CN105085478A - Isoquinoline sulfanilamide derivatives, and pharmaceutical composition and pharmaceutical application thereof - Google Patents

Isoquinoline sulfanilamide derivatives, and pharmaceutical composition and pharmaceutical application thereof Download PDF

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Publication number
CN105085478A
CN105085478A CN201410175401.0A CN201410175401A CN105085478A CN 105085478 A CN105085478 A CN 105085478A CN 201410175401 A CN201410175401 A CN 201410175401A CN 105085478 A CN105085478 A CN 105085478A
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acid
acceptable salt
base
pharmacy acceptable
group
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CN105085478B (en
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吴凌云
姚元山
陈兆国
陈曙辉
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NANJING MINGDE NEW DRUG RESEARCH AND DEVELOPMENT Co Ltd
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NANJING MINGDE NEW DRUG RESEARCH AND DEVELOPMENT Co Ltd
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Priority to CN201410175401.0A priority Critical patent/CN105085478B/en
Priority to PCT/CN2015/077046 priority patent/WO2015165342A1/en
Priority to TW104113439A priority patent/TWI650315B/en
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    • 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
    • A61K31/55—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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

Abstract

The invention discloses a kind of isoquinoline sulfanilamide derivatives as an RHO kinases inhibitor and a pharmaceutical composition thereof, and also relates to pharmaceutical application of the derivatives. Concretely, the invention relates to compounds shown as a formula (I) or (II) or pharmaceutically acceptable salts.

Description

Isoquinoline 99.9 sulphone amide derivative and pharmaceutical composition thereof and pharmaceutical applications
Technical field
The present invention relates to a class as the isoquinoline 99.9 sulphone amide derivative of RHO kinase inhibitor and pharmaceutical composition thereof, and relate to its pharmaceutical applications.Particularly, the present invention relates to compound or its pharmacy acceptable salt shown in formula (I) or (II).
Background technology
Fasudil is a kind of newtype drug with extensive pharmacological action; for RHO kinase inhibitor; by increasing the active vasodilation of Myosin light chain phosphatase; reduce the tension force of endotheliocyte; improve cerebral tissue microcirculation, do not produce and increase the weight of robber's blood of brain, simultaneously can antagonism inflammatory factor; neuroprotective anti-apoptotic, promotes neurotization.This result shows that Fasudil Hydrochloride is to the recovery promoting neural function, alleviates clinical symptom, and reducing disability rate has certain curative effect.Therefore for basic unit due to by economic condition restriction and to disease cognitive degree; extreme early thromboembolism treatment can not realize; but for reducing the further progress of disease; in therapeutic time window, rebuild blood circulation seem most important; and Fasudil Hydrochloride has remarkable neuroprotective to ischemic cerebrovascular disease and therapeutic action; be worth the use in clinical especially basic unit, reduce disability rate, improve the quality of living.
WO2004106325 discloses a compounds, belongs to the prodrug of fasudil, and its general structure is such as formula shown in (B-I):
Although there is above-claimed cpd in prior art to can be used as RHO kinase inhibitor, they activity, solvability, pharmacokinetics, druggability etc. in have much room for improvement.
Summary of the invention
The object of the present invention is to provide compound or its pharmacy acceptable salt shown in formula (I) or (II),
It is characterized in that,
R 1, R 2separately be selected from R 3c (=O) O-, (R 4o) 2p (=O) O-;
R 3be selected from C 1-6alkyl, (R 5) (R 6) N-, R 7o-, phenyl, pyridyl, thienyl, furyl;
R 4, R 5, R 6, R 7separately be selected from H or C 1-3alkyl;
Described C 1-6alkyl, C 1-3alkyl is optionally by R 01replaced;
R 01be selected from F, Cl, Br, I, OH, NH 2, R 01number be 1,2 or 3.
In a scheme of the present invention, above-mentioned R 3be selected from propyl group, butyl, dimethylamino;
Above-mentioned R in a scheme of the present invention 3be selected from sec.-propyl, the tertiary butyl, dimethylamino.
In a scheme of the present invention, above-mentioned R 1, R 2separately be selected from
In a scheme of the present invention, above-mentioned pharmacy acceptable salt is as shown in (III) or (IV):
Wherein, X is selected from mineral acid or organic acid.
In a scheme of the present invention, above-mentioned X is selected from trifluoromethanesulfonic acid, hydrochloric acid, Hydrogen bromide, nitric acid, carbonic acid, bicarbonate radical, phosphoric acid, phosphoric acid one hydrogen root, dihydrogen phosphate, sulfuric acid, bisulfate ion, hydroiodic acid HI, phosphorous acid etc., acetic acid, propionic acid, isopropylformic acid, toxilic acid, propanedioic acid, phenylformic acid, succsinic acid, suberic acid, FUMARIC ACID TECH GRADE, lactic acid, amygdalic acid, phthalic acid, Phenylsulfonic acid, tosic acid, citric acid, tartrate, methylsulfonic acid, amino acid or glucuronic acid.
Above-claimed cpd or its pharmacy acceptable salt in a scheme of the present invention, it is selected from:
Another object of the present invention is to provide a kind of pharmaceutical composition, and it contains the above-claimed cpd or its pharmacy acceptable salt and pharmaceutically acceptable carrier for the treatment of significant quantity.
Another object of the present invention is to provide above-claimed cpd or its pharmacy acceptable salt or aforementioned pharmaceutical compositions to treat the application in the medicine of the relevant various illness that vasoconstriction causes in preparation, and wherein said relevant various illnesss comprise cerebral vasospasm, stenocardia, glaucoma, hypertension, fibrosis caused by cerebral embolism, cerebral ischemia, brain injury, vertebrobasilar insufficiency, subarachnoid hemorrhage.
Here adopted term " pharmaceutically acceptable ", for those compounds, material, composition and/or formulation, they are within the scope of reliable medical judgment, be applicable to use with the contact tissue of human and animal, and there is no too much toxicity, pungency, anaphylaxis or other problem or complication, match with rational interests/Hazard ratio.
Term " pharmacy acceptable salt " refers to the salt of the compounds of this invention, prepared by the have compound of specified substituent and the acid of relative nontoxic or alkali that are found by the present invention.When containing relatively acid functional group in compound of the present invention, can by obtaining base addition salt by the mode that the alkali of q.s contacts with the neutral form of this compounds in pure solution or suitable inert solvent.Pharmaceutically acceptable base addition salt comprises sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salt.When containing the functional group of alkalescence relatively in compound of the present invention, can by obtaining acid salt by the mode that the acid of q.s contacts with the neutral form of this compounds in pure solution or suitable inert solvent.The example of pharmaceutically acceptable acid salt comprises inorganic acid salt, and described mineral acid comprises such as hydrochloric acid, Hydrogen bromide, nitric acid, carbonic acid, bicarbonate radical, phosphoric acid, phosphoric acid one hydrogen root, dihydrogen phosphate, sulfuric acid, bisulfate ion, hydroiodic acid HI, phosphorous acid etc.; And organic acid salt, described organic acid comprises acid as similar in acetic acid, propionic acid, isopropylformic acid, toxilic acid, propanedioic acid, phenylformic acid, succsinic acid, suberic acid, FUMARIC ACID TECH GRADE, lactic acid, amygdalic acid, phthalic acid, Phenylsulfonic acid, tosic acid, citric acid, tartrate and methylsulfonic acid etc.; Also comprise the salt of amino acid (as arginine etc.), and if the organic acid salt such as glucuronic acid are (see Bergeetal., " PharmaceuticalSalts ", JournalofPharmaceuticalScience66:1-19 (1977)).Some specific compound of the present invention contains alkalescence and acid functional group, thus can be converted into arbitrary alkali or acid salt.
