CN104387430B - Barrenwort glycosides compounds and its application - Google Patents
Barrenwort glycosides compounds and its application Download PDFInfo
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- CN104387430B CN104387430B CN201410586851.9A CN201410586851A CN104387430B CN 104387430 B CN104387430 B CN 104387430B CN 201410586851 A CN201410586851 A CN 201410586851A CN 104387430 B CN104387430 B CN 104387430B
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
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Abstract
The present invention relates to class barrenwort glycosides compounds of formula (I), or the stereoisomer of compound, geometric isomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug shown in formula (I).The invention also discloses the preparation method of pharmaceutical composition and the compounds of this invention or its drug regimen composition compound containing such compound and its application in the activity, the development for promoting gonad, preventing and treating sexual dysfunction disease for suppressing phosphate.
Description
Technical field
The present invention relates to barrenwort glycosides compounds, its preparation method and its activity in suppression phosphate, promotion property
Application in the development of gland, preventing and treating sexual dysfunction disease.
Background technology
Icariin is a kind of flavonoid glycoside compound in Berberidaceae barrenwort, the widest as China's application
A kind of general, the longest nourishing class Chinese medicine.Icariin can increase cardiovascular and cerebrovascular vessel blood flow, promote hemopoietic function, immune work(
Can and bone metabolism, the effects such as with kidney invigorating and YANG supporting, defying age, antitumor.Ning,H(Ning,et al.,
UrologyUrology,2006,68(6):1350-1354) with Agli Mario Dell (Agli, et al., Journal of
Natural Products,2008,71:1513) find that icariin and its derivant have the activity for suppressing phosphate -5
With the development for promoting gonad.(Xin, et al., the Asian J Androl.2003,5 (1) such as Xin:Research discovery 15-18),
Icariin is stronger than PDE4 to the rejection ability of PDE5 167.67 times.Icariin points out which to be possible to the high selectivity of PDE5
Become the medicine of the treatment erection disturbance of low side effect.
Sildenafil citrate (sldenafil) are developed by Pfizer companies, and first in listing in 1998
The medicine for the treatment of ED, but clinically there is the side effect such as headache, flush, visual disorder in which.Possess high activity and high selection
Property PDE5 inhibitor be focus that at present research and development prevent sexual dysfunction medicine.Icariin is used as China's Chinese medicine
Conventional composition in tonic invigorator prescription, remains as the heat in Field of Drug Discovery to the research of Herba Epimedii and its derivant
Point.
Content of the invention
The present invention relates to barrenwort glycosides compounds, its preparation method and its activity in suppression phosphate, promotion property
Application in the development of gland, preventing and treating sexual dysfunction disease.
On the one hand, the present invention relates to leading to the compound of formula (I), or the stereoisomer of compound, geometry are different shown in formula (I)
Structure body, tautomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug：
Wherein,
R1For cycloheteroalkylalkyl, aminoalkyl, NaOS (=O)2O- glucopyranosyls or NaOS (=O)2O-(CH2) n-, its
Described in cycloheteroalkylalkyl, aminoalkyl and NaOS (=O)2O-(CH2) n- independently optionally by H, alkyl, amino, halogen or
One or more substituent groups in alkoxyl are replaced；With
N is 2,3 or 4.
Wherein in some embodiments, the present invention has the compound as shown in formula (II), or compound shown in formula (II)
Stereoisomer, geometric isomer, tautomer, nitrogen oxides, raceme, hydrate, solvate, metabolite,
Pharmaceutically acceptable salt or prodrug：
Wherein in some embodiments, R1For C2-C6Heterocyclic radical C1-C6Alkyl, C1-C4Aminoalkyl, NaOS (=O)2O- pyrans
Glucosyl group or NaOS (=O)2-(CH2) n-, wherein described C2-C6Heterocyclic radical C1-C6Alkyl, C1-C4Aminoalkyl and NaOS (=
O)2O-(CH2) n- is independently optionally by H, C1-C3Alkyl, amino, halogen or C1-C3One or more in alkoxyl take
Replaced for base.
