WO2015165342A1 - 异喹啉磺胺衍生物及其药物组合物和制药用途 - Google Patents

异喹啉磺胺衍生物及其药物组合物和制药用途 Download PDF

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WO2015165342A1
WO2015165342A1 PCT/CN2015/077046 CN2015077046W WO2015165342A1 WO 2015165342 A1 WO2015165342 A1 WO 2015165342A1 CN 2015077046 W CN2015077046 W CN 2015077046W WO 2015165342 A1 WO2015165342 A1 WO 2015165342A1
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acid
group
pharmaceutically acceptable
acceptable salt
compound according
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English (en)
French (fr)
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吴凌云
姚元山
陈兆国
陈曙辉
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Medshine Discovery Inc
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Medshine Discovery Inc
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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

Definitions

  • the present invention relates to a class of isoquinoline sulfonamide derivatives as RHO kinase inhibitors and pharmaceutical compositions thereof, and to their pharmaceutical use.
  • the invention relates to a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof.
  • Fasudil is a novel drug with a wide range of pharmacological effects. It is a RHO kinase inhibitor that dilates blood vessels by increasing the activity of myosin light chain phosphatase, reduces the tension of endothelial cells, improves brain microcirculation, and does not produce Increase the brain's stealing blood, at the same time can antagonize inflammatory factors, protect nerves against apoptosis, and promote nerve regeneration. The results indicate that fasudil hydrochloride has a certain effect on promoting the recovery of nerve function, alleviating clinical symptoms and reducing the morbidity rate.
  • ultra-early thrombolytic therapy can not be achieved, but in order to reduce the further progress of the disease, it is essential to reconstruct the local blood circulation within the treatment time window, while the phlegm hydrochloride It has significant neuroprotective and therapeutic effects on ischemic cerebrovascular disease and is worthy of use in the clinic, especially at the grassroots level, reducing disability and improving quality of life.
  • WO2004106325 discloses a class of compounds which are prodrugs of fasudil and have the structural formula shown as formula (B-I):
  • RHO kinase inhibitors Although the above compounds exist in the prior art as RHO kinase inhibitors, they need to be improved in terms of activity, solubility, pharmacokinetics, drug-forming properties and the like.
  • R 3 is selected from C 1-6 alkyl, (R 5 )(R 6 )N-, R 7 O-, phenyl, pyridyl, thienyl, furyl;
  • R 4 , R 5 , R 6 , and R 7 are each independently selected from an alkyl group selected from H or C 1-3 ;
  • the C 1-6 alkyl group, C 1-3 alkyl group is optionally substituted by R 01 ;
  • R 01 is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , and the number of R 01 is 1, 2 or 3.
  • R 3 is selected from the group consisting of a propyl group, a butyl group, and a dimethylamino group
  • the above R 3 is selected from the group consisting of isopropyl, tert-butyl, and dimethylamino.
  • R 1 and R 2 are each independently selected from the group consisting of
  • the above pharmaceutically acceptable salt is as shown in (III) or (IV):
  • X is selected from the group consisting of inorganic acids or organic acids.
  • the above X is selected from the group consisting of trifluoromethanesulfonic acid, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, Hydroiodic acid, phosphorous acid, etc., acetic acid, propionic acid, isobutyric acid, maleic acid, C Diacid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, amino acid or Portuguese Uronic acid.
  • the above compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the above compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • Another object of the present invention is to provide the use of the above compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, for the preparation of a medicament for treating various disorders associated with vasoconstriction, wherein the various disorders involved include the brain Embolism, cerebral ischemia, brain injury, vertebral artery insufficiency, cerebral vasospasm caused by subarachnoid hemorrhage, angina pectoris, glaucoma, hypertension, fibrosis.
  • pharmaceutically acceptable as used herein is intended to mean that those compounds, materials, compositions and/or dosage forms are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues. Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts.
  • an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and me
  • the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the neutral form of the compound.
  • the parent form of the compound differs from the form of its various salts by certain physical properties, such as differences in solubility in polar solvents.
  • a "pharmaceutically acceptable salt” is a derivative of a compound of the invention wherein the parent compound is modified by salt formation with an acid or with a base.
  • pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like.
  • Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example salts formed from non-toxic inorganic or organic acids.
  • non-toxic salts include, but are not limited to, those derived from inorganic acids and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, Benzenesulfonic acid, benzoic acid, hydrogencarbonate, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, Hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionethane, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, Pamoic acid, pantothenic acid, phenylacetic acid, phen
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
  • such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid.
  • a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.
  • the compounds provided herein also exist in the form of prodrugs.
  • Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the invention.
  • prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo setting.
  • Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention. Certain compounds of the invention may exist in polycrystalline or amorphous form.
  • Certain compounds of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the invention.
  • the compounds of the invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, and the diastereomeric a conformation, a (D)-isomer, a (L)-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to It is within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.
  • optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer.
  • a diastereomeric salt is formed with a suitable optically active acid or base, and then subjected to fractional crystallization as is known in the art or Chromatography is carried out for diastereomeric resolution and then the pure enantiomer is recovered.
  • Chromatography is carried out for diastereomeric resolution and then the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C). Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • pharmaceutically acceptable carrier refers to any formulation or carrier medium that is capable of delivering an effective amount of an active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects to the host or patient, including water, oil, Vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, tackifiers, transdermal enhancers and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts. For additional information on vectors, reference is made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are hereby incorporated by reference.
  • excipient generally refers to the carrier, diluent and/or vehicle required to formulate an effective pharmaceutical composition.
  • an "effective amount” or “therapeutically effective amount” with respect to a pharmaceutical or pharmacologically active agent refers to a sufficient amount of a drug or agent that is non-toxic but that achieves the desired effect.
  • an "effective amount” of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.
  • active ingredient refers to a chemical entity that is effective in treating a target disorder, disease or condition.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, including variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable.
  • it means that two hydrogen atoms are substituted.
  • Ketone substitution does not occur on the aryl group.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with at most two R, and each case has an independent option.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • substituents When a bond of a substituent can be cross-linked to two atoms on a ring, the substituent can be bonded to any atom on the ring.
  • substituents do not indicate which atom is attached to a compound included in the chemical structural formula including but not specifically mentioned, such a substituent may be bonded through any atomic phase thereof. Combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • alkyl and heteroalkyl radicals (including what are commonly referred to as alkylene, alkenyl, heteroalkyl, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl and heterocycloalkenyl)
  • R', R", R"', R"" and R""' are each independently preferably hydrogen, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted aryl group (for example, an aryl group substituted by 1 to 3 halogens), a substituted or unsubstituted alkyl group, an alkoxy group, or a thioalkyl group oxygen a group or an aralkyl group.
  • each R group is independently selected, as when more than one R', R", R"' Each of these groups, R"" and R""' groups.
  • R' and R" When R' and R" are attached to the same nitrogen atom, they can form a 5-, 6- or 7-member with the nitrogen atom. ring.
  • -NR'R is intended to include, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl.
  • alkyl is intended to include carbon.
  • a group bonded to a non-hydrogen group such as a haloalkyl group (e.g., -CF 3 , -CH 2 CF 3 ) and an acyl group (e.g., -C(O)CH 3 , -C(O)CF 3 ,- C(O)CH 2 OCH 3 , etc.).
  • a non-hydrogen group such as a haloalkyl group (e.g., -CF 3 , -CH 2 CF 3 ) and an acyl group (e.g., -C(O)CH 3 , -C(O)CF 3 ,- C(O)CH 2 OCH 3 , etc.).
