1.40 (1H, m), 1.40-1.70 (3H, m), .00 (2H, m), 2.00-2.30 (6H, m), 2.35—2.55 (7H, m), 2.80—2.95 (2H, m), 2.95—3.10 (1H, m), .25 (2H, m), 3.45—3.70 (2H, m), 7.02 (2H, brs), 8.65 (1H, 'brs) id="p-473" id="p-473"
[0473] nd 1-49 1H-NMR (DMSO-d6) 8 ppm: 0.75—0.90 (3H, m), 1.25-1.70 (10H, m), 1.80—2.00 (2H, m), 2.00—2.25 (6H, In), 2.25-2.50 (7H, m), 2.80—2.95 (2H, m), 2.95-3.10 (1H, In), 3.15—3.30 (2H, m), 3.45-3.65 (2H, m), 7.01 (2H, brs), 8.57 (1H, brs) Compound 1-50 1H-NMR (CDC13) 8 ppm: 1.18 (3H, t, J=7.0Hz), 1.40-1.60 (1H, m), 1.65-1.85 (1H, m), 1.95-2.10 (2H, m), .50 (14H, m), 2.55—2.70 (1H, m), 2.85-3.05 (2H, m), 3.30-3.65 (7H, m), 3.80-4.15 (2H, m), 4.60-4.75 (2H, m), 9.24 (1H, br) Compound 1-51 1H-NMR (CDC13) 5 ppm: 1.25 (3H, t, J=7.1Hz), 1.48-1.60 (1H, m), 1.70—1.84 (1H, m), .11 (2H, m), 2.16-2.27 (1H, m), 2.30-2.48 (2H, m), 2.34 (3H, s), 2.61-2.71 (1H, m), 2.76-2.84 (2H, m), 2.89—3.13 (3H, m), .61 (2H, m), 3.64 (3H, s), .93 (2H, m), 4.69 (2H, s), 6.66-6.71 (1H, m), 7.32-7.37 (1H, m), 9.13-9.37 (1H, m) Compound 1-52 1H—NMR (DMSO'dé) 8 ppm: 1.20-1.40 (1H, m), 1.50-1.70 (1H, m), 1.80-2.25 (15H, m), .70 (4H, m), 2.80—2.95 (2H, m), .15 (1H, m), 3.20-3.30 (2H, m), 3.70—3.90 (2H, m), 7.02 (2H, brs), 8.61 (1H, brs) Compound 1-53 1H—NMR(CDC13) 8 ppm: 1.26 (3H, t, J=7.0Hz), 1.45-1.59 (1H, m), 1.69—1.86 (1H, m), 1.93-2.12 (2H, m), 2.15-2.28 (1H, m), 2.31—2.48 (2H, m), 2.34 (3H, s), 2.61—2.72 (1H, m), 2.87—3.12 (3H, m), 3.51-3.71 (2H, m), 3.76—3.97 (2H, m), 4.06-4.21 (2H, m), 4.71 (2H, s), 6.89-6.98 (1H, m), 7.06-7.10 (1H, m), 7.45-7.50 (1H, m), 9.36-9.49 (1H, m) . id="p-478" id="p-478"
[0478] Compound 1-54 1H-NMR (CDC13) 5 ppm: 1.40—1.70 (2H, m), 1.80—2.10 (4H, m), 2.10-2.50 (14H, m), 2.50-2.80 (3H, m), 2.85-3.00 (3H, m), 3.30-3.45 (2H, m), 3.65-3.95 (2H, m), 4.68 (2H, brs), 7.10-7.24 (3H, m), 7.24-7.32 (2H, m), 9.24 (1H, brs) Compound 1-55 1H-NMR (CDC13) 5 ppm: 0.97 (3H, d, J=6.5Hz), 1.26 (3H, t, z), 1.50-1.66 (1H, m), 1.69-1.86 (1H, m), 1.94-2.12 (2H, m), 2.15—2.29 (1H, m), 2.26 (6H, s), 2.30-2.53 (2H, m), 2.34 (3H, s), 2.60—2.77 (2H, m), 2.90-3.25 (4H, m), 3.30-3.41 (1H, m), 3.78-3.96 (2H, m), 4.66 (2H, s), 9.10-9.37 (1H, m) Compound 1-56 1H-NMR (CDC13) 8 ppm: 0.93 (9H, s), 1.45-1.60 (1H, m), 1.65-1.85 (10H, m), 1.90-2.10 (2H, m), 2.10—2.50 (14H, m), 2.60-2.75 (1H, m), .00 (2H, m), 3.15-3.30 (1H, m), 3.30-3.45 (2H, m), 3.65-3.95 (2H, 1n), 4.60-4.75 (2H, m), 8.77 (1H, br) Compound 1-57 1H—NMR (CDC13) 6 ppm: 1.21 (3H, d, J=6.5Hz), 1.26 (3H, t, J=7.0Hz), 1.47-1.65 (1H, m), 1.68-1.87 (1H, m), .11 (2H, m), 2.13—2.28 (2H, m), 2.25 (6H, s), 2.29-2.50 (3H, m), 2.34 (3H, s), 2.61-2.74 (1H, m), 2.90—3.13 (3H, m), 3.77-4.03 (3H, In), 4.65 (2H, s), 9.04-9.31 (1H, m) [a] 2": -78.58° (c-=0.31, MeOH) nd 1—58 ' 1H-NMR (CDC13) 5 ppm: 0.94 (3H, t, J=7.3Hz), 1.30—1.42 (2H, m), .86 (6H, m), 1.95—2.12 (2H, m), 2.15-2.51 (5H, m), 2.22 (6H, s), 2.34 (3H, s), 2.61-2.73 (1H, m), 2.90-3.18 (3H, m), 3.27—3.38 (2H, m), 3.62-3.88 (2H,m), 4.66 (2H, s), 9.07-9.43 (1H, Compound 1—59 1H—NMR (CDC13) 5 ppm: 0.94 (3H, t, J=7.4Hz), 1.29-1.42 (2H, m), 1.44-1.85 (8H, m), 1.96-2.12 (2H, m), 2.14—2.49 (5H, m), 2.21 (6H, s), 2.34 (3H, s), 2.62-2.74 (1H, m), 2.88-3.18 (3H, m), 3.24—3.35 (2H, m), 3.62—3.89 (2H, m), 4.67 (2H, s), .37 (1H, Compound 1-60 1H-NMR (CDC13) 6 ppm: 0.94 (3H, t, J=7.4Hz), 1.00 (12H, d, J=6.5Hz), 1.28-1.42 (2H, m), 1.45-1.64 (3H, m), 1.69-1.86 (1H, m), 1.95-2.12 (2H, m), .28 (1H, m), 2.30-2.51 (2H, m), 2.34 (3H, s), .61 (2H, m), 2.62-2.73 (1H, m), 2.88—3.16 (5H, m), 3.21-3.34 (2H, m), 3.64—3.88 (2H, m), 4.64 (2H, s), 9.00-9.36 (1H, m) Compound 1-61 1H—NMR (DMSO-ds) 5 ppm: 1.50—2.50 (23H, m), 2.80-2.95 (2H, m), .15 (1H, m), 3.15-3.30 (2H, m), 3.50-3.75 (2H, m), 7.02 (2H, brs), 8.65 (1H, brs) ‘[0486] Compound 1-62 1H—NMR (CDC13) 6 ppm: 0.94 (3H, t, J=7.4Hz), 1.45-1.90 (6H, m), 1.95-2.15 (2H, m), 2.15-2.50 (14H, m), .75 (1H, m), 2.90-3.15 (3H, m), 3.25-3.40 (2H, m), 3.60-3.85 (2H, m), 4.65-4.75 (2H, m), 9.26 (1H, brs) Compound 1-63 1H-NMR (CDC13) 6 ppm: 0.94 (3H, t, J=7.4Hz), 1.45-1.85 (8H, m), 1.95-2.15 (2H, m), 2.15—2.30 (9H, m), 2.30-2.50 (5H, m), 2.60-2.75 (1H, m), 2.90-3.15 (3H, m), 3.25-3.35 (2H, m), 3.60—3.85 (2H, m), 4.65-4.75 (2H, m), 9.26 (1H, brs) Compound 1-64 1H—NMR (CDC13) 8 ppm: 0.94 (3H, t, J=7.3Hz), .43 (2H, m), 1.48-1.84 (4H, m), 1.92-2.11 (2H, In), 2.15-2.27 (1H, m), 2.28—2.44 (5H, m), 2.31 (3H, s), 2.34 (3H, s), 2.46-2.55 (1H, m), 2.61-2.72 (1H, m), 2.90-3.14 (3H, m), 3.38-3.47 (2H, m), 3.57-3.91 (4H, m), 4.05-4.21 (2H, m), 4.70 (2H, 5), 961-1005 (1H, m) id="p-489" id="p-489"
[0489] Compound 1-65 1H—NMR ) 5 ppm: 1.03 (6H, s), 1.26 (3H, t, z), 1.48-1.69 (1H, m), 1.71-1.86 (1H, m), 1.94-2.13 (2H, m), 2.16-2.28 (1H, m), 2.23 (6H, s), 2.30-2.43 (1H, m), 2.34 (3H, s), 2.45-2.54 (1H, m), 2.62—2.72 (1H, m), 2.89—3.14 (3H, m), 3.27 (2H, d, J=5.0Hz), 3.78—3.97 (2H, m), 4.66 (2H, s), 9.05-9.42 (1H, m) Compound 1—66 IH—NMR (CDC13) 8 ppm: 0.95 (3H, t, J=7.3Hz), 1.29-1.43 (2H, m), 1.47-1.66 (3H, m), 1.70—1.86 (1H, m), 1.96-2.14 (2H, m), 2.16—2.73 (14H, m), 2.29 (3H, s), 2.34 (3H, s), 2.89-3.14 (3H, m), 3.36-3.46 (2H, m), 3.65-3.88 (2H, m), 4.64 (2H, s), .38 (1H, Compound 1-67 lH—NMR (CDC13) 8 ppm: 1.02 (6H, t, J=7.2Hz), 1.40-1.55 (1H, m), 1.65-1.85 (1H, m), .10 (2H, m), 2.10-2.45 (6H, m), .75 (7H, m), 2.80-3.10 (2H, m), 3.25-3.47 (6H, m), 3.47-3.60 (2H, m), 3.85-4.05 (2H, m), 4.63 (2H, brs) Compound 1—68 1H—NMR (CDC13) 6 ppm: 1.30—1.90 (8H, m), 1.90-2.10 (2H, m), 2.10-2.55 (12H, m), 2.55-2.75 (1H, m), 2.80—3.10 (2H, m), 3.30-3.45 (6H, m), 3.45—3.60 (2H, m), 3.80—4.05 (2H, m), 4.62 (2H, brs) nd 1-69 1H-NMR (CDC13) 5 ppm: 1.30-2.10 (8H, m), .50 (14H, m), 2.55-2.75 (1H, m), 2.80-3.10 (2H, m), 3.20-3.60 (8H, m), 3.90—4.05 (2H, m), 4.78 (2H, b1s) Compound 1—70 1H-NMR(CDC13) 8 ppm: 1.35-1.65 (3H, m), 1.70—1.85 (1H, m), 1.95—2.10 (2H, m), 2.10-2.50 (16H, m), 2.55—2.70 (1H, m), 2.80—3.10 (2H, m), 3.20—3.45 (6H, m), 3.50—3.60 (2H, m), 3.85-4.05 (2H, m), 4.90 (2H, brs) Compound 1-71 1H—NMR (CDC13) 6 ppm: 1.03 (6H, t, J=7.2Hz), 1.43—1.57 (1H, m), 1.68-1.85 (1H, m), 1.94—2.11 (2H, m), 2.17-2.29 (1H, m), 2.30-2.46 (2H, m), 2.34 (3H, s), 2.51-2.62 (6H, m), 2.62-2.72 (1H, m), 2.90—3.03 (2H, m), 3.09—3.21 (1H, m), .42 (2H, m), 3.37 (3H, s), 4.66 (2H, s), 9.12-9.36 (1H, m) id="p-496" id="p-496"