Wherein in some embodiments, R1For morpholinyl ethyl, 2- methyl morpholine base ethyls, 3- methyl morpholine base ethyls,
Morpholinyl methyl, morpholinyl propyl, morpholinyl butyl, morpholinyl amyl group, morpholinyl hexyl, piperidinoethyl, piperidino methyl,
Piperazinyl, pyrrolidinylmethyl, pyrrolidinyl ethyl, pyrrolidinylpropyl, NaOS (=O)2O- glucopyranosyls,
NaOS (=O)2O-(CH2)2-, NaOS (=O)2O-(CH2)3-, NaOS (=O)2O-(CH2)4-, dimethylamino ethyl, amino second
Base or dimethylamino-propyl.
In other embodiment, the present invention has the compound of one of,
Or the stereoisomer of said structure, geometric isomer, tautomer, nitrogen oxides, raceme, hydrate,
Solvate, metabolite, metabolic precursor thereof, pharmaceutically acceptable salt or prodrug.
On the other hand, the present invention relates to a kind of pharmaceutical composition, compound of the described pharmaceutical composition comprising the present invention, and
Its pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or combinations thereof.
On the other hand, the present invention relates to the use of the compounds of this invention or its pharmaceutical composition in phosphate esterase active is suppressed
On the way.
On the other hand, the present invention relates to the compounds of this invention or its pharmaceutical composition are used for protecting, processing, treating in preparation
Purposes in sexual dysfunction medicine.
Another aspect of the present invention is related to the preparation of formula (I) or the compound shown in formula (II), separate and purification method.
Content noted earlier only outlines certain aspects of the invention, but in terms of being not limited to these.In terms of these and its
Content in terms of him is made more specific complete description below.
Specific embodiment
Definition and general terms
Certain embodiments of the present invention are will now be described in more detail, the example is by the structural formula and chemical formula explanation that encloses.This
Invention intention covers all of replacement, modification and equivalent technical solutions, and they are included in such as the present invention of claim definition
In the range of.Those skilled in the art will appreciate that many can be used in reality with similar or equivalent method described herein and material
Trample the present invention.The present invention is not limited to method described herein and material.In the document, patent and similar material for being combined one
Or many different from the application or conflicting in the case of (including but not limited to defined term, term application, described
Technology, etc.), be defined by the application.
There are unless otherwise stated or in context significantly conflict, article " one " used herein, " one (kind) "
" described " is intended to include " at least one " or " one or more ".Therefore, these articles used herein refer to one or
The article of more than one (i.e. at least one) object.For example, " component " refers to one or more components, it is possible to have more than one
Component be taken into account in the embodiment of the embodiment using or use.
Term " study subject " used in the present invention refers to animal.Typically described animal is mammal.Tested right
As for example also referring to primate (the such as mankind, sex), cattle, sheep, goat, horse, dog, cat, rabbit, rat, little
Mus, fish, bird etc..In certain embodiments, the study subject is primate.In other embodiments, described receive
Examination is to liking people.
Term " patient " used in the present invention refers to people or other animals.In some embodiments, " patient " is
Refer to people.
" stereoisomer " is referred to identical chemical constitution, but the spatially different change of arrangement mode of atom or group
Compound.Stereoisomer includes enantiomer, diastereomer, conformer (rotamer), geometric isomer
(cis/trans) isomer, atropisomer, etc..
" chirality " be have with its mirror image can not overlap property molecule；And " achirality " refer to can be overlap with its mirror image
Molecule.
" enantiomer " refers to two isomers that can not be overlapped but be mutually mirror image relationship of a compound.
" diastereomer " refers to the stereoisomerism of two or more chiral centres and its molecule not mirror image each other
Body.Diastereomer has different physical propertys, such as fusing point, boiling point, spectral quality and reactivity.Diastereomer is mixed
Compound can be by high resolution analysises operation such as electrophoresis and chromatograph, and such as HPLC is separating.
Stereochemical definitions used in the present invention and rule typically follow S.P.Parker, Ed., McGraw-Hill
Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York；and
Eliel,E.and Wilen,S.,“Stereochemistry of Organic Compounds”,John Wiley &
Sons,Inc.,New York,1994.
Many organic compound are present with optical active forms, i.e., they have rotates the plane of linearly polarized light
Ability.When optically active compound is described, represent molecule with regard to one or more handss using prefix D and L or R and S
The absolute configuration at property center.Prefix d and l or (+) and (-) are the symbols for linearly polarized light rotation caused by appointed compound,
Wherein (-) or l represent that compound is left-handed.Prefix is dextrorotation for the compound of (+) or d.A kind of specific stereoisomerism
Body is enantiomer, and the mixture of this isomer is referred to as enantiomeric mixture.The 50 of enantiomer:50 mixture
Referred to as racemic mixture or racemic modification, when chemical reaction or during without stereo selectivity or during stereospecificity,
May occur in which such case.
