CN105085478B - Isoquinolin sulphone amide derivative and its pharmaceutical composition and pharmaceutical applications - Google Patents
Isoquinolin sulphone amide derivative and its pharmaceutical composition and pharmaceutical applications Download PDFInfo
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- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The invention discloses a kind of isoquinolin sulphone amide derivatives and its pharmaceutical composition as RHO kinase inhibitor, and are related to its pharmaceutical applications.In particular it relates to compound shown in formula (I) or (II) or its pharmaceutically acceptable salt.
Description
Technical field
The present invention relates to a kind of isoquinolin sulphone amide derivatives and its pharmaceutical composition as RHO kinase inhibitor, and relate to
And its pharmaceutical applications.In particular it relates to compound shown in formula (I) or (II) or its pharmaceutically acceptable salt.
Background technique
Fasudil is a kind of newtype drug with extensive pharmacological action, is RHO kinase inhibitor, by increasing flesh ball
The activity expansion blood vessel of protein light chain phosphatase, reduces the tension of endothelial cell, improves brain tissue microcirculation, do not generate and aggravate
Robber's blood of brain, at the same can antagonism inflammatory factor, protect neural anti-apoptotic, promote nerve regneration.This is the result shows that hydrochloric acid method relaxes ground
Recovery of that nervous function is promoted, mitigates clinical symptoms, and reducing disability rate has certain curative effect.Therefore for base due to by
The restriction of economic condition and to disease cognitive degree, extreme early thromboembolism treatment can not achieve, but to reduce the further of disease
Progress, rebuilding blood circulation in therapeutic time window seems most important, and Fasudic hydrochloride has to ischemic brain blood
The significant neuroprotection of pipe disease and therapeutic effect are worth reducing disability rate in the use of clinical especially base, improve life matter
Amount.
WO2004106325 discloses a kind of compound, belongs to the prodrug of Fasudil, general structure such as formula (B- I) institute
Show:
Although above compound, which exists in the prior art, can be used as RHO kinase inhibitor, they are in activity, dissolution
Property, pharmacokinetics, druggability etc. have much room for improvement.
Summary of the invention
The purpose of the present invention is to provide compound shown in formula (I) or (II) or its pharmaceutically acceptable salt,
It is characterized in that
R1、R2Separately it is selected from R3C (=O) O-, (R4O)2P (=O) O-；
R3Selected from C1-6Alkyl, (R5)(R6)N-、R7O-, phenyl, pyridyl group, thienyl, furyl；
R4、R5、R6、R7Separately selected from selected from H or C1-3Alkyl；
The C1-6Alkyl, C1-3Alkyl is optionally by R01It is replaced；
R01Selected from F, Cl, Br, I, OH, NH2, R01Number be 1,2 or 3.
In a scheme of the invention, above-mentioned R3Selected from propyl, butyl, dimethylamino；
Above-mentioned R in a scheme of the invention3Selected from isopropyl, tert-butyl, dimethylamino.
In a scheme of the invention, above-mentioned R1、R2Separately it is selected from
In a scheme of the invention, above-mentioned pharmaceutically acceptable salt is such as shown in (III) or (IV):
Wherein, X is selected from inorganic acid or organic acid.
In a scheme of the invention, above-mentioned X is selected from trifluoromethanesulfonic acid, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate
Root, phosphoric acid, one hydrogen radical of phosphoric acid, dihydrogen phosphate, sulfuric acid, bisulfate ion, hydroiodic acid, phosphorous acid etc., acetic acid, propionic acid, isobutyric acid,
Maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzene sulfonic acid,
P-methyl benzenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, amino acid or glucuronic acid.
Above compound or its pharmaceutically acceptable salt in a scheme of the invention, are selected from:
It is another object of the present invention to provide a kind of pharmaceutical composition, the above compound containing therapeutically effective amount
Or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.
It is another object of the present invention to provide above compound or its pharmaceutically acceptable salt or said medicine groups
The application in the drug of the various illnesss of correlation caused by object treats vessel retraction in preparation is closed, wherein the relevant various illnesss
Including cerebral angiospasm caused by cerebral embolism, cerebral ischemia, cerebral injury, vertebrobasilar insufficiency, subarachnoid hemorrhage, the heart
Colic pain, glaucoma, hypertension, fibrosis.
Term " pharmaceutically acceptable " adopted here is for those compounds, material, composition and/or agent
For type, they contact use within the scope of reliable medical judgment, suitable for the tissue with human and animal, without
Excessive toxicity, irritation, allergic reaction or other problems or complication match with reasonable interests/Hazard ratio.
Term " pharmaceutically acceptable salt " refers to the salt of the compounds of this invention, by present invention discover that have specific substitution
It is prepared by the compound of base and the acid of relative nontoxic or alkali.It, can when in the compound of the present invention containing relatively acid functional group
To pass through the side for using the alkali of sufficient amount to contact with the neutral form of this kind of compound in pure solution or suitable atent solvent
Formula obtains base addition salts.Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salt.
It, can be by pure solution or suitable atent solvent when in the compound of the present invention containing relatively alkaline functional group
Acid-addition salts are obtained with the mode that the acid of sufficient amount is contacted with the neutral form of this kind of compound.Pharmaceutically acceptable acid addition
The example of salt includes inorganic acid salt, and the inorganic acid includes such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate radical, phosphoric acid, phosphorus
A sour hydrogen radical, dihydrogen phosphate, sulfuric acid, bisulfate ion, hydroiodic acid, phosphorous acid etc.；And acylate, the organic acid include
As acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid,
Phthalic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, citric acid, the tartaric acid acid similar with methanesulfonic acid etc.；Further include amino acid (such as
Arginine etc.) salt, and such as glucuronic acid organic acid salt (referring to Berge et al., " Pharmaceutical
Salts",Journal of Pharmaceutical Science66:1-19(1977)).Certain specific chemical combination of the invention
Object contains alkalinity and acid functional group, so as to be converted into any alkali or acid-addition salts.
Preferably, it contacts salt with alkali or acid in a usual manner, then separates parent compound, thus again in raw compounds
Property form.The forms of the parent fo of compound and its various salt is the difference is that certain physical properties, such as in polarity
Different solubility in solvent.
" pharmaceutically acceptable salt " used herein belongs to the derivative of the compounds of this invention, wherein by with acid at
Salt modifies the parent compound at the mode of salt with alkali.The example of pharmaceutically acceptable salt includes but is not limited to: base
Such as the inorganic acid or acylate of amine, the alkali metal of acid group such as carboxylic acid or organic salt etc..Pharmaceutically acceptable salt packet
The quaternary ammonium salt of conventional avirulent salt or parent compound is included, such as nontoxic inorganic acid or organic acid are formed by salt.Often
The avirulent salt of rule includes but is not limited to the salt that those are derived from inorganic acid and organic acid, the inorganic acid or organic acid choosing
From Aspirin, 2- ethylenehydrinsulfonic acid, acetic acid, ascorbic acid, benzene sulfonic acid, benzoic acid, bicarbonate radical, carbonic acid, lemon
Lemon acid, edetic acid(EDTA), ethane disulfonic acid, ethane sulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic, hydrobromic acid, salt
Acid, hydriodate, hydroxyl, hydroxyl naphthalene, isethionic acid, lactic acid, lactose, dodecyl sodium sulfonate, maleic acid, malic acid, mandelic acid, first
Alkyl sulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, poly galacturonic, propionic acid, salicylic acid, stearic acid, Asia
Acetic acid, succinic acid, sulfamic acid, p-aminobenzene sulfonic acid, sulfuric acid, tannin, tartaric acid and p-methyl benzenesulfonic acid.
Pharmaceutically acceptable salt of the invention can pass through conventional chemical side by the parent compound containing acid group or base
Method synthesis.Under normal circumstances, the preparation method of such salt is: in the mixture of water or organic solvent or both, via trip
It reacts from acid or these compounds of alkali form with the alkali appropriate of stoichiometry or acid to prepare.It is generally preferable that ether, acetic acid
The non-aqueous medias such as ethyl ester, ethyl alcohol, isopropanol or acetonitrile.
In addition to the form of salt, there is also prodrug forms for compound provided by the present invention.Compounds described herein
Chemical change easily occurs in physiological conditions for prodrug to be converted to the compound of the present invention.In addition, pro-drug can be with
The compound of the present invention is switched to by chemistry or biochemical method in environment in vivo.
Certain compounds of the invention can exist with nonsolvated forms or solvation form, including hydrate shape
Formula.In general, solvation form is suitable with non-solvated form, it is intended to be included within the scope.Of the invention
Certain compounds can exist with polycrystalline or amorphous form.
Certain compounds of the invention can have asymmetric carbon atom (optical centre) or double bond.It is racemic modification, non-right
Isomers, geometric isomer and single isomers is reflected to be included within the scope of the present invention.
The diagrammatic representation of the compound of raceme, ambiscalemic and scalemic or enantiomer-pure herein is come
From Maehr, J.Chem.Ed.1985,62:114-120.1985,62:114-120.Unless otherwise indicated, with wedge key and void
Line key indicates the absolute configuration of a Stereocenter.When compound described herein contains in olefinic double bond or other geometry asymmetry
The heart, unless otherwise prescribed, they include E, Z geometric isomer.Similarly, all tautomeric forms are included in the present invention
Within the scope of.