  • Two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with a substituent of the formula -TC(O)-(CRR')qU-, wherein T and U are independently selected From -NR-, -O-, CRR'- or a single bond, q is an integer from 0 to 3.
  • two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with a substituent of the formula -A(CH2)r B-, wherein A and B are independently selected From -CRR'-, -O-, -NR-, -S-, -S(O)-, S(O) 2 -, -S(O) 2 NR'- or a single bond, r is 1 to 4 The integer.
  • a single bond on the new ring thus formed can be replaced with a double bond.
  • two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with a substituent of the formula -A(CH2)r B-, wherein s and d are each independently An integer selected from 0 to 3, X is -O-, -NR', -S-, -S(O)-, -S(O) 2 - or -S(O) 2 NR'-.
  • the substituents R, R', R" and R"' are each independently preferably selected from hydrogen and substituted or unsubstituted (C 1 -C 6 )alkyl.
  • halo or halogen
  • haloalkyl is intended to include both monohaloalkyl and polyhaloalkyl.
  • halo(C 1 -C 4 )alkyl is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Wait.
  • haloalkyl groups include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • Alkoxy represents the above alkyl group having a specified number of carbon atoms attached through an oxygen bridge.
  • the C 1-6 alkoxy group includes a C 1 , C 2 , C 3 , C 4 , C 5 and C 6 alkoxy groups.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- Pentyloxy.
  • Cycloalkyl includes saturated cyclic groups such as cyclopropyl, cyclobutyl or cyclopentyl.
  • the 3-7 cycloalkyl group includes C 3 , C 4 , C 5 , C 6 and C 7 cycloalkyl groups.
  • Alkenyl includes hydrocarbon chains in a straight or branched configuration wherein one or more carbon-carbon double bonds, such as vinyl and propylene groups, are present at any stable site on the chain.
  • halo or halogen refers to fluoro, chloro, bromo and iodo.
  • hetero denotes a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), including atoms other than carbon (C) and hydrogen (H), and radicals containing such heteroatoms, including, for example, oxygen (O).
  • N nitrogen
  • S sulfur
  • Si silicon
  • Ge germanium
  • Al aluminum
  • ring means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. So-called rings include single rings, interlocking rings, spiral rings, parallel rings or bridge rings. The number of atoms on the ring is usually defined as the number of elements of the ring. For example, "5 to 7-membered ring” means 5 to 7 atoms arranged in a circle. Unless otherwise specified, the ring optionally contains from 1 to 3 heteroatoms.
  • 5- to 7-membered ring includes, for example, phenylpyridine and piperidinyl; on the other hand, the term “5- to 7-membered heterocycloalkyl ring” includes pyridyl and piperidinyl, but does not include phenyl.
  • ring also includes ring systems containing at least one ring, each of which "ring” independently conforms to the above definition.
  • heterocycle or “heterocyclyl” means a stable monocyclic, bicyclic or tricyclic ring containing a hetero atom or a heteroatom group which may be saturated, partially unsaturated or unsaturated ( Aromatic) which comprise a carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles may be fused to a phenyl ring to form a bicyclic ring.
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p).
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the heterocyclic ring can be attached to the side groups of any hetero atom or carbon atom to form a stable structure. If the resulting compound is stable, the heterocycles described herein can undergo substitutions at the carbon or nitrogen sites.
  • the nitrogen atom in the heterocycle is optionally quaternized.
  • a preferred embodiment is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred embodiment is that the total number of S and O atoms in the heterocycle does not exceed one.
  • aromatic heterocyclic group or "heteroaryl” as used herein means a stable 5, 6, or 7 membered monocyclic or bicyclic or aromatic ring of a 7, 8, 9 or 10 membered bicyclic heterocyclic group, It contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S.
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p). It is worth noting that the total number of S and O atoms on the aromatic heterocycle does not exceed one.
  • Bridged rings are also included in the definition of heterocycles.
  • a bridged ring is formed when one or more atoms (ie, C, O, N, or S) join two non-adjacent carbon or nitrogen atoms.
  • Preferred bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a three ring. In the bridged ring, a substituent on the ring can also be present on the bridge.
  • heterocyclic compounds include, but are not limited to, acridinyl, octanoyl, benzimidazolyl, benzofuranyl, benzofuranylfuranyl, benzindenylphenyl, benzoxazolyl, benzimidin Oxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, oxazolyl, 4aH-carbazolyl, Porphyrin, chroman, chromene, porphyrin-decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b] Tetrahydrofuranyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-carbazolyl, nonenyl,
  • hydrocarbyl or its subordinate concept (such as alkyl, alkenyl, alkynyl, phenyl, etc.) by itself or as part of another substituent means straight-chain, branched or cyclic
  • the hydrocarbon radical or a combination thereof may be fully saturated, unitary or polyunsaturated, may be monosubstituted, disubstituted or polysubstituted, and may include divalent or polyvalent radicals having a specified number of carbon atoms (eg, C1 ) -C 10 represents 1 to 10 carbons).
  • Hydrocarbyl includes, but is not limited to, aliphatic hydrocarbyl groups including chain and cyclic, including but not limited to alkyl, alkenyl, alkynyl groups including, but not limited to, 6-12 members.
  • An aromatic hydrocarbon group such as benzene, naphthalene or the like.
  • alkyl refers to a straight or branched chain of atoms or a combination thereof, which may be fully saturated, unitary or polyunsaturated, and may include divalent and multivalent radicals.
  • saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl).
  • a homolog or isomer of a methyl group, a cyclopropylmethyl group, and an atomic group such as n-pentyl, n-hexyl, n-heptyl, n-octyl.
  • the unsaturated alkyl group has one or more double or triple bonds, and examples thereof include, but are not limited to, a vinyl group, a 2-propenyl group, a butenyl group, a crotyl group, a 2-isopentenyl group, and a 2-(butadienyl group). ), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and Structure.
  • heterohydrocarbyl or its subordinate concept (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.), by itself or in combination with another term, means a stable straight chain, branched chain. Or a cyclic hydrocarbon radical or a combination thereof having a number of carbon atoms and at least one heteroatom.
  • heteroalkyl by itself or in conjunction with another term refers to a stable straight chain, branched hydrocarbon radical or combination thereof, having a number of carbon atoms and at least one heteroatom.
  • the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized.
  • the heteroatoms B, O, N and S can be located at any internal position of the heterohydrocarbyl group (including where the hydrocarbyl group is attached to the rest of the molecule).
  • Up to two heteroatoms may be consecutive, for example, -CH 2 -NH-OCH 3.
  • alkoxy alkylamino and “alkylthio” (or thioalkoxy) are customary expressions and refer to those alkane which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.
  • Base group alkoxy
  • cycloalkyl refers to any heterocyclic alkynyl group, etc., by itself or in combination with other terms, denotes a cyclized “hydrocarbyl group” or “heterohydrocarbyl group”, respectively.
  • a hetero atom may occupy a position at which the hetero ring is attached to the rest of the molecule.
  • cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocyclic groups include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.
  • aryl denotes a polyunsaturated, aromatic hydrocarbon substituent which may be monosubstituted, disubstituted or polysubstituted, It may be monocyclic or polycyclic (preferably 1 to 3 rings) which are fused together or covalently linked.
  • heteroaryl refers to an aryl (or ring) containing one to four heteroatoms. In an illustrative example, the heteroatoms are selected from the group consisting of B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • Non-limiting examples of aryl or heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyridyl Azyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxan Azyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thiophene , 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, indolyl, 2-benzimidazolyl, 5-indenyl
  • aryl groups when used in conjunction with other terms (eg, aryloxy, arylthio, aralkyl), include aryl and heteroaryl rings as defined above.