According to the selection of starting material and method, the compounds of this invention can with possible isomer or they
Mixture, the form of such as racemic modification and non-corresponding isomer mixture (this depends on the quantity of asymmetric carbon atom) deposits
?.Optically active (R)-or (S)-isomer can use chiral synthon or chiral reagent to prepare, or be torn open using routine techniquess
Point.If compound contains a double bond, substituent group may be E or Z configurations；If containing dibasic cycloalkanes in compound
Base, the substituent group of cycloalkyl may have cis or trans configuration.
The mixture of any stereoisomer of gained can be separated into according to the difference in component physicochemical properties
Pure or substantially pure geometric isomer, enantiomer, diastereomer, for example, by chromatography and/or fractional crystallization
Method.
Term " tautomer " or " tautomeric form " refer to that Tong Guo the mental retardation with different-energy builds (low
Energy barrier) mutual inversion of phases constitutional isomer.If tautomerism is possible (as in the solution), can reach
The chemical equilibrium of tautomer.For example, (also referred to as proton translocation mutually makes a variation proton tautomer (protontautomer)
Structure body (prototropic tautomer)) include migrating the mutual inversion of phases to carry out by proton, such as keto-enol isomerization and
Imine-enamine isomerizations.Valence tautomerism body (valence tautomer) include by the restructuring of some bonding electronss come
The mutual inversion of phases for carrying out.The instantiation of ketoenol tautomerization is that pentane -2,4- diketone and the amyl- 3- alkene -2- ketone of 4- hydroxyls are mutual
The change of tautomeric.Another example tautomeric is phenol-keto tautomerism.One of phenol-keto tautomerism is concrete real
Example is the change of pyridine -4- alcohol and pyridine -4 (1H) -one tautomer.Unless otherwise noted, the compounds of this invention is all
Tautomeric forms are within the scope of the present invention.
Term " prodrug " used in the present invention, represents a compound and is converted into the compound shown in formula (I) in vivo.
Such conversion is hydrolyzed by prodrug in blood or is affected for precursor structure through enzymatic conversion in blood or tissue.This
Bright pro-drug compounds can be ester, and in existing invention, ester can be used as the phenyl ester class that have of prodrug, aliphatic
(C1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamatess and amino acid esters.One for example in the present invention
Compound includes hydroxyl, you can be acylated the compound for obtaining prodrug form.Other prodrug forms include
Phosphate ester, such as these phosphate compounds are obtained through the di on parent.Beg for regard to prodrug is complete
By may be referred to documents below：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery
Systems,Vol.14of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible
Carriers in Drug Design,American Pharmaceutical Association and Pergamon
Press,1987,J.Rautio et al,Prodrugs:Design and Clinical Applications,Nature
Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al,Prodrugs of
Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008,51,2328-2345.
" metabolite " refers to specific compound or its salt in vivo by the product obtained by metabolism.One change
The metabolite of compound can be identified by technology known to art that its activity can pass through the present invention such as and retouch
Adopt as stating and experimentally characterized.Such product can be by compound being administered through peroxidating, reducing, water
Solution, amidated, desamido- are acted on, esterification, degreasing, and enzymatic lysises etc. method is obtained.Correspondingly, the present invention includes compound
Metabolite, including compound and the mammal of the present invention are fully contacted the metabolite produced by a period of time.
" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salt of the compound of the present invention.Medicine
On, acceptable salt is known to us in art, such as document：S.M.Berge et al.,
J.Pharmaceutical Sciences,66：Described in 1-19,1977.The salt that pharmaceutically acceptable nontoxic acid is formed
Include, but is not limited to, reacting the inorganic acid salt to be formed with amino group has a hydrochlorate, hydrobromate, phosphate, sulfate,
Perchlorate, and acylate such as acetate, oxalates, maleate, tartrate, citrate, succinate, malonic acid
Salt, or these salt are obtained by described additive method such as ion exchange on books document.Other are pharmaceutically acceptable
Salt include adipate, alginate, Ascorbate, aspartate, benzene sulfonate, benzoate, bisulphate, boric acid
Salt, butyrate, Camphora hydrochlorate, camsilate, cyclopentyl propionate, digluconate, lauryl sulfate, ethyl sulfonic acid
Salt, formates, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproic acid
Salt, hydriodate, 2- hydroxy-ethanesulfonate salts, lactobionate, lactate, laruate, lauryl sulfate, malate,
Malonate, mesylate, 2- naphthalene sulfonates, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, mistake
Sulfate, 3- phenylpropionic acid salt, picrate, pivalate, propionate, stearate, rhodanate, tosilate,
Undecylate, valerate, etc..The salt obtained by appropriate alkali includes alkali metal, alkaline-earth metal, ammonium and N+(C1-4Alkyl)4
Salt.The present invention is also intended to contemplate the quaternary ammonium salt formed by the compound of any group comprising N.Water solublity or oil-soluble or
Dispersion product can be obtained by quaternization.Alkali metal or alkali salt include sodium, lithium, potassium, calcium, magnesium, etc..Pharmacy
Upper acceptable salt further includes the amine cation that appropriate, nontoxic ammonium, quaternary ammonium salt and gegenions are formed, such as halogenation
Thing, hydroxide, carboxylate, hydrosulphate, phosphoric acid compound, nitric acid compound, C1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.
The officinal salt of the present invention can be synthesized by parent compound, alkalescence or acidic moiety with conventional chemical processes.
In general, such salt can by make the free acid form of these compounds and stoichiometry suitable alkali (as Na, Ca,
The hydroxide of Mg or K, carbonate, bicarbonate etc.) reaction, or by making the free alkali form and chemistry of these compounds
The suitable acid reaction of metered amount is being prepared.Such reaction is generally carried out in water or organic solvent or the mixture of the two.
Usually, in the case of appropriate, need using non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile.?
Such as " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack Publishing Company,
Easton, Pa., (1985)；" pharmaceutical salts handbook：Property, selection and application (Handbook of Pharmaceutical
Salts：Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim,
Germany, 2002) in can find the list of the suitable salt of other.
" solvate " of the present invention refers to the association formed by one or more solvent molecules with compound of the invention
Thing.The solvent for forming solvate is included, but is not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, second
Acid, ethylaminoethanol.Term " hydrate " refers to that solvent molecule is the associated complex formed by water.
In addition, compound disclosed by the invention, include their salt, it is also possible to their hydrate forms or include its
The form of solvent (such as ethanol, DMSO, etc.) is obtained, for their crystallization.The present invention discloses compound can be with pharmacy
Upper acceptable solvent (including water) inherently or passes through design forming solvate；Therefore, it is contemplated that including solvation
And unsolvated form.
When term " blocking group " or " PG " refer to a substituent group with other reacted with functional groups, it is commonly used to hinder
Break or protect special feature.For example, " blocking group of amino " refers to that a substituent group is connected to block with amino group
Or in protection compound amino feature, suitable amido protecting group includes acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl
(BOC, Boc), benzyloxycarbonyl group (CBZ, Cbz) and 9- fluorenes methylene oxygen carbonyl (Fmoc).Similarly, " hydroxy-protective group " refers to hydroxyl
The substituent group of base is used for the feature for blocking or protecting hydroxyl, and suitable blocking group includes acetyl group and silicyl." carboxyl
Blocking group " refers to the substituent group of carboxyl for blocking or protecting the feature of carboxyl, general carboxyl-protecting group includes-
CH2CH2SO2Ph, cyano ethyl, 2- (TMS) ethyl, 2- (TMS) ethoxyl methyl, 2- is (to toluene
Sulfonyl) ethyl, 2- (p-nitrophenyl sulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitro-ethyl, etc..For protection
The general description of group refers to document：T W.Greene,Protective Groups in Organic Synthesis,
John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme,
Stuttgart,2005.
The as used in the present invention any disease of term " treatment " or disease, wherein some embodiment middle fingers improve disease
Disease or disease (slowing down or prevent or mitigate the development of disease or its at least one clinical symptoms).In other embodiments
In, " treatment " refers to mitigation or improves at least one body parameter, including the body parameter that may not be discovered by patient.Another
In a little embodiments, " treatment " refers to and (for example stablizes perceptible symptom) from body or physiologically (for example stablize body
Parameter) or above-mentioned two in terms of adjust disease or disease.In other embodiments, " treat " and refer to prevention or postpone disease or disease
The outbreak of disease, generation or deterioration.