Preferably, make salt and alkali or acid contact in a usual manner, then be separated parent compound, thus the neutral form of raw compounds again.The difference of the form of the parent fo salt various with it of compound is some physical properties, such as, different solubility in polar solvent.
" pharmacy acceptable salt " used herein belongs to the derivative of the compounds of this invention, wherein, by modifying described parent compound with sour salify or with the mode of alkali salify.The example of pharmacy acceptable salt includes but not limited to: base ratio is as the basic metal or organic salt etc. of the mineral acid of amine or organic acid salt, acid group such as carboxylic acid.Pharmacy acceptable salt comprises conventional avirulent salt or the quaternary ammonium salt of parent compound, the salt that such as nontoxic mineral acid or organic acid are formed.Conventional avirulent salt includes but not limited to that those are derived from mineral acid and organic acid salt, described mineral acid or organic acid are selected from Aspirin, 2-ethylenehydrinsulfonic acid, acetic acid, xitix, Phenylsulfonic acid, phenylformic acid, bicarbonate radical, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethane sulfonic acid, fumaric acid, glucoheptose, glyconic acid, L-glutamic acid, oxyacetic acid, Hydrogen bromide, hydrochloric acid, hydriodate, hydroxyl, hydroxyl naphthalene, isethionic acid, lactic acid, lactose, dodecyl sodium sulfonate, toxilic acid, oxysuccinic acid, amygdalic acid, methanesulfonic, nitric acid, oxalic acid, pamoic acid, pantothenic acid, toluylic acid, phosphoric acid, poly galacturonic, propionic acid, Whitfield's ointment, stearic acid, sub-acetic acid, succsinic acid, thionamic acid, Sulphanilic Acid, sulfuric acid, tannin, tartrate and tosic acid.
Pharmacy acceptable salt of the present invention can be synthesized by conventional chemical processes by the parent compound containing acid group or base.Generally, the preparation method of such salt is: in water or organic solvent or both mixtures, and these compounds via free acid or alkali form are prepared with stoichiometric suitable alkali or acid-respons.Usually, the non-aqueous media such as preferred ether, ethyl acetate, ethanol, Virahol or acetonitrile.
Except the form of salt, also there is prodrug forms in compound provided by the present invention.Easily there is chemical transformation in physiological conditions thus change into compound of the present invention in the prodrug of compound described herein.In addition, prodrug can be switched to compound of the present invention by chemistry or biochemical method in environment in vivo.
Some compound of the present invention can exist with nonsolvated forms or solvation form, comprises hydrate forms.Generally speaking, solvation form is suitable with non-solvated form, is included within scope of the present invention.Some compound of the present invention can exist with polycrystalline or amorphous form.
Some compound of the present invention can have unsymmetrical carbon (optical center) or double bond.Racemic modification, diastereomer, geometrical isomer and single isomer all comprise within the scope of the present invention.
The graphic interpretation of the compound of raceme, ambiscalemicandscalemic or enantiomer-pure is from Maehr, J.Chem.Ed.1985,62:114-120 herein.1985,62:114-120.Except as otherwise noted, the absolute configuration of a Stereocenter is represented with webge groove and dotted line key.When compound described herein contains olefinic double bond or other geometry asymmetric center, unless otherwise prescribed, they comprise E, Z geometrical isomer.Similarly, all tautomeric forms include within the scope of the present invention.
Specific geometry or stereoisomer form can be there is in compound of the present invention.The present invention imagines this all compounds, comprise cis and trans-isomer(ide), (-)-and (+)-to enantiomorph, (R)-and (S)-enantiomorph, diastereomer, (D)-isomer, (L)-isomer, and racemic mixture and other mixtures, the such as mixture of enantiomer or diastereomer enrichment, all these mixtures all belong within scope of the present invention.Other unsymmetrical carbon can be there is in the substituting groups such as alkyl.All these isomer and their mixture, include within the scope of the present invention.
The chiral synthesize that can pass through or chiral reagent or other routine techniquess prepare optically active (R)-and (S)-isomer and D and L isomer.If expect a kind of enantiomorph of the present invention's compound, can be prepared by asymmetric synthesis or the derivatization with chiral auxiliary(reagent), wherein gained non-enantiomer mixture is separated, and auxiliary group split to provide pure needed for enantiomer.Or, when containing basic functionality (as amino) or acidic functionality (as carboxyl) in molecule, the salt of diastereomer is formed with suitable optically active acid or alkali, then carry out diastereomer fractionation by Steppecd crystallization known in the field or chromatography, then reclaim and obtain pure enantiomorph.In addition, enantiomer is separated normally by using chromatography to complete with diastereomer, and described chromatography adopts chiral stationary phase, and optionally combine with chemical derivatization (such as generating carbaminate by amine).
Compound of the present invention can comprise the atom isotope of unnatural proportions on the atom of one or more this compound of formation.Such as, using radiation compound isotopically labelled, such as tritium ( 3h), iodine-125 ( 125i) or C-14 ( 14c).The conversion of all isotopics of compound of the present invention, no matter whether radioactivity, all comprises within the scope of the present invention.
Term " pharmaceutically acceptable carrier " refers to the biological activity that can send significant quantity active substance of the present invention, not interferon activity material and any preparation had no side effect to host or patient or the representational carrier of mounting medium comprise water, oil, vegetables and mineral substance, cream base, lotion base, ointment base etc.These matrix comprise suspension agent, tackifier, transdermal enhancer etc.Their preparation by the technician in cosmetic field or part drug field known.About other information of carrier, can with reference to Remington:TheScienceandPracticeofPharmacy, 21stEd., Lippincott, Williams & Wilkins (2005), the content of the document is incorporated to herein by way of reference.
Term " vehicle " typically refers to carrier, thinner and/or medium required for preparation drug composition effective.
For medicine or pharmacologically active agents, term " significant quantity " or " treatment significant quantity " refer to nontoxic but enough consumptions of the medicine that can produce a desired effect or medicament.For the oral dosage form in the present invention, in composition a kind of " significant quantity " of active substance refer to in said composition during another kind of active substance coupling in order to the required consumption that produces a desired effect.The determination of significant quantity varies with each individual, and depend on age and the generalized case of acceptor, also depend on concrete active substance, significant quantity suitable in case can be determined according to routine test by those skilled in the art.
Term " activeconstituents ", " therapeutical agent ", " active substance " or " promoting agent " refers to a kind of chemical entities, and it can disorderly, the disease of therapeutic goal or illness effectively.
Term " is substituted " any one or more hydrogen atoms referred in specific atoms and is substituted with a substituent, and comprises the variant of heavy hydrogen and hydrogen, as long as the valence state of specific atoms is normal and after replacing compound is stable.When substituting group is ketone group (namely=O), mean that two hydrogen atoms are substituted.Ketone replacement can not occur on aromatic base.Term " is optionally substituted " and refers to and can be substituted, and also can not be substituted, and unless otherwise prescribed, substituent kind and number can be arbitrary on the basis that chemically can realize.
When any variable (such as R) occurs once in the composition or structure of compound, its definition is at each occurrence all independently.Therefore, such as, if group replace by 0-2 R, then described group can optionally at the most replace by two R, and the R in often kind of situation has independently option.In addition, the combination of substituting group and/or its variant to be only only when such combination can produce stable compound and to be allowed to.
Can be cross connected to two atomic time on a ring when a substituent key, this substituting group can with the arbitrary atom phase bonding on this ring.Do not indicate in cited substituting group its by which atom be connected to chemical structure of general formula comprise but the compound specifically do not mentioned time, this substituting group can pass through its any atom phase bonding.The combination of substituting group and/or its variant is only only when such combination can produce stable compound and is allowed to.