  • aralkyl is intended to include those radicals to which an aryl group is attached to an alkyl group (eg, benzyl, phenethyl, pyridylmethyl, and the like), including wherein the carbon atom (eg, methylene) has been, for example, oxygen.
  • alkyl groups substituted by an atom such as phenoxymethyl, 2-pyridyloxymethyl 3-(1-naphthyloxy)propyl and the like.
  • leaving group refers to a functional group or atom which may be substituted by another functional group or atom by a substitution reaction (for example, an affinity substitution reaction).
  • substituent groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters and the like; acyloxy groups such as acetoxy, trifluoroacetoxy and the like.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, e.g., tert-butoxycarbonyl (Boc) Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1, 1-di -(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-
  • hydroxy protecting group refers to a protecting group suitable for use in preventing hydroxy side reactions.
  • Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and t-butyl groups; acyl groups such as alkanoyl groups (e.g., acetyl); arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
  • alkyl groups such as methyl, ethyl and t-butyl groups
  • acyl groups such as alkanoyl groups (e.g., acetyl)
  • arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluoreny
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.
  • the present invention employs the following abbreviations: aq for water; HATU for O-7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent; CDI stands for carbonyl Diimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for ethyl acetate EtOH stands for ethanol; MeOH stands for methanol; CBz stands for benzyloxycarbonyl and is an amine protecting group; BOC
  • the compound is either by hand or Software naming, commercially available compounds using the supplier catalog name.
  • the compound of the present invention is highly efficient, low in toxicity, and has achieved remarkable and unexpected progress in activity, half-life, solubility and pharmacokinetics, and is more suitable for pharmaceuticals.
  • Isoquinoline 1a (47.5 mL, 405 mmol) was slowly added to 22 mL of concentrated sulfuric acid, thoroughly stirred into small pieces, and then added to 200 mL of 20% fuming sulfuric acid, and allowed to stand at room temperature for two days. Then, it was poured into 700 g of ice water and allowed to stand overnight, and the obtained suspension was filtered, and the filter cake was washed twice with water (100 mL ⁇ 2), and dried to obtain isoquinoline-5-sulfonic acid 1b (50 g, yield: 60%). Used directly in the next step
  • Isoquinoline-5-sulfonic acid 1b (4.0 g, 0.019 mol) was added to 25 mL of thionyl chloride at room temperature, followed by the addition of 0.1 mL of N,N-dimethylformamide. After the reaction was heated to reflux for two hours, excess thionyl chloride was evaporated under reduced pressure, and the residue was evaporated and washed with cold dichloromethane (10mL?). The title product isoquinoline-5-sulfonyl chloride 1c (3.9 g, yellow solid, yield: 100%) was obtained.
  • Isoquinoline-5-sulfonyl chloride 1c (3.00 g, 11.3 mmol) was dissolved in 20 mL of dichloromethane, and 1,4-diazepane-1-carboxylic acid tert-butyl was added at 0 ° C under nitrogen. Ester (2.60 g, 13.0 mmol) and N,N-diisopropylethylamine (7.5 mL, 35.0 mmol). The resulting reaction solution was stirred at room temperature for 16 hours until the reaction was completed.
  • the animals were subjected to carotid cannulation (for plasma sample collection), and the rats were restored to at least 3 days after surgery, and the experiment was performed after no abnormality was observed.