As described in the invention, the compound of the present invention optionally can be replaced by one or more substituent groups, such as
General formula compound above, or as special example inside embodiment, subclass, and the class compound included by the present invention.
Should be appreciated that " optionally substituted " this term can exchange use with " substituted or non-substituted " this term.In general, art
Language " substituted " represent to structure in one or more hydrogen atoms replaced by concrete substituent group.Unless table in terms of other
Bright, an optional substituted radical can be replaced each commutable position in group.When in given structural formula not
One or more substituent groups that only position can be selected from concrete group are replaced, then substituent group can be with identical or different
Replace in each position.
In addition, it is necessary to illustrate, unless otherwise explicitly point out, the describing mode for being adopted in the present invention
" each ... independently be " and " ... be each independently " and " ... independently be " can be exchanged, and all should be interpreted broadly, and which both may be used
To refer in different groups, do not affected between expressed concrete option mutually between same-sign, it is also possible to represent in phase
In same group, do not affected between expressed concrete option mutually between same-sign.
" optional " or " optionally " means that event described later or environment may or may not occur, the explanation
Including the occasion that the thing or environment occur or do not occur.For example, " optionally by alkyl-substituted heterocyclic group " means
Alkyl can with but necessarily exist, the explanation includes that heterocyclic group is not replaced by alkyl by alkyl-substituted scene and heterocyclic group
Scene.
In each several part of this specification, the present invention discloses the substituent group of compound and discloses according to radical species or scope.Special
Do not point out, the present invention includes each independent sub-combinations thereof of each member of these radical species and scope.For example, term
“C1-C6Alkyl " refers in particular to individually disclosed methyl, ethyl, C3Alkyl, C4Alkyl, C5Alkyl and C6Alkyl.
Term " amino " refers to " NH2”.
Term " halogen " refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
Term " NaOS (O)2O- glucopyranosyls " represent the group such as right structure：
Term " heterocyclic radical " and " heterocycle " are used interchangeably herein, all referring to the saturation comprising 3-12 annular atom or portion
Point undersaturated is monocyclic, bicyclic or tricyclic, and wherein at least one annular atom is selected from nitrogen, sulfur and oxygen atom.Unless otherwise indicated,
Heterocyclic radical can be carbon-based or nitrilo, and-CH2- group can optionally by-C (O)-replacement.The sulphur atom of ring can be optionally
It is oxidized to S- oxides.The nitrogen-atoms of ring can optionally be oxidized to N- oxygen compounds.Some of them embodiment is, heterocycle
It is carbon atom to contain 2-10 annular atom in base；Other embodiment is, former for carbon containing 2-6 annular atom in heterocyclic radical
Son.The example of heterocyclic radical include, but not limited to N- piperidyls, piperidin-4-yl, piperazine -4- bases, N- pyrrolidinyls, pyrrolidine -
3- bases, pyrrolidin-2-yl, tetrahydrofuran base, oxazolidinyl, Oxyranyle, azelidinyl, oxetanylmethoxy, thia ring
Butyl, 2- pyrrolinyls, 3- pyrrolinyls, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, dihydrofuran base, four
Hydrogen thienyl, dihydro-thiophene base, 1,3- dioxy cyclopenta, two sulfur cyclopenta, THP trtrahydropyranyl, dihydro pyranyl, tetrahydric thiapyran
Base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, dialkyl group, dithiane base, thiophene alkyl, homopiperazine base, high piperidines
Base, oxepane alkyl, thia cycloheptyl alkyl, oxygen azepineBase, diazaBase, sulfur azepineBase, indoline base, 1,2,
3,4- tetrahydro isoquinolyls, 1,3- benzodioxole bases, 2- oxa- -5- azabicyclos [2.2.1] hept- 5- bases.In heterocyclic radical-
CH2- group is included, but not limited to 2- oxo-pyrrolidine bases, oxo -1,3-thiazoles alkyl, 2- piperazines by the example of-C (O)-replacement
Pyridine ketone group, 3,5- dioxy piperazines piperidinyl and hybar X base.In heterocyclic radical, the oxidized example of sulphur atom includes, but not limited to
Sulfolane base, 1,1- dioxothiomorpholinyls.