The compound of the present invention may exist specific geometry or stereoisomer form.It is contemplated by the invention that all is this kind of
Compound, including cis and trans isomer, (-)-and (+)-to enantiomer, (R)-and (S)-enantiomer, diastereoisomer,
(D)-isomers, (L)-isomers and its racemic mixture and other mixtures, such as enantiomter or diastereomer richness
The mixture of collection, all these mixtures are within the scope of the present invention.May be present in the substituent groups such as alkyl it is other not
Symmetric carbon atom.All these isomers and their mixture, are included within the scope of the present invention.
Can by chiral synthesis or chiral reagent or other routine techniques prepare optically active (R)-and (S)-
Isomers and D and L isomers.If expecting a kind of enantiomer of certain compound of the invention, asymmetric syntheses can be passed through
Or prepared by the derivatization with chiral auxiliary, wherein gained non-enantiomer mixture is separated, and auxiliary group is split
It opens to provide pure required enantiomter.Alternatively, when containing basic functionality (such as amino) or acidic functionality (such as in molecule
Carboxyl) when, the salt of diastereoisomer is formed with optically active acid appropriate or alkali, then passes through known in the field point
One step crystallizing or chromatography carry out diastereoisomer fractionation, and then recycling obtains pure enantiomer.In addition, enantiomter and
The separation of diastereoisomer is usually to be completed by using chromatography, and the chromatography uses chiral stationary phase, and optionally
Ground combines (such as generating carbaminate by amine) with chemical derivatization.
The compound of the present invention can include the original of unnatural proportions on one or more atoms for constituting the compound
Daughter isotope.For example, radioisotope labeled compound can be used, such as tritium (3H), iodine-125 (125I) or C-14 (14C).This
The transformation of all isotopics of the compound of invention, no matter radioactivity whether, be included within the scope of the present invention.
Term " pharmaceutically acceptable carrier " is to refer to deliver effective quantity active material of the present invention, do not interfere active matter
The bioactivity of the matter and any preparation having no toxic side effect to host or patient or the representative carrier of mounting medium include
Water, oil, vegetables and minerals, cream base, lotion base, ointment bases etc..These matrix include suspending agent, tackifier, transdermal rush
Into agent etc..Their preparation is well known to the technical staff in cosmetic field or topical remedy field.Other letters about carrier
Breath can refer to Remington:The Science and Practice of Pharmacy, 21st Ed.,
Lippincott, Williams&Wilkins (2005), the content of the document are incorporated herein by reference.
Term " excipient " typically refers to carrier, diluent and/or medium required for preparing drug composition effective.
For drug or pharmacologically active agents, term " effective quantity " or " therapeutically effective amount " refer to nontoxic but can reach
To the drug of desired effect or enough dosages of medicament.For the peroral dosage form in the present invention, a kind of active material in composition
" effective quantity " refer to when being combined with active material another in the composition for the required dosage that achieves the desired results.Have
The determination of effect amount varies with each individual, and age and ordinary circumstance depending on receptor also depend on specific active material, close in case
Suitable effective quantity can be determined by those skilled in the art according to routine test.
Term " active constituent ", " therapeutic agent ", " active material " or " activating agent " refer to a kind of chemical entities, it can have
The therapeutic purpose disorder of effect ground, disease or illness.
Term " substituted " refers to that any one or more hydrogen atoms in specific atoms are substituted with a substituent, including weight
The variant of hydrogen and hydrogen, as long as the compound after the valence state of specific atoms is normal and substitution is stable.When substituent group is
When ketone group (i.e.=O), it is meant that two hydrogen atoms are substituted.Ketone substitution does not occur on aromatic radical.Term " is optionally substituted
" refer to and can be substituted, can not also be substituted, unless otherwise prescribed, the type and number of substituent group in chemistry can be with
It can be arbitrary on the basis of realization.
When any variable (such as R) occurs more than once in the composition of compound or structure, in every case
Under definition be all independent.Thus, for example, the group can be optionally if a group is replaced 0-2 R
At most replaced two R, and R in each case has independent option.In addition, the group of substituent group and/or its variant
Conjunction is only just allowed in the case where such group of credit union generates stable compound.
When the key of a substituent group can be cross connected to two atomic time on a ring, this substituent group can be with this
Arbitrary atom on a ring is mutually bonded.When not indicating it is connected to chemical knot by which atom in cited substituent group
Include in structure general formula but be not specifically mentioned compound when, this substituent group can be mutually bonded by its any atom.Substituent group
And/or the combination of its variant is only just allowed in the case where such group of credit union generates stable compound.
Alkyl and miscellaneous alkyl atomic group (including be commonly known as alkylidene, alkenyl, sub- miscellaneous alkyl, miscellaneous thiazolinyl, alkynyl,
Those of naphthenic base, Heterocyclylalkyl, cycloalkenyl and heterocycloalkenyl group) substituent group be commonly referred to as " alkyl substituent ", it
Can be one or more of selected from but not limited to following groups :-R ' ,-OR ' ,=O ,=NR ' ,=N-OR ' ,-NR ' R " ,-
SR ', halogen ,-SiR ' R " R " ', OC (O) R ' ,-C (O) R ' ,-CO2R’、-CONR’R”、-OC(O)NR’R”、-NR”C(O)R’、
NR’C(O)NR”R”’、-NR”C(O)2R ' ,-NR " " '-C (NR ' R " R ' ")=NR " ", NR " " C (NR ' R ")=NR ' " ,-S (O)
R’、-S(O)2R’、-S(O)2NR’R”、NR”SO2R’、-CN、–NO2、-N3、-CH(Ph)2With fluoro (C1-C4) alkyl, substituent group
Number is 0~(2m '+1), and wherein m ' is the sum of carbon atom in this kind of atomic group.R', R ", R " ', R ' ' ' ' and R ' ' ' ' ' it is respective
Independently preferred hydrogen, substituted or unsubstituted miscellaneous alkyl, substituted or unsubstituted aryl are (such as by 1~3 halogen
Substituted aryl), substituted or unsubstituted alkyl, alkoxy, thio alkoxy group or aralkyl.When chemical combination of the invention
When object includes more than one R group, for example, each R group is independently to be subject to selection, as when there are more than one
R', R ", R " ', R ' ' ' ' and these groups each of when R ' ' ' ' ' group.When R' and R " is attached to the same nitrogen-atoms, it
5-, 6- or 7- member ring can be formed in conjunction with the nitrogen-atoms.For example,-NR'R " be intended to include but are not limited to 1- pyrrolidinyl and
4- morpholinyl.According in the above-mentioned discussion about substituent group, it will be understood by those skilled in the art that term " alkyl " be intended to include
The group that carbon atom bonding is constituted together in non-hydrogen group, such as halogenated alkyl (such as-CF3、-CH2CF3) and acyl group (such as-C (O)
CH3、-C(O)CF3、-C(O)CH2OCH3Deng).
Similar to substituent group described in alkyl radicals, aryl and heteroaryl substituent are commonly referred to collectively as " aryl substituent ",
' ,-NR ' R " ,-SR ' ,-halogen ,-SiR ' R " R " ', OC (O) R ' ,-C (O) R ' ,-CO2R ' ,-CONR ' selected from such as-R ' ,-OR
R " ,-OC (O) NR ' R " ,-NR " C (O) R ', NR ' C (O) NR " R " ' ,-NR " C (O) 2R ' ,-NR " " '-C (NR ' R " R ' ")=NR " ",
NR " " C (NR ' R ")=NR ' " ,-S (O) R ' ,-S (O)2R’、-S(O)2NR’R”、NR”SO2R’、-CN、–NO2、-N3、-CH(Ph)2、
Fluorine (C1-C4) alkoxy and fluorine (C1-C4) alkyl etc., the quantity of substituent group be 0 to chemical valence open on aromatic rings sum
Between；Wherein R ', R ", R " ', R " " and R " " ' preferably independently be selected from hydrogen, substituted or unsubstituted alkyl, be substituted or not by
Substituted miscellaneous alkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.When chemical combination of the invention
When object includes more than one R group, for example, each R group is independently to be subject to selection, as when there are more than one
R ', R ", R " ', R " " and R " " ' group when each of these groups.
Two substituent groups on the adjacent atom of aryl or heteroaryl ring can be optionally-T-C (O)-by general formula
Replaced the substituent group of (CRR ') q-U-, wherein T and U is independently selected from-NR- ,-O-, CRR'- or singly-bound, q be 0 to 3 it is whole
Number.Alternatively, two substituent groups on the adjacent atom of aryl or heteroaryl ring can be optionally-A by general formula
(CH2) replaced the substituent group of r B-, wherein A and B is independent is selected from-CRR '-,-O- ,-NR- ,-S- ,-S (O)-, S (O)2-、-
S(O)2NR '-or singly-bound, r are 1~4 integers.Optionally, a singly-bound on the new ring being consequently formed could alternatively be double
Key.Alternatively, two substituent groups on the adjacent atom of aryl or heteroaryl ring can be optionally-A by general formula
(CH2) replaced the substituent group of r B-, wherein s and d is independently selected from 0~3 integer, and X is-O- ,-NR ' ,-S- ,-S
(O)-、-S(O)2Or-S (O)2NR'-.Substituent R, R ', R " and R " ' preferably separately are selected from hydrogen and are substituted or are not taken
(the C in generation1-C6) alkyl.