The substituting group of alkyl and assorted alkyl radicals (comprising those groups being commonly called alkylidene group, alkenyl, sub-assorted alkyl, assorted thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, cycloalkenyl group and heterocycloalkenyl) is commonly referred to as " alkyl substituent ", and they can be selected from but to be not limited in following groups one or more :-R ' ,-OR ' ,=O ,=NR ' ,=N-OR ' ,-NR ' R " ,-SR ', halogen ,-SiR ' R " R " ', OC (O) R ' ,-C (O) R ' ,-CO 2r ' ,-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 " SO 2r ' ,-CN, – NO 2,-N 3,-CH (Ph) 2with fluoro (C 1-C 4) alkyl, substituent 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 ' ' ' ' ' preferably hydrogen, substituted or unsubstituted assorted alkyl, substituted or unsubstituted aryl (such as by 1 ~ 3 aryl substituted with halogen), substituted or unsubstituted alkyl, alkoxyl group, thio alkoxy group or aralkyl independently of one another.When compound of the present invention comprises more than one R group, such as, each R group is selected independently, as when there is more than one R', R ", R " ', R ' ' ' ' and R ' ' ' ' ' group time these groups each.As R' and R " when being attached to same nitrogen-atoms, they can be combined with this nitrogen-atoms and form 5-, 6-or 7-ring.Such as ,-NR'R " is intended to include but are not limited to 1-pyrrolidyl and 4-morpholinyl.According to above-mentioned about in substituent discussion, it will be understood by those skilled in the art that the group that term " alkyl " is intended to comprise carbon atom bonding and forms in non-hydrogen group, as haloalkyl (such as-CF 3,-CH 2cF 3) and acyl group (such as-C (O) CH 3,-C (O) CF 3,-C (O) CH 2oCH 3deng).
Similar to substituting group described in alkyl radicals, aryl and heteroaryl substituent are generally referred to as " aryl substituent ", be selected from such as-R ',-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 " SO 2r ' ,-CN, – NO 2,-N 3,-CH (Ph) 2, fluorine (C 1-C 4) alkoxyl group and fluorine (C 1-C 4) alkyl etc., substituent quantity is open between valent sum on 0 to aromatic nucleus, wherein R ', R ", R " ', R " " and R " " ' preferred from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted assorted alkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl independently.When compound of the present invention comprises more than one R group, such as, each R group is selected independently, as existence more than one R ', R ", R " ', R " " and R " " ' group time these groups each.
Two substituting groups on the adjacent atom of aryl or heteroaryl ring can optionally be replaced by the substituting group of general formula by – T-C (O)-(CRR ') q-U-, wherein T and U is independently selected from-NR-,-O-, CRR'-or singly-bound, and q is the integer of 0 to 3.Alternatively, two substituting groups on the adjacent atom of aryl or heteroaryl ring can optionally be replaced by the substituting group of general formula by – A (CH2) rB-, wherein A and B independently Xuan Zi – CRR '-,-O-,-NR-,-S-,-S (O)-, S (O) 2-,-S (O) 2nR '-or singly-bound, r is the integer of 1 ~ 4.Optionally, a singly-bound on the new ring formed thus can replace with double bond.Alternatively, two substituting groups on the adjacent atom of aryl or heteroaryl ring can optionally be replaced by the substituting group of general formula by – A (CH2) rB-, wherein s and d independently be selected from 0 ~ 3 integer, X Shi – O-,-NR ' ,-S-,-S (O)-,-S (O) 2-Huo – S (O) 2nR '-.Substituent R, R ', R " and R " ' separately preferred from hydrogen and substituted or unsubstituted (C 1-C 6) alkyl.
Unless otherwise prescribed, term " halo element " or " halogen " itself or represent fluorine, chlorine, bromine or iodine atom as another substituent part.In addition, term " haloalkyl " is intended to comprise single haloalkyl and multi-haloalkyl.Such as, term " halo (C 1-C 4) alkyl " be intended to include but are not limited to trifluoromethyl, 2,2,2-trifluoroethyls, 4-chlorobutyl and 3-bromopropyl etc.
The example of haloalkyl includes but are not limited to: trifluoromethyl, trichloromethyl, pentafluoroethyl group, and pentachloro-ethyl." alkoxyl group " represents the abovementioned alkyl with given number carbon atom connected by oxo bridge.C 1-6alkoxyl group comprises C 1, C 2, C 3, C 4, C 5and C 6alkoxyl group.The example of alkoxyl group includes but not limited to: methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, sec-butoxy, tert.-butoxy, n-pentyloxy and S-pentyloxy." cycloalkyl " comprises saturated cyclic group, as cyclopropyl, cyclobutyl or cyclopentyl.3-7 cycloalkyl comprises C 3, C 4, C 5, C 6and C 7cycloalkyl." alkenyl " comprises the hydrocarbon chain of straight or branched configuration, wherein any on this chain stable site exists one or more carbon-to-carbon double bond, such as vinyl and propenyl.
Term " halogen " or " halogen " refer to fluorine, chlorine, bromine and iodine.
Unless otherwise prescribed, term " is mixed " and is represented heteroatoms or heteroatoms group (namely containing heteroatomic atomic group), comprise atom beyond carbon (C) and hydrogen (H) and containing these heteroatomic atomic groups, such as comprise 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 be substituted-C (=O) N (H)-,-N (H)-,-C (=NH)-,-S (=O) 2n (H)-or-S (=O) N (H)-.
Unless otherwise prescribed, " ring " represents substituted or unsubstituted cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, cycloalkynyl radical, heterocycle alkynyl, aryl or heteroaryl.So-called ring comprises monocycle, connection ring, volution ring or bridged ring.The number of ring atom is generally defined as first number of ring, and such as, " 5 ~ 7 ring " refers to around arrangement 5 ~ 7 atoms.Unless otherwise prescribed, this ring optionally comprises 1 ~ 3 heteroatoms.Therefore, " 5 ~ 7 ring " comprises such as phenylpyridine and piperidyl; On the other hand, term " 5 ~ 7 yuan of heterocycloalkyl rings " comprises pyridyl and piperidyl, but does not comprise phenyl.Term " ring " also comprises the ring system containing at least one ring, and each " ring " wherein meets above-mentioned definition all independently.
Unless otherwise prescribed, term " heterocycle " or " heterocyclic radical " mean stable monocycle, dicyclo or three rings rolled into a ball containing heteroatoms or heteroatoms, they can be saturated, part is undersaturated or undersaturated (aromatics), they comprise carbon atom and 1,2,3 or 4 ring hetero atom independently selected from N, O and S, and wherein above-mentioned any heterocycle can be fused on a phenyl ring and form dicyclo.Nitrogen and sulfur heteroatom can optionally oxidized (namely NO and S (O) p).Nitrogen-atoms can be that be substituted or unsubstituted (i.e. N or NR, wherein R other substituting groups of being H or being defined herein).The side base that this heterocycle can be attached to any heteroatoms or carbon atom forms stable structure.If the compound produced is stable, can there is the replacement on carbon potential or nitrogen position in heterocycle as herein described.Assorted ring nitrogen is optionally quaternized.A preferred version is, when the sum of S and O atom in heterocycle is more than 1, these heteroatomss are not adjacent to each other.Another preferred version is, in heterocycle, the sum of S and O atom is no more than 1.As used herein, term " aromatic heterocyclic group " or " heteroaryl " mean 5,6,7 yuan of stable monocycles or the aromatic nucleus of dicyclo or 7,8,9 or 10 yuan of bicyclic heterocyclic radicals, and it comprises carbon atom and 1,2,3 or 4 ring hetero atom independently selected from N, O and S.Nitrogen-atoms can be that be substituted or unsubstituted (i.e. N or NR, wherein R other substituting groups of being H or being defined herein).Nitrogen and sulfur heteroatom can optionally oxidized (namely NO and S (O) p).It should be noted that the sum of S and O atom on aromatic heterocycle is no more than 1.Bridged ring is also contained in the definition of heterocycle.Bridged ring is formed when one or more atom (i.e. C, O, N or S) connects two non-conterminous carbon atoms or nitrogen-atoms.Preferred bridged ring includes but not limited to: a carbon atom, two carbon atoms, a nitrogen-atoms, two nitrogen-atoms and carbon-nitrogen bases.It should be noted that a bridge always converts monocycle to three rings.In bridged ring, the substituting group on ring also can appear on bridge.