Terminology used in the present invention " alkyl " or " alkyl group ", represent contain 1 to 20 carbon atom, the straight chain of saturation or
Side chain univalent hydrocarbyl group, wherein, the alkyl group can optionally by the substituent group institute of one or more present invention descriptions
Replace.In some embodiments, alkyl group contains 1-12 carbon atom；In another embodiment, alkyl group contains
1-6 carbon atom；In yet another embodiment, alkyl group contains 1-4 carbon atom；In yet another embodiment, alkyl base
1-3 carbon atom is contained in group.The example of alkyl group includes, but is not limited to, methyl (Me ,-CH3), ethyl (Et ,-
CH2CH3), n-pro-pyl (n-Pr ,-CH2CH2CH3), isopropyl (i-Pr ,-CH (CH3)2), normal-butyl (n-Bu ,-
CH2CH2CH2CH3), isobutyl group (i-Bu ,-CH2CH(CH3)2), sec-butyl (s-Bu ,-CH (CH3)CH2CH3), the tert-butyl group (t-
Bu、-C(CH3)3), n-pentyl (- CH2CH2CH2CH2CH3), 2- amyl groups (- CH (CH3)CH2CH2CH3), 3- amyl group (- CH
(CH2CH3)2), 2- methyl -2- butyl (- C (CH3)2CH2CH3), 3- methyl -2- butyl (- CH (CH3)CH(CH3)2), 3- methyl-
1- butyl (- CH2CH2CH(CH3)2), 2-methyl-1-butene base (- CH2CH(CH3)CH2CH3), n-hexyl (-
CH2CH2CH2CH2CH2CH3), 2- hexyls (- CH (CH3)CH2CH2CH2CH3), 3- hexyls (- CH (CH2CH3)(CH2CH2CH3))、2-
Methyl -2- amyl groups (- C (CH3)2CH2CH2CH3), 3- methyl -2- amyl groups (- CH (CH3)CH(CH3)CH2CH3), 4- methyl -2- penta
Base (- CH (CH3)CH2CH(CH3)2), 3- methyl -3- amyl groups (- C (CH3)(CH2CH3)2), 2- methyl -3- amyl group (- CH
(CH2CH3)CH(CH3)2), 2,3- dimethyl -2- butyl (- C (CH3)2CH(CH3)2), 3,3- dimethyl -2- butyl (- CH (CH3)
C(CH3)3), n-heptyl, n-octyl, etc..Described alkyl group can optionally by one or more described in the invention
Substituent group is replaced.
Term " alkylidene " is represented and removes saturation obtained by two hydrogen atoms from the straight or branched alkyl of saturation
Bivalent hydrocarbon radical group.Unless otherwise detailed instructions, alkylidene group contains 1-12 carbon atom.In one embodiment, alkylene
Base group contains 1-6 carbon atom；In another embodiment, alkylidene group contains 1-4 carbon atom；In another embodiment party
In case, alkylidene group contains 1-3 carbon atom；Also in one embodiment, alkylidene group contains 1-2 carbon atom.This
The example of sample includes methylene (- CH2-), ethylidene (- CH2CH2-), isopropylidene (- CH (CH3)CH2-) etc..
Term " cycloheteroalkylalkyl " represents the alkyl that one or more heterocyclic radicals replace, wherein, heterocyclyl groups and alkyl
Group has implication as described in the present invention.In some embodiments, cycloheteroalkylalkyl is C2-C10The C that heterocyclic radical replaces1-C6
Alkyl；In other embodiments, cycloheteroalkylalkyl is C2-C6The C that heterocyclic radical replaces1-C6Alkyl；In other embodiment party
In case, cycloheteroalkylalkyl is C2-C6The C that heterocyclic radical replaces1-C4Alkyl.Such embodiment includes, but not limited to morpholinyl
Propyl group, 2- morpholinyl ethyls, morpholinyl methyl, morpholinyl ethyl, morpholinyl propyl, morpholinyl butyl, morpholinyl amyl group, morpholine
Base hexyl, pyrrolidinylmethyl, pyrrolidinyl ethyl, pyrrolidinylpropyl, pyrrolidin-2-yl-methyl, pyrrolidin-2-yl-second
Base, pyrrolidin-2-yl-propyl group, pyrrolidin-2-yl-butyl, piperidino methyl, piperidinoethyl, piperizinylmethyl, piperidyl
Propyl group, etc..Described heterocyclic-alkyl-group can optionally independently by one or more replacements described in the invention
Base is replaced.