[0496] Compound 1—72 1H—NMR (CDC13) 5 ppm: 1.26 (3H, t, J=7.1Hz), 1.48-1.62 (1H, m), 1.70-1.86 (1H, m), 1.94—2.13 (2H, m), 2.17-2.30 (1H, m), 2.27 (6H, s), 2.32-2.56 (4H, m), 2.34 (3H, s), 2.62-2.73 (1H, m), 2.90-3.13 (3H, m), 3.41-3.64 (6H, m), 3.76-3.96 (2H, m), 4.67 (2H, s), 9.12-9.55 (1H, m) Compound 1-73 . lH—NMR (CDC13) 5 ppm: 1.26 (3H, t, z), 1.47-1.62 (1H, m), 1.70-1.87 (1H, m), 1.96-2.13 (2H, m), 2.16-2.49 (3H, m), 2.30 (3H, s), 2.35 (3H, s), 257—273 (2H, m), 2.85-3.13 (5H, m), .40 (2H, m), 3.42—3.50 (2H, m), 3.78-3.96 (2H, m), 4.66 (2H, s), 9.23—9.43 (1H, m) Compound 1-74 1H—NMR (CDC13) 8 ppm: 1.35—1.67 (7H, m), 1.70-1.85 (1H, m), 1.95-2.12 (2H, m), 2.17—2.29 (1H, m), 2.30—2.53 (8H, m), 2.35 (3H, s), 2.61-2.72 (1H, m), 2.90-3.03 (2H, m), 3.08—3.20 (1H, m), 3.34-3.46 (2H, m), 3.37 (3H, s), 4.65(2H, s), .38 (1H, m) Compound 1-75 MS(ESI, 18(M+H)+ [05 00] Compound 1-76 1H-NMR ) 5 ppm: 1.40-1.55 (1H, m), 1.65—1.90 (4H, m), .12 (3H, m), 2.13-2.26 (1H, m), 2.26-2.46 (5H, m), 2.47—2.74 (7H, m), 2.85-3.10 (2H, m), 3.25-3.47 (6H, m), 3.47-3.61 (2H, m), 3.81-4.07 (2H, m), 4.79 (2H, brs) Compound 1-77 1H-NMR (CDC13) 8 ppm: 0.92 (6H, s), 1.43-1.57 (1H, m), 1.68—1.88 (1H, m), 1.96—2.12 (2H, m), .47 (3H, m), 2.16 (2H, s), 2.29 (6H, s), 2.35 (3H, s), 2.59—2.72 (1H, m), 2.88-3.27 (3H, m), 3.21 (2H, d, J=5.5Hz), 3.36 (3H, s), 4.64 (2H, s), 9.35-9.51 (1H, m) Compound 1-78 1H—NMR(CDC13) 5 ppm: 1.18 (3H, t, J=6.9Hz), 1.39-1.55 (1H, m), 1.55-1.83 (3H, 1n), .10 (2H, m), 2.14-2.27 (1H, m), 2.23 (6H, s), 2.28-2.44 (4H, m), 2.32 (3H, s), 2.54-2.74 (1H, m), 2.83-3.09 (2H, m), 3.23-3.37 (2H, m), 3.40-3.65 (5H, m), 3.77-4.14 (2H, m), 4.66 (2H, s), 8.42—9.79 (1H, m) Compound 1—79 1H-NMR (CDC13) 5 ppm: 1.18 (3H, t, J=6.9Hz), 1.38-1.85 (6H, m), 1.95-2.10 (2H, m), 2.13-2.45 (5H, m), 2.22 (6H, s), 2.32 (3H, s), 2.58-2.70 (1H, m), 2.85-3.10 (2H, m), 3.20-3.34 (2H, m), 3.39-3.63 (5H, m), 3.78—4.11 (2H, m), 4.63 (2H, s), 8.30-9.74 (1H, Compound 1-80 1H—NMR (CDC13) 5 ppm: 0.35-0.45 (2H, m), 0.45-0.60 (2H, m), .05 (1H, m), 1.45-1.65 (1H, m), 1.65-1.90 (3H, m), 1.95-2.15 (2H, m), 2.15-2.50 (14H, m), 2.60—2.75 (1H, m), .05 (2H, m), 3.15-3.40 (3H, m), 3.70-3.85 (2H, m), 4.60—4.70 (2H, m), 9.28 (1H, brs) Compound 1-81 1H—NMR (CDC13) 5 ppm: 1.03 (6H, s), 1.38-1.55 (1H, m), 1.69—1.84 (1H, m), 1.95-2.12 (2H, m), 2.12-2.28 (1H, m), 2.23 (6H, s), 2.29-2.47 (2H, m), 2.32 (3H, s), 2.56-2.72 (1H, m), 2.85-3.10 (2H, m), 3.17-3.29 (2H, m), 3.30—3.47 (1H, m), 3.34 (3H, s), 3.48-3.61 (2H, m), 3.77-4.04 (2H, m), 4.61 (2H, s) id="p-506" id="p-506"
[0506] Compound 1-82 1H—NMR (CDC13) 8 ppm: 0.94 (3H, t, z), 1.03 (6H, s), .87 (4H, m), 1.94-2.12 (2H, m), 2.14-2.29 (1H, m), 2.23 (6H, s), 2.29-2.43 (1H, m), 2.34 (3H, s), .54 (1H, m), 2.61—2.72 (1H, m), 2.87-3.18 (3H, m), 3.27 (2H, d, J=5.0Hz), 3.59-3.88 (2H, m), 4.69 (2H, s), 8.85—9.59 (1H,1n) Compound 1-83 1H—NMR (CDC13) 6 ppm: 0.88—0.98 (3H, m), 0.92 (6H, s), 1.47-1.86 (4H, m), 1.95-2.11 (2H, m), 2.12-2.52 (3H, m), 2.16 (2H, s), 2.29 (6H, s), 2.34 (3H, s), 2.58-2.75 (1H, m), 2.89-3.16 (3H, m), 3.20 (2H, d, J=5.5Hz), 3.62-3.85 (2H, m), 4.66 (2H, s), 9.22—9.48 (1H, m) nd 1-84 1H-NMR (CDC13) 6 ppm: 0.88 (6H, t, J=7.5Hz), 1.26 (3H, t, J=7.1Hz), 1.37-1.66 (5H, m), 1.70-1.87 (1H, m), 1.94-2.13 (2H, m), 2.15-2.54 (12H, m), 2.59-2.73 (1H, m), .18 (3H, m), 3.31 (2H, d, J=4.8Hz), 3.75-3.97 (2H, m), 4.65 (2H, s), 8.96-9.55 (1H, m) Compound 1-85 1H-NMR (CDC13) 8 ppm: 0.92 (6H, s), 1.25 (3H, t', J=7.1Hz), 1.46-1.66 (1H, m), 1.71-1.87 (1H, m), 1.95-2.12 (2H, m), 2.12-2.53 (3H, m), 2.16 (2H, s), 2.29 (6H, s), 2.34 (3H, s), 2.60-2.74 (1H, m), 2.89—3.17(3H, m), 3.21 (2H, d, J=5.5Hz), 3.77-3.94 (2H, m), 4.65 (2H, s), 9.23-9.50 (1H, m) [05 1 0] Compound 1—86 1H-NMR (CDC13) 6 ppm: 1.25 (3H, t, J=7.1Hz), 1.43-1.61 (1H, m), 1.69-1.85 (1H, m), 1.91—2.12 (2H, m), 2.15-2.28 (1H, m), 2.30—2.46 (2H, m), 2.34 (3H, s), 2.60-2.73 (1H, m), 2.86—3.15 (3H, m), 2.97 (3H, s), 3.41-3.57 (4H. m), 3.76-3.93 (2H, m), 4.65 (2H, s), 6.64—6.79 (3H, m), 7.17-7.26 (2H, m), 9.25-9.41 (1H, m) Compound 1—87 1I-I-NMR (CDC13) 8 ppm: 0.95 (3H, t, z), 1.29-1.42 (2H, m), 1.45—1.66 (2H, m), 1.68-1.84 (1H, m), 1.93-2.11 (2H, m), .52 (3H, m), 2.28 (3H, s), 2.33 (3H, s), 2.53-2.72 (5H, m), 2.87-3.13 (4H, m), 3.34—3.46 (2H, m), 3.53-3.92 (4H, m), 4.64 (2H, s), 9.40-9.72 (1H, m) Compound 1-88 1H-NMR (CDC13) 8 ppm: 0.95 (3H, t,rJ=7.3Hz), 1.02 (6H, t, J=7.1Hz), 1.30-1.44 (2H, m), .73 (4H, m), 1.99-2.46 (3H, m), 2.49-2.80 (9H, m), 2.84—3.03 (2H, m), 3.09—3.41 (3H, m), 3.63-3.89 (2H, m), 4.64 (2H, s), 8.81-9.57 (1H, m) [05 13] Compound 1-89 1H—NMR (CDC13) 5 ppm: 0.95 (3H, t, J=7.3Hz), 1.30—1.48 (4H, m), 1.49-1.71 (8H, m), 1.98-2.54 (9H, m), 2.57-2.79 (3H, m), 2.83-3.04 (2H, m), 3.14-3.28 (1H, m), .47 (2H, m), 3.64-3.87 (2H, m), 4.66 (2H, s), 8.82-9.51 (1H, m) [05 14] Compound 1-90 1H-NMR (ODC13) 5 ppm: 0.96 (3H, t, J=7.3Hz), 1.31-1.44 (2H, m), 1.48—1.69 (4H, m), 1.99—2.29 (2H, m), 2.26 (6H, s), 2.32—2.49 (3H, m), 2.55-2.79 (3H, m), 2.83-3.04 (2H, m), 3.15—3.29 (1H, m), .45 (2H, m), 3.64-3.88 (2H, m), 4.66 (2H, s), 8.93-9.47 (1H, m) Compound 1-91 1H-NMR (CDC13) 8 ppm: .00 (3H, m), 1.20-1.40 (3H, m), 1.40-1.90 (4H, m), 1.90-2.10 (1H, m), .30 (7H, m), 2.30—2.80 (8H, m), 2.80-3.10 (3H, m), 3.25—3.50 (2H, m), 3.80—3.95 (2H, m), .70 (2H, m), 9.31 (1H, brs) Compound 1-92 lH-NMR (CDC13) 6ppm: 0.95-1.10 (3H, m), ~1.50-1.65 (1H, m), 1.95-2.10 (2nH, m), 2.15—2.30 (7H, m), 2.35—2.50 (4H, m), 2.50-3.10 (7H, m), 3.35-3.45 (2H, m), 3.80—3.95 (2H, m), 4.66 (2H, s), 9.31 (1H, brs) Compound 1—93 1H—NMR (CDC13) 5 ppm: 1.40-1.54 (1H, m), 1.69-1.88 (3H, m), 1.96—2.12 (2H, m), 2.15-2.47 (5H, m), 2.22 (6H, s), 2.32 (3H, s), .73 (1H, m), 2.87—3.07 (2H, m), 3.23-3.87 (5H, m), 4.47 (1H,.t, J=4.8Hz), 4.58 (1H, t, J=4.8Hz), 4.65 (2H, s), 9.87-10.42 (1H, m) Compound 1—94 1H—NMR ) 5 ppm: 0.94 (3H, t, J=7.6Hz), 1.40-1.90 (4H, m), 1.90-2.15 (4H, m), 2.20-2.55 (13H, m), 2.80-3.20 (4H, m), 3.30—3.50 (2H, m), 3.60-3.90 (4H, m), 5.99 (2H, s), 9.30 (1H, brs) [05 19] Compound 1-95 1H—NMR (CDC13) 5 ppm: 0.84 (3H, t, J=7.2Hz), 1.10—1.70 (4H, m), 1.70-2.05 (2H, m), 2.05-2.28 (10H, m), 2.28-2.41 (3H, m), 2.60-2.75 (1H, m), 2.80-2.95 (2H, m), 2.95-3.15 (1H, m), 3.15-3.30 (2H, 1n), 3.45-3.75 (3H, m), 6.51 (2H, brs), 6.92 (2H, s), 8.64 (1H, brs) Compound 1-96 1H-NMR (CDC13) 5 ppm: 1.19-1.31 (3H, m), 1.46-1.64 (3H, m), 1.71-1.86 (1H, m), 1.90-2.30 (7H, m), 2.27 (3H, s), 2.30—2.50 (2H, m), 2.34 (3H, s), .80 (3H, m), 2.90-3.22 (3H, m), 3.64-3.97 ), 4.64 (2H, s), 9.13-9.39 (1H,'m) Compound 1—97 lH-NMR(CDC13,) 8 ppm: 0.95 (3H, t, J=7.3Hz), 1.29-1.67 (7H, m), 1.71—1.86 (1H, m), 1.90—2.12 (4H, m), 2.16—2.28 (1H, m), 2.30—2.51 (2H, m), 2.35 (3H,'s), 2.63-2.75 (3H, m), 2.90—3.12 (5H, m), 3.62-3.92 (3H, m), 4.65 (2H, s), 9.18-9.40 (1H, m) Compound 1-98 1H—NM’R (CDC13) 6 ppm: 1.20—1.34 (3H, m), 1.46-1.62 (1H, m), .85 (1H, m), 1.95—2.15 (2H, m), 2.15—2.30 (1H, m), 2.30-2.50 (8H, m), 2.60—2.75 (1H, m), 2.80-3.15 (5H, m), 3.60-3.75 (2H, m), 3.76-3.95 (2H, m), 4.35-4.50 (1H, m), 4.60-4.75 (2H, m), 9.50-9.65 (1H, m) Compound 1—99 1H—NMR(CDC13) 5 ppm: 0.80-1.00 (3H, m), 1.40-1.90 (4H, m), 1.90-2.15 (2H, m), .29 (1H, m), 2.29—2.50 (8H, m), 2.60-2.75 (1H, m), .15 (5H, m), 3.55-3.85 (4H, m), 4.35-4.50 (1H, m), .75 (2H, m), 9.50-9.65 (1H, m) Compound 1-100 1H—NMR (CDC13) 5 ppm: 0.90-1.00 (3H, m), 1.50-2.10 (5H, m), 2.15-2.31 (7H, m), 2.31-2.55 (4H, m), .77 (2H, m), 2.77-2.94 (1H, m), 2.94-3.17 (4H, m), 3.35—3.45 (2H, m), 3.51-3.86 (2H, m), 4.40-4.80 (4H, m), 9.24 (1H, brs) Compound 1-101 1H-NMR (CDC13) 5 ppm: 0.96 (3H, t, J=7.2Hz), 1.40-1.85 (2H, m), 1.90-2.10 (1H, m), 2.15-2.35 (7H, m), 2.35-2.55 (3H, m), 2.55—2.75 (2H, m), 2.80-2.95 (3H, m), 2.95-3.35 (5H, In), 3.35-3.45 (2H, m), 3.60—3.85 (2H, m), 4.65 (2H, brs), 9.19 (1H, brs) Compound 1-102 MS(ESI, m/z):507(M+H)+ id="p-527" id="p-527"
[0527] Compound 1-103 1H—NMR (CDC13) 6 ppm: 0.93 (6H, s), 1.26 (3H, t, J=7.1Hz), 1.50-1.65 (1H, m), 1.70-1.85 (1H, m), 1.95-2.35 (10H, m), 2.35—2.55 (1H, m), 2.55-2.75 (2H, m), 2.80—3.00 (2H, m), 3.00-3.40 (6H, m), 3.70-3.95 (2H, m), 4.70 (2H, s), 9.32 (1H, brs) id="p-528" id="p-528"
[0528] Compound 1—104 1H—NMR (CDC13) 8 ppm: 0.30—0.45 (2H, m), 0.45-0.55 (2H, m), 0.92 (6H, s), 0.95-1.05 (1H, m), 1.50-1.70 (1H, m), .85 (1H, m), 2.00-2.13 (2H, m), 2.13-2.55 (14H, m), 2.60-2.75 (1H, m), 2.90-3.10 (2H, m), 3.15-3.35 (3H, m), 3.70-3.90 (2H, m), 4.64 (2H, brs), 9.39 (1H, brs) = 99.540 (c=0.31, MeOH) Compound 1-105 1H-NMR(CDC13) 8 ppm: 1.03 (6H, t, J=7.2Hz), 1.26 (3H, t, z), 1.49-1.65 (1H, m), 1.70-1.90 (1H, m), 1.90-2.15 (2H, m), 2.15-2.30 (1H, m), 2.30-2.75 (12H, m), 2.80-3.15 (3H, m), 3.30-3.45 (2H, m), 3.75-4.00 (2H, m), 4.66 (2H, brs), 9.23 (1H, brs) [a]D27= -100.82o (c=0.34, MeOH) Compound 1—106 1H-NMR(CDC13) 6 ppm: 1.15-1.32 (3H, m), 1.35 (6H, s), 170-185 (1H, m), .14 (2H, m), 2.14-2.55 (15H, m), 2.60-2.75 (1H, 111), 2903.15 (3H, m), 3.74-3.92 (2H, m), 4.63 (2H, brs), 9.31 (1H, brs) 28 = -85.40° (c=0.30, MeOH) Compound 1-107 1H-NMR (CDC13) 8 ppm: 0.88 (6H, t, J=7.6Hz), 1.26 (3H, t, J=7.0Hz), 1.40-1.65 (5H, m), .85 (1H, m), 1.95-2.15 (2H, m), 5 (11H, m), 2.49 (1H, t, J=11.2Hz), 2.60-2.75 (1H, m), 2.90-3.15 (3H, m), 3.31 (2H, d, J=4.7Hz), 3.80-3.95 (2H, m), 4.64 (2H, s), 9.24 (1H, brs) ng= -86.48° (c=0.29, MeOH) Compound 1-108 1H-NMR (CDC13) 5 ppm : 1.26 (3H, t, J=7:0Hz), 1.50-1.60 (1H, m), 1.70-1.85 (1H, m), 1.95-2.15 (2H, m), 215-225 (1H, m), 2.26 (6H, s), 2.30-2.45 (7H, m), 2.60-2.75 (1H, m), 2.90-3.15 (3H, m), 3.35-3.45 (2H, In), 3.75-3.95 (2H, m), 4.66 (2H, s), 9.27 (1H, brs) [a]D27= —118.60° (c=0.31, MeOH) Compound 1-109 1H—NMR (CDC13) 5 ppm: 0.35-0.45 (2H, m), 0.45-0.60 (2H, m), 0.90-1.10 (1H, m), 1.50-1.65 (1H, m), 1.70—1.90 (1H, m), .15 (2H, m), 2.15-2.55 (14H, m), .75 (1H,- m), 2.90-3.05 (2H, m), 3.15-3.30 (1H, m), 3.35-3.45 (2H, m), 3.70-3.85 (2H, m), 4.70 (2H, s), 9.25 (1H, hrs) [a] 27= -89.37° (c=0.35, MeOH) Compound 1-110 lH—NMR (CDC13) 5 ppm: 0.96 (3H, t, J=7.4Hz), 1.40-1.80 (4H, m), 2.00-2.50 (11H, m), 2.55—2.80 (3H, m), 2.80-3.05 (2H, m), 3.15-3.30 (1H, m), 3.30-3.45 (2H, m), 3.60—3.85 (2H, m), 4.66 (2H, s), .50 (1H, m) [053 5] Example 2-1 N—[(4aR*,6R*,8aR*)—3—Cyano[({ [2-(dimethylamino)ethyl]carbamoyl} (propy1)ami- no)carbony1]—8-n1ethyl-4H,4aH,5H,6H,7H,8H,8aH,9H-thieno[3,2-g]quinolin—Z-yl]— acetamide (compound 2-1) To 1-{ [(4aR*,6R*,8aR*)aminocyanomethy1—4H,4aH,5H,6H,7H,8H, 8aH,9H—thieno[3,2-g]quinolin-6—y1]carbonyl} —3-[2-(dimethylamino)ethyl]-1 lurea (example 1—15) (100mg) was added acetic acid (2mL) and the mixture was heated at 135°C and refluxed for 12 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. To the residue were added ethyl acetate and a saturated s on of sodium bicarbonate. After the separated organic layer was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 0%-5% methanol/ethyl acetate, gradient elution) to give the title compound (26mg). The structure was illustrated in Table 11. 1H—NMR (CD013) 5 ppm: 0.94 (3H, t, J=7.2Hz), 1.50-1.90 (4H, m), 1.90-2.20 (2H, m), 2.20-2.40 (12H, m), 2.40-2.60 (4H, m), 2.70-2.90 (1H, m), 2.90-3.20 (3H, m), 3.30-3.50 (2H, m), 3.60-3.90(2H, m), 8.54 (1H, s), 9.26 (1H, brs) Example 2-2 Methyl N-[(4aR*,6R*,8aR*)—3—cyano [({ [2-(dimethylamino)ethyl]carbamoyl} (pro- pyl)amino)carbony1]—8—methyl-4H,4aH,5H,6H,7H,8H,8aH,9H—thieno[3,2-g]quinolin yl] ate (compound 2-2) To a mixture of 1,1'—carbonyldiimidazole (13mg) and ene chloride (lmL) was added 4-dimethylaminopyridine (8mg), followed by 1-{ [(4aR*,6R*,8aR*)amino—3—cyano-8—methy1-4H,4aH,5H,6H,7H,8H,8aH,9H-thieg] quinolin-6—y1] carbonyl}[2-(dimethylamino)ethy1]propylurea (example 1—15) (30mg) while ng under ice bath cooling, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added 1,1 '—carbonyldiimidazole (13mg), followed by 4-dimethy1aminopyridine (8mg) and warmed to room temperature and stirred for 1 hour. To the reaction mixture was added 1,1 '—carbonyldiimidazole (50mg), followed by 4-dimethylaminopyridine (32mg) while stirring at room temperature and stirred at the same temperature for 12 hours. To the reaction mixture was added methanol (0.003mL) while stirring at room temperature and stirred at the same temperature for 1 hour. The mixture was purified by aminopropyl silica gel column chromatography t: 0%—10% methanol/methylene chloride, gradient n) to give the title compound (18mg). The structure was illustrated in Table 11. 1H-NMR ) 5 ppm: 0.95 (3H, t, J=7.2Hz), .90 (4H, m), 1.90—2.20 (2H, m), 2.20—2.34 (1H, In), 2.26 (6H, s), 2.36 (3H, s), 2.38-2.54 (4H, m), 2.70-2.85 (1H, m), .15 (3H, m), 3.35-3.45 (2H, m), 3.60-3.85 (2H, m), 3.67 (3H, s), 7.12 (1H, brs), 9.26 (1H, brs) Compound 2-3 was prepared in a manner r to those as described in example 2-2 using 1-{[(4aR*,6R*,8aR*)aminocyanomcthyl-4H,4aH,5H,I 6H,7H,8H,8aH,9H-thieno[3,2—g]quinolinyl]carbony1}-3—[3-(dimethylamino)-2,2—di- methylpropyl]-l-ethylurea (example 1—85) instead of 1-{[(4aR*,6R*,8aR*)ami- yanomethy1-4H,4aH,5H,6H,7H,8H,8aH,9H-thieno[3,2-g]quinolinyl]car— bonyl}[2—(dimethylamino)ethyl]-l-propylurea (example 1-15). This was illustrated in Table 11.