The example of heterogeneous ring compound includes but not limited to: acridyl, azocine base, benzimidazolyl-, benzofuryl, benzo sulfydryl furyl, benzo mercaptophenyl, benzoxazolyl, benzoxazoles quinoline base, benzothiazolyl, benzotriazole base, benzo tetrazyl, benzisoxa oxazolyl, benzisothiazole base, benzimidazoline base, carbazyl, 4aH-carbazyl, carbolinyl, chromanyl, chromene, cinnolines base decahydroquinolyl, 2H, 6H-1,5,2-dithiazine base, dihydrofuran is [2,3-b] tetrahydrofuran base also, furyl, furazan base, imidazolidyl, imidazolinyl, imidazolyl, 1H-indazolyl, indoles thiazolinyl, indolinyl, indolizine base, indyl, 3H-indyl, isatino base, isobenzofuran-base, pyrans, pseudoindoyl, iso-dihydro-indole-group, pseudoindoyl, indyl, isoquinolyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydro isoquinolyl, oxadiazoles base, 1,2,3-oxadiazoles base, 1,2,4-oxadiazoles base, 1,2,5-oxadiazoles base, 1,3,4-oxadiazoles base, oxazolidinyl, oxazolyl, isoxazolyl, oxindole base, pyrimidyl, phenanthridinyl, phenanthroline base, azophenlyene, thiodiphenylamine, benzo xanthinyl, phenol oxazines base, phthalazinyl, piperazinyl, piperidyl, piperidone base, 4-piperidone base, piperonyl, pteridyl, purine radicals, pyranyl, pyrazinyl, pyrazolidyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyrido oxazole, pyridine-imidazole, pyridothiazole, pyridyl, pyrimidyl, pyrrolidyl, pyrrolinyl, 2H-pyrryl, pyrryl, pyrazolyl, quinazolyl, quinolyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuran base, tetrahydro isoquinolyl, tetrahydric quinoline group, tetrazyl, 6H-1,2,5-thiadiazine base, 1,2,3-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,2,5-thiadiazolyl group, 1,3,4-thiadiazolyl group, thianthrenyl, thiazolyl, isothiazolyl thienyl, thienyl, thieno-oxazolyl, thieno-thiazolyl, Thienoimidazole base, thienyl, triazinyl, 1,2,3-triazoles base, 1,2,4-triazolyl, oso-triazole base, 1,3,4-triazolyl and xanthenyl.Also comprise condensed ring and spirocyclic compound.
Unless otherwise prescribed, term " alkyl " or its subordinate concept (such as alkyl, thiazolinyl, alkynyl, phenyl etc.) itself or as another substituent part represent straight chain, side chain or the hydrocarbon atomic group of ring-type or its combination, it can be completely saturated, unit or polynary undersaturated, can be monosubstituted, two replacements or polysubstituted, divalence or polyad group can be comprised, there is the carbon atom of specified quantity (as C 1-C 10represent 1 to 10 carbon)." alkyl " includes but not limited to aliphatic group and aryl radical, and described aliphatic group comprises chain and ring-type, specifically includes but not limited to alkyl, thiazolinyl, alkynyl, and described aryl radical includes but not limited to the aryl radical of 6-12 unit, such as benzene, naphthalene etc.In certain embodiments, atomic group that is that term " alkyl " represents straight chain or side chain or their combination, can be completely saturated, unit or polynary undersaturated, can comprise divalence and polyad group.The example of stable hydrocarbon atomic group includes but not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl, isobutyl-, sec-butyl, isobutyl-, cyclohexyl, (cyclohexyl) methyl, Cvclopropvlmethvl, and the homologue of the atomic group such as n-pentyl, n-hexyl, n-heptyl, n-octyl or isomer.Unsaturated alkyl has one or more double bond or triple bond, the example includes but not limited to vinyl, 2-propenyl, butenyl, crot(on)yl, 2-isopentene group, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1-and 3-proyl, 3-butynyl, and more senior homologue and isomer.
Unless otherwise prescribed, term " assorted alkyl " or its subordinate concept (such as assorted alkyl, assorted thiazolinyl, assorted alkynyl, heteroaryl etc.) itself or combine with another term the straight chain representing stable, side chain the hydrocarbon atomic group of ring-type or its combine, be made up of the carbon atom of certain number and at least one heteroatoms.In certain embodiments, term " assorted alkyl " itself or combine with another term the straight chain representing stable, the hydrocarbon atomic group of side chain or its composition, be made up of the carbon atom of certain number and at least one heteroatoms.In an exemplary embodiment, heteroatoms is selected from B, O, N and S, and wherein nitrogen and sulphur atom are optionally oxidized, and nitrogen heteroatom is optionally quaternized.Heteroatoms B, O, N and S can be positioned at any interior location (comprising the position that this alkyl is attached to molecule rest part) of assorted alkyl.Example includes but not limited to-CH 2-CH 2-O-CH 3,-CH 2-CH 2-NH-CH 3,-CH 2-CH 2-N (CH 3)-CH 3,-CH 2-S-CH 2-CH 3,-CH 2-CH 2,-S (O)-CH 3,-CH 2-CH 2-S (O) 2-CH 3,-CH=CH-O-CH 3,-CH 2-CH=N-OCH 3he – CH=CH-N (CH 3)-CH 3.Two heteroatomss can be continuous print, such as-CH at the most 2-NH-OCH 3.
Term " alkoxyl group ", " alkylamino " and " alkylthio " (or thio alkoxy) belong to idiomatic expression, refer to those alkyl groups being connected to the rest part of molecule respectively by Sauerstoffatom, amino or a sulphur atom.
Unless otherwise prescribed, term " cyclic hydrocarbon radical ", " heterocycle alkyl " or its subordinate concept (such as aryl, heteroaryl, cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, cycloalkynyl radical, heterocycle alkynyl etc.) itself or combine " alkyl " that represent cyclisation respectively with other terms, " assorted alkyl ".In addition, with regard to assorted alkyl or heterocycle alkyl (such as assorted alkyl, Heterocyclylalkyl), heteroatoms can occupy the position that this heterocycle is attached to molecule rest part.The example of cycloalkyl includes but not limited to cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, suberyl etc.The limiting examples of heterocyclic radical comprises 1-(1,2,5,6-tetrahydro pyridyl), piperidino, 2-piperidyl, 3-piperidyl, 4-morpholinyl, morpholinyl, tetrahydrofuran (THF)-2-base, tetrahydrofuran (THF) indol-3-yl, tetramethylene sulfide-2-base, tetramethylene sulfide-3-base, 1-piperazinyl and 2-piperazinyl.
Unless otherwise prescribed, term " aryl " represents polyunsaturated aromatic hydrocarbon substituting group, can be monosubstituted, two to replace or polysubstituted, it can be monocycle or many rings (preferably 1 to 3 ring), and they condense together or covalently bound.Term " heteroaryl " refers to containing one to four heteroatomic aryl (or ring).In an exemplary embodiment, heteroatoms is selected from B, N, O and S, and wherein nitrogen and sulphur atom are optionally oxidized, and nitrogen-atoms is optionally quaternized.Heteroaryl is connected to the rest part of molecule by heteroatoms.The non-limiting example of aryl or heteroaryl comprises phenyl, 1-naphthyl, 2-naphthyl, 4-xenyl, 1-pyrryl, 2-pyrryl, 3-pyrryl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, 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, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purine radicals, 2-benzimidazolyl-, 5-indyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl and 6-quinolyl.The substituting group of any one aryl above-mentioned and heteroaryl ring system is selected from acceptable substituting group hereinafter described.