Term " alkoxyl " represents that alkyl group is connected with molecule remainder by oxygen atom, and wherein alkyl group has
Implication as described in the present invention.Unless otherwise detailed instructions, the alkoxy base contains 1-12 carbon atom.In an embodiment party
In case, alkoxy base contains 1-6 carbon atom；In another embodiment, alkoxy base contains 1-4 carbon atom；?
In another embodiment, alkoxy base contains 1-3 carbon atom.The alkoxy base can be optionally one or more
The substituent group of present invention description is replaced.The example of alkoxy base is included, but is not limited to, methoxyl group (MeO ,-OCH3), second
Epoxide (EtO ,-OCH2CH3), 1- propoxyl group (n-PrO, n- propoxyl group ,-OCH2CH2CH3), 2- propoxyl group (the third oxygen of i-PrO, i-
Base ,-OCH (CH3)2), 1- butoxy (n-BuO, n- butoxy ,-OCH2CH2CH2CH3), 2- methyl-l- propoxyl group (i-BuO, i-
Butoxy ,-OCH2CH(CH3)2), 2- butoxy (s-BuO, s- butoxy ,-OCH (CH3)CH2CH3), 2- methyl -2- propoxyl group
(t-BuO, t- butoxy ,-OC (CH3)3), 1- amoxys (n- amoxys ,-OCH2CH2CH2CH2CH3), 2- amoxy (- OCH
(CH3)CH2CH2CH3), 3- amoxys (- OCH (CH2CH3)2), 2- methyl -2- butoxy (- OC (CH3)2CH2CH3), 3- methyl-
2- butoxy (- OCH (CH3)CH(CH3)2), 3- methyl-l- butoxy (- OCH2CH2CH(CH3)2), 2- methyl-l- butoxy (-
OCH2CH(CH3)CH2CH3), etc..
Term " aminoalkyl " or " aminoalkyl " include the C replaced by one or more amino1-10Straight or branched alkyl
Group.Some of them embodiment is that aminoalkyl is the C replaced by one or more amino groups1-6" the amino of lower level
Alkyl "；Other embodiment is that aminoalkyl is the C replaced by one or more amino groups1-4" the amino of lower level
Alkyl "；Further embodiments are that aminoalkyl is the C replaced by one or more amino groups1-3" the amino of lower level
Alkyl ".Such example is included, but is not limited to, amino methyl, amino-ethyl, aminopropyl, ammonia butyl, ammonia amyl group, ammonia oneself
Base, etc..Described aminoalkyl groups can optionally independently by one or more substituent group institutes described in the invention
Replace.
Term " ED " is the abbreviation of " erection disturbance ", i.e. male erectile dysfunction.
Term " is treated ", unless otherwise described, is referred to the process of reverse, mitigation, is suppressed disease or disease, or prevention is so
Disease or disease.Noun " treatment " used herein refers to the behavior for the treatment of, and treatment therein is as defined above.
Any structural formula that the present invention is given be also intended to expression these compounds not by the form of isotope enrichment and with
The form of position element enrichment.The structure that the compound of isotope enrichment is described with the formula that the present invention is given, except one or many
Individual atom is replaced by the atom with selected atomic weight or mass number.The Exemplary isotopes that can be introduced in the compounds of this invention
Including the isotope of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as2H、3H、11C、13C、14C、15N、17O、18O、18F、31P、32P、35S、36Cl and125I.
Additionally, higher isotope is particularly deuterium (i.e.,2H or D) replacement some treatment advantages can be provided, these advantages are
Brought by metabolic stability is higher.For example, Half-life in vivo increases or volume requirements reduce or therapeutic index obtains improving band
Come.It should be appreciated that the deuterium in the present invention is seen as the substituent group of formula (I) compound.Can be determined with isotope enrichment factor
Such higher isotope adopted is particularly the concentration of deuterium.Term " isotope enrichment factor " used in the present invention refers to specified same
Ratio between the isotope abundance and natural abundance of position element.If the substituent group of the compounds of this invention is designated as deuterium, the change
Compound have for each D-atom that specifies at least 3500 (at each specified D-atoms 52.5% deuterium mix), at least 4000
(60% deuterium is mixed), at least 4500 (67.5% deuterium is mixed), at least 5000 (75% deuterium is mixed), at least 5500
(82.5% deuterium mix), at least 6000 (90% deuterium is mixed), at least 6333.3 (95% deuterium is mixed), at least 6466.7
The isotope enrichment of (97% deuterium is mixed), at least 6600 (99% deuterium is mixed) or at least 6633.3 (99.5% deuterium is mixed)
The factor.The pharmaceutically useful solvate of the present invention includes that wherein recrystallisation solvent can be the such as D that isotope replaces2O, acetone-d6、
DMSO-d6Those solvates.