Unless otherwise prescribed, term " halogenated element " or " halogen " itself or a part as another substituent group indicate fluorine,
Chlorine, bromine or iodine atom.In addition, term " halogenated alkyl " is intended to include monohaloalkyl alkyl and multi-haloalkyl.For example, term " halogen
Generation (C1-C4) alkyl " be intended to include but are not limited to trifluoromethyl, 2,2,2- trifluoroethyls, 4- chlorobutyl and 3- bromopropyl etc.
Deng.
The example of halogenated alkyl includes but are not limited to: trifluoromethyl, trichloromethyl, pentafluoroethyl group and five chloroethyls.
" alkoxy " represents the abovementioned alkyl with given number carbon atom connected by oxygen bridge.C1-6Alkoxy includes C1、C2、C3、
C4、C5And C6Alkoxy.The example of alkoxy includes but is not limited to: methoxyl group, ethyoxyl, positive propoxy, isopropoxy, just
Butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- amoxy." naphthenic base " includes saturation ring group, such as cyclopropyl, ring
Butyl or cyclopenta.3-7 naphthenic base includes C3、C4、C5、C6And C7Naphthenic base." alkenyl " includes the hydrocarbon of straight chain or branched chain
Wherein there are one or more carbon-to-carbon double bonds, such as vinyl and acrylic on stabilization site any on the chain in chain.
Term " halogen " or " halogen " refer to fluorine, chlorine, bromine and iodine.
Unless otherwise prescribed, " miscellaneous " the expression hetero atom of term or hetero atom group (containing heteroatomic atomic group), including
Atom other than carbon (C) and hydrogen (H) and contain these heteroatomic atomic groups, for example including oxygen (O), nitrogen (N), sulphur (S), silicon
(Si), germanium (Ge), aluminium (Al), boron (B) ,-O- ,-S- ,=O ,=S ,-C (=O) O- ,-C (=O)-,-C (=S)-,-S (=
O) ,-S (=O)2, and optionally by substituted-C (=O) N (H)-,-N (H)-,-C (=NH)-,-S (=O)2N (H)-or-S
(=O) N (H)-.
Unless otherwise prescribed, " ring " indicates substituted or unsubstituted naphthenic base, Heterocyclylalkyl, cycloalkenyl, heterocycle alkene
Base, cycloalkynyl radical, heterocycle alkynyl, aryl or heteroaryl.So-called ring includes monocycle, connection ring, loop coil and ring or bridged ring.It is former on ring
The number of son is generally defined as first number of ring, for example, " 5~7 member ring " refers to around 5~7 atoms of arrangement.Unless otherwise rule
Fixed, which optionally includes 1~3 hetero atom.Therefore, " 5~7 member ring " includes such as phenylpyridine and piperidyl；Another party
Face, term " 5~7 membered heterocycloalkyl ring " includes pyridyl group and piperidyl, but does not include phenyl.Term " ring " further includes containing extremely
The ring system of a few ring, each of these " ring " independently conforms to above-mentioned definition.
Unless otherwise prescribed, term " heterocycle " or " heterocycle " mean the stable monocycle rolled into a ball containing hetero atom or hetero atom,
Bicyclic or tricyclic, they can be saturation, part it is unsaturated or unsaturated (aromatics), they include carbon atom and 1,
2,3 or 4 ring hetero atoms independently selected from N, O and S, wherein above-mentioned any heterocycle can be fused to formation pair on a phenyl ring
Ring.Nitrogen and sulfur heteroatom can optionally be oxidized (i.e. NO and S (O) p).Nitrogen-atoms can be it is substituted or unsubstituted (i.e. N or
NR, wherein R is H or other substituent groups of defined mistake herein).The heterocycle can be attached to any hetero atom or carbon atom
To form stable structure in side group.If generate compound be it is stable, carbon potential can occur for heterocycle as described herein
Or the substitution on nitrogen position.Miscellaneous ring nitrogen is optionally quaternized.One preferred embodiment is, when S in heterocycle and O atom
When sum is more than 1, these hetero atoms are not adjacent to each other.Another preferred embodiment is that the sum of S and O atom is no more than in heterocycle
1.As used herein, term " aromatic heterocyclic group " or " heteroaryl " mean stable 5,6,7 unit monocycles or it is bicyclic or 7,8,9 or
The aromatic rings of 10 membered bicyclic heterocycles, it includes carbon atom and 1,2,3 or 4 ring hetero atom independently selected from N, O and S.Nitrogen
Atom can be substituted or unsubstituted (i.e. N or NR, wherein R is H or other substituent groups of defined mistake herein).Nitrogen
(i.e. NO and S (O) p) can be optionally oxidized with sulfur heteroatom.It is worth noting that, the sum of S and O atom does not surpass on aromatic heterocycle
Cross 1.Bridged ring is also contained in the definition of heterocycle.When one or more atoms (i.e. C, O, N or S) connects two non-conterminous carbon originals
Bridged ring is formed when son or nitrogen-atoms.Preferred bridged ring includes but is not limited to: a carbon atom, two carbon atoms, a nitrogen-atoms,
Two nitrogen-atoms and a carbon-to-nitrogen base.It is worth noting that, monocycle is always converted into tricyclic by a bridge.In bridged ring, on ring
Substituent group can also appear on bridge.
The example of heterocyclic compound includes but is not limited to: acridinyl, azocine base, benzimidazolyl, benzofuranyl, benzene
And sulfydryl furyl, benzo mercaptophenyl, benzoxazolyl, benzoxazoles quinoline base, benzothiazolyl, benzotriazole base, benzo
Tetrazole radical, benzo isoxazolyl, benzisothia oxazolyl, benzimidazoline base, carbazyl, 4aH- carbazyl, carboline base, benzo two
Hydrogen pyranose, chromene, cinnoline base decahydroquinolyl, 2H, 6H-1,5,2- dithiazine base, dihydrofuran simultaneously [2,3-b] tetrahydrofuran
Base, furyl, furazanyl, imidazolidinyl, imidazolinyl, imidazole radicals, 1H- indazolyl, indoles alkenyl, indolinyl, middle nitrogen
Indenyl, indyl, 3H- indyl, isatino base, isobenzofuran-base, pyrans, isoindolyl, iso-dihydro-indole-group, different Yin
Diindyl base, indyl, isoquinolyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridines base, octahydro isoquinoline
Quinoline base, 1,2,3- oxadiazoles base, 1,2,4- oxadiazoles base, 1,2,5- oxadiazoles base, 1,3,4- oxadiazoles base, is disliked at oxadiazoles base
Oxazolidinyl, oxazolyl, isoxazolyl, hydroxyindole base, pyrimidine radicals, phenanthridinyl, phenanthroline, azophenlyene, phenthazine, benzo xanthine
Base, phenol oxazines base, phthalazinyl, piperazinyl, piperidyl, piperidone base, 4- piperidone base, piperonyl, pteridyl, purine radicals, pyrrole
Mutter base, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyrido oxazole, pyridine-imidazole, pyridothiazole,
Pyridyl group, pyrimidine radicals, pyrrolidinyl, pyrrolinyl, 2H- pyrrole radicals, pyrrole radicals, pyrazolyl, quinazolyl, quinolyl, 4H- quinoline
Piperazine base, quinoxalinyl, quininuclidinyl, tetrahydrofuran base, tetrahydro isoquinolyl, tetrahydric quinoline group, tetrazole radical, 6H-1,2,5- thiophenes
Diazine, 1,2,3- thiadiazolyl group, 1,2,4- thiadiazolyl group, 1,2,5- thiadiazolyl group, 1,3,4- thiadiazolyl group, thianthrene group, thiophene
Oxazolyl, isothiazolyl thienyl, thienyl, thieno oxazolyl, thiophene benzothiazolyl, Thienoimidazole base, thienyl, triazine
Base, 1,2,3- triazolyl, 1,2,4- triazolyl, 1,2,5- triazolyl, 1,3,4- triazolyl and xanthyl.It further include condensed ring and spiral shell
Cycle compound.
Unless otherwise prescribed, term " alkyl " or its subordinate concept (such as alkyl, alkenyl, alkynyl, phenyl etc.) sheet
Body indicates straight chain, branch or cricoid hydrocarbon atomic group or combinations thereof as a part of of another substituent group, can be
Fully saturated, unit or polynary unsaturated, can be it is monosubstituted, two replace or polysubstituted, may include divalent or more
Valence atomic group, carbon atom (such as C with specified quantity1-C10Indicate 1 to 10 carbon)." alkyl " includes but is not limited to aliphatic hydrocarbon
Base and aryl radical, the aliphatic group include chain and ring-type, are specifically including but not limited to alkyl, alkenyl, alkynyl, the virtue
Fragrant alkyl includes but is not limited to aryl radical of 6-12 member, such as benzene, naphthalene etc..In some embodiments, term " alkyl " indicates
Straight chain or branch atomic group or their combination can be fully saturated, unit or polynary unsaturated, may include
Divalent and polyad group.The example of saturated hydrocarbons atomic group includes but is not limited to methyl, ethyl, n-propyl, isopropyl, positive fourth
Base, tert-butyl, isobutyl group, sec-butyl, isobutyl group, cyclohexyl, (cyclohexyl) methyl, Cvclopropvlmethvl and n-pentyl, just oneself
The homologue or isomers of the atomic groups such as base, n-heptyl, n-octyl.Unsaturated alkyl has one or more double or triple bonds,
The example includes but is not limited to vinyl, 2- acrylic, cyclobutenyl, crotyl, 2- isopentene group, 2- (butadienyl), 2,4-
Pentadienyl, 3- (Isosorbide-5-Nitrae-pentadienyl), acetenyl, 1- and 3- propinyl, 3- butynyl and more advanced homologue and different
Structure body.