For simplicity, aryl is comprising aryl as defined above and heteroaryl ring with (such as aryloxy, arylthio, aralkyl) during other term conbined usage.Therefore, term " aralkyl " is intended to comprise those atomic groups (such as benzyl, styroyl, pyridylmethyl etc.) that aryl is attached to alkyl, comprise wherein carbon atom (as methylene radical) by those alkyl that such as Sauerstoffatom replaces, such as phenoxymethyl, 2-pyridine oxygen methyl 3-(1-naphthyloxy) propyl group etc.
Term " leavings group " refer to can by another kind of functional group or atom by substitution reaction (such as nucleophilic substitution reaction) the functional group that replaces or atom.Such as, representational leavings group comprises triflate; Chlorine, bromine, iodine; Sulfonate group, as methanesulfonates, tosylate, brosylate, p-toluenesulfonic esters etc.; Acyloxy, as acetoxyl group, trifluoroacetyl oxygen base etc.
Term " protecting group " includes but not limited to " amino protecting group ", " hydroxyl protecting group " or " sulfhydryl protected base ".Term " amino protecting group " refers to the blocking group being suitable for stoping side reaction on amino nitrogen position.Representational amino protecting group includes but not limited to: formyl radical; Acyl group, such as alkanoyl (as ethanoyl, tribromo-acetyl base or trifluoroacetyl group); Alkoxy carbonyl, as tert-butoxycarbonyl (Boc); Arylmethoxycarbonyl groups, as carbobenzoxy-(Cbz) (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc); Arylmethyl, as benzyl (Bn), trityl (Tr), 1,1-bis--(4'-p-methoxy-phenyl) methyl; Silyl, as trimethyl silyl (TMS) and t-butyldimethylsilyl (TBS) etc.Term " hydroxyl protecting group " refers to the protecting group being suitable for stoping hydroxyl side reaction.Representative hydroxyl protecting group includes but not limited to: alkyl, as methyl, ethyl and the tertiary butyl; Acyl group, such as alkanoyl (as ethanoyl); Arylmethyl, as benzyl (Bn), to methoxy-benzyl (PMB), 9-fluorenyl methyl (Fm) and diphenyl methyl (diphenyl-methyl, DPM); Silyl, as trimethyl silyl (TMS) and t-butyldimethylsilyl (TBS) etc.
Compound of the present invention can be prepared by multiple synthetic method well-known to those skilled in the art, comprise and be equal to substitute mode in embodiment, its embodiment formed with the combination of other chemical synthesis process and the art technology enumerated known by personnel below, preferred embodiment include but not limited to embodiments of the invention.
All solvents used in the present invention are commercially available, can use without the need to being further purified.Reaction is generally carried out under inert nitrogen, in anhydrous solvent.Proton magnetic resonance (PMR) data are recorded on BrukerAvanceIII400 (400MHz) spectrometer, and chemical shift represents with (ppm) at tetramethylsilane low field place.Mass spectrum adds the upper mensuration of 6110 (& 1956A) in Agilent 1200 series.LC/MS or ShimadzuMS comprises a DAD:SPD-M20A (LC) and ShimadzuMicromass2020 detector.The electric spray ion source (ESI) that mass spectrograph operates under being equipped with a plus or minus pattern.
The present invention adopts following initialism: aq represents water; HATU represents O-7-azepine benzo triazol-1-yl)-N, N, N', N'-tetramethyl-urea 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 dichloride; PE represents sherwood oil; DIAD represents diisopropyl azo-2-carboxylic acid; DMF represents DMF; DMSO represents methyl-sulphoxide; EtOAc represents ethyl acetate; EtOH represents ethanol; MeOH represents methyl alcohol; CBz represents carbobenzoxy-(Cbz), is a kind of amine protecting group group; It is a kind of amine protecting group group that BOC represents tert-butyl carbonyl; HOAc represents acetic acid; NaCNBH 3represent sodium cyanoborohydride; R.t. room temperature is represented; O/N representative is spent the night; THF represents tetrahydrofuran (THF); Boc 2o represents two-di-tert-butyidicarbonate; TFA represents trifluoroacetic acid; DIPEA represents diisopropyl ethyl amine; SOCl 2represent sulfur oxychloride; CS 2represent dithiocarbonic anhydride; TsOH represents tosic acid; NFSI represents the fluoro-N-of N-(benzenesulfonyl) benzsulfamide; NCS represents 1-chlorine tetramethyleneimine-2,5-diketone; N-Bu 4nF represents tetrabutylammonium; IPrOH represents 2-propyl alcohol; Mp represents fusing point.
Compound manually or software is named, and commercial compound adopts supplier's directory name.
Carry out efficient liquid phase chromatographic analysis by the Shimadzu LC20AB system of being furnished with ShimadzuSIL-20A automatic sampler and Japanese Shimadzu DAD:SPD-M20A detector, adopt XtimateC18 (3 μm of fillers, specification is 2.1x300mm) chromatographic column.The method of 0-60AB_6 minute: application linear gradient, wash-out is started with 100%A (A is the aqueous solution of 0.0675%TFA), and terminating wash-out with 60%B (B is the MeCN solution of 0.0625%TFA), whole process is 4.2 minutes, then with 60%B wash-out 1 minute.Chromatographic column reequilibrate is reached 100:0 in 0.8 minute, and total run time is 6 minutes.The method of 10-80AB_6 minute: application linear gradient, wash-out is started with 90%A (A is the aqueous solution of 0.0675%TFA), and terminating wash-out with 80%B (B is the acetonitrile solution of 0.0625%TFA), whole process is 4.2 minutes, then with 80%B wash-out 1 minute.Chromatographic column reequilibrate is reached 90:10 in 0.8 minute, and total run time is 6 minutes.Column temperature is 50 DEG C, and flow velocity is 0.8mL/min.Diode-array detector scanning wavelength is 200-400nm.
The silica GF254 of Sanpont-group carries out thin-layer chromatographic analysis (TLC), conventional ultra-violet lamp irradiates and detects spot, also additive method is adopted to inspect spot in some cases, in these cases, (about 1g Vanillin is dissolved in 100mL10%H with iodine (add about 1g iodine in 10g silica gel and thoroughly mix), Vanillin 2sO 4in obtained), triketohydrindene hydrate (buying from Aldrich) or special developer (thoroughly mixing (NH 4) 6mo 7o 244H 2o, 5g (NH 4) 2ce (IV) (NO 3) 6, 450mLH 2the dense H2SO of O and 50mL 4and obtain) launch thin layer plate, inspect compound.Adopt Still, W.C.; Kahn, M.; AndMitra, M.JournalofOrganicChemistry, the similar approach of disclosed technology in 1978,43,2923-2925., 40-63 μm of (230-400 order) silica gel of Silicycle carries out flash column chromatography.The common solvent of flash column chromatography or thin-layer chromatography is the mixture of methylene chloride/methanol, ethyl acetate/methanol and hexane/ethyl acetate.
Gilson-281PrepLC322 system adopts the gloomy UV/VIS-156 detector of gill be prepared stratographic analysis, the chromatographic column adopted is AgellaVenusilASBPrepC18,5 m, 150x21.2mm; PhenomenexGeminiC18,5 m, 150x30mm; BostonSymmetrixC18,5 m, 150x30mm; Or PhenomenexSynergiC18,4 m, 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 water 3h 2o, total run time is 8-15 minute.