  • Oral administration dose was 10 mg/kg, and whole blood was collected and plasma samples were prepared at 0, 5 min, 15 min, 30 min, 60 min, 2 h, 4 h, 6 h, 8 h, 24 h after administration. All samples were quantitatively detected in the plasma of the experimental animals by liquid chromatography coupled-mass spectrometry. The measured concentrations were calculated using the WinNonlin non-compartment model and the plasma concentration-time data was used to calculate T 1/2. , C max , T max , AUC (0-t) and AUC (0- ⁇ ) and other parameters, and plot the plasma concentration-time curve.
  • peak plasma concentration +> 1000nM
  • peak plasma time + ⁇ 20min
  • unit exposure +> 100nM.hr / ⁇ mol.

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Abstract

本发明公开了一类作为RHO激酶抑制剂的异喹啉磺胺衍生物及其药物组合物，并涉及其制药用途。具体地，本发明涉及式（I）或（Ⅱ）所示化合物或其药学上可接受的盐。

Description

异喹啉磺胺衍生物及其药物组合物和制药用途 技术领域
本发明涉及一类作为RHO激酶抑制剂的异喹啉磺胺衍生物及其药物组合物，并涉及其制药用途。具体地，本发明涉及式(I)或(Ⅱ)所示化合物或其药学上可接受的盐。
背景技术
法舒地尔是一种具有广泛药理作用的新型药物，为RHO激酶抑制物，通过增加肌球蛋白轻链磷酸酶的活性扩张血管，降低内皮细胞的张力，改善脑组织微循环，不产生和加重脑的盗血，同时可拮抗炎性因子，保护神经抗凋亡，促进神经再生。本结果表明盐酸法舒地尔对促进神经功能的恢复，减轻临床症状，减少病残率有一定疗效。因此对于在基层由于受经济条件的制约以及对疾病认识程度，超早期溶栓治疗不能实现，但为减少疾病的进一步进展，在治疗时间窗内重建局部血循环显得至关重要，而盐酸法舒地尔具有对缺血性脑血管病的显著神经保护和治疗作用，值得在临床尤其是基层的使用，减少致残率，提高生活质量。
WO2004106325公开了一类化合物，属于法舒地尔的前药，其结构通式如式(B-Ⅰ)所示：
Figure PCTCN2015077046-appb-000001
尽管现有技术中存在上述化合物可作为RHO激酶抑制剂，但是它们在活性、溶解性、药代动力学、成药性的等方面有待改进。
发明内容
本发明的目的在于提供式(I)或(Ⅱ)所示化合物或其药学上可接受的盐，
Figure PCTCN2015077046-appb-000002
Figure PCTCN2015077046-appb-000003
其特征是，
R1、R2分别独立地选自R3C(＝O)O-、(R4O)2P(＝O)O-；
R3选自C1-6烷基、(R5)(R6)N-、R7O-、苯基、吡啶基、噻吩基、呋喃基；
R4、R5、R6、R7分别独立地选自选自H或C1-3烷基；
所述C1-6烷基、C1-3烷基任选地被R01所取代；
R01选自F、Cl、Br、I、OH、NH2，R01的数目为1、2或3。
本发明的一个方案中，上述R3选自丙基、丁基、二甲氨基；
本发明的一个方案中上述R3选自异丙基、叔丁基、二甲氨基。
本发明的一个方案中，上述R1、R2分别独立地选自
Figure PCTCN2015077046-appb-000004
Figure PCTCN2015077046-appb-000005
本发明的一个方案中，上述药学上可接受的盐如(Ⅲ)或(Ⅳ)所示：
Figure PCTCN2015077046-appb-000006
其中，X选自无机酸或有机酸。
本发明的一个方案中，上述的X选自三氟甲磺酸、盐酸、氢溴酸、硝酸、碳酸，碳酸氢根、磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等、乙酸、丙酸、异丁酸、马来酸、丙 二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸、甲磺酸、氨基酸或葡糖醛酸。
本发明的一个方案中上述化合物或其药学上可接受的盐，其选自：
Figure PCTCN2015077046-appb-000007
本发明的另一个目的在于提供一种药物组合物，其含有治疗有效量的上述化合物或其药学上可接受的盐和药学上可接受的载体。
本发明的另一个目的在于提供上述化合物或其药学上可接受的盐或上述药物组合物在制备治疗血管收缩引起的相关各种病症的药物中的应用，其中所述相关的各种病症包括脑栓塞、脑缺血、脑损伤、椎底动脉供血不足、蛛网膜下腔出血所引起的脑血管痉挛、心绞痛、青光眼、高血压、纤维化。
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐(参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977))。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一 碱或酸加成盐。
优选地，以常规方式使盐与碱或酸接触，再分离母体化合物，由此再生化合物的中性形式。化合物的母体形式与其各种盐的形式的不同之处在于某些物理性质，例如在极性溶剂中的溶解度不同。
本文所用的“药学上可接受的盐”属于本发明化合物的衍生物，其中，通过与酸成盐或与碱成盐的方式修饰所述母体化合物。药学上可接受的盐的实例包括但不限于：碱基比如胺的无机酸或有机酸盐、酸根比如羧酸的碱金属或有机盐等等。药学上可接受的盐包括常规的无毒性的盐或母体化合物的季铵盐，例如无毒的无机酸或有机酸所形成的盐。常规的无毒性的盐包括但不限于那些衍生自无机酸和有机酸的盐，所述的无机酸或有机酸选自2-乙酰氧基苯甲酸、2-羟基乙磺酸、乙酸、抗坏血酸、苯磺酸、苯甲酸、碳酸氢根、碳酸、柠檬酸、依地酸、乙烷二磺酸、乙烷磺酸、富马酸、葡庚糖、葡糖酸、谷氨酸、乙醇酸、氢溴酸、盐酸、氢碘酸盐、羟基、羟萘、羟乙磺酸、乳酸、乳糖、十二烷基磺酸、马来酸、苹果酸、扁桃酸、甲烷磺酸、硝酸、草酸、双羟萘酸、泛酸、苯乙酸、磷酸、多聚半乳糖醛、丙酸、水杨酸、硬脂酸、亚乙酸、琥珀酸、氨基磺酸、对氨基苯磺酸、硫酸、单宁、酒石酸和对甲苯磺酸。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。一般地，优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。
除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。
本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。本发明的某些化合物可以以多晶或无定形形式存在。
本发明的某些化合物可以具有不对称碳原子(光学中心)或双键。外消旋体、非对映异构体、几何异构体和单个的异构体都包括在本发明的范围之内。
本文中消旋体、ambiscalemic and scalemic或者对映体纯的化合物的图示法来自Maehr,J.Chem.Ed.1985,62:114-120。1985年，62：114-120。除非另有说明，用楔形键和虚线键表示一个立体中心的绝对构型。当本文所述化合物含有烯属双键或其它几何不对称中心，除非另有规定，它们包括E、Z几何异构体。同样地，所有的互变异构形式均包括在本发明的范围之内。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分 子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的分步结晶法或色谱法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚(3H)，碘-125(125I)或C-14(14C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
术语“药学上可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者患者无毒副作用的任何制剂或载体介质代表性的载体包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。它们的制剂为化妆品领域或局部药物领域的技术人员所周知。关于载体的其他信息，可以参考Remington:The Science and Practice of Pharmacy,21st Ed.,Lippincott,Williams&Wilkins(2005)，该文献的内容通过引用的方式并入本文。
术语“赋形剂”通常是指配制有效的药物组合物所需要载体、稀释剂和/或介质。