Unless otherwise prescribed, term " miscellaneous alkyl " or its subordinate concept (such as miscellaneous alkyl, miscellaneous thiazolinyl, miscellaneous alkynyl, heteroaryl
Base etc.) itself or combine the stable straight chain of expression, branch or cricoid hydrocarbon atomic group with another term or combinations thereof,
It is made of the carbon atom and at least one hetero atom of certain amount.In some embodiments, term " miscellaneous alkyl " itself or with
Another term joint indicates stable straight chain, branch hydrocarbon atomic group or combinations thereof object, there is the carbon atom and extremely of certain amount
Few hetero atom composition.In an exemplary embodiment, hetero atom is selected from B, O, N and S, wherein nitrogen and sulphur atom optionally by
Oxidation, nitrogen heteroatom are optionally quaternized.Hetero atom B, O, N and S can be located at miscellaneous alkyl any interior location (including this
Alkyl is attached to the position of molecule rest part).Example includes but is not limited to-CH2-CH2-O-CH3、-CH2-CH2-NH-CH3、-
CH2-CH2-N(CH3)-CH3、-CH2-S-CH2-CH3、-CH2-CH2、-S(O)-CH3、-CH2-CH2-S(O)2-CH3,-CH=CH-O-
CH3、-CH2- CH=N-OCH3With-CH=CH-N (CH3)-CH3.At most two hetero atoms can be continuously, such as-CH2-NH-
OCH3。
Term " alkoxy ", " alkylamino " and " alkylthio group " (or thio alkoxy) belongs to idiomatic expression, refers to and leads to respectively
It crosses an oxygen atom, amino or sulphur atom and is connected to those of rest part of molecule alkyl group.
Unless otherwise prescribed, term " cyclic hydrocarbon radical ", " heterocyclic hydrocarbyl " or its subordinate concept (such as aryl, heteroaryl, ring
Alkyl, Heterocyclylalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl radical, heterocycle alkynyl etc.) itself or combine with other terms distinguish table
Show " alkyl ", " miscellaneous alkyl " of cyclisation.In addition, for miscellaneous alkyl or heterocyclic hydrocarbyl (such as miscellaneous alkyl, Heterocyclylalkyl), miscellaneous original
Son can take up the position that the heterocycle is attached to molecule rest part.The example of naphthenic base includes but is not limited to cyclopenta, hexamethylene
Base, 1- cyclohexenyl group, 3- cyclohexenyl group, suberyl etc..The non-limiting example of heterocycle includes 1- (1,2,5,6- tetrahydropyridine
Base), 1- piperidyl, 2- piperidyl, 3- piperidyl, 4- morpholinyl, morpholinyl, tetrahydrofuran -2- base, tetrahydrofuran indoles -
3- base, thiophane -2- base, thiophane -3- base, 1- piperazinyl and 2- piperazinyl.
Unless otherwise prescribed, term " aryl " indicates the aromatics hydrocarbon substituent of how unsaturated, can be monosubstituted, two substitutions
Or it is polysubstituted, it can be monocycle or polycyclic (preferably 1 to 3 ring), they are fused together or are covalently attached.Term is " miscellaneous
Aryl " refers to containing one to four heteroatomic aryl (or ring).In an exemplary embodiment, hetero atom be selected from B, N, O and
S, wherein nitrogen and sulphur atom are optionally oxidized, and nitrogen-atoms is optionally quaternized.Heteroaryl can be connected to point by hetero atom
The rest part of son.The non-limiting embodiment of aryl or heteroaryl includes phenyl, 1- naphthalene, 2- naphthalene, 4- xenyl, 1- pyrrole
Cough up base, 2- pyrrole radicals, 3- pyrrole radicals, 3- pyrazolyl, 2- imidazole radicals, 4- imidazole radicals, pyrazinyl, 2- oxazolyl, 4- oxazolyl, 2-
Phenyl -4- oxazolyl, 5- oxazolyl, 3- isoxazolyl, 4- isoxazolyl, 5- isoxazolyl, 2- thiazolyl, 4- thiazolyl, 5-
Thiazolyl, 2- furyl, 3- furyl, 2- thienyl, 3- thienyl, 2- pyridyl group, 3- pyridyl group, 4- pyridyl group, 2- pyrimidine
Base, 4- pyrimidine radicals, 5- benzothiazolyl, purine radicals, 2- benzimidazolyl, 5- indyl, 1- isoquinolyl, 5- isoquinolyl,
2- quinoxalinyl, 5- quinoxalinyl, 3- quinolyl and 6- quinolyl.The substituent group of above-mentioned any one aryl and heteroaryl ring system
Selected from acceptable substituent group described below.
For simplicity, aryl when being used in combination with other terms (such as aryloxy group, arylthio, aralkyl) includes such as
The aryl and heteroaryl ring of upper definition.Therefore, term " aralkyl " is intended to include that aryl is attached to those of alkyl atomic group (example
Such as benzyl, phenethyl, pyridylmethyl), including wherein carbon atom (such as methylene) by such as oxygen atom replace that
A little alkyl, such as phenoxymethyl, 2- pyridine oxygen methyl 3- (1- naphthoxy) propyl etc..
Term " leaving group " refer to can by another functional group or atom by substitution reaction (such as it is affine replace it is anti-
Answer) replaced functional group or atom.For example, representative leaving group includes triflate；Chlorine, bromine, iodine；Sulphonic acid ester
Base, such as methanesulfonates, tosylate, brosylate, p-methyl benzenesulfonic acid ester；Acyloxy, such as acetoxyl group, trifluoro second
Acyloxy etc..
Term " protecting group " includes but is not limited to " amino protecting group ", " hydroxyl protection base " or " sulfhydryl protected base ".Term
" amino protecting group " refers to suitable for the blocking group for preventing side reaction on ammonia nitrogen position.Representative amino protecting group includes
But it is not limited to: formoxyl；Acyl group, such as alkanoyl (such as acetyl group, trichloroacetyl or trifluoroacetyl group)；Alkoxy carbonyl
Base, such as tert-butoxycarbonyl (Boc)；Arylmethoxycarbonyl groups, such as benzyloxycarbonyl group (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc)；Aryl
Methyl, such as benzyl (Bn), trityl (Tr), 1,1- bis--(4'- methoxyphenyl) methyl；Silicyl, such as trimethyl first silicon
Alkyl (TMS) and t-butyldimethylsilyl (TBS) etc..Term " hydroxyl protection base " refers to suitable for prevention hydroxyl
The protecting group of side reaction.Representative hydroxyl protection base includes but is not limited to: alkyl, such as methyl, ethyl and tert-butyl；Acyl group, example
Such as alkanoyl (such as acetyl group)；Aryl methyl, such as benzyl (Bn), to methoxy-benzyl (PMB), 9- fluorenyl methyl (Fm) and two
Phenyl methyl (benzhydryl, DPM)；Silicyl, such as trimethyl silyl (TMS) and t-butyldimethylsilyl
(TBS) etc..
The compound of the present invention can be prepared by a variety of synthetic methods well-known to those skilled in the art, including under
The combination of specific embodiment that face is enumerated, itself and other chemical synthesis process is formed by embodiment and art technology
Equivalent replacement mode known to upper personnel, preferred embodiment include but is not limited to the embodiment of the present invention.
All solvents used in the present invention are commercially available, and can be used without being further purified.Reaction is usually lazy
Under property nitrogen, carried out in anhydrous solvent.Proton magnetic resonance (PMR) data are recorded in Bruker Avance III400 (400MHz)
On spectroscope, chemical shift is indicated with (ppm) at tetramethylsilane low field.Mass spectrum is in 1200 series of Agilent plus 6110 (&
It is measured on 1956A).LC/MS or Shimadzu MS includes a DAD:SPD-M20A (LC) and Shimadzu
Micromass2020 detector.Mass spectrograph is equipped with the electric spray ion source (ESI) operated under a positive or negative mode.
The present invention uses following initialisms: aq represents water；HATU represents O-7- azepine benzo triazol-1-yl)-N, N, N',
N'- tetramethylurea hexafluorophosphate；EDC represents N- (3- dimethylaminopropyl)-N'- ethyl-carbodiimide hydrochloride；m-
CPBA represents 3- chloroperoxybenzoic acid；Eq represents equivalent, equivalent；CDI represents carbonyl dimidazoles；DCM represents methylene chloride；PE generation
Table petroleum ether；DIAD represents diisopropyl azo-2-carboxylic acid；DMF represents n,N-Dimethylformamide；DMSO represents dimethyl sulfoxide；
EtOAc represents ethyl acetate；EtOH represents ethyl alcohol；MeOH represents methanol；CBz represents benzyloxycarbonyl group, is a kind of amine protecting group group；
It is a kind of amine protecting group group that BOC, which represents tert-butyl carbonyl,；HOAc represents acetic acid；NaCNBH3Represent sodium cyanoborohydride；R.t. generation
Table room temperature；O/N is represented overnight；THF represents tetrahydrofuran；Boc2O represents two carbonic ester of di-t-butyl；TFA represents trifluoro second
Acid；DIPEA represents diisopropyl ethyl amine；SOCl2Represent thionyl chloride；CS2Represent carbon disulfide；TsOH is represented to toluene sulphur
Acid；NFSI represents N- fluoro- N- (benzenesulfonyl) benzsulfamide；NCS represents 1- chlorine pyrrolidine-2,5-dione；n-Bu4NF represents fluorine
Change tetrabutylammonium；IPrOH represents 2- propyl alcohol；Mp represents fusing point.