SFC analysis is carried out by the Agilent1260InfinitySFC system with Agilent1260 automatic sampler and AgilentDAD:1260 detector.Chromatographic column adopts ChiralcelOD-H250x4.6mmI.D., 5um or ChiralpakAS-H250x4.6mmI.D., 5 m or ChiralpakAD-H250x4.6mmI.D., 5 m.The chromatographic condition of OD-H_5_40_2.35ML: ChiralcelOD-H chromatographic column (specification is 250x4.6mmI.D., m filler), moving phase is 40% ethanol (0.05%DEA)-CO 2; Flow velocity is 2.35mL/min; Determined wavelength is 220nm.AS-H_3_40_2.35ML chromatographic condition: ChiralpakAS-H chromatographic column (specification is 250x4.6mmI.D., 5 m fillers); Moving phase is 40% methyl alcohol (0.05%DEA)-CO 2; Flow velocity is 2.35mL/min, and determined wavelength is 220nm.OD-H_3_40_2.35M chromatographic condition: ChiralcelOD-H chromatographic column (specification is 250x4.6mmI.D, 5 m fillers), moving phase is 40% methyl alcohol (0.05%DEA)-CO 2, flow velocity is 2.35mL/min, and determined wavelength is 220nm.AD-H_2_50_2.35ML chromatographic condition: ChiralpakAD-H chromatographic column (specification is 250x4.6mmI.D, 5mm filler), moving phase is 50% methyl alcohol (0.1%MEA)-CO 2, flow velocity is 2.35mL/min, and determined wavelength is 220nm.
The WatersThar80Pre-SFC system using GilsonUV detector carries out preparative SFC analysis, the chromatographic column adopted is that (specification is 250x4.6mmI.D to ChiralcelOD-H, 5 m fillers) or ChiralpakAD-H (specification is 250x4.6mmI.D, 5 m fillers).When flow velocity is about 40-80mL/min, with ethanol-carbonic acid gas or the methyl alcohol-carbonic acid gas eluting compounds of low gradient, wherein methyl alcohol or ethanol contain 0.05%NH 3h 2o, 0.05%DEA or 0.1%MEA, total run time is 20-30 minute.
Unless otherwise prescribed, compound manually or software is named, and commercial compound adopts supplier's directory name.
Compared with prior art, the compounds of this invention is efficient, low toxicity, all achieves significantly even unforeseeable progress, be more suitable for pharmacy in activity, transformation period, solubleness and pharmacokinetics etc.
Embodiment
Describe the present invention below by embodiment, but and do not mean that any unfavorable restriction of the present invention.Describe in detail the present invention herein, wherein also disclose its specific embodiment mode, to those skilled in the art, will be apparent carrying out various changes and modifications for the specific embodiment of the invention without departing from the spirit and scope of the present invention.
Embodiment 1
(5-((Isosorbide-5-Nitrae-Diazesuberane-1-base) alkylsulfonyl)-1-oxo isoquinoline 99.9-2 (1H)-Ji) methyl tert-butyl ester
The first step
Slowly joined in the 22mL vitriol oil by isoquinoline 99.9 1a (47.5mL, 405mmol), fully stir into fritter, then join in the oleum of 200mL20%, room temperature places two days.Then to pour in 700g frozen water and hold over night, the suspension liquid obtained filters, and filter cake washes with water twice (100mLx2), dry, and (50g, productive rate: 60%) are directly used in next step reaction to obtain isoquinoline-5-sulfonic acid 1b
1HNMR(400MHz,D 2O):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
Under room temperature, isoquinoline-5-sulfonic acid 1b (4.0g, 0.019mol) is joined in the sulfur oxychloride of 25mL, then add the DMF of 0.1mL.Reaction reflux is after two hours, and decompression evaporates unnecessary sulfur oxychloride, the cold washed with dichloromethane (10mLx2) of residue on evaporation.Drying obtains target product isoquinoline 99.9-5-SULPHURYL CHLORIDE 1c (3.9g, yellow solid, productive rate: 100%).
MS-ESI calculated value [M+H] +227 measured values 227.
3rd step
By isoquinoline 99.9-5-SULPHURYL CHLORIDE 1c (3.00g; 11.3mmol) be dissolved in 20mL methylene dichloride; 0 DEG C of priority adds 1 under nitrogen protection; 4-Diazesuberane-1-carboxylic acid tert-butyl ester (2.60g; 13.0mmol) and N; N-diisopropyl ethyl amine (7.5mL, 35.0mmol).Gained reaction solution stirring at room temperature 16 hours is until reaction terminates.With methylene dichloride (100mL) and water (100mL) dilution; dichloromethane extraction (100mLx2); merge organic phase anhydrous sodium sulfate drying; filter; filtrate reduced in volume, obtains target compound 4-(isoquinoline 99.9-5-base alkylsulfonyl)-Isosorbide-5-Nitrae-Diazesuberane-1-carboxylic acid tert-butyl ester 1d (4.5g with silicagel column (0-100% ethyl acetate/petroleum ether) purifying; colorless oil, productive rate: 100%).
MS-ESI calculated value [M+H] +392, measured value 392.
4th step
0 DEG C by 4-(isoquinoline 99.9-5-base alkylsulfonyl)-1; 4-Diazesuberane-1-carboxylic acid tert-butyl ester 1d (5.38g; add m-chloro peroxide benzene carboxylic acid (4.80g in 200mL dichloromethane solution 13.8mmol) in batches; 27.6mmol), stirring at room temperature 2 hours are then risen to until reaction terminates.5-((4-(tert-butoxycarbonyl)-1 is obtained with chromatography silica gel column purification (0-100% ethyl acetate/petroleum ether) after direct solvent evaporated; 4-Diazesuberane-1-base) alkylsulfonyl) isoquinoline 99.9-2-oxide compound 1e (4.9g; yellow oily liquid, productive rate: 86%).
1HNMR(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) alkylsulfonyl) isoquinoline 99.9-2-oxide compound 1e (5.70g, 14.0mmol) to be dissolved in 50mL diacetyl oxide and to stir 2 hours until reaction terminates at 100 DEG C.Reaction solution concentrating under reduced pressure, except being dissolved in the tetrahydrofuran (THF) of 50mL by resistates after desolventizing, adds after the aqueous sodium hydroxide solution of 100mL30% in stirring at room temperature 0.5 hour.Regulate the pH of reaction solution to 7 with dilute hydrochloric acid after decompression removing tetrahydrofuran (THF); the suspension liquid obtained is filtered; filter cake use water (10mLx2) washs; dry; obtain 4-((1-oxo-1,2-dihydro-isoquinoline-5-base) alkylsulfonyl)-Isosorbide-5-Nitrae-Diazesuberane-1-carboxylic acid tert-butyl ester 1f (3g; pale red solid, productive rate: 75%).
1HNMR(400MHz,CDCl 3):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) alkylsulfonyl)-1; 4-Diazesuberane-1-carboxylic acid tert-butyl ester 1f (5.50g; 13.5mmol) be dissolved in 110mL HMPA; sodium hydride (0.595g is slowly added under 0 DEG C of condition; react 15 minutes 14.9mmol) and at the same temperature; then chloromethyl isobutyrate (2.24g is dripped to reaction solution; 14.9mmol), rise to room temperature after adding and react 1 hour.After question response terminates, reaction solution is slowly added drop-wise in frozen water (200mL); extract by ethyl acetate (100mL × 3); organic phase anhydrous sodium sulfate drying; filter; concentrated; resistates obtains 4-((2-((isobutyl acyloxy) methyl)-1-oxo-1 by chromatography silica gel column purification (0-100% ethyl acetate/petroleum ether); 2-dihydro-isoquinoline-5-base) alkylsulfonyl)-1; 4-Diazesuberane-1-carboxylic acid tert-butyl ester 1g (5.8g; white solid, productive rate: 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) alkylsulfonyl)-1; 4-Diazesuberane-1-carboxylic acid tert-butyl ester 1g (5.80g; 11.4mmol) be dissolved in the methylene dichloride of 690mL; trifyl trimethyl silane (5.06g is slowly dripped under 0 DEG C and nitrogen protection; 22.8mmol), control temperature is within the scope of 0-5 DEG C.Reaction solution drips 2,6-lutidine (3.66g, 34.2mmol) after reacting 45 minutes wherein, continues reaction 1 hour until reaction terminates at 0-5 DEG C.Reaction solution is slowly joined in frozen water (200mL); extract with methylene dichloride (100mL × 3); organic phase anhydrous sodium sulfate drying; filter; the concentrated residue with Ethyl acetate recrystallization obtained obtains (5-((1; 4-Diazesuberane-1-base) alkylsulfonyl)-1-oxo isoquinoline 99.9-2 (1H)-Ji) methyl tert-butyl ester 1 (2.5g, faint yellow solid, productive rate: 54%).