The compounds of this invention and pharmaceutical composition, preparation and administration
Formula (I) compound of the present invention or formula (II) compound, can be with one or more pharmaceutically acceptable load
Body, excipient, diluent, adjuvant, vehicle or combinations thereof make pharmaceutical composition jointly.The pharmaceutical composition can be made
Into dosage forms such as solid orally ingestible, liquid oral medicine, injections.For example, pharmaceutical composition can with tablet, capsule, pill,
Powder, slow releasing agent, solution, the form oral administration of suspension；Pharmaceutical composition can also be with sterile liquid, suspension or emulsion
Form parenteral injection is administered；Pharmaceutical composition can also be administered local in the form of ointment or cream；Pharmaceutical composition also may be used
With rectally in the form of suppository.Pharmaceutical composition can make unit dosage forms, and which is suitable to the single administration of exact dose.
The solid and liquid oral medicine include：Tablet, dispersible tablet, enteric coatel tablets, chewable tablet, oral cavity disintegration tablet, capsule, syrup
Agent, granule, oral solution, injection.Non-intestinal drug delivery agent can make the dosage forms such as injection, freeze-dried powder, locally
Administration can make such as cream, ointment, patch, spray etc..But it is not limited to this.Oral formulations used can contain example
Such as one or more coloring agent, sweeting agent, correctivess and/or preservative.
Lactose or starch can be adopted as the carrier of the solid orally ingestible；Using gelatin, methylcellulose, hydroxypropyl first
Cellulose, polyvinylpyrrolidone, starch slurry etc. are used as binding agent；Using starch, sodium carboxymethyl cellulose, carboxymethylstach sodium,
Low-substituted hydroxypropyl methylcellulose, polyvinylpolypyrrolidone, Microcrystalline Cellulose are used as disintegrating agent；Using Pulvis Talci, micropowder silica gel, stearic acid
Glyceride, calcium stearate or magnesium are used as antiadhesives and lubricant.
Suitable pharmaceutically acceptable excipient for tablet formulation includes for example, inert diluent such as Lactose, sodium carbonate, phosphorus
Sour calcium or Calcium Carbonate；Granulation and disintegrating agent such as corn starch and alginic acid；Binding agent such as starch；Lubricant such as stearic acid
Magnesium, stearic acid or Pulvis Talci；Preservative such as ethylparaben or propyl ester, and antioxidant, such as ascorbic acid.Tablet
Preparation can be uncoated, it would however also be possible to employ coating is follow-up in gastrointestinal tract to change its disintegration and active component
Absorption, or its stability and/or outward appearance is improved, in any case, can use conventional coating agents known to the field
And method.
The preparation method of the solid orally ingestible is comprised the following steps：By active component and carrier and optionally with
A disintegrate additive composition mixture, then makes aqueous solution, alcohol or the aqueous alcohol solution of the mixture and binding agent
Wet method or dry granulation are carried out in suitable equipment, other disintegrating agents, lubricant and antiplastering aid is subsequently added and is made suitably
Preparation.
Pharmaceutical composition of the present invention can also be in the form of oil-in-water Emulsion.Oil phase can be vegetable oil, such as olive
Olive oil or Oleum Arachidis hypogaeae semen, or mineral oil, such as liquid paraffin or their mixture.Appropriate emulsifying agent can be for example,
Natural gum such as arabic gum or tragacanth, natural phospholipid such as soybean lecithin, and derived from fatty acid and hexitol
The ester or partial ester (such as NOFABLE SO-901) of acid anhydride, and the condensation product of the partial ester and oxirane, for example,
The series compound of the present invention can also be administered by non-bowel form.Preferred parenteral administration is administered for injection.
Syrup and elixir can be prepared with sweeting agent (such as glycerol, Propylene Glycol, Sorbitol, aspartame or sucrose),
And can also contain demulcent, preservative, correctivess and/or coloring agent.
Described pharmaceutical composition can also be the form of Injectable sterile aqueouss or Oil suspensions, and which can be according to known
Method is prepared using one or more suitable dispersion or wetting agent and