Compound manually orSoftware name, commercial compound use supplier's directory name.
With the Shimadzu equipped with Shimadzu SIL-20A autosampler and Japanese Shimadzu DAD:SPD-M20A detector
LC20AB system carries out efficient liquid phase chromatographic analysis, using Xtimate C18 (3 μm of fillers, specification 2.1x300mm) chromatography
Column.0-60AB_6 minutes methods: applying linear gradient, starts to elute with 100%A (aqueous solution that A is 0.0675%TFA),
And elution is terminated with 60%B (the MeCN solution that B is 0.0625%TFA), whole process is 4.2 minutes, is then eluted with 60%B
1 minute.Reached 100:0 for chromatographic column rebalancing 0.8 minute, total run time is 6 minutes.10-80AB_6 minutes methods: it answers
With linear gradient, start to elute with 90%A (aqueous solution that A is 0.0675%TFA), and (B is 0.0625%TFA's with 80%B
Acetonitrile solution) terminate elution, whole process is 4.2 minutes, then with 80%B elution 1 minute.Chromatographic column rebalancing 0.8 is divided
Clock reaches 90:10, and total run time is 6 minutes.Column temperature is 50 DEG C, flow velocity 0.8mL/min.Diode array detector scanning
Wavelength is 200-400nm.
Thin-layer chromatographic analysis (TLC) is carried out on the silica GF254 of Sanpont-group, commonly uses ultraviolet lamp irradiation inspection
Spotting out also inspects spot using other methods in some cases, in these cases, (about 1g is added in 10g silica gel with iodine
Iodine is simultaneously thoroughly mixed), vanillic aldehyde (dissolution about 1g vanillic aldehyde in 100mL10%H2SO4In be made), ninhydrin (from
Aldrich is bought) or special color developing agent (be thoroughly mixed (NH4)6Mo7O24·4H2O、5g(NH4)2Ce(IV)(NO3)6、450mL
H2The dense H2SO of O and 50mL4And be made) expansion lamellae, inspect compound.Using Still, W.C.；Kahn,M.；and Mitra,
M.Journal of Organic Chemistry, the similar approach of technology disclosed in 1978,43,2923-2925.,
Flash column chromatography is carried out on 40-63 μm of (230-400 mesh) silica gel of Silicycle.Flash column chromatography or thin-layer chromatography it is common
Solvent is the mixture of methylene chloride/methanol, ethyl acetate/methanol and hexane/ethyl acetate.
Preparation chromatography point is carried out using the gloomy UV/VIS-156 detector of gill in Gilson-281Prep LC322 system
Analysis, used chromatographic column is Agella Venusil ASB Prep C18,5m, 150x21.2mm；Phenomenex
Gemini C18,5m,150x30mm；Boston Symmetrix C18,5m,150x30mm；Or Phenomenex
Synergi C18,4m,150x30mm.When flow velocity is about 25mL/min, with the acetonitrile/water eluting compounds of low gradient, wherein
Contain 0.05%HCl, 0.25%HCOOH or 0.5%NH in water3·H2O, total run time are 8-15 minutes.
With with Agilent1260 autosampler and Agilent DAD:1260 detector
Agilent1260Infinity SFC system carries out SFC analysis.Chromatographic column uses Chiralcel OD-H250x4.6mm
I.D., 5um Chiralpak AS-H250x4.6mm I.D., 5m Chiralpak AD-H250x4.6mm I.D.,
5m.The chromatographic condition of OD-H_5_40_2.35ML: (specification is 250x4.6mm I.D. to Chiralcel OD-H chromatographic column, and m is filled out
Material), mobile phase is 40% ethyl alcohol (0.05%DEA)-CO2；Flow velocity is 2.35mL/min；Detection wavelength is 220nm.AS-H_3_
40_2.35ML chromatographic condition: Chiralpak AS-H chromatographic column (specification is 250x4.6mm I.D., 5m filler)；Mobile phase is
40% methanol (0.05%DEA)-CO2；Flow velocity is 2.35mL/min, Detection wavelength 220nm.OD-H_3_40_2.35M chromatography
Condition: Chiralcel OD-H chromatographic column (specification is 250x4.6mm I.D, 5m filler), mobile phase is 40% methanol (0.05%
DEA)-CO2, flow velocity 2.35mL/min, Detection wavelength 220nm.AD-H_2_50_2.35ML chromatographic condition: Chiralpak
AD-H chromatographic column (specification is 250x4.6mm I.D, 5mm filler), mobile phase is 50% methanol (0.1%MEA)-CO2, flow velocity is
2.35mL/min, Detection wavelength 220nm.
Preparative SFC analysis, institute are carried out in the Waters Thar80Pre-SFC system using Gilson UV detector
The chromatographic column used is Chiralcel OD-H (specification is 250x4.6mm I.D, 5m filler) or Chiralpak AD-H (rule
Lattice are 250x4.6mm I.D, 5m filler).When flow velocity is about 40-80mL/min, with ethyl alcohol-carbon dioxide of low gradient or
Methanol-carbon dioxide eluting compounds, wherein methanol or ethyl alcohol contain 0.05%NH3·H2O, 0.05%DEA or 0.1%
MEA, total run time are 20-30 minutes.
Unless otherwise prescribed, compound manually orSoftware name, commercial compound use supplier
Directory name.
Compared with prior art, the compounds of this invention is efficient, less toxic, in activity, half-life period, solubility and pharmacokinetics
Etc. achieve significant or even unexpected progress, more suitable for pharmacy.
Specific embodiment
Below by embodiment, the present invention will be described in detail, but is not meant to any unfavorable limitation of the present invention.
The present invention is described in detail herein, wherein its specific embodiment mode is also disclosed, to those skilled in the art
Speech, carrying out various changes and modifications for the specific embodiment of the invention without departing from the spirit and scope of the present invention will
It is obvious.
Embodiment 1
(- 2 (1H)-yl of 5- ((1,4- Diazesuberane -1- base) sulfonyl) -1- oxo isoquinolin) methyl tert-butyl ester
The first step
Isoquinolin 1a (47.5mL, 405mmol) is slowly added into the 22mL concentrated sulfuric acid, fritter is sufficiently stirred into, then
It is added in the oleum of 200mL20%, is placed at room temperature for two days.It is subsequently poured into 700g ice water and stands overnight, obtain
Suspension filtering, filter cake is washed with water twice (100mL x2), dry, obtain isoquinoline-5-sulfonic acid 1b (50g, yield:
60%) it, is directly used in and reacts in next step
1H NMR(400MHz,D2O):δ9.66(s,1H),8.94-8.92(m,1H),8.62-8.60(m,2H),8.58-
8.56(m,1H),8.50-8.48(m,1H),7.99-7.95(m,1H).
MS-ESI calculated value [M+H]+210, measured value 210.
Second step
Isoquinoline-5-sulfonic acid 1b (4.0g, 0.019mol) is added in the thionyl chloride of 25mL at room temperature, is then added
The N,N-dimethylformamide of 0.1mL.After reaction is heated to reflux two hours, decompression evaporates extra thionyl chloride, evaporation residue
(10mL x2) is washed with cold methylene chloride.Be dried to obtain target product isoquinolin -5- sulfonic acid chloride 1c (3.9g, yellow solid,
Yield: 100%).
MS-ESI calculated value [M+H]+227 measured values 227.
Third step
Isoquinolin -5- sulfonic acid chloride 1c (3.00g, 11.3mmol) is dissolved in 20mL methylene chloride, under nitrogen protection 0
DEG C 1,4- Diazesuberane -1- carboxylic acid tert-butyl ester (2.60g, 13.0mmol) and N, N- diisopropyl ethyl amine is successively added
(7.5mL,35.0mmol).Gained reaction solution is stirred at room temperature 16 hours until reaction terminates.With methylene chloride (100mL) and water
(100mL) dilution, methylene chloride extract (100mL x2), merge organic phase and are dried, filtered with anhydrous sodium sulfate, filtrate decompression is dense
Contracting, purifies to obtain target compound 4- (isoquinolin -5- base sulfonyl)-Isosorbide-5-Nitrae-with silicagel column (0-100% ethyl acetate/petroleum ether)
Diazesuberane -1- carboxylic acid tert-butyl ester 1d (4.5g, colorless oil, yield: 100%).
MS-ESI calculated value [M+H]+392, measured value 392.
4th step
0 DEG C by 4- (isoquinolin -5- base sulfonyl) -1,4- Diazesuberane -1- carboxylic acid tert-butyl ester 1d (5.38g,
M-chloro peroxide benzene carboxylic acid (4.80g, 27.6mmol) is added portionwise in 200mL dichloromethane solution 13.8mmol), then rises to
It is stirred at room temperature 2 hours until reaction terminates.Chromatography silica gel column purification (0-100% ethyl acetate/petroleum is used after direct solvent evaporated
Ether) obtain 5- ((4- (tert-butoxycarbonyl) -1,4- Diazesuberane -1- base) sulfonyl) isoquinolin -2- oxide 1e
(4.9g, yellow oily liquid, yield: 86%).