1HNMR(400MHz,D 2O):δ8.41(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
((5-((Isosorbide-5-Nitrae-Diazesuberane-1-base) alkylsulfonyl)-1-oxo isoquinoline 99.9-2 (1H)-Ji) methyl) phosphonic acids
The first step
4-(isoquinoline 99.9-5-base alkylsulfonyl)-1; 4-Diazesuberane-1-carboxylic acid tert-butyl ester 1d (4.10g; 11.2mmol) be dissolved in the ethyl acetate of 30mL, drip the saturated hydrogen chloride solution of 20mL ethyl acetate in 0 DEG C, reaction solution was in room temperature reaction 0.5 hour.The suspension liquid obtained is filtered, and filter cake ethyl acetate washing (10mLx2), drying obtains 5-((Isosorbide-5-Nitrae-Diazesuberane-1-base) alkylsulfonyl) isoquinoline 99.9 2a (2.6g, white solid, productive rate: 87%).
Second step
To 5-((1 under nitrogen protection; 4-Diazesuberane-1-base) alkylsulfonyl) isoquinoline 99.9 2a (4.00g; N is added in 80mL dichloromethane solution 11.1mmol); dinethylformamide (5.90mL; 33.3mmol); then chloroformic acid benzyl ester (2.10g, 12.2mmol) is dripped in 0 DEG C.After dropwising, reaction solution is risen to room temperature and after reacting 2 hours; with 50mL water dilute reaction solution; methylene dichloride (30mLx2) extracts; organic phase anhydrous sodium sulfate drying, filters, filtrate reduced in volume; 4-(isoquinoline 99.9-5-base alkylsulfonyl)-1 is obtained with Silica gel chromatography (0 ~ 100% ethyl acetate/petroleum ether); 4-diaza-1-benzyl carboxylate 2b (6.4g, colourless oil liquid, productive rate: 100%).
1HNMR(400MHz,CDCl 3):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.
3rd step
4-(isoquinoline 99.9-5-base alkylsulfonyl)-1; 4-diaza-1-benzyl carboxylate 2b (7.4g; 17.4mmol) obtain 5-((4-((benzyloxy) carbonyl)-1 according to the synthetic method of embodiment 1; 4-Diazesuberane-1-base) alkylsulfonyl) isoquinoline 99.9-2-oxide compound 2c (5.0g; yellow oil, productive rate: 65%).
MS-ESI calculated value [M+H] +442, measured value 442.
4th step
By 5-((4-((benzyloxy) carbonyl)-1; 4-Diazesuberane-1-base) alkylsulfonyl) isoquinoline 99.9-2-oxide compound 2c (5.00g; 11.3mmol) be dissolved in 70mL acetic anhydride, be heated to 130 DEG C of reactions 4 hours.Question response terminates rear underpressure distillation and removes unnecessary diacetyl oxide, and resistates is dissolved in the tetrahydrofuran (THF) of 50mL, and adds the sodium hydroxide of 100mL30%.Reaction solution stirring at room temperature 0.5 hour; then underpressure distillation removes tetrahydrofuran (THF) and adjusts pH to arrive neutrality reaction solution; the suspension liquid obtained filters; filtration cakes torrefaction obtains 4-((1-oxo-1; 2-dihydro-isoquinoline-5-base) alkylsulfonyl)-1; 4-diaza-1-benzyl carboxylate 2d (4.5g, brown solid, productive rate: 90%).
MS-ESI calculated value [M+H] +442, measured value 442.
5th step
4-((1-oxo-1; 2-dihydro-isoquinoline-5-base) alkylsulfonyl)-1; 4-diaza-1-benzyl carboxylate 2d (1.00g; 2.27mmol) with chloromethyl phosphate dibenzyl ester (816mg; 2.5mmol) obtain 4-((2-((two (benzyloxy) phosphoryl) methyl)-1-oxo-1 according to the synthetic method of embodiment 1; 2-dihydro-isoquinoline-5-base) alkylsulfonyl)-1; 4-diaza-1-benzyl carboxylate 2e (140mg; brown oil, productive rate: 8.5%).
1HNMR(400MHz,CDCl 3):δ8.41(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-((two (benzyloxy) phosphoryl) methyl)-1-oxo-1; 2-dihydro-isoquinoline-5-base) alkylsulfonyl)-1; 4-diaza-1-benzyl carboxylate 2e (100mg; wet palladium carbon (70mg is added in 20mL tetrahydrofuran (THF) 0.140mmol) and the mixed solvent of 2.5mL water; 10%), room temperature reaction 4 hours in an atmosphere of hydrogen.Reaction terminates rear diatomite filtration; concentrated, obtain ((5-((Isosorbide-5-Nitrae-Diazesuberane-1-base) alkylsulfonyl)-1-oxo isoquinoline 99.9-2 (1H)-Ji) methyl) phosphonic acids 2 (63mg; white solid, productive rate: 100%).
1HNMR(400MHz,D 2O):δ8.60(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) alkylsulfonyl)-1; 4-Diazesuberane-1-carboxylic acid tert-butyl ester 1f (200mg; 0.49mmol) obtain 4-((2-((benzoyloxy) methyl)-1-oxo-1 according to the synthetic method of embodiment 1; 2-dihydro-isoquinoline-5-base) alkylsulfonyl)-1; 4-Diazesuberane-1-carboxylic acid tert-butyl ester 3a (150mg; white solid, productive rate: 56%).
1HNMR(400MHz,DMSO-6d):δ8.54(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) alkylsulfonyl)-1; 4-Diazesuberane-1-carboxylic acid tert-butyl ester 3a (150mg; 0.28mmol) obtain (5-(1 according to the synthetic method of embodiment 1; 4-Diazesuberane-1-base) alkylsulfonyl)-1-oxo isoquinoline 99.9-2 (1H)-Ji) benzene carboxylic acid methyl esters 3 (50mg; white solid, productive rate: 41%).
1HNMR(400MHz,D 2O):δ8.48(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
5-((1; 4-Diazesuberane-1-base) alkylsulfonyl)-1-oxo isoquinoline 99.9-2 (1H)-Ji) oxygen base) methyl pivalate 4; ((5-((Isosorbide-5-Nitrae-Diazesuberane-1-base) alkylsulfonyl) isoquinolyl-1) oxygen base) methyl pivalate 4 '
The first step
4-((1-oxo-1, 2-dihydro-isoquinoline-5-base) alkylsulfonyl)-1, 4-Diazesuberane-1-carboxylic acid tert-butyl ester 1f (0.50g, 1.23mmol) obtain 4-((1-oxo-2-((new pentane acyloxy) methyl)-1 according to the synthetic method of embodiment 1, 2-dihydro-isoquinoline-5-base) alkylsulfonyl)-1, 4-diaza-1-carboxylic acid tert-butyl ester 4a1 and 4-((1-((new pentane acyloxy) methoxyl group) isoquinoline 99.9-5-base) alkylsulfonyl)-1, mixture (the 0.34g of 4-Diazesuberane-1-carboxylic acid tert-butyl ester 4a2, white solid, productive rate: 50%).