针对药物或药理学活性剂而言，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型，组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
术语“活性成分”、“治疗剂”，“活性物质”或“活性剂”是指一种化学实体，它可以有效地治疗目标紊乱、疾病或病症。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为酮基(即＝O)时，意味着两个氢原子被取代。酮取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个取代基的键可以交叉连接到一个环上的两个原子时，这种取代基可以与这个环上的任意原子相键合。当所列举的取代基中没有指明其通过哪一个原子连接到化学结构通式中包括但未具体提及的化合物时，这种取代基可以通过其任何原子相键合。取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
烷基和杂烷基原子团(包括通常被称为亚烷基、链烯基、亚杂烷基、杂烯基、炔基、环烷基、杂环烷基、环烯基和杂环烯基的那些基团)的取代基一般被称为“烷基取代基”，它们可以选自但不限于下列基团中的一个或多个：-R’、-OR’、＝O、＝NR’、＝N-OR’、-NR’R”、-SR’、卤素、-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)2和氟代(C1-C4)烷基,取代基的数目为0～(2m’+1),其中m’是这类原子团中碳原子的总数。R'、R”、R”'、R””和R””’各自独立地优选氢、被取代或未被取代的杂烷基、被取代或未被取代的芳基(例如被1～3个卤素取代芳基)、被取代或未被取代的烷基、烷氧基、硫代烷氧基基团或芳烷基。当本发明的化合物包括一个以上的R基团时，例如，每一个R基团是独立地加以选择的，如同当存在一个以上的R'、R”、R”'、R””和R””’基团时的每个这些基团。当R'和R”附着于同一个氮原子时，它们可与该氮原子结合形成5-，6-或7-元环。例如，-NR'R“意在包括但不仅限于1-吡咯烷基和4-吗啉基。根据上述关于取代基的讨论中，本领域技术人员可以理解，术语“烷基”意在包括碳原子键合于非氢基团所构成的基团，如卤代烷基(例如-CF3、-CH2CF3)和酰基(例如-C(O)CH3、-C(O)CF3、-C(O)CH2OCH3等)。
与烷基原子团所述取代基相似，芳基和杂芳基取代基一般统称为“芳基取代基”，选自例如-R’、-OR’、-NR’R”、-SR’、-卤素,-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)2、氟(C1-C4)烷氧基和氟(C1-C4)烷基等，取代基的数量为0到芳香环上开放化合价的总数之间；其中R’、R”、R”’、R””和R””’独立地优选自氢、被取代或未被取代的烷基、被取代或未被取代的杂烷基、被取代或未被取代的芳基和被取代或未被取代的杂芳基。当本发明的化合物包括一个以上的R基团时，例如，每个R基团是独立地加以选择的，如同当存在一个以上R’、R”、R”’、R””和R””’基团时的每个这些基团。
芳基或杂芳基环的相邻原子上的两个取代基可以任选地被通式为–T-C(O)-(CRR’)q-U-的取代基所取代，其中T和U独立地选自-NR-、-O-、CRR'-或单键，q是0到3的整数。作为替代选择，芳基或杂芳基环的相邻原子上的两个取代基可以任选地被通式为–A(CH2)r B-的取代基所取代，其中A和B独立的选自–CRR’-、-O-、-NR-、-S-、-S(O)-、S(O)2-、-S(O)2NR’-或单键，r是1～4的整数。任选地，由此形成的新环上的一个单键可以替换为双键。作为替代选择，芳基或杂芳基环的相邻原子上的两个取代基可以任选地被通式为–A(CH2)r B-的取代基所取代，其中s和d分别独立的选自0～3的整数，X是–O-、-NR’、-S-、-S(O)-、-S(O)2-或–S(O)2NR’-。取代基R、R’、R”和R”’分别独立地优选自氢和被取代或未被取代的(C1-C6)烷基。
除非另有规定，术语“卤代素”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。此外，术语“卤代烷基”意在包括单卤代烷基和多卤代烷基。例如，术语“卤代(C1-C4)烷基”意在包括但不仅限于三氟甲基、2，2，2-三氟乙基、4-氯丁基和3-溴丙基等等。
卤代烷基的实例包括但不仅限于：三氟甲基、三氯甲基、五氟乙基，和五氯乙基。“烷氧基”代表通过氧桥连接的具有特定数目碳原子的上述烷基。C1-6烷氧基包括C1、C2、C3、C4、C5和C6的烷氧基。烷氧基的例子包括但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基和S-戊氧基。“环烷基”包括饱和环基，如环丙基、环丁基或环戊基。3-7环烷基包括C3、C4、C5、C6和C7环烷基。“链烯基”包括直链或支链构型的烃链，其中该链上任何的稳定位点上存在一个或多个碳-碳双键，例如乙烯基和丙烯基。
术语“卤”或“卤素”是指氟、氯、溴和碘。
除非另有规定，术语“杂”表示杂原子或杂原子团(即含有杂原子的原子团)，包括碳(C)和氢(H)以外的原子以及含有这些杂原子的原子团，例如包括氧(O)、氮(N)、硫(S)、硅(Si)、锗(Ge)、铝(Al)、硼(B)、-O-、-S-、＝O、＝S、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O)2-，以及任选被被取代的-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O)2N(H)-或-S(＝O)N(H)-。
除非另有规定，“环”表示被取代或未被取代的环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基、芳基或杂芳基。所谓的环包括单环、联环、螺环、并环或桥环。环上原子的数目通常被定义为环的元数，例如，“5～7元环”是指环绕排列5～7个原子。除非另有规定，该环任选地包含1～3个杂原子。因此，“5～7元环”包括例如苯基吡啶和哌啶基；另一方面，术语“5～7元杂环烷基环”包括吡啶基和哌啶基，但不包括苯基。术语“环”还包括含有至少一个环的环系，其中的每一个“环”均独立地符合上述定义。
除非另有规定，术语“杂环”或“杂环基”意指稳定的含杂原子或杂原子团的单环、双环或三环，它们可以是饱和的、部分不饱和的或不饱和的(芳族的)，它们包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子，其中上述任意杂环可以稠合到一个苯环上形成双环。氮和硫杂原子可任选被氧化(即NO和S(O)p)。氮原子可以是被取代的或未取代的(即N或NR，其中R是H或本文已经定义过的其他取代基)。该杂环可以附着到任何杂原子或碳原子的侧基上从而形成稳定的结构。如果产生的化合物是稳定的，本文所述的杂环可以发生碳位或氮位上的取代。杂环中的氮原子任选地被季铵化。一个优选方案是，当杂环中S及O原子的总数超过1时，这些杂原子彼此不相邻。另一个优选方案是，杂环中S及O原子的总数不超过1。如本文所用，术语“芳族杂环基团”或“杂芳基”意指稳定的5、6、7元单环或双环或7、8、9或10元双环杂环基的芳香环，它包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子。氮原子可以是被取代的或未取代的(即N或NR，其中R是H或本文已经定义过的其他取代基)。氮和硫杂原子可任选被氧化(即NO和S(O)p)。值得注意的是，芳香杂环上S和O原子的总数不超过1。桥环也包含在杂环的定义中。当一个或多个原子(即C、O、N或S)连接两个不相邻的碳原子或氮原子时形成桥环。优选的桥环包括但不限于：一个碳原子、两个碳原子、一个氮原子、两个氮原子和一个碳-氮基。值得注意的是，一个桥总是将单环转换成三环。桥环中，环上的取代基也可以出现在桥上。