1H NMR(400MHz,DMSO-d6):δ9.11(s,1H),8.40-8.35(m,1H),8.35-8.30(m,1H),
8.20-8.15(m,1H),7.80-7.75(m,2H),3.52-3.42(m,8H),1.85-1.65(m,2H),1.37(s,9H).
MS-ESI calculated value [M+H]+408, measured value 408.
5th step
By 5- ((4- (tert-butoxycarbonyl) -1,4- Diazesuberane -1- base) sulfonyl) isoquinolin -2- oxide 1e
(5.70g, 14.0mmol) is dissolved in 50mL acetic anhydride stirs 2 hours until reaction terminates at 100 DEG C.Reaction solution is concentrated under reduced pressure
Residue is dissolved in the tetrahydrofuran of 50mL after removing solvent, is added after the sodium hydrate aqueous solution of 100mL30% in room
Temperature stirring 0.5 hour.The pH to 7 for adjusting reaction solution after tetrahydrofuran with dilute hydrochloric acid is removed under reduced pressure, obtained suspension is filtered,
Filter cake is washed with water (10mL x2), dry, obtains 4- ((1- oxo -1,2- dihydro-isoquinoline -5- base) sulfonyl)-Isosorbide-5-Nitrae-two
Azepan -1- carboxylic acid tert-butyl ester 1f (3g, pale red solid, yield: 75%).
1H NMR(400MHz,CDCl3):δ11.57(s,1H),8.50-8.45(m,1H),8.20-8.15(m,1H),8.08
(s,1H),7.85-7.80(m,1H),7.65-7.60(m,1H),3.50-3.30(m,8H),2.05-1.95(m,2H),1.44
(s,9H).
MS-ESI calculated value [M+H]+408, measured value 408.
6th step
Under nitrogen protection by 4- ((1- oxo -1,2- dihydro-isoquinoline -5- base) sulfonyl) -1,4- diaza cycloheptyl
Alkane -1- carboxylic acid tert-butyl ester 1f (5.50g, 13.5mmol) is dissolved in 110mL hexamethylphosphoramide, under the conditions of 0 DEG C slowly
Sodium hydride (0.595g, 14.9mmol) is added and reacts at the same temperature 15 minutes, it is different that chloromethyl then is added dropwise to reaction solution
Butyrate (2.24g, 14.9mmol) is warmed to room temperature after adding and reacts 1 hour.To which reaction solution is slowly added dropwise after reaction
It in ice water (200mL), is extracted with ethyl acetate (100mL × 3), organic phase is dried, filtered with anhydrous sodium sulfate, is concentrated, residual
Excess obtains 4- ((2- ((isobutyl acyloxy) methyl) -1- by chromatography silica gel column purification (0-100% ethyl acetate/petroleum ether)
Oxo -1,2- dihydro-isoquinoline -5- base) sulfonyl) (5.8g, white are solid for-Isosorbide-5-Nitrae-Diazesuberane -1- carboxylic acid tert-butyl ester 1g
Body, yield: 85%).
MS-ESI calculated value [M+H]+508, measured value 508.
7th step
By 4- ((2- ((isobutyl acyloxy) methyl) -1- oxo -1,2- dihydro-isoquinoline -5- base) sulfonyl) -1,4- two
Azepan -1- carboxylic acid tert-butyl ester 1g (5.80g, 11.4mmol) is dissolved in the methylene chloride of 690mL, in 0 DEG C and nitrogen
It is slowly added dropwise under protection trifyl trimethyl silane (5.06g, 22.8mmol), controls temperature within the scope of 0-5 DEG C.Instead
2,6- lutidines (3.66g, 34.2mmol) is added dropwise thereto after answering liquid to react 45 minutes, the reaction was continued at 0-5 DEG C 1 hour
Until reaction terminates.Reaction solution is slowly added into ice water (200mL), is extracted with methylene chloride (100mL × 3), organic phase
It is dried, filtered with anhydrous sodium sulfate, the residue with Ethyl acetate being concentrated to get is recrystallized to give (5- ((Isosorbide-5-Nitrae-diaza cycloheptyl
Alkane -1- base) sulfonyl) -2 (1H)-yl of -1- oxo isoquinolin) methyl tert-butyl ester 1 (2.5g, faint yellow solid, yield: 54%).
1H NMR(400MHz,D2O): δ 8.41 (d, J=8.4Hz, 1H), 8.13 (d, J=8.0Hz, 1H), 7.58-7.54
(m, 2H), 7.14 (d, J=8.0Hz, 1H), 5.92 (s, 2H), 3.67-3.64 (m, 2H), 3.50-3.40 (m, 2H), 3.35-
3.30 (m, 4H), 2.65-2.55 (m, 1H), 2.15-2.00 (m, 2H), 1.07 (d, J=7.2Hz, 6H)
MS-ESI calculated value [M+H]+408, measured value 408.
Embodiment 2
((- 2 (1H)-yl of 5- ((1,4- Diazesuberane -1- base) sulfonyl) -1- oxo isoquinolin) methyl) phosphonic acids
The first step
4- (isoquinolin -5- base sulfonyl)-Isosorbide-5-Nitrae-Diazesuberane -1- carboxylic acid tert-butyl ester 1d (4.10g, 11.2mmol)
It is dissolved in the ethyl acetate of 30mL, the saturation hydrogen chloride solution of 20mL ethyl acetate is added dropwise in 0 DEG C, reaction solution is in room temperature reaction
0.5 hour.Obtained suspension filtering, filter cake washs (10mL x2) with ethyl acetate, is dried to obtain 5- ((Isosorbide-5-Nitrae-diaza
Cycloheptane -1- base) sulfonyl) isoquinolin 2a (2.6g, white solid, yield: 87%).
Second step
To 5- ((1,4- Diazesuberane -1- base) sulfonyl) isoquinolin 2a (4.00g, 11.1mmol) under nitrogen protection
80mL dichloromethane solution in be added N,N-dimethylformamide (5.90mL, 33.3mmol), then in 0 DEG C of dropwise addition chloro-carbonic acid
Benzyl ester (2.10g, 12.2mmol).After being warmed to room temperature after being added dropwise by reaction solution and reacting 2 hours, with 50mL water diluting reaction
Liquid, methylene chloride (30mL x2) extraction, organic phase are dried, filtered with anhydrous sodium sulfate, and silica gel chromatograph is used in filtrate decompression concentration
Method purifying (0~100% ethyl acetate/petroleum ether) obtains 4- (isoquinolin -5- base sulfonyl) -1,4- diaza -1- benzyl carboxylate
Ester 2b (6.4g, colourless oil liquid, yield: 100%).
1H NMR(400MHz,CDCl3):δ9.36(s,1H),8.75-8.65(m,1H),8.45-8.35(m,1H),8.32-
8.25(m,1H),8.23-8.15(m,1H),7.82-7.62(m,1H),7.40-7.20(m,5H),5.09(s,2H),3.75-
3.54(m,4H),3.50-3.32(m,4H),2.11-1.92(m,2H).
MS-ESI calculated value [M+H]+426, measured value 426.
Third step
4- (isoquinolin -5- base sulfonyl) -1,4- diaza -1- benzyl carboxylate 2b (7.4g, 17.4mmol) is according to implementation
The synthetic method of example 1 obtains 5- ((4- ((benzyloxy) carbonyl) -1,4- Diazesuberane -1- base) sulfonyl) isoquinolin -2-
Oxide 2c (5.0g, yellow oil, yield: 65%).
MS-ESI calculated value [M+H]+442, measured value 442.
4th step
By 5- ((4- ((benzyloxy) carbonyl) -1,4- Diazesuberane -1- base) sulfonyl) isoquinolin -2- oxide 2c
(5.00g, 11.3mmol) is dissolved in 70mL acetic anhydride, is heated to 130 DEG C and is reacted 4 hours.To be evaporated under reduced pressure after reaction
Extra acetic anhydride is removed, residue is dissolved in the tetrahydrofuran of 50mL, and the sodium hydroxide of 100mL30% is added.Reaction
Liquid is stirred at room temperature 0.5 hour, and then vacuum distillation removes tetrahydrofuran and by reaction solution tune pH to neutrality, obtained suspension mistake
Filter, filtration cakes torrefaction obtain 4- ((1- oxo -1,2- dihydro-isoquinoline -5- base) sulfonyl)-Isosorbide-5-Nitrae-diaza -1- benzyl carboxylate 2d
(4.5g, brown solid, yield: 90%).
MS-ESI calculated value [M+H]+442, measured value 442.
5th step
4- ((1- oxo -1,2- dihydro-isoquinoline -5- base) sulfonyl) -1,4- diaza -1- benzyl carboxylate 2d (1.00g,
2.27mmol) according to the synthetic method of embodiment 1 obtains 4- with chloromethyl phosphate dibenzyl ester (816mg, 2.5mmol) ((2- is ((double
(benzyloxy) phosphoryl) methyl) -1- oxo -1,2- dihydro-isoquinoline -5- base) sulfonyl) -1,4- diaza -1- benzyl carboxylate
2e (140mg, brown oil, yield: 8.5%).