IH—NMR (CDC13) 5 ppm: 0.92 (6H, s), 1.25 (3H, t', J=7.0Hz), 1.50-1.65 (1H, m), 1.70-1.90 (1H, m), .15 (2H, m), 2.17 (2H, s), 2.20-2.55 (12H, m), 2.65-2.80 (1H, m), 295-3 .25 (5H, m), 3.75-3.95 (5H, m), 7.70 (1H, br), 9.37 (1H, brs) id="p-538" id="p-538"
[0538] Example 3-1 1-{ [(4aR*,6R*,8aR*)Cyano-8—methyl(methy1amino)—4H,4aH,5H,6H,7H,8H,Sal-1,9 H-thieno[3 ,2-g]quinolinyl]carbonyl}[2-(dimethylamino)ethyl]-1 —propylurea di hydrochloride salt (compound 3-1) To (3 'R* ,4'aR* ,8'aR*)-1'-methy1-N-propyloctahydro—1'H—spiro[1,3 -dioxola— ne—2,6'—quinoline]-3'—carboxamide (reference example 4-5) (2.137g) was added 2mol/L hydrochloric acid(100mL) and the mixture was stirred at room temperature for 2 hours.
The reaction mixture was made ne with potassium carbonate. The mixture was extracted with methylene de/methanol mixed solvent (methylene chloride:methanol=9 : 1). After the organic layer was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure to give (3R*,4aR*,8aR*)methy1oxo-N-propyl-decahydroquinolinecarboxamide (1 .840g). 1H—NMR (CDC13) 5 ppm: 0.85-1.00 (4H, m), 1.40—1.90 (5H, m), 1.90—2.00 (1H, m), 2.10-2.25 (1H, m), 2.25-2.55 (9H, m), 2.95-3.05 (1H, m), 3.15-3.25 (2H, m), 5.43 (1H, brs) To a mixture of (3R*,4aR*,8aR*)methyl—6-oxo-N-.propyldecahydroquino- linecarboxamide (1.819g) and ethanol (72mL) were added malononitrile (622mg), morpholine (0.943mL), followed by elemental sulfer (303mg) while stirring at room temperature, and the mixture was heated at 54°C and stirred for 1.5 hours. After cooling to room ature, the reaction e was concentrated under d pressure.
The residue was triturated with ethyl acetate to give (4aR*,6R*,8aR*)amino-3 -cya- no—8-methy1-N-propyl—4H,4aH,5H,6H,7H,8H,8aH,9H—thieno[3,2-g]quinolinecarbo- xamide (1.99lg). 1H—NMR (DMSO-ds) 5 ppm: 0.83 (3H, t, J=7.4Hz), 1.20-1.45 (3H, m), .65 (1H, m), 1.75-1.95 (2H, m), 2.00-2.25 (6H, m), 2.35-2.60 (2H, m), 2.75-3.05 (4H, m), 7.00 - (2H, s), 7.81 (1H, t, z) A mixture of (4aR*,6R*,8aR*)aminocyanomethyl—N-propyl-4H,4aH, 5H,6H,7H,8H,8aH,9H-thieno[3,2-g]quinoline—6-carboxamide (1.99g) and (diethoxymethoxy)ethane (20mL) was heated at 155°C and stirred for 3 hours. After cooling to room temperature, it was diluted with diethyl ether and the solid was collected by filtration to give ethyl N-[(4aR*,6R*S,8aR*)—3-cyanomethy1—6-(propyl— carbamoyl)-4H,4aH,5H,6H,7H,8H,8aH,9H-thieno[3,Z-g]quinolin-Z-yl]carboximidate (1 .70g).
MS(ESI, m/z):389(M+H)+ To a e of ethyl N—[(4aR*,6R*,8aR*)cyanomethy1(propylcar— bamoyl)-4H,4aH,5H,6H,7H,8H,8aH,9H—thieno[3,2—g]quinolin-Z-yl]carboximidate (499mg) and ethanol (13mL)was added sodium borohydride (59mg) while stirring under ice bath cooling, and the mixture was stirred at the same temperature for 2.5 hours. To the reaction mixture was added water, and extracted with methylene de.
After the separated organic layer was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure to give (4aR*,6R*,8aR*)cyanomethyl(me- thylamino)—N—propyl-4H,4aH,5H,6H,7H,8H,8aH,9H—thieno [3,2—g]quinoline—6-carbox- amide (446mg). 1H—NMR ) 5 ppm: 0.93 (3H, t, J=7.4Hz), 1.40—1.60 (3H, m), 1.65-1.80 (1H, m), 1.95-2.10 (2H, m), 2.15—2.30 (1H, m), 2.30—2.55 (6H, m), 2.60-2.70 (1H, m), 2.90-3.10 (5H, m), 3.15-3.30 (2H, m), 4.75-4.85 (1H, m), 5.40—5.50 (1H, m) To a mixture of (4aR*,6R*,8aR*)—3-cyanomethyl(methylamino)-N-pro- pyl—4H,4aH,5H,6H,7H,8H,8aH,9H-thieno[3,2-g]quinolinecarboxamide (446mg) and acetonitrile (12mL) was added thylaminopyridine (79mg), followed by t—butyldicarbonate (561mg) while stirring at room temperature, and the mixture was stirred at the same ature for 12 hours. To the reaction mixture was added water, and extracted with ethyl acetate. After the separated organic layer was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure. The e was purified by aminopropyl silica gel column chromatography (eluent: 0%—5% methanol/ethyl acetate, gradient elution) to give tert-butyl N-[(4aR*,6R*,8aR*)—3 -cya- no—8-methyl(propylcarbamoyl)-4H,4aH,5H,6H,7H,8H,8aH,9H—thieno[3,2-g]quino- lin-2—yl]-N-methylcarbamate (5 17mg). 1H—NMR (CDC13) 5 ppm: 0.93 (3H, t, J=7.4Hz), 1.45-1.60 (12H, m), 1.65-1.85 (1H, m), .10 (2H, m), 2.20-2.55 (7H, m), .85 (1H, m), 2.95-3.15 (5H, m), 3.15-3.30 (2H, m), 5.40-5.50 (1H, m) To a mixture of tert-butyl N—[(4aR*,6R*,8aR*)—3-cyanomethyl-6—(propyl- carbamoyl)-4H,4aH,5H,6H,7H,8H,8aH,9H—thieno[3,2-g]quinolin—Z-yl]-N-methyl- ate(412mg) and tetrahydrofi1ran(5mL) was added a lmol/L sodium hexamethyldisilazide-tetrahydrofuran solution (1.2mL) at -40°C. After stirring at the same temperature for 20 minutes, 4-nitropheny1 chloroformate (242mg) was added to the mixture, and then stirred for 1 hour. After warming to room temperature and stirring for 1.5 hours, water and ethyl acetate were added. After the separated organic layer was dried over anhydrous sodium e, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 80%—100% ethyl acetate/hexane, gradient elution) to give 4-nitropheny1 N—{ [(4aR*,6R*,8aR*){[(te- rt—butoxy)carbonyl](methyl)amino}cyano—8-methyl-4H,4aH,5H,6H,7H,8H,8aH,9H— thieno[3,2-g]quinolin—6—y1]carbonyl}-N-propylcarbamate (405mg). 1H—NMR (CDC13) 5 ppm: 0.98 (3H, t, J=7.5Hz), 1.35-1.52 (1H, m), 1.50 (9H, s), .76 (2H, m), 1.76-1.86 (1H, m), 2.01-2.11 (1H, m), 2.14-2.34 (2H, m), 2.35 (3H, s), 2.37-2.53 (2H, m), 2.71—2.82 (1H, m), .12 (2H, m), 3.38 (3H, s), 3.71-3.92 (3H, m), 7.32-7.40 (2H, m), 8.28-8.36 (2H, m) To a mixture of 4-nitropheny1 N-{[(4aR*,6R*,8aR*)-2—{[(tert-butoxy)carbo- nyl](methyl)amino}—3-cyanomethyl—4H,4aH,5H,6H,7H,8H,8aH,9H-thieno[3,2—g]- quinolin—6-yl]carbonyl}-N-propylcarbamate (200mg) and tetrahydrofuran (3mL) was added methyl ethylenediamine mL) while stirring at room temperature, and the mixture was stirred at the same temperature for 22 hours. The reaction e was concentrated under reduced re. The residue was purified by aminopropyl silica gel column chromatography (eluent: 0%—5% methanol/ethyl acetate, gradient elution) to give tert-butyl N-[(4aR*,6R*,8aR*)-3—cyano[({[2-(dimethylamino)ethyl]- carbamoyl}(propyl)amino)carbonyl]—8-methyl-4H,4aH,5H,6H,7H,8H,8aH,9H—thieno- [3,2—g]quinolin—2-yl]—N—methylcarbamate (160mg). 1H-NMR(CDC13‘) 5 ppm: 0.95 (3H, t, J=7.4Hz), 1.51 (9H, s), 1.51-1.172 (3H, m), 1.73-1.90 (1H, m), .15 (2H, m), 2.24—2.39 (1H, m), 2.26 (6H, s), 2.36 (3H, s), 2.40—2.54 (4H, m), 2.74—2.86 (1H, m), 2.93-3.18 (3H, m), 3.32—3.47 (5H, m), 3.63-3.86 (2H, m), 9.12-9.42 (1H, m) To a mixture of tert-butyl Na[(4aR*,6R*,8aR*)cyano-6—[({ [2~(dimethy1a.mi- no)ethyl]carbamoy1}(propy1)amino)carbonyl]—8-methyl-4H,4aH,5H,6H,7H,8H,8aH,9H- thieno[3,2-g]quinoliny1]-N-methylcarbamate (160mg) and ethyl acetate (10mL) was added a 4mol/L hydrogen chloride—ethyl acetate on (SmL) while ng at room temperature, and the mixture was stirred at the same temperature for 11 hours. To the on mixture was added a 4mol/L hydrogen chloride-ethyl acetate solution (SmL) while stirring at room temperature, and then d at the same temperature for 13 hours.
The solid was collected by filtration to give the title compound (compound 3—1) (116mg). The structure was illustrated in Table 11. 1'H-NMR (DMSO-de) 8 ppm: 0.87 (3H, t, J=7.4Hz), .61 (3H, m), 2.09-2.30 (3H, m), 2.57-2.72 (1H, m), 3.08-3.42 (5H, m), 3.42-3.87 (19H, m), 7.59—7.75 (1H, m), 8.64-8.83 (1H, m), 10.02-10.29 (1H, m), 11.37-11.55 (1H, m) .