杂环化合物的实例包括但不限于：吖啶基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并巯基呋喃基、苯并巯基苯基、苯并恶唑基、苯并恶唑啉基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异恶唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、苯并二氢吡喃基、色烯、噌啉基十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、吲哚烯基、二氢吲哚基、中氮茚基、吲哚基、3H-吲哚基、isatino基、异苯并呋喃基、吡喃、异吲哚基、异二氢吲哚基、异吲哚基、吲哚基、异喹啉基、异噻唑基、异恶唑基、亚甲二氧基苯基、吗啉基、萘啶基，八氢异喹啉基、恶二唑基、1,2,3-恶二唑基、1,2,4-恶二唑基、1,2,5-恶二唑基、1,3,4-恶二唑基、恶唑烷基、恶唑基、异恶唑基、羟吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪、吩噻嗪、苯并黄嘌呤基、酚恶嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、蝶啶基、 嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑基、哒嗪基、吡啶并恶唑、吡啶并咪唑、吡啶并噻唑、吡啶基、嘧啶基、吡咯烷基、吡咯啉基、2H-吡咯基、吡咯基、吡唑基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、四唑基，6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、异噻唑基噻吩基、噻吩基、噻吩并恶唑基、噻吩并噻唑基、噻吩并咪唑基、噻吩基、三嗪基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基和呫吨基。还包括稠环和螺环化合物。
除非另有规定，术语“烃基”或者其下位概念(比如烷基、烯基、炔基、苯基等等)本身或者作为另一取代基的一部分表示直链的、支链的或环状的烃原子团或其组合，可以是完全饱和的、单元或多元不饱和的，可以是单取代、二取代或多取代的，可以包括二价或多价原子团，具有指定数量的碳原子(如C1-C10表示1至10个碳)。“烃基”包括但不限于脂肪烃基和芳香烃基，所述脂肪烃基包括链状和环状，具体包括但不限于烷基、烯基、炔基，所述芳香烃基包括但不限于6-12元的芳香烃基，例如苯、萘等。在一些实施例中，术语“烷基”表示直链的或支链的原子团或它们的组合，可以是完全饱和的、单元或多元不饱和的，可以包括二价和多价原子团。饱和烃原子团的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、异丁基、环己基、(环己基)甲基、环丙基甲基，以及正戊基、正己基、正庚基、正辛基等原子团的同系物或异构体。不饱和烷基具有一个或多个双键或三键，其实例包括但不限于乙烯基、2-丙烯基、丁烯基、巴豆基、2-异戊烯基、2-(丁二烯基)、2，4-戊二烯基、3-(1，4-戊二烯基)、乙炔基、1-和3-丙炔基，3-丁炔基，以及更高级的同系物和异构体。
除非另有规定，术语“杂烃基”或者其下位概念(比如杂烷基、杂烯基、杂炔基、杂芳基等等)本身或者与另一术语联合表示稳定的直链的、支链的或环状的烃原子团或其组合，有一定数目的碳原子和至少一个杂原子组成。在一些实施例中，术语“杂烷基”本身或者与另一术语联合表示稳定的直链的、支链的烃原子团或其组合物，有一定数目的碳原子和至少一个杂原子组成。在一个典型实施例中，杂原子选自B、O、N和S，其中氮和硫原子任选地被氧化，氮杂原子任选地被季铵化。杂原子B、O、N和S可以位于杂烃基的任何内部位置(包括该烃基附着于分子其余部分的位置)。实例包括但不限于-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-OCH3和–CH＝CH-N(CH3)-CH3。至多两个杂原子可以是连续的，例如-CH2-NH-OCH3。
术语“烷氧基”、“烷氨基”和“烷硫基”(或硫代烷氧基)属于惯用表达，是指分别通过一个氧原子、氨基或硫原子连接到分子的其余部分的那些烷基基团。
除非另有规定，术语“环烃基”、“杂环烃基”或者其下位概念(比如芳基、杂芳基、环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基等等)本身或与其他术语联合分别表示环化的“烃基”、“杂烃基”。此外，就杂烃基或杂环烃基(比如杂烷基、杂环烷基)而言，杂原子可以占据该杂环附着于分子其余部分的位置。环烷基的实例包括但不限于环戊基、环己基、1-环己烯基、3-环己烯基、环庚基等。杂环基的非限制性实例包括1-(1,2,5,6-四氢吡啶基)、1-哌啶基、2-哌啶基，3-哌啶基、4-吗啉基、3-吗啉基、四氢呋喃-2-基、四氢呋喃吲哚-3-基、四氢噻吩-2-基、四氢噻吩-3-基，1-哌嗪基和2-哌嗪基。
除非另有规定，术语“芳基”表示多不饱和的芳族烃取代基，可以是单取代、二取代或多取代的，它 可以是单环或多环(优选1至3个环)，它们稠合在一起或共价连接。术语“杂芳基”是指含有一至四个杂原子的芳基(或环)。在一个示范性实例中，杂原子选自B、N、O和S，其中氮和硫原子任选地被氧化，氮原子任选地被季铵化。杂芳基可通过杂原子连接到分子的其余部分。芳基或杂芳基的非限制性实施例包括苯基、1-萘基、2-萘基、4-联苯基、1-吡咯基、2-吡咯基、3-吡咯基、3-吡唑基、2-咪唑基、4-咪唑基、吡嗪基、2-恶唑基、4-恶唑基、2-苯基-4-恶唑基、5-恶唑基、3-异恶唑基、4-异恶唑基、5-异恶唑基、2-噻唑基、4-噻唑基、5-噻唑基、2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-苯并噻唑基、嘌呤基、2-苯并咪唑基、5-吲哚基、1-异喹啉基、5-异喹啉基、2-喹喔啉基、5-喹喔啉基、3-喹啉基和6-喹啉基。上述任意一个芳基和杂芳基环系的取代基选自下文所述的可接受的取代基。
为简便起见，芳基在与其他术语联合使用时(例如芳氧基、芳硫基、芳烷基)包括如上定义的芳基和杂芳基环。因此，术语“芳烷基”意在包括芳基附着于烷基的那些原子团(例如苄基、苯乙基、吡啶基甲基等)，包括其中碳原子(如亚甲基)已经被例如氧原子代替的那些烷基，例如苯氧基甲基、2-吡啶氧甲基3-(1-萘氧基)丙基等。
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲和取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明采用下述缩略词：aq代表水；HATU代表O-7-氮杂苯并三唑-1-基)-N，N，N'，N'-四甲基脲六氟磷酸盐；EDC代表N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐；m-CPBA代表3-氯过氧苯甲酸；eq代表当量、等量；CDI代表羰基二咪唑；DCM代表二氯甲烷；PE代表石油醚；DIAD代表偶氮二羧酸二异丙酯；DMF代表N，N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；CBz代表苄氧羰基，是一种胺保护基团；BOC代表叔丁基羰基是一种胺保护基团；HOAc代表乙酸；NaCNBH3代表氰基硼氢化钠；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；Boc2O代表二-叔丁基二碳酸酯；TFA代表三氟乙酸；DIPEA代表二异丙基乙基胺；SOCl2代 表氯化亚砜；CS2代表二硫化碳；TsOH代表对甲苯磺酸；NFSI代表N-氟-N-(苯磺酰基)苯磺酰胺；NCS代表1-氯吡咯烷-2,5-二酮；n-Bu4NF代表氟化四丁基铵；iPrOH代表2-丙醇；mp代表熔点。
化合物经手工或者
Figure PCTCN2015077046-appb-000008
软件命名，市售化合物采用供应商目录名称。
除非另有规定，化合物经手工或者
Figure PCTCN2015077046-appb-000009
软件命名，市售化合物采用供应商目录名称。
与现有技术相比，本发明化合物高效、低毒，在活性、半衰期、溶解度和药代动力学等方面均取得了显著甚至预料不到的进步，更适合于制药。
具体实施方式
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
实施例1
(5-((1,4-二氮杂环庚烷-1-基)磺酰基)-1-氧代异喹啉-2(1H)-基)甲基异丁酯
Figure PCTCN2015077046-appb-000010
第一步
将异喹啉1a(47.5mL，405mmol)缓慢加入到22mL浓硫酸中，充分搅拌成小块，然后加入到200mL 20％的发烟硫酸中，室温放置两天。然后倒入700g冰水中并静置过夜，得到的悬浊液过滤，滤饼用水洗涤两遍(100mLx2)，干燥，得到异喹啉-5-磺酸1b(50g，产率：60％)，直接用于下一步反应
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计算值[M+H]+210,实测值210.
第二步
室温下将异喹啉-5-磺酸1b(4.0g,0.019mol)加入到25mL的氯化亚砜中，然后加入0.1mL的N,N-二甲基甲酰胺。反应加热回流两小时后，减压蒸掉多余的氯化亚砜，蒸发残渣用冷的二氯甲烷洗涤(10mLx2)。干燥得到目标产物异喹啉-5-磺酰氯1c(3.9g，黄色固体，产率：100％)。
MS-ESI计算值[M+H]+227实测值227。
第三步