1H NMR(400MHz,CDCl3): δ 8.41 (d, J=8.0Hz, 1H), 8.26 (d, J=8.0Hz, 1H), 8.20-
8.10(m,1H),8.05-8.00(m,1H),7.55-7.50(m,1H),7.40-7.15(m,15H),6.25-6.20(m2H),
5.15-5.10(m,2H),5.05(s,2H),5.04(s,2H),3.70-3.50(m,4H),3.45-3.30(m,4H),2.00-
1.90(m,2H).
MS-ESI calculated value [M+H]+716, measured value 716.
6th step
To 4- ((2- ((bis- (benzyloxy) phosphoryls) methyl) -1- oxo -1,2- dihydro-isoquinoline -5- base) sulfonyl) -
The 20mL tetrahydrofuran of 1,4- diaza -1- benzyl carboxylate 2e (100mg, 0.140mmol) and the in the mixed solvent of 2.5mL water add
Enter wet palladium carbon (70mg, 10%), is reacted at room temperature 4 hours in an atmosphere of hydrogen.Diatomite filters after reaction, dense
Contracting, obtains ((- 2 (1H)-yl of 5- ((Isosorbide-5-Nitrae-Diazesuberane -1- base) sulfonyl) -1- oxo isoquinolin) methyl) phosphonic acids 2
(63mg, white solid, yield: 100%).
1H NMR(400MHz,D2O): δ 8.60 (d, J=8.0Hz, 1H), 8.31-8.23 (m, 1H), 7.80-7.60 (m,
2H), 7.31 (d, J=7.6Hz, 1H), 5.64 (s, 2H), 3.60-3.30 (m, 6H), 3.10-3.00 (m, 2H), 1.95-1.70
(m,2H).
MS-ESI calculated value [M+H]+402, measured value 402.
Embodiment 3
The first step
4- ((1- oxo -1,2- dihydro-isoquinoline -5- base) sulfonyl) -1,4- Diazesuberane -1- carboxylic acid tert-butyl ester
1f (200mg, 0.49mmol) according to the synthetic method of embodiment 1 obtain 4- ((2- ((benzoyloxy) methyl) oxo-1-1-,
2- dihydro-isoquinoline -5- base) sulfonyl) (150mg, white solid produce-Isosorbide-5-Nitrae-Diazesuberane -1- carboxylic acid tert-butyl ester 3a
Rate: 56%).
1H NMR (400MHz, DMSO-6d): δ 8.54 (d, J=8.0Hz, 1H), 8.23 (d, J=8.0Hz, 1H), 7.93-
7.98 (m, 2H), 7.85 (d, J=8.0Hz, 1H), 7.51-7.55 (m, 2H), 7.20-7.15 (m, 1H), 6.18 (s, 2H),
4.05-4.02(m,1H),3.41-3.47(m,4H),3.37-3.41(m,2H),2.69-2.67(m,1H),2.00-1.98(m,
2H),1.78-1.75(m,2H),1.36(s,9H).
Second step
4- ((2- ((benzoyloxy) methyl) -1- oxo -1,2- dihydro-isoquinoline -5- base) sulfonyl) -1,4- phenodiazine
Trioxepane -1- carboxylic acid tert-butyl ester 3a (150mg, 0.28mmol) obtains (5- (1,4- phenodiazine according to the synthetic method of embodiment 1
Trioxepane -1- base) sulfonyl) -2 (1H)-yl of -1- oxo isoquinolin) benzene carboxylic acid methyl esters 3 (50mg, white solid, yield:
41%).
1H NMR(400MHz,D2O): δ 8.48 (d, J=8.0Hz, 1H), 8.11 (d, J=7.6Hz, 1H), 8.00-7.95
(m, 2H), 7.70 (d, J=8.0Hz, 1H), 7.60-7.55 (m, 2H), 7.43 (d, J=7.6Hz, 2H), 7.16 (d, J=
8.0Hz,1H),6.16(s,2H),3.59-3.56(m,2H),3.38-3.36(m,2H),3.29-3.23(m,4H),2.02-
2.00(m,2H).
Embodiment 4
- 2 (1H)-yl of 5- ((1,4- Diazesuberane -1- base) sulfonyl) -1- oxo isoquinolin) oxygroup) methyl new penta
Acid esters 4, ((5- ((1,4- Diazesuberane -1- base) sulfonyl) isoquinolyl-1) oxygroup) methyl pivalate 4 '
The first step
4- ((1- oxo -1,2- dihydro-isoquinoline -5- base) sulfonyl) -1,4- Diazesuberane -1- carboxylic acid tert-butyl ester
1f (0.50g, 1.23mmol) according to the synthetic method of embodiment 1 obtain 4- ((1- oxo -2- ((new pentane acyloxy) methyl) -1,
2- dihydro-isoquinoline -5- base) sulfonyl) -1,4- diaza -1- carboxylic acid tert-butyl ester 4a1 and 4- ((1- ((new pentane acyloxy) methoxy
Base) isoquinolin -5- base) sulfonyl) (0.34g, white are solid for-Isosorbide-5-Nitrae-Diazesuberane -1- carboxylic acid tert-butyl ester 4a2 mixture
Body, yield: 50%).
4a1:1H NMR(400MHz,CDCl3): δ 8.53 (d, J=8.4Hz, 1H), 8.42-8.30 (m, 1H), 8.18 (d, J
=6.4Hz, 1H), 8.04 (d, J=6.4Hz, 1H), 7.65-7.60 (m, 1H), 6.31 (s, 2H), 3.64-3.45 (m, 4H),
3.40-3.30(m,4H),2.05-1.90(m,2H),1.43(s,9H),1.21(s,9H).
MS-ESI calculated value [M+H]+522, measured value 522.
4a2:1H NMR(400MHz,CDCl3): δ 8.72 (d, J=8.0Hz, 1H), 8.25-8.20 (m, 1H), 7.60-
7.55 (m, 1H), 7.46 (d, J=8.0Hz, 1H), 7.30-7.27 (m, 1H), 5.98 (s, 2H), 3.64-3.45 (m, 4H),
3.40-3.30(m,4H),2.05-1.90(m,2H),1.47(s,9H),1.23(s,9H).
MS-ESI calculated value [M+H]+522, measured value 522.
Second step
4- ((1- oxo -2- ((new pentane acyloxy) methyl) -1,2- dihydro-isoquinoline -5- base) sulfonyl) -1,4- phenodiazine
Miscellaneous -1- carboxylic acid tert-butyl ester 4a1 and 4- ((1- ((new pentane acyloxy) methoxyl group) isoquinolin -5- base) sulfonyl) -1,4- diaza
Cycloheptane -1- carboxylic acid tert-butyl ester 4a2 (100mg, 0.19mmol) obtains 5- ((1,4- diaza according to the synthetic method of embodiment 1
Cycloheptane -1- base) sulfonyl) -2 (1H)-yl of -1- oxo isoquinolin) oxygroup) methyl pivalate 4 and ((5- ((1,4- phenodiazine
Trioxepane -1- base) sulfonyl) isoquinolyl-1) oxygroup) methyl pivalate 4 ' (50mg, faint yellow solid, yield:
53%).
4:1H NMR(400MHz,CDCl3): δ 8.65 (d, J=8.0Hz, 1H), 8.19 (d, J=7.6Hz, 1H), 7.53
(t, J=6.0Hz, 1H), 7.39 (d, J=8.0Hz, 1H), 7.26 (d, J=8.0Hz, 1H), 5.93 (s, 2H), 3.50-3.30
(m,4H),3.05-2.90(m,4H),1.90-1.75(m,2H),1.18(s,9H).
MS-ESI calculated value [M+H]+422, measured value 422.
4’:1H NMR(400MHz,CDCl3): δ 8.55 (d, J=8.0Hz, 1H), 8.31 (m, 1H), 8.19 (d, J=
6.4Hz, 1H), 8.00 (d, J=6.4Hz, 1H), 7.64 (t, J=8.0Hz, 1H), 6.31 (s, 2H), 3.70-3.60 (m, 2H),
3.58-3.50(m,2H),3.36-3.25(m,4H),2.20-2.10(m,2H),1.21(s,9H).
MS-ESI calculated value [M+H]+422, measured value 422.
Embodiment 5
(5- ((1,4- Diazesuberane -1- base) sulfonyl) -1- oxo isoquinolin -2 (1H) base) dimethylamino carboxylic acid
Methyl esters
The first step
Under nitrogen protection by 4- ((1- oxo -1,2- dihydro-isoquinoline -5- base) sulfonyl) -1,4- diaza cycloheptyl
Alkane -1- carboxylic acid tert-butyl ester 1f (200mg, 0.49mmol), dimethylamino carboxylic acid chloromethyl ester (149mg, 0.98mmol) and potassium carbonate
The 20mL tetrahydrofuran solution of (224mg, 1.47mmol) is heated to reflux 24 hours.To which reaction solution is cooled to room after reaction
Temperature removes solvent, obtains 4- ((2- (((dimethylamino formoxyl) oxygen with thin-layer chromatography (50% ethyl acetate/petroleum ether) is prepared
Base) methyl) -1- oxo -1,2- dihydro-isoquinoline -5- base) sulfonyl) -1,4- Diazesuberane -1- carboxylic acid tert-butyl ester 5a
(100mg, white solid, yield: 39%).
MS-ESI calculated value [M+H]+509, measured value 509.