Example 3-2 1-{ [(4aR*,6R*,8aR*)-3~Cyanomethy1(methylamino)-4H,4aH,5H,6H,7H,8H,8aH,9 H—thieno[3,2-g]quinolin—6-y1]carbonyl}[3-(dimethylamino)propyl]—1-propylurea di hydrochloride salt(compound 3—2) To a mixture of 4-nitrophenyl N-{[(4aR*,6R*,8aR*)-2—{ [(tert—butoxy)carb- ony1](methyl)amino}cyanomethyl-4H,4aH,5H,6H,7H,8H,8aH,9H-thieno[3,2-g]- quinolinyl]carbony1}-N-propylcarbamate (200mg) and tetrahydrofiiran (3mL) was added (3-aminopropy1)dimethylamine (0.082mL) while stirring at room temperature, and then stirred at the same temperature for 22 hours. The reaction mixture was concentrated under reduced re. The residue was purified by aminopropyl silica gel column chromatography (eluent: 0%—5% ol/ethyl acetate, gradient elution) to give tert-butyl N-[(4aR*,6R*,8aR*)-3—cyano[({[3-(dimethylamino)propyl]carba- moyl}(propyl)amino)carbonyl]methy1-4H,4aH,5H,6H,7H,8H,8aH,9H—thieno— [3 ,2—g]quinolinyl]—N-methylcarbamate (1 18mg). lH—NMR(CDC13) 6 ppm: 0.95 (3H, t, J=7.5Hz), 1.50-1.76 (5H, m), 1.51 (9H, s), 1.76-1.88 (1H, m), .16 (2H, m), 2.20—2.40 (3H, m), 2.23 (6H, s), 2.37 (3H, s), 2.40-2.56 (2H, m), 2.75-2.85 (1H, m), 2.94-3.03 (1H, m), 3.03-3.17 (2H, m), 3.27-3.38 (2H, m), 3.40 (3H, s), 3.63-3.84 (2H, m), 9.15-9.35 (1H, m) id="p-547" id="p-547"
[0547] To a mixture of utyl N—[(4aR*,6R*,8aR*)cyano—6-[({ [3-(dimethyl- propyl]carbamoyl}(propyl)amino)carbonyl]methyl-4H,4aH,5H,6H,7H,8H,8a H,9H-thieno[3,2-g]quinolin—2-yl]-N-methylcarbamate (118mg) and ethyl acetate (1 OmL) was added a 4mol/L hydrogen chloride-ethyl acetate solution (5mL) while stirring at room temperature, and the mixture was stirred at the same ature for 11 hours. To the reaction mixture were added a 4mol/L hydrogen chloride-ethyl acetate solution (SmL) while stirring at room ature, and then stirred at the same temperature for 14 hours. The solid was collected by filtration to give the title compound (compound 3-2) . The structure was illustrated in Table 11. 2O 1H—NMR (DMSO-dg) 6 ppm: 0.86 (3H, t, J=7.4Hz), 1.40—1.61 (3H, In), 1.82-1.96 (2H, m), 2.06-2.29 (3H, m), 2.50-4.00 (25H, m), 7.58—7.74 (1H, m), 8.44-8.76 (1H, m), 9.91-10.15 (1H, m), 11.33—11.55 (1H, m) Example 4-1 1-{ [(4aR,6R,8aR)Aminocyanornethyl—4H,4aH,5H,6H,7H,8H,8aH,9H-thieno- [3,2-g]quinolin-o-yl]carbonyl} [2-(dimethylamino)ethy1]— 1 -propylurea di hydrochloride salt (compound 4—1) To a mixture of aR,6R,8aR)—2—aminocyan0—8-methyl-4H,4aH,5H, 6H,7H,8H,8aH,9H-thieno[3,2-g]quinolin—6—yl]carbonyl}[2-(dimethylamino)eth— yl]—l-propylurea (compound 1-1) (10.0g) and ethanol (200mL) was added dropwise a mixture of lZmol/L hydrochloric acid L) and ethanol (3OmL) while stirring under ice bath cooling, and the mixture was stirred at the same temperature for 3 hours.
The resulting solid was collected by ion, and washed twice with ethanol (ZOmL) to give 1- { [(4aR,6R,8aR)—2-a1nino-3~cyan0methyl—4H,4aH,5H,6H,7H,8H,8aH,9H— thieno [3 ,2-g] quinolinyl]carbonyl} (dimethylamino)ethyl]— l -propylurea di hydrochloride salt (1 1 .5 g).
A e of l-{[(4aR,6R,8aR)-2—aminocyan078-methyl—4H,4aH,5H,6H,7H, 8H,8aH,9H-thieno [3 ,2-g]quinolinyl]carbonyl} -3 -[2—(din1ethy1amino)ethyl]— l -propy- lurea di hydrochloride salt (8.0g), ethanol (80mL) and water (6.5mL) was dissolved by heating at 60°C while strring. To the solution was added dropwise ethanol (80mL) and heated at the same temperature for 1 hour. While stirring at the same temperature, ethanol (160mL) was additionally added se, and it was stirred at room temperature for 1 hour, then for 1 hour under ice bath cooling. The resulting solid was collected by filtration, and washed twice with ethanol (10mL). After the obtained solid was air-dried overnight and dried at 75°C for 5 hours under reduced pressure, it was additionally air-dried overnight to give the title compound (7.3g) as a crystal. The ,20 ure was illustrated in Table 11. 1H—NMR (MeOH—d4) 5 ppm: 0.97 (3H, t, J=7.4Hz), .75 (_3H, m), 2.15—2.40 (3H, m), 2.65-2.85 (2H, m), 2.97 (9H, s), 3.15-3.45 (5H, m), 3.55-3.90 (6H, m) The crude crystal of compound 4—4 was prepared by carrying out a salt formation reaction in a manner similar to those as described in example 4—1 using the ponding octahydrothienoquinoline instead of 1—{ [(4aR,6R,8aR)aminocya— no—8—methyl-4H,4aH,5H,6H,7H,8H,8aH,9H-thieno[3,2-g]quinolin—6-y1]carbonyl} [2— (dimethylamino)ethyl]propylurea. The crude crystal was recrystallized from ethanol and water to give nd 4—4 as a crystal. The structure was illustrated in Table 11.
Example 4-2 l-{ [(4aR,6R,8aR)—2—Amino-3—cyanomethy1—4H,4aH,5H,6H,7H,8H,8aH,9H—thieno- [3 ,2-g]quinolinyl]carbonyl}-3 -[(2S)-1 -(dimethylamino)propan—2-yl]- l -ethylurea di hydrochloride salt und 4-2) To a mixture of 1-{[(4aR,6R,8aR)amino-3—cyanomet-hyl-4H,4aH,5H,6H, 7H,8H,8aH,9H-thieno[3,2—g]quinolinyl]carbonyl}[(ZS)(dimethylamino)pro- pan-2—yl]—l-ethylurea (compound 1-5 7) (0.88g) and 2-propanol (17.6mL) was added 12mol/L hydrochloric acid (0.36mL) while stirring under water bath cooling. To the solution was added dropwise diisopropyl ether (17.6mL), and stirred at the room temperature for 1 hour, then for 1 hour under ice bath cooling. The resulting solid was collected by filtration, and washed twice with ld 2-propanol/diisopropyl ether mixed solvent (2-propanol: diisopropyl ether = 1:1) (4.4mL) to give l-{ [(4aR,6R,8aR)—2-amino-3—cyanomethyl-4H,4aH,5H,6H,7H,8H,8aH,9H-thieno— [3 ,2—g]quinolin—6—y1]carbonyl} -3 -[(ZS)-1 -(dimethylamino)propany1] — l -ethylurea di hydrochloride salt (0.92g).
A mixture of 1-{[(4aR,6R,8aR)aminocyano—8—methyl-4H,4aH,5H,6H,7H, 8H,8aH,9H—thieno [3 ,Z-g]quinolin—6-yl]carbonyl } ~3-[(ZS)(dimethylamino)pro- pan—2—yl]-l—ethylurea di hydrochloride salt (1.0g), acetonitrile (4.0mL) and water (2.0mL) was dissolved by heating at 60°C while stirring. To the solution was added se acetonitrile (20mL) and cooled to the room temperature. While stirring at the same temperature, acetonitrile (lSmL) was additionally added dropwise, and it was stirred for 35 minutes under ice bath g. The ing solid was collected by filtration, and washed three times with ice-cold acetonitrile mixed solvent (water: acetonitrile =1 :50) (5.0mL). The obtained solid was dried at 50°C for 13 hours under reduced pressure to give the title nd ) as a crystal. The structure was illustrated in Table 11. 1H—NMR (DMSO-d6) 6 ppm: 1.11 (3H, t, J=7.0Hz), 1.22 (3H, d, J=6.8Hz), 1.40-1.60 (1H, m); 2.10-2.30 (3H, m), .70 (1H, m), 2.70-2.90 (10H, m), 3.05-3.30 (3H, m), 3.45-3.60 (1H, m), 3.60—3.80 (3H, m), 4.10-4.30 (1H, m), 7.18 (2H, s), 8.45-8.70 (1H, m), 9.75—9.95 (1H, m), 11.25-11.60 (1H, m) [05 51] The crude crystal of compound 4-3 was prepared by carrying out a salt formation reaction in a manner similar to those as described in example 4—2 using the corresponding octahydrothienoquinoline instead of 1-{ [(4aR,6R,8aR)aminocya- n0—8-methyl-4H,4aH,5H,6H,7H,8H,8aH,9H-thieno[3,2-g]quinolin—6-yl]carbonyl}~3- [(ZS)(dimethylamino)propan—2—yl]-1—ethylurea. The crude crystal was recrystallized from itrile and water to give compound 4—3 as a crystal. The structure was illustrated in Table 11. id="p-552" id="p-552"
[0552] [Table 11] Com ound Com ouud Struculre o. No.
The ures of compound 2-1 to 2-3 and 3-1 to 3-2 in Table 11 indicate relative configuration, and the structures of compound 4-1 to 4-4 in Table 11 indicate absolute configuration. id="p-553" id="p-553"
[0553] The physical data of compounds 4-3 to 4-4 were shown below.