将异喹啉-5-磺酰氯1c(3.00g,11.3mmol)溶解于20mL二氯甲烷中，在氮气保护下0℃先后加入1,4-二氮杂环庚烷-1-羧酸叔丁酯(2.60g,13.0mmol)和N,N-二异丙基乙基胺(7.5mL,35.0mmol)。所得反应液室温搅拌16小时直到反应结束。用二氯甲烷(100mL)和水(100mL)稀释，二氯甲烷萃取(100mLx2),合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱(0-100％乙酸乙酯/石油醚)纯化得目标化合物4-(异喹啉-5-基磺酰基)-1,4-二氮杂环庚烷-1-羧酸叔丁酯1d(4.5g,无色油状物，产率：100％)。MS-ESI计算值[M+H]+392,实测值392。
第四步
0℃将4-(异喹啉-5-基磺酰基)-1,4-二氮杂环庚烷-1-羧酸叔丁酯1d(5.38g,13.8mmol)的200mL二氯甲烷溶液中分批加入间氯过氧苯羧酸(4.80g，27.6mmol)，然后升至室温搅拌2小时直至反应结束。直接蒸干溶剂后用色谱硅胶柱纯化(0-100％乙酸乙酯/石油醚)得到5-((4-(叔丁氧基羰基)-1,4-二氮杂环庚烷-1-基)磺酰基)异喹啉-2-氧化物1e(4.9g,黄色油状液体，产率：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计算值[M+H]+408,实测值408。
第五步
将5-((4-(叔丁氧基羰基)-1,4-二氮杂环庚烷-1-基)磺酰基)异喹啉-2-氧化物1e(5.70g,14.0mmol)溶于50mL乙酸酐中在100℃下搅拌2小时直到反应结束。反应液减压浓缩除去溶剂后将残余物溶解于50mL的四氢呋喃中，加入100mL30％的氢氧化钠水溶液后于室温搅拌0.5小时。减压除去四氢呋喃后用稀盐酸调节反应液的pH到7，将得到的悬浊液过滤，滤饼用水(10mLx2)洗涤，干燥，得到4-((1-氧代-1,2-二氢异喹啉-5-基)磺酰基)-1,4-二氮杂环庚烷-1-羧酸叔丁酯1f(3g，浅红色固体，产率：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计算值[M+H]+408,实测值408。
第六步
在氮气保护下将4-((1-氧代-1,2-二氢异喹啉-5-基)磺酰基)-1,4-二氮杂环庚烷-1-羧酸叔丁酯1f(5.50g,13.5mmol)溶解于110mL六甲基磷酰三胺中，于0℃条件下缓慢加入氢化钠(0.595g,14.9mmol)并在同一温度下反应15分钟，然后向反应液滴加氯甲基异丁酸酯(2.24g,14.9mmol)，加完后升至室温并反应 1小时。待反应结束后将反应液慢慢滴加到冰水(200mL)中，用乙酸乙酯(100mL×3)萃取，有机相用无水硫酸钠干燥，过滤，浓缩，残余物通过色谱硅胶柱纯化(0-100％乙酸乙酯/石油醚)得到4-((2-((异丁酰氧基)甲基)-1-氧代-1,2-二氢异喹啉-5-基)磺酰基)-1,4-二氮杂环庚烷-1-羧酸叔丁酯1g(5.8g，白色固体，产率：85％)。
MS-ESI计算值[M+H]+508,实测值508。
第七步
将4-((2-((异丁酰氧基)甲基)-1-氧代-1,2-二氢异喹啉-5-基)磺酰基)-1,4-二氮杂环庚烷-1-羧酸叔丁酯1g(5.80g,11.4mmol)溶解于690mL的二氯甲烷中，在0℃和氮气保护下缓慢滴加三氟甲磺酰基三甲基硅烷(5.06g,22.8mmol)，控制温度在0-5℃范围内。反应液反应45分钟后向其中滴加2,6-二甲基吡啶(3.66g,34.2mmol)，在0-5℃继续反应1小时直到反应结束。把反应液缓慢加入到冰水(200mL)中，用二氯甲烷(100mL×3)萃取，有机相用无水硫酸钠干燥，过滤，浓缩得到的残留物用乙酸乙酯重结晶得到(5-((1,4-二氮杂环庚烷-1-基)磺酰基)-1-氧代异喹啉-2(1H)-基)甲基异丁酯1(2.5g，淡黄色固体，产率：54％)。
1H NMR(400MHz,D2O):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计算值[M+H]+408,实测值408。
实施例2
((5-((1,4-二氮杂环庚烷-1-基)磺酰基)-1-氧代异喹啉-2(1H)-基)甲基)膦酸
Figure PCTCN2015077046-appb-000011
第一步
4-(异喹啉-5-基磺酰基)-1,4-二氮杂环庚烷-1-羧酸叔丁酯1d(4.10g，11.2mmol)溶解于30mL的乙酸乙酯中，于0℃滴加20mL乙酸乙酯的饱和氯化氢溶液，反应液于室温反应0.5小时。把得到的悬浊液过滤，滤饼用乙酸乙酯洗涤(10mLx2),干燥得到5-((1,4-二氮杂环庚烷-1-基)磺酰基)异喹啉2a(2.6g,白色固体，产率：87％)。
第二步
氮气保护下向5-((1,4-二氮杂环庚烷-1-基)磺酰基)异喹啉2a(4.00g,11.1mmol)的80mL二氯甲烷溶液中加入N,N-二甲基甲酰胺(5.90mL,33.3mmol),然后于0℃滴加氯甲酸苄酯(2.10g,12.2mmol)。滴加完毕后将反应液升至室温并反应2小时后，用50mL水稀释反应液，二氯甲烷(30mLx2)萃取，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶色谱法纯化(0～100％乙酸乙酯/石油醚)得到4-(异喹啉-5-基磺酰基)-1,4-二氮杂-1-羧酸苄酯2b(6.4g,无色油状液体，产率：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计算值[M+H]+426,实测值426。
第三步
4-(异喹啉-5-基磺酰基)-1,4-二氮杂-1-羧酸苄酯2b(7.4g,17.4mmol)按照实施例1的合成方法得到5-((4-((苄氧基)羰基)-1,4-二氮杂环庚烷-1-基)磺酰基)异喹啉-2-氧化物2c(5.0g,黄色油状物，产率：65％)。
MS-ESI计算值[M+H]+442,实测值442。
第四步
将5-((4-((苄氧基)羰基)-1,4-二氮杂环庚烷-1-基)磺酰基)异喹啉-2-氧化物2c(5.00g,11.3mmol)溶解于70mL醋酸酐中，加热到130℃反应4小时。待反应结束后减压蒸馏除去多余的乙酸酐，残余物溶解于50mL的四氢呋喃中，并加入100mL30％的氢氧化钠。反应液室温搅拌0.5小时，然后减压蒸馏除去四氢呋喃并将反应液调pH到中性，得到的悬浊液过滤，滤饼干燥得到4-((1-氧代-1,2-二氢异喹啉-5-基)磺酰基)-1,4-二氮杂-1-羧酸苄酯2d(4.5g,棕色固体，产率：90％)。
MS-ESI计算值[M+H]+442,实测值442。
第五步
4-((1-氧代-1,2-二氢异喹啉-5-基)磺酰基)-1,4-二氮杂-1-羧酸苄酯2d(1.00g,2.27mmol)和氯甲基磷酸二苄酯(816mg,2.5mmol)按照实施例1的合成方法得到4-((2-((双(苄氧基)磷酰基)甲基)-1-氧代-1,2-二氢异喹啉-5-基)磺酰基)-1,4-二氮杂-1-羧酸苄酯2e(140mg，棕色油状物，产率：8.5％)。
1H NMR(400MHz,CDCl3):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(m 2H),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计算值[M+H]+716,实测值716。
第六步
向4-((2-((双(苄氧基)磷酰基)甲基)-1-氧代-1,2-二氢异喹啉-5-基)磺酰基)-1,4-二氮杂-1-羧酸苄酯2e(100mg,0.140mmol)的20mL四氢呋喃和2.5mL水的混合溶剂中加入湿钯碳(70mg,10％),在一个大气压氢气氛中室温反应4小时。反应结束后硅藻土过滤，浓缩，得((5-((1,4-二氮杂环庚烷-1-基)磺酰基)-1-氧代异喹啉-2(1H)-基)甲基)膦酸2(63mg,白色固体，产率：100％)。
1H NMR(400MHz,D2O):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计算值[M+H]+402,实测值402。
实施例3
Figure PCTCN2015077046-appb-000012
第一步
4-((1-氧代-1,2-二氢异喹啉-5-基)磺酰基)-1,4-二氮杂环庚烷-1-羧酸叔丁酯1f(200mg,0.49mmol)按照实施例1的合成方法得到4-((2-((苯甲酰氧基)甲基)-1-氧代-1,2-二氢异喹啉-5-基)磺酰基)-1,4-二氮杂环庚烷-1-羧酸叔丁酯3a(150mg,白色固体，产率：56％)。
1H NMR(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).
第二步
4-((2-((苯甲酰氧基)甲基)-1-氧代-1,2-二氢异喹啉-5-基)磺酰基)-1,4-二氮杂环庚烷-1-羧酸叔丁酯3a(150mg,0.28mmol)按照实施例1的合成方法得到(5-(1,4-二氮杂环庚烷-1-基)磺酰基)-1-氧代异喹啉-2(1H)-基)苯羧酸甲酯3(50mg,白色固体，产率：41％)。
1H NMR(400MHz,D2O):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).