Second step
At room temperature, by 4- ((2- (((dimethylamino formoxyl) oxygroup) methyl) -1- oxo -1,2- dihydro-isoquinoline -5-
Base) sulfonyl)-Isosorbide-5-Nitrae-Diazesuberane -1- carboxylic acid tert-butyl ester 5a (0.25g, 0.45mmol) is added to 4mL hydrogen chloride gas
Saturation Isosorbide-5-Nitrae-dioxane solution in, and persistently stirred 0.5 hour in room temperature.To which reaction solution is concentrated after reaction, use
Prepare thin layer chromatography board (ethyl acetate) isolated (5- ((1,4- Diazesuberane -1- base) sulfonyl) -1- oxo isoquinoline
Quinoline -2 (1H) base) dimethylamino carboxylate methyl ester 5 (150mg, faint yellow solid, yield: 74%).
1H NMR (400MHz, DMSO-d6): δ 8.92 (brs, 1H), 8.52-8.59 (m, 1H), 8.25 (d, J=7.6Hz,
1H), 7.69-7.75 (m, 1H), 7.18 (d, J=7.6Hz, 1H), 5.93 (s, 2H), 4.85-4.80 (m, 1H), 3.65-3.60
(m, 2H), 3.46 (t, J=5.73Hz, 2H), 3.21 (brs, 4H), 2.00 (brs, 2H), 1.38 (d, J=6.39Hz, 2H),
1.25-1.20(m,3H).
MS-ESI calculated value [M+H]+409, measured value 409.
Embodiment 6
(- 2 (1H)-yl of 5- ((1,4- Diazesuberane -1- base) sulfonyl) -1- oxo isoquinolin) methyl carbonic acid isopropyl
Ester
The first step
4- ((1- oxo -1,2- dihydro-isoquinoline -5- base) sulfonyl) -1,4- Diazesuberane -1- carboxylic acid tert-butyl ester
1f (150mg, 0.39mmol) and chloromethyl propylene carbonate (77mg, 0.51mmol) pass through according to the synthetic method of embodiment 1
Two-step reaction obtains (- 2 (1H)-yl of 5- ((1,4- Diazesuberane -1- base) sulfonyl) -1- oxo isoquinolin) methyl carbonic acid
Isopropyl ester 6 (53mg, white solid, yield: 32%).
1H NMR (400MHz, DMSO-d6): δ 8.92 (brs, 1H), 8.60-8.55 (m, 1H), 8.25 (d, J=7.6Hz,
1H), 7.73 (t, J=7.6Hz, 1H), 7.17 (d, J=7.6Hz, 1H), 5.93 (s, 2H), 4.84-4.78 (m, 1H), 3.62
(brs, 2H), 3.48-3.45 (m, 2H), 3.21 (brs, 4H), 2.00 (brs, 2H), 1.37 (d, J=6.4Hz, 2H), 1.23
(d, J=6.4Hz, 4H)
MS-ESI calculated value [M+H]+424, measured value 424.
Experimental example 1: rat kinetic test
Experiment purpose:
Detection compound generates the speed and active pharmaceutical ingredient exposed amount of active pharmaceutical ingredient in vivo.Experimental material:
Male SD rat, weight 200-250g are purchased from Shanghai Slac Experimental Animal Co., Ltd.
Experimental implementation:
Before experiment, animal carries out arteria carotis intubation (acquiring for plasma sample), and rat is postoperative at least to restore 3 days, observation
For testing after without exception.Oral administration dosage be 10mg/kg, 0,5min, 15min, 30min, 60min, 2h after administration,
4h, 6h, 8h acquire whole blood for 24 hours and prepare plasma sample.All samples are coupled mass spectrum mass spectrometric hyphenated technique pair with liquid chromatogram
To drug compound, content carries out quantitative detection in experimental animal blood plasma, and surveyed concentration value uses the non-compartment model of WinNonlin,
According to plasma concentration v. time data, T is calculated1/2,Cmax,Tmax,AUC(0-t)And AUC(0-∞)Etc. parameters, and draw plasma concentration-
Time graph
Experimental result:
1 rat power blood test result of table
Note: Cmax :+> 1000nM；Blood medicine time to peak :+< 20min；Unit exposed amount :+> 100nM.hr/ μ
mol。
Claims (9)
1. compound shown in formula (I) or its pharmaceutically acceptable salt,
It is characterized in that
R1Selected from R3C (=O) O-, (R4O)2P (=O) O-；R3Selected from C1‐6Alkyl, R7O‐；
R4、R7Separately selected from selected from H or C1‐3Alkyl；
The C1‐6Alkyl, C1‐3Alkyl is optionally by R01It is replaced；
R01Selected from F, Cl, Br, I, OH, NH2, R01Number be 1,2 or 3.
2. compound according to claim 1 or its pharmaceutically acceptable salt, characterized in that the R3Selected from propyl, fourth
Base；
3. compound according to claim 2 or its pharmaceutically acceptable salt, characterized in that the R3Selected from isopropyl,
Tert-butyl.
4. compound according to claim 1 or its pharmaceutically acceptable salt, characterized in that the R1It is selected from
5. compound according to claim 1 or its pharmaceutically acceptable salt, characterized in that described pharmaceutically acceptable
Salt such as shown in (III):
Wherein, X is selected from inorganic acid or organic acid.
6. compound according to claim 5 or its pharmaceutically acceptable salt, characterized in that the X is selected from trifluoro
Methanesulfonic acid, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate radical, phosphoric acid, one hydrogen radical of phosphoric acid, dihydrogen phosphate, sulfuric acid, hydrogen sulfate
Root, hydroiodic acid, phosphorous acid, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, anti-butylene two
Acid, lactic acid, mandelic acid, phthalic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, amino acid or glucose
Aldehydic acid.
7. compound according to claim 1 or its pharmaceutically acceptable salt, are selected from:
8. a kind of pharmaceutical composition, compound described in any one according to claim 1~7 containing therapeutically effective amount or
Its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.
9. compound or its pharmaceutically acceptable salt described in any one or according to claim 8 according to claim 1~7
Application in the drug of the various illnesss of correlation caused by the pharmaceutical composition treats vessel retraction in preparation, wherein the phase
The various illnesss closed include cerebral embolism, cerebral ischemia, cerebral injury, vertebrobasilar insufficiency, caused by subarachnoid hemorrhage
Cerebral angiospasm, angina pectoris, glaucoma, hypertension, fibrosis.
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| EP1074545A1 (en) * | 1998-04-23 | 2001-02-07 | Hiroyoshi Hidaka | Isoquinolinesulfonamide derivatives and drugs containing the same as the active ingredient |
| WO2003047591A1 (en) * | 2001-11-30 | 2003-06-12 | Asahi Kasei Pharma Corporation | Remedies for primary pulmonary hypertension |
| WO2004106325A1 (en) * | 2003-05-29 | 2004-12-09 | Schering Aktiengesellschaft | Prodrugs of 1-(1-hydroxy-5-isoquinolinesulfonyl)homopiperazine |
| JP2007223999A (en) * | 2006-02-27 | 2007-09-06 | D Western Therapeutics Institute Inc | New isoquinoline derivative and medicine containing the same |
| CN102448941A (en) * | 2009-06-19 | 2012-05-09 | 株式会社D.西医疗法研究所 | Substituted isoquinoline derivatives |
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| DE3583287D1 (en) * | 1984-12-27 | 1991-07-25 | Asahi Chemical Ind | SUBSTITUTED ISOCHINOLINSULFONYL COMPOUNDS. |
| EP0885888B1 (en) * | 1996-02-02 | 2003-08-13 | Dr.HIDAKA Hiroyoshi | Isoquinoline derivatives and drugs |
| DE10233737A1 (en) * | 2002-07-24 | 2004-02-05 | Morphochem Aktiengesellschaft für kombinatorische Chemie | Use of modulators of the signal transduction pathway via the protein kinase Fyn for the treatment of tumor diseases |
| JPWO2004024717A1 (en) * | 2002-09-12 | 2006-01-05 | 麒麟麦酒株式会社 | Isoquinoline derivative having kinase inhibitory activity and medicament containing the same |
| RU2440988C2 (en) * | 2005-07-26 | 2012-01-27 | Санофи-Авентис | CYCLOHEXYLAMINIZOQUINOLONE AS Rho-KINASE INHIBITORS |
| KR20090094338A (en) * | 2006-12-27 | 2009-09-04 | 사노피-아벤티스 | Substituted isoquinoline and isoquinolinone derivatives |
| CN102088853A (en) * | 2008-05-12 | 2011-06-08 | 安内斯蒂克斯公司 | Compounds for improving learning and memory |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| EP1074545A1 (en) * | 1998-04-23 | 2001-02-07 | Hiroyoshi Hidaka | Isoquinolinesulfonamide derivatives and drugs containing the same as the active ingredient |
| WO2003047591A1 (en) * | 2001-11-30 | 2003-06-12 | Asahi Kasei Pharma Corporation | Remedies for primary pulmonary hypertension |
| WO2004106325A1 (en) * | 2003-05-29 | 2004-12-09 | Schering Aktiengesellschaft | Prodrugs of 1-(1-hydroxy-5-isoquinolinesulfonyl)homopiperazine |
| JP2007223999A (en) * | 2006-02-27 | 2007-09-06 | D Western Therapeutics Institute Inc | New isoquinoline derivative and medicine containing the same |
| CN102448941A (en) * | 2009-06-19 | 2012-05-09 | 株式会社D.西医疗法研究所 | Substituted isoquinoline derivatives |
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