Compound 4-3 1H-NMR(DMSO-d6) 5 ppm: 0.94. (6H, t, J=7.6Hz), 1.14 (3H, t, J=6.9Hz), 1.45-1.65 (1H, m), 1.65-1.85 (4H, m), 2.05-2.35 (3H, m), .85 (11H, m), 3.05-3.30 (2H, m), .90 (6H, m), 7.18 (2H, s), 8.75—9.10 (1H, m), 9.55-9.80 (1H, m), 11.40-11.70 (1H, Compound 4-4 lH-NMR (DMSO'd6) 6 ppm: 1.12 (3H, t, J=7.1Hz), 1.40-1.60 (1H, m), 2.05-2.30 (3H, m), 2.55-2.90 (11H, m), 3.05—3.25 (2H, m), 3.45-3.85 (6H, m), 7.18 (2H, s), 8.55—8.85 (1H, 1n), 10.00—10.25 (1H, m), 11.25—11.60 (1H, m) [05 56] Test Example 1 Identification test of stimulating activities on human dopamine D2 receptor 1) Construction of human dopamine D2 receptor expression plasmid The PCR was performed using forward primer depicted as sequence ID No.1, reverse primer depicted as sequence ID No.2 and Herculase (Stratagene) as template of human brain cDNA (Japan Becton, Dickinson and Company). The PCR product was inserted into a plasmid (pcDNA3.1/V5-His-Topo(registered mark), ogen). The PCR product-inserted plasmid was transformed in E.coli (One Shot TOP10 Chemically Competent, Invitrogen). That E.coli was ted in LB agar medium contained 50 ug/mL llin for a day. A ed colony was incubated in LB medium contained 50 ug/mL ampicillin and PCR product—inserted plasmid was purified with QIAprep Spin ep Kit (QIAGEN). The base sequence of protein expression site in the plasmid nce ID No.3) accorded to the base sequence of human dopamine D2 receptor (NM_000795) registered on the public database (NCB1), except 1 base. But, the sequence of amino acids translated. by base sequence of that plasmid accorded to it of human dopamine D2 receptor (NM_000795) registered on NCBI completely. Therefore, the ns induced fiom this plasmid were identified with human dopamine D2 receptor. The pcDNA3.1/V5-His—Topo (registered mark) that the base sequence depicted as sequence ID No.3 was inserted, was fied as human dopamine D2 receptor expression plasmid. [05 57] 2) ation ofhuman dopamine D2 receptor expression cells (1) Cell culture HEK 293 cells (Dainippon Sumitomo Pharma Co., Ltd.) were cultured in 5% C02 incubator at 37°C in D-MEM (Dulbecco’s d Eagle Medium) liquid medium (low glucose, pyruvic acid and L-glutamine were contained, Invitrogen) in which penicillin-streptomycin solution (Invitrogen, final concentration: 100 U/mL as penicillin, 100 ug/mL as streptomycin) and fetal bovine serum (final concentration: 10%). (2) The passage of cells Mostly confluent HEK293 cells were washed with PBS (Phosphate ed Saline, Invitrogen), ed by exfoliation with 0.05% trypsin—EDTA (Invitrogen) and they were suspended with above-mentioned liquid medium. After centrifuging, the supernatant was removed and the cells were diluted with medium and cell number was counted. After that, the cells were scattered at appropriate cell concentration. id="p-559" id="p-559"
[0559] (3) Establishment of HEK293 cells expressed human dopamine D2 receptor stably Human dopamine D2 or expression d was digested with Seal and changed to linear plasmid. The linear plasmid was transfected in HEK293 cells using lipofection method (Lipofectamine (registered mark)2000 (Invitrogen)). After procurement ofneomycin resistant cell using 1 mg/mL Geneticin (registered mark)(Invitrogen), cell line was-selected according to the method of 3) seeing below. 3) Identification and selection of HEK293 cells expressed human dopamine D2 receptor stably (1) The passage of cells ' y confluent HEK293 cells expressed human dopamine D2 or stably were washed with PBS, followed by exfoliation with 0.05% trypsin—EDTA and D-MEM liquid medium (low glucose, pyruvic acid and L-glutamine were contained) containing Geneticin(registered mark) (final concentration: 0.1 mg/mL) as antibiotics and fetal bovine serum (final concentration: 10%) was added. After centrifiiging, the supernatant was d and the cells were diluted with above-mentioned liquid medium. After counting cell , the cells were scattered at riate concentration. (2) Preparation of cells Mostly confluent HEK293 cells expressed human dopamine D2 receptor stably were washed with PBS, ed by exfoliation with 0.05% trypsin—EDTA and the cells were suspended in D-MEM liquid medium (phenol red-free, low e and pyruvic acid were contained, Invitrogen) containing fetal bovine serum (final concentration: %) and GlutaMax(registered mark)I (Invitrogen, final concentration: 2 mM). The suspension was scattered at 5><104 cells/100 uL/well on poly-D-lysine-coated 96-well microplate (BD BioCoat (registered mark), Japan Becton, Dickinson and Company).
The scattered cells were cultured in 5% CO2 incubator at 37°C. To change signal of human dopamine D2 receptor CAMP reaction interacting Gi/o protein to carcium reaction, pLECl-quS-HA (Molecular Devices) was transfected in that cells according to the procedure seeing below. (3) Transfection ofpLECl-quS-HA pLECl-quS-HA and Lipofectamine(registered 000 were diluted to 0.008 g/L and 0.016 g/L each other with OPTI-MEM(registered mark)I Reduced-Serum Medium (Invitrogen) and incubated at room temperature. After incubation, the quS-HA—diluted solution and Lipofectamine (registered mark)2000—diluted solution were mixed at an equal volume and incubated at room temperature to form a complex. The complex was sed at 50 uL/well on the cells prepared above. The cells were incubated in 5% C02 incubator at 37°C for 2 days and used in measurement of intracellular calcium concentration. (4) Identification with measurement of intracellular calcium concentration The measurement of intracellular calcium concentration induced by each test compound was med using the forced expression cells ned above. Each dimethyl sulfoxide (DMSO) solution contained test compounds at 30 mM was diluted to appropriate concentration with assay buffer (Hank’s Balanced Salt Solution (HBSS, Invitrogen), 20 mM HEPES (Invitrogen), 1.3 mM calcium chloride, 0.5 mM magnesium chloride and 0.4 mM magnesium sulfate were contained, pH7.4).
The forced expression cells were washed with assay , and 100 uL/well of fluorescent calcium indicator (F1uo-4 NW m Assay Kit (Molecular ProbesTM)) was added and incubated in 5% C02 incubator at 37°C. After tion, 50 uL/well of each test compound was added, and the concentration of intracellular calcium was measured as fluorescent signal with FlexStation (registered mark) 11 (Molecular Devices). The cell line expressed human dopamine D2 receptor stably having good response was named as hD2R#7 cells. 4) ation of membrane homogenates from hD2R#7 cells ( 1) The e of hD2R#7 cells Mostly confluent hD2R#7 cells were washed with PBS, followed by exfoliation with 0.05% trypsin—EDTA and D-MEM liquid medium (low glucose, pyruvic acid and L-glutamine were contained) containing cin (registered mark) (final concentration: 0.1 mg/mL) as antibiotics and fetal bovine serum (final concentration: %) were added. After centrifuging, the supernatant was removed and the cells were diluted with above-mentioned liquid medium. After counting cell number, and the cells were scattered at appropriate concentration. (2) Preparation of membrane homogenates from hD2R#7 cells The cells, which were grown to confluence in 150mm dishes (IWAKI), were harvested with ic buffer (50 mM Tris (Sigma), 2 mM ethylenediamine-tetraacetic acid (Invitrogen), and 125 mM sodium chloride (Wako Pure Chemicals), pH 7.4) and centrifuged at 1880 > ) Determination of stimulating activites n dopamine D2 receptor The stimulating activities of human dopamine D2 receptor was determined by measuring the binding potential of [35S]—g1_1anosine 5’-[gamma-thio]triphosphate ([35S]GTP1(S, PerkinElmer) according to the method described by Newman-Tancredi A. et a1. (Naunyn-Schmiedeberg’s Arch Pharmacol, 1999, vol.359, pp.447-453) with a minor modification. Test compounds and dopamine hydrochloride ) as positive control were dissolved in dimethyl sulfoxide (CARLBIOCHEM), resulting in 30 mM.
The both compounds were d with assay buffer (50 mM Tris, 100 mM sodium chloride, 5 mM magnesium chloride (Nacalai), 1 mM nediamine-tetraacetic acid, 1 mM dithiothreitol (Wako Pure Chemicals), 10 "M guanosine diphosphate (Wako Pure Chemicals) and 0.5% bovine serum albumin (Sigma), pH 7.4) to a final concentration of 100 pM (only test compounds), 1 nM, 10 nM, 100 nM, 1 uM, 10 uM and .100 uM (only dopamine hydrochloride). The above membrane homogenates and [3SS]GTPyS were diluted with assay buffer to a final concentration of 0.06 mg/mL and 0.6 nM, respectively. The serial diluted compounds (50 uL), the diluted membrane homogenates (50 uL) and the diluted [35S]GTP1(S (50 uL) were mixed on multi-screen 96-well plate (Millipore) and shaken lightly at room temperature for 60 minutes. The reaction was terminated by vacuum filtration with three times washes of ice-cold wash buffer (50 mM Tris, 100 mM sodium chloride, 5 mM magnesium chloride, and 1 mM ethylenediamine—tetraacetic acid, pH 7.4). After drying the bottoms of the plate at 60°C, MicroScinti-40 nElmer) (30 uL) was added in the plate. The tops of the plate were sealed by TopSeal-A (PerkinElmer), and the radioactivity was determined in a TopCount gistered PerkinElmer) after shaking lightly for 5—10 minutes. The data was ed by ear regression and sigmoidal dose—response curve fitting using GraphPad PRISM 4.0 Pad Software), and values of ECso (concentration of the compound producing half the maximal effect of the compound) were calculated. The data was presented as mean value (n = 2). As comparative examples, ropinirole as non-ergot dopamine D2 receptor agonist and pergolide as ergot dopamine D2 receptor agonist, were examined in a similar fashion. These s wereshown in Table 12. id="p-567" id="p-567"
[0567] [Table 12] These results y showed that the compounds of the present invention exhibited potent stimulating ties of human dopamine D2 receptor. [05 69] Test e 2 Identification test of stimulating activities on human serotonin 5-HTZB receptor 1) Construction of human serotonin 5-HT23 or sion plasmid The PCR was performed using forward primer depicted as sequence ID No.4, reverse primer depicted as sequence ID N05 and KOD—Plus—Ver.2 O) as te ofhuman brain hippocampus cDNA ech). The PCR product was inserted into a plasmid(pcDNA3.1N5-His—Topo(registered mark». The PCR product-inserted plasmid was transformed in E.coli (One Shot TOP 1 0 Chemically Competent). That E.coli was incubated in LB agar medium contained 50 ug/mL ampicillin for a day. A selected colony was incubated in LB medium contained 50 ug/mL ampicillin and PCR product-inserted plasmid was purified with QIAprep Spin Miniprep Kit (QIAGEN). The base sequence ofprotein expression site in the plasmid nce ID No.6) accorded to '15 the base sequence ofhuman serotonin 5-HT23 receptor 0867) registered on the public database (NCBI) completely. Therefore, the proteins induced from this vector were identified with human serotonin 5-HT23 receptor. The pcDNA3.1/V5—I-Iis-Topo(registered mark) that the base sequence depicted as ce ID No.6 was inserted, was identified as human serotonin 5~HTZB receptor expression plasmid. 2) Preparation ofhuman serotonin 5-HT213 receptor expression cells (1) Cell culture HEK 293 cells were cultured in 5 % C02 incubator at 37°C in D-MEM liquid medium (low glucose, pyruvic acid and L-glutainine were contained) in which penicillin-streptomycin solution (final concentration: 100 U/mL as penicillin, 100 ug/mL as streptomycin) as antibiotics and fetal bovine serum (final concentration: 10%) were contained. [05 7 1 ] (2) The passage of a cell Mostly confluent HEK293 cells were washed with PBS, followed by exfoliation with 0.05% trypsin—EDTA and above-mentioned liquid medium was added.
After centrifilging, the supernatant was removed and the cells were diluted with medium.