4a1: 1HNMR(400MHz,CDCl 3):δ8.53(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: 1HNMR(400MHz,CDCl 3):δ8.72(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) alkylsulfonyl)-1, 4-diaza-1-carboxylic acid tert-butyl ester 4a1 and 4-((1-((new pentane acyloxy) methoxyl group) isoquinoline 99.9-5-base) alkylsulfonyl)-1, 4-Diazesuberane-1-carboxylic acid tert-butyl ester 4a2 (100mg, 0.19mmol) obtain 5-((1 according to the synthetic method of embodiment 1, 4-Diazesuberane-1-base) alkylsulfonyl)-1-oxo isoquinoline 99.9-2 (1H)-Ji) oxygen base) methyl pivalate 4 and ((5-((1, 4-Diazesuberane-1-base) alkylsulfonyl) isoquinolyl-1) oxygen base) methyl pivalate 4 ' (50mg, faint yellow solid, productive rate: 53%).
4: 1HNMR(400MHz,CDCl 3):δ8.65(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’: 1HNMR(400MHz,CDCl 3):δ8.55(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-((Isosorbide-5-Nitrae-Diazesuberane-1-base) alkylsulfonyl)-1-oxo isoquinoline 99.9-2 (1H) base) dimethylamino carboxylate methyl ester
The first step
Under nitrogen protection by 4-((1-oxo-1; 2-dihydro-isoquinoline-5-base) alkylsulfonyl)-1; 4-Diazesuberane-1-carboxylic acid tert-butyl ester 1f (200mg; 0.49mmol), dimethylamino carboxylic acid chloromethyl ester (149mg; 0.98mmol) and the 20mL tetrahydrofuran solution reflux 24 hours of salt of wormwood (224mg, 1.47mmol).After question response terminates, reaction solution is cooled to room temperature; except desolventizing; 4-((2-(((dimethylamino formyl radical) oxygen base) methyl)-1-oxo-1 is obtained with Preparative TLC chromatography (50% ethyl acetate/petroleum ether); 2-dihydro-isoquinoline-5-base) alkylsulfonyl)-1; 4-Diazesuberane-1-carboxylic acid tert-butyl ester 5a (100mg; white solid, productive rate: 39%).
MS-ESI calculated value [M+H] +509, measured value 509.
Second step
Under room temperature; by 4-((2-(((dimethylamino formyl radical) oxygen base) methyl)-1-oxo-1; 2-dihydro-isoquinoline-5-base) alkylsulfonyl)-1; 4-Diazesuberane-1-carboxylic acid tert-butyl ester 5a (0.25g; 0.45mmol) join saturated 1 of 4mL hydrogen chloride gas; in 4-dioxane solution, and room temperature Keep agitation 0.5 hour.After question response terminates, reaction solution is concentrated; be separated with Preparative TLC chromatoplate (ethyl acetate) and obtain (5-((1; 4-Diazesuberane-1-base) alkylsulfonyl)-1-oxo isoquinoline 99.9-2 (1H) base) dimethylamino carboxylate methyl ester 5 (150mg; faint yellow solid, productive rate: 74%).
1HNMR(400MHz,DMSO-d6):δ8.92(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
(5-((Isosorbide-5-Nitrae-Diazesuberane-1-base) alkylsulfonyl)-1-oxo isoquinoline 99.9-2 (1H)-Ji) methyl carbonic acid isopropyl ester
The first step
4-((1-oxo-1; 2-dihydro-isoquinoline-5-base) alkylsulfonyl)-1; 4-Diazesuberane-1-carboxylic acid tert-butyl ester 1f (150mg; 0.39mmol) with chloromethyl propylene carbonate (77mg; 0.51mmol) obtain (5-((1 according to the synthetic method of embodiment 1 through two-step reaction; 4-Diazesuberane-1-base) alkylsulfonyl)-1-oxo isoquinoline 99.9-2 (1H)-Ji) methyl carbonic acid isopropyl ester 6 (53mg; white solid, productive rate: 32%).
1HNMR(400MHz,DMSO-d6):δ8.92(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 produces speed and the active pharmaceutical ingredient exposed amount of active pharmaceutical ingredient in vivo.Experiment material: male SD rat, body weight 200-250g, purchased from Shanghai Slac Experimental Animal Co., Ltd..
Experimental implementation:
Before experiment, animal carries out carotid artery intubate (for plasma sample collection), rat postoperative at least recover 3 days, observe without exception after for experiment.Oral administration dosage is 10mg/kg, and after administration, 0,5min, 15min, 30min, 60min, 2h, 4h, 6h, 8h, 24h gathers whole blood and prepares plasma sample.All samples uses liquid chromatography coupling mass spectrum mass spectrometric hyphenated technique to carry out detection by quantitative to drug compound content in laboratory animal blood plasma, and institute surveys the non-compartment model of concentration value utilization WinNonlin, according to plasma concentration v. time data, and calculating T 1/2, C max, T max, AUC (0-t)and AUC (0-∞)etc. parameter, and draw plasma concentration v. time curve.
Experimental result:
Table 1 rat power blood test result
Note: Cmax :+>1000nM; Blood medicine time to peak :+<20min; Unit exposed amount :+>100nM.hr/ μm of ol.

Claims (9)

1. compound shown in formula (I) or (II) or its pharmacy acceptable salt,
It is characterized in that,
R 1, R 2separately be selected from R 3c (=O) O-, (R 4o) 2p (=O) O-;
R 3be selected from C 1-6alkyl, (R 5) (R 6) N-, R 7o-, phenyl, pyridyl, thienyl, furyl;
R 4, R 5, R 6, R 7separately be selected from H or C 1-3alkyl;
Described C 1-6alkyl, C 1-3alkyl is optionally by R 01replaced;
R 01be selected from F, Cl, Br, I, OH, NH 2, R 01number be 1,2 or 3.
2. compound according to claim 1 or its pharmacy acceptable salt, is characterized in that, described R 3be selected from propyl group, butyl, dimethylamino.
3. compound according to claim 2 or its pharmacy acceptable salt, is characterized in that, described R 3be selected from sec.-propyl, the tertiary butyl, dimethylamino.
4. compound according to claim 1 or its pharmacy acceptable salt, is characterized in that, described R 1, R 2separately be selected from
5. compound according to claim 1 or its pharmacy acceptable salt, is characterized in that, described pharmacy acceptable salt is as shown in (III) or (IV):
Wherein, X is selected from mineral acid or organic acid.
6. compound according to claim 5 or its pharmacy acceptable salt, it is characterized in that, described X is selected from trifluoromethanesulfonic acid, hydrochloric acid, Hydrogen bromide, nitric acid, carbonic acid, bicarbonate radical, phosphoric acid, phosphoric acid one hydrogen root, dihydrogen phosphate, sulfuric acid, bisulfate ion, hydroiodic acid HI, phosphorous acid etc., acetic acid, propionic acid, isopropylformic acid, toxilic acid, propanedioic acid, phenylformic acid, succsinic acid, suberic acid, FUMARIC ACID TECH GRADE, lactic acid, amygdalic acid, phthalic acid, Phenylsulfonic acid, tosic acid, citric acid, tartrate, methylsulfonic acid, amino acid or glucuronic acid.
7. compound according to claim 1 or its pharmacy acceptable salt, it is selected from:
8. a pharmaceutical composition, it contains the compound according to claim 1 ~ 7 any one or its pharmacy acceptable salt and pharmaceutically acceptable carrier for the treatment of significant quantity.
9. the application in the medicine of the relevant various illness that the compound according to claim 1 ~ 7 any one or its pharmacy acceptable salt or pharmaceutical composition according to claim 8 cause in preparation treatment vasoconstriction, wherein said relevant various illnesss comprise cerebral vasospasm, stenocardia, glaucoma, hypertension, fibrosis caused by cerebral embolism, cerebral ischemia, brain injury, vertebrobasilar insufficiency, subarachnoid hemorrhage.
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