实施例4
5-((1,4-二氮杂环庚烷-1-基)磺酰基)-1-氧代异喹啉-2(1H)-基)氧基)甲基新戊酸酯4,((5-((1,4-二氮杂环庚烷-1-基)磺酰基)异喹啉-1-基)氧基)甲基新戊酸酯4’
Figure PCTCN2015077046-appb-000013
第一步
4-((1-氧代-1,2-二氢异喹啉-5-基)磺酰基)-1,4-二氮杂环庚烷-1-羧酸叔丁酯1f(0.50g,1.23mmol)按照实施例1的合成方法得到4-((1-氧代-2-((新戊酰氧基)甲基)-1,2-二氢异喹啉-5-基)磺酰基)-1,4-二氮杂-1-羧酸叔丁酯4a1和4-((1-((新戊酰氧基)甲氧基)异喹啉-5-基)磺酰基)-1,4-二氮杂环庚烷-1-羧酸叔丁酯4a2的混合物(0.34g，白色固体，产率：50％)。
4a1:1H NMR(400MHz,CDCl3):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计算值[M+H]+522,实测值522。
4a2:1H NMR(400MHz,CDCl3):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计算值[M+H]+522,实测值522。
第二步
4-((1-氧代-2-((新戊酰氧基)甲基)-1,2-二氢异喹啉-5-基)磺酰基)-1,4-二氮杂-1-羧酸叔丁酯4a1和4-((1-((新戊酰氧基)甲氧基)异喹啉-5-基)磺酰基)-1,4-二氮杂环庚烷-1-羧酸叔丁酯4a2(100mg,0.19mmol)按照实施例1的合成方法得到5-((1,4-二氮杂环庚烷-1-基)磺酰基)-1-氧代异喹啉-2(1H)-基)氧基)甲基新戊酸酯4和((5-((1,4-二氮杂环庚烷-1-基)磺酰基)异喹啉-1-基)氧基)甲基新戊酸酯4’(50mg,淡黄色固体，产率：53％)。
4:1H NMR(400MHz,CDCl3):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计算值[M+H]+422,实测值422。
4’:1H NMR(400MHz,CDCl3):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计算值[M+H]+422,实测值422。
实施例5
(5-((1,4-二氮杂环庚烷-1-基)磺酰基)-1-氧代异喹啉-2(1H)基)二甲氨基羧酸甲酯
Figure PCTCN2015077046-appb-000014
第一步
在氮气保护下将4-((1-氧代-1,2-二氢异喹啉-5-基)磺酰基)-1,4-二氮杂环庚烷-1-羧酸叔丁酯1f(200mg，0.49mmol)、二甲氨基羧酸氯甲酯(149mg，0.98mmol)和碳酸钾(224mg，1.47mmol)的20mL四氢呋喃溶液加热回流24小时。待反应结束后将反应液冷却至室温，除去溶剂，用制备薄层层析(50％乙酸乙酯/石油醚)得到4-((2-(((二甲氨基甲酰基)氧基)甲基)-1-氧代-1,2-二氢异喹啉-5-基)磺酰基)-1,4-二氮杂环庚烷-1-羧酸叔丁酯5a(100mg，白色固体，产率：39％)。
MS-ESI计算值[M+H]+509,实测值509。
第二步
室温下，将4-((2-(((二甲氨基甲酰基)氧基)甲基)-1-氧代-1,2-二氢异喹啉-5-基)磺酰基)-1,4-二氮杂环庚烷-1-羧酸叔丁酯5a(0.25g，0.45mmol)加入到4mL氯化氢气体的饱和1,4-二氧六环溶液中，并在室温持续搅拌0.5小时。待反应结束后将反应液浓缩，用制备薄层层析板(乙酸乙酯)分离得到(5-((1,4-二氮杂环庚烷-1-基)磺酰基)-1-氧代异喹啉-2(1H)基)二甲氨基羧酸甲酯5(150mg，淡黄色固体，产率：74％)。
1H NMR(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计算值[M+H]+409,实测值409。
实施例6
(5-((1,4-二氮杂环庚烷-1-基)磺酰基)-1-氧代异喹啉-2(1H)-基)甲基碳酸异丙酯
Figure PCTCN2015077046-appb-000015
第一步
4-((1-氧代-1,2-二氢异喹啉-5-基)磺酰基)-1,4-二氮杂环庚烷-1-羧酸叔丁酯1f(150mg,0.39mmol)和氯甲基碳酸异丙酯(77mg,0.51mmol)按照实施例1的合成方法经过两步反应得到(5-((1,4-二氮杂环庚烷-1-基)磺酰基)-1-氧代异喹啉-2(1H)-基)甲基碳酸异丙酯6(53mg,白色固体，产率：32％)。
1H NMR(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计算值[M+H]+424,实测值424。
实验例1：大鼠动力学测试
实验目的：
检测化合物在体内产生活性药物成分的速度和活性药物成分暴露量。实验材料:
雄性SD大鼠,体重200-250g，购自上海斯莱克实验动物有限公司.
实验操作:
实验前，动物进行颈动脉插管(用于血浆样品采集)，大鼠术后至少恢复3天，观察无异常后用于实验。口服给药给药剂量为10mg/kg，给药后0，5min，15min，30min，60min，2h，4h，6h，8h，24h采集全血并制备血浆样品。所有样品运用液相色谱偶联质谱质谱联用技术对给药化合物在实验动物血浆中含量进行定量检测，所测浓度值运用WinNonlin非房室模型,根据血浆浓度-时间数据，计算T1/2,Cmax,Tmax,AUC(0-t)和AUC(0-∞)等参数,并且绘制血浆浓度-时间曲线.
实验结果：
表1 大鼠动力血测试结果
Figure PCTCN2015077046-appb-000016
注：血药峰值浓度:+>1000nM；血药峰值时间:+<20min；单位暴露量:+>100nM.hr/μmol。

Claims (9)

  1. 式(I)或(Ⅱ)所示化合物或其药学上可接受的盐，
    Figure PCTCN2015077046-appb-100001
    其特征是，
    R1、R2分别独立地选自R3C(＝O)O-、(R4O)2P(＝O)O-；
    R3选自C1-6烷基、(R5)(R6)N-、R7O-、苯基、吡啶基、噻吩基、呋喃基；
    R4、R5、R6、R7分别独立地选自选自H或C1-3烷基；
    所述C1-6烷基、C1-3烷基任选地被R01所取代；
    R01选自F、Cl、Br、I、OH、NH2，R01的数目为1、2或3。
  2. 根据权利要求1所述的化合物或其药学上可接受的盐，其特征是，所述R3选自丙基、丁基、二甲氨基；
  3. 根据权利要求2所述的化合物或其药学上可接受的盐，其特征是，所述R3选自异丙基、叔丁基、二甲氨基。
  4. 根据权利要求1所述的化合物或其药学上可接受的盐，其特征是，所述R1、R2分别独立地选自
    Figure PCTCN2015077046-appb-100002
  5. 根据权利要求1所述的化合物或其药学上可接受的盐，其特征是，所述药学上可接受的盐如(Ⅲ)或(Ⅳ)所示：
    Figure PCTCN2015077046-appb-100003
    Figure PCTCN2015077046-appb-100004
    其中，X选自无机酸或有机酸。
  6. 根据权利要求5所述的化合物或其药学上可接受的盐，其特征是，所述的X选自三氟甲磺酸、盐酸、氢溴酸、硝酸、碳酸，碳酸氢根、磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等、乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸、甲磺酸、氨基酸或葡糖醛酸。
  7. 根据权利要求1所述的化合物或其药学上可接受的盐，其选自：
    Figure PCTCN2015077046-appb-100005
  8. 一种药物组合物，其含有治疗有效量的根据权利要求1～7任意一项所述的化合物或其药学上可接受的盐和药学上可接受的载体。
  9. 根据权利要求1～7任意一项所述的化合物或其药学上可接受的盐或根据权利要求8所述的药物组合物在制备治疗血管收缩引起的相关各种病症的药物中的应用，其中所述相关的各种病症包括脑栓塞、脑缺血、脑损伤、椎底动脉供血不足、蛛网膜下腔出血所引起的脑血管痉挛、心绞痛、青光眼、高血压、纤维化。
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