After counting cell number of the diluted cells, the cells were scattered at appropriate cell tration. [05 72] (3) Preparation of cells Mostly confluent HEK293 cells were washed with PBS, ed by exfoliation with 0.05% trypsin—EDTA and the cells were suspended in D-MEM liquid medium (phenol red—free, low glucose, pyruvic acid were contained) containing fetal bovine serum (final concentration: 10%) and GlutaMax (registered mark)I (final concentration: 2 mM). The suspension was scattered at 5><104 cells/100 uL/well on poly—D-lysine-coated 96-well late (BD t (registered mark)). The scattered cells were cultured in 5% C02 incubator at 37°C. Human nin 5-HTZB receptor expression plasmid was transfected in that cells according to the procedure seeing below. id="p-573" id="p-573"
[0573] (4) Transfection ofhuman serotonin 5—HT23 or plasmid Human serotonin 5-HTZB receptor expression plasmid and Lipofectamine (registered mark) 2000 (lnvitrogen) were diluted to 0.008 g/L and 0.016 g/L each other with OPTI-MEM (registered mark)l Reduced—Serum Medium and incubated at room temperature. After tion, the human serotonin 5-HTZB receptor exoression plasmid-diluted liquid and Lipofectamine (registered mark) 2000-diluted liquid were mixed at an equal volume and ted at room temperature to form a complex. The x was dispensed at 50 uL/well on the cells prepared above. The cells were incubated in 5% CO2 incubator at 37°C for 2 days. After incubation, the cells were used as human serotonin 5-HT2B receptor forced expression cells for measurement of intracellular calcium concentration. 3) Determination of stimulating activities of human serotonin 5-HT2B receptor The stimulating activities of human serotonin 5-HT2B receptor was determined by measuring of intracellular calcium concentration. The 30 mM dimethyl sulfoxide (DMSO) solution ned test compounds or serotonin hydrochloride (Sigma) as positive control, was diluted with assay buffer ), 20 mM HEPES, 1.3 mM calcium chloride, 0.5 mM magnesium chloride and 0.4 mM magnesium sulfate were contained, pH7.4) to appropriate concentration.
The forced expression cells were washed with assay , and 100 uL/well of fluorescent calcium indicator (Flu0-4 NW Calcium Assay Kit) was added and ted in 5% CO2 incubator at 37°C. After incubation, 50 l of each test nd was added, and the concentration of intracellular calcium was measured as fluorescent signal with FlexStation (registered mark) II (Molecular Devices). The data was analyzed by nonlinear regression and sigmoidal dose-response curve fitting using GraphPad PRISM 4.0, and values of EC50 (concentration of the compound producing half the maximal effect of the compound) were ated. The data was presented as mean value (11 = 2).
As comparative examples, ropinirole as non-ergot dopamine D2 receptor agonist and pergolide as ergot dopamine D2 receptor agonist, were examined in a similar fashion.
These results were shown in Table 13.
[Table 13] These results clearly showed that the compounds of the present ion exhibited extremely minor stimulating activities of human serotonin 5-HTZB receptor as compared with ropinirole and pergolide. [05 77] Test Example 3 The drug efficiency evaluation in eral 6-hydroxydopamine—lesioned hemi-parkisonian rats 1) Materials The following materials were used: 6-hydroxydopamine hydrochloride (6-OHDA, Sigma); desipramine hydrochloride (desipramine, Sigma); L-ascorbic acid (Sigma); pentobarbital sodium (somnopentyl injection, Kyoritsu Seiyaku); R—(—)-apomorphine hydrochloride hemihydrate (apomorphine, Sigma); ropinirole hydrochloride (ropinirole; Sequoia); 0.5% methyl cellulose solution (Wako Pure Chemicals); N,N—Dimethylacetamide (DMA, Wako Pure Chemicals); hloric acid (Wako Pure Chemicals); distilled water-(Otsuka Pharmaceutical Factory,Inc.); physiological saline (Otsuka Pharmaceutical Factory,lnc.). 6-OHDA was dissolved at 2 mg/mL in a physiolosical saline solution ning 0.2% L-ascorbic acid. Desipramine was dissolved at 10 mg/mL in a physiolosical saline solution in a hot-water bath. Apomorphine was dissolved at 0.1 mg/mL in a physiolosical saline solution. Ropinirole was ved in distilled water.
Test compounds were dissolved in a solution containing 2% DMA, 100 or 200 mol% hydrochloric acid, and 98% of a 0.5% methyl cellulose solution. , [0578] 2) Preparation of 6-OHDA—lesioned model ation of 6-OHDA-lesioned model was performed according to the method described by Koga K. et al. (Eur J Pharmacol, 2000, 8, P.249-255) with a minor modification. Male Sprague—Dawley rats (6»weeks-old, s River Laboratories Japan Inc.) were anaesthetized with eritoneal somnopentyl (45 mg/kg) ion and placed in a stereotaxic frame (Narishige). In order to prevent 6-OHDA-induced damage of noradrenergic neurons, desipramine (25 mg/kg) was intraperitoneally injected 30 minutes before the 6-OHDA injection. After the bregma identification via a middle calvarial incision, the skull was d using a dental drill at the site of 6-OHDA injection. The lesion was made by injecting 6—OHDA (8 ug in 4 uL at a speed of 1 uL/minute) unilaterally into the left medial forebrain bundle by using a ion cannula (30 gauge needle) connected to a microsyringe (Hamilton) (the lesion coordinates; A/P -2.5 mm, L/M —l.8 mm, and V/D ~8.0 mm, from the bregma point and surface ofthe skull). The cannula was carefully removed from the animal after keeping placed on the lesion site for 5 minutes. The skull was filled its hole with dental , disinfected, and the scalp on was surgically sutured. Animals recovered from anesthesia were housed as usual until the day ofthe experiment. 3) Determining of lateral rotational behavior Three weeks after the lesion, rats were tested on the basis of their contralateral rotational behavior (single rotation was defined as a 360° turn) in response to 0.1 mg/kg rphine given subcutaneously. For behavioral observation, rats were placed in plastic cylinders of a er of 30 cm, and its contralateral rotational behaviors were videotaped and quantified by rat-rotation auto counting system R-RACS (Kissei Wellcom). On the experimental day, animals were fasted overnight, and test compounds were orally administrated at doses of 10 mg/kg. The drug potency was measured until up to 24 hours after administration as the number of contralateral rotation. Duration of the response was defined as a total time period except for a time period that the animal exhibited less than 10 counts of rotation per 5 minutes for more than 60 minutes period.
Total number of rotations and the duration ofthe response in mental period were presented as mean value. As comparative example, role as non-ergot dopamine D2 receptor agonist, was examined in a similar fashion. These results were shown in Table [058.0] [Table 14] rotatlons 1 — 1 1101. 3 9431. 8 1 —-3 845.0 4478.3 1 — 4 1131. 3 6338. 8 1 — 2 4 766. 3 5230.0 1 — 4 3 843. 8 7557. 5 1 —4 6 1158.8 10329.8 1 —95 7 1190 0 9976 5 1 — 1 0 7 1068. 3 4033. 3 1 — 1 0 8 698.8 2577. 5 As a result of these experiments, it was recognaized that the compounds of the present invention have remarkable asting drug effects as compared with ropinirole.
INDUSTRIALAPPLICABILITY Compounds of the present invention exhibt excellent dopamine D2 receptor stimulating activitities, and are accordingly useful for treating or ting Parkinson’s disease, restless legs me or hyperprolactinemia.
SEQUENCE LISTING FREE TEXT [SEQ ID No.1] Sequence ID No.1 indicates the sequence of forward primer employed to amplify the DNA sequence shown in sequence ID No. 3.
[SEQ ID No.2] Sequence ID No.2 indicates the sequence of reverse primer employed to amplify the DNA sequence shown in sequence ID No. 3.
[SEQ ID No.3] Sequence ID No.3 indicates the DNA sequence, which was intended to s the recombinant human ne D2 receptor, amplified by using primer pair shown in sequence ID No.1 and 2.
[SEQ ID No.4] ce ID No.4 indicates the sequence of forward primer employed to amplify the DNA sequence shown in sequence ID No. 6.
[SEQ ID No.5] Sequence ID No.5 indicates the sequence of reverse primer employed to amplify the DNA sequence shown in sequence ID No. 6.
[SEQ ID No.6] Sequence ID No.6 tes the DNA ce, which was intended to express the recombinant human serotonin 5-HT23 receptor, amplified by using primer pair shown in sequence ID No.4 and 5.

Claims (18)

1. A compound represented by the general formula (I): 5 or a pharmaceutically able salt thereof, wherein R1 is any one of the following a) to d): a) a cyano group, b) a carbamoyl group, 10 c) a C2-7 alkoxycarbonyl group, or d) a carboxy group; R2 and R3 are each independently a hydrogen atom, a C1-6 alkyl group, a C1-7 acyl group, or a C2-7 alkoxycarbonyl group; R4 is a hydrogen atom, a C1-6 alkyl group, or a halo-C1-6 alkyl group; 15 R５is any one of the following a) to j): a) a C1-6 alkyl group, b) a halo-C1-6 alkyl group, c) a cycloalkyl group, d) a benzo-fuzed cycloalkyl group, 20 e) a cycloalkyl-C1-6 alkyl group, f) an aralkyl group, wherein the ring of the l group is unsubstituted or substituted with 1 to 5 substituents independently ed from the group consisting of a halogen atom, a C1-6 alkyl group, a halo-C1-6 alkyl group, a C1-6 alkoxy group, and a hydroxy-C1-6 alkyl group, g) a heteroaryl-C1-6 alkyl group, wherein the ring of the heteroaryl-C1-6 alkyl group is 5 unsubstituted or substituted with 1 to 3 substituents ndently selected from the group consisting of a C1-6 alkyl group, a halo-C1-6 alkyl group, and a C1-6 alkoxy group, h) a C2-6 alkenyl group, i) a C1-6 alkoxy-C1-6 alkyl group, or j) a R10 R11 N-C1-6 alkyl group; 10 R6 and R7 are each independently any one of the following a) to k): a) a hydrogen atom, b) a C1-6 alkyl group, c) a halo-C1-6 alkyl group, d) a heterocycloalkyl group, 15 e) a heterocycloalkyl-C1-6 alkyl group, f) an l group, wherein the ring of the aralkyl group is unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of a halogen atom, a C1-6 alkyl group, a 1-6 alkyl group, a C1-6 alkoxy group, and a R10 R11 N-C1-6 alkyl group, 20 g) a heteroaryl-C1-6 alkyl group, wherein the ring of the heteroaryl-C1-6 alkyl group is unsubstituted or substituted with 1 to 3 substituents ndently selected from the group consisting of a C1-6 alkyl group, a halo-C1-6 alkyl group, and a C1-6 alkoxy group, h) a C1-6 alkoxy-C1-6 alkyl group, 25 i) a R12 R13 N-C1-6 alkyl group, j) a R12 R13 N-C1-6 alkoxy-C1-6 alkyl group, or k) a R12 R13 N-C(O)-C1-6 alkyl group; R10 and R11 are each independently a hydrogen atom, a C1-6 alkyl group or a hydroxy-C1-6 alkyl group, or R10 and R11 , together with the nitrogen atom to which they are bonded, form a cyclic amino group unsubstituted or substituted with 1 or 2 C1-6 alkyl groups; and 5 R12 and R13 are each independently a hydrogen atom, a C1-6 alkyl group, a hydroxy-C1-6 alkyl group or an aryl group, or R12 and R13 , together with the nitrogen atom to which they are bonded, form a cyclic amino group unsubstituted or substituted with 1 or 2 C1-6 alkyl groups. 10
2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is a cyano group.
3. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 are a hydrogen atom.
4. The nd according to claim 3, or a pharmaceutically acceptable salt thereof, n R4 is a hydrogen atom or a C1-6 alkyl group.
5. The compound according to claim 4, or a pharmaceutically 20 able salt thereof, wherein R6 is a hydrogen atom; and R7 is any one of the following a) to i): a) a C1-6 alkyl group, b) a halo-C1-6 alkyl group, 25 c) a heterocycloalkyl-C1-6 alkyl group, d) an aralkyl group, wherein the ring of the aralkyl group is tituted or substituted with 1 to 5 substituents independently ed from the group consisting of a halogen atom, a C1-6 alkyl group, a halo-C1-6 alkyl group, a C1-6 alkoxy group, and a R10 R11 N-C1-6 alkyl group, e) a heteroaryl-C1-6 alkyl group, wherein the ring of the heteroaryl-C1-6 alkyl group is unsubstituted or substituted with 1 to 3 substituents independently selected from the 5 group consisting of a C1-6 alkyl group, a halo-C1-6 alkyl group, and a C1-6 alkoxy group, f) a C1-6 alkoxy-C1-6 alkyl group, g) a R12 R13 N-C1-6 alkyl group, h) a R12 R13 N-C1-6 alkoxy-C1-6 alkyl group, or 10 i) a R12 R13 N-C(O)-C1-6 alkyl group.
6. The compound according to claim 5, or a pharmaceutically able salt thereof, n R５is any one of the ing a) to h): 15 a) a C1-6 alkyl group, b) a halo-C1-6 alkyl group, c) a cycloalkyl-C1-6 alkyl group, d) an aralkyl group, wherein the ring of the aralkyl group is unsubstituted or substituted with 1 to 5 substituents ndently selected from the group consisting of 20 a halogen atom, a C1-6 alkyl group, a halo-C1-6 alkyl group, a C1-6 alkoxy group, and a hydroxy-C1-6 alkyl group, e) a heteroaryl-C1-6 alkyl group, wherein the ring of the heteroaryl-C1-6 alkyl group is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of a C1-6 alkyl group, a halo-C1-6 alkyl group, and 25 a C1-6 alkoxy group, f) a C2-6 alkenyl group, g) a C1-6 alkoxy-C1-6 alkyl group, or h) a R10 R11 N-C1-6 alkyl group.
7. The compound according to claim 6, or a pharmaceutically acceptable salt thereof, wherein 5 R6 is a hydrogen atom; and R7 is: any one of the following a) to f) a) a C1-6 alkyl group, b) a halo-C1-6 alkyl group, c) an aralkyl group, wherein the ring of the aralkyl group is unsubstituted or 10 substituted with 1 to 5 substituents independently selected from the group consisting of a halogen atom, a C1-6 alkyl group, a halo-C1-6 alkyl group, a C1-6 alkoxy group, and a R10 R11 N-C1-6 alkyl group, d) a heteroaryl-C1-6 alkyl group, wherein the ring of the heteroaryl-C1-6 alkyl group is unsubstituted or substituted with 1 to 3 substituents independently selected from the 15 group consisting of a C1-6 alkyl group, a halo-C1-6 alkyl group, and a C1-6 alkoxy group, e) a C1-6 -C1-6 alkyl group, or f) a R12 R13 N-C1-6 alkyl group. 20
8. The compound according to claim 7, or a pharmaceutically acceptable salt thereof, n R4 is a methyl group; R５is any one of the ing a) to f): a) a C1-6 alkyl group, 25 b) a cycloalkyl-C1-6 alkyl group, c) an aralkyl group, wherein the ring of the l group is unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of a halogen atom, a C1-6 alkyl group, a halo-C1-6 alkyl group, a C1-6 alkoxy group, and a hydroxy-C1-6 alkyl group, d) a heteroaryl-C1-6 alkyl group, wherein the ring of the aryl-C1-6 alkyl group is unsubstituted or substituted with 1 to 3 substituents independently selected from the 5 group consisting of a C1-6 alkyl group, a halo-C1-6 alkyl group, and a C1-6 alkoxy group, e) a C1-6 alkoxy-C1-6 alkyl group, or f) a R10 R11 N-C1-6 alkyl group; R6 is a en atom; and 10 R7 is any one of the following a) to d): a) a C1-6 alkyl group, b) an aralkyl group, wherein the ring of the aralkyl group is unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of a halogen atom, a C1-6 alkyl group, a halo-C1-6 alkyl group, a C1-6 alkoxy group, and a 15 R10 R11 N-C1-6 alkyl group, c) a heteroaryl-C1-6 alkyl group, wherein the ring of the heteroaryl-C1-6 alkyl group is unsubstituted or tuted with 1 to 3 substituents independently selected from the group consisting of a C1-6 alkyl group, a 1-6 alkyl group, and a C1-6 alkoxy group, or 20 d) a R12 R13 N-C1-6 alkyl group.
9. The compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein R５is any one of the following a) to d): 25 a) a C1-6 alkyl group, b) a cycloalkyl-C1-6 alkyl group, c) a C1-6 alkoxy-C1-6 alkyl group, or d) a R10R11N-C1-6 alkyl group; and R7 is any one of the following a) to b): a) a C1-6 alkyl group, or b) a R12R13N-C1-6 alkyl group.
10. The compound according to claim 1, or a pharmaceutically able salt thereof, wherein the compound is represented by the general formula (II): 10 in which the configuration at 4a, 6 and 8a positions is represented by a relative configuration.
11. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein 15 the nd is represented by the general formula (III): in which the uration at 4a, 6 and 8a positions is represented by an absolute configuration. 5
12. A compound selected from the group consisting of: 1-{[(4aR, 6R, 8aR)aminocyanomethyl-4H, 4aH, 5H, 6H, 7H, 8H, 8aH, eno[3,2-g]quinolinyl]carbonyl}[2-(dimethylamino)ethyl]propylurea; 1-{[(4aR, 6R, 8aR)aminocyanomethyl-4H, 4aH, 5H, 6H, 7H, 8H, 8aH, eno[3,2-g]quinolinyl]carbonyl}butyl[2-(diethylamino)ethyl]urea; 10 1-{[(4aR, 6R, 8aR)aminocyanomethyl-4H, 4aH, 5H, 6H, 7H, 8H, 8aH, 9H-thieno[3,2-g]quinolinyl]carbonyl}[3-(dimethylamino)-2,2-dimethylpropyl ]ethlylurea; 1-{[(4aR, 6R, 8aR)aminocyanomethyl-4H, 4aH, 5H, 6H, 7H, 8H, 8aH, 9H-thieno[3,2-g]quinolinyl]carbonyl}ethyl[2-(pyrrolidinyl)ethyl]urea; 15 1-{[(4aR*, 6R*, 8aR*)aminocyanomethyl-4H, 4aH, 5H, 6H, 7H, 8H, 8aH, 9H-thieno[3,2-g]quinolinyl]carbonyl}butyl[2-(dimethylamino)- ethyl]urea; 1-{[(4aR*, 6R*, 8aR*)aminocyanomethyl-4H, 4aH, 5H, 6H, 7H, 8H, 8aH, 9H-thieno[3,2-g]quinolinyl]carbonyl}[2-(dimethylamino)ethyl](2-phe- 20 nylethyl)urea; 1-{[(4aR*, 6R*, 8aR*)aminocyanomethyl-4H, 4aH, 5H, 6H, 7H, 8H, 8aH, eno[3,2-g]quinolinyl]carbonyl}[2-(dimethylamino)ethyl](3-methylbutyl )urea; 1-{[(4aR*, 6R*, 8aR*)aminocyanomethyl-4H, 4aH, 5H, 6H, 7H, 8H, 8aH, 9H-thieno[3,2-g]quinolinyl]carbonyl}butyl[2-(piperidinyl)ethyl]urea; 5 1-{[(4aR*, 6R*, 8aR*)aminocyanomethyl-4H, 4aH, 5H, 6H, 7H, 8H, 8aH, eno[3,2-g]quinolinyl]carbonyl}[2-(dimethylamino)ethyl](2,2-dimethylpropyl )urea; 1-{[(4aR, 6R, 8aR)aminocyanomethyl-4H, 4aH, 5H, 6H, 7H, 8H, 8aH, 9H-thieno[3,2-g]quinolinyl]carbonyl}[(2S)(dimethylamino)propanyl] 10 ethlylurea; 1-{[(4aR*, 6R*, 8aR*)aminocyanomethyl-4H, 4aH, 5H, 6H, 7H, 8H, 8aH, 9H-thieno[3,2-g]quinolinyl]carbonyl}[2-(dimethylamino)methylpropyl ]propylurea; 1-{[(4aR*, 6R*, 8aR*)aminocyanomethyl-4H, 4aH, 5H, 6H, 7H, 8H, 15 8aH, 9H-thieno[3,2-g]quinolinyl]carbonyl}[2-(dimethylamino)ethylbutyl ]ethylurea; 1-{[(4aR, 6R, 8aR)aminocyanomethyl-4H, 4aH, 5H, 6H, 7H, 8H, 8aH, 9H-thieno[3,2-g]quinolinyl]carbonyl}(cyclopropylmethyl)[3-(dimethylamino )-2,2-dimethylpropyl]urea; 20 1-{[(4aR, 6R, 8aR)aminocyanomethyl-4H, 4aH, 5H, 6H, 7H, 8H, 8aH, eno[3,2-g]quinolinyl]carbonyl}[2-(diethylamino)ethyl]ethylurea; 1-{[(4aR, 6R, 8aR)aminocyanomethyl-4H, 4aH, 5H, 6H, 7H, 8H, 8aH, 9H-thieno[3,2-g]quinolinyl]carbonyl}[1-(dimethylamino)methylpropanyl]- 1-ethylurea; 25 1-{[(4aR, 6R, 8aR)aminocyanomethyl-4H, 4aH, 5H, 6H, 7H, 8H, 8aH, 9H-thieno[3,2-g]quinolinyl]carbonyl}[2-(dimethylamino)ethylbutyl]ethylurea 1-{[(4aR, 6R, 8aR)aminocyanomethyl-4H, 4aH, 5H, 6H, 7H, 8H, 8aH, eno[3,2-g]quinolinyl]carbonyl}[2-(dimethylamino)ethyl]ethylurea; and aR, 6R, 8aR)aminocyanomethyl-4H, 4aH, 5H, 6H, 7H, 8H, 8aH, 9H-thieno[3,2-g]quinolinyl]carbonyl}-(cyclopropylmethyl)[2-(dimethylami- 5 no)ethyl]urea; or a pharmaceutically acceptable salt thereof.
13. A pharmaceutical composition which comprises a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof.
14. A pharmaceutical agent comprising (1) a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, and (2) at least one anti-Parkinson drug selected from L-dopa, ne D 2 receptor agonists, anticholinergic agents, adenosine A2A receptor antagonists, NMDA or antagonists, 15 monoamine oxidase B inhibitors, COMT tors, aromatic L-amino acid oxylase inhibitors, droxidopa, melevodopa, threodops, zonisamide and amantadine hydrochloride.
15. The compound according to claim 1, substantially as herein described with 20 reference to any one of the Examples thereof.
16. The compound according to claim 12, substantially as herein described with reference to any one of the Examples thereof. 25
17. The pharmaceutical composition according to claim 13, wherein the compound is substantially as herein described with reference to any one of the Examples thereof.
18. The pharmaceutical agent according to claim 14, wherein the nd is substantially as herein described with reference to any one of the Examples thereof.
NZ615293A 2011-03-14 2012-03-12 Novel octahydrothienoquinoline derivative, pharmaceutical composition comprising derivative, and use of these NZ615293B2 (en)

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JP2011-055154 2011-03-14
JP2011055154 2011-03-14
PCT/JP2012/056252 WO2012124649A1 (en) 2011-03-14 2012-03-12 Novel octahydrothienoquinoline derivative, pharmaceutical composition comprising derivative, and use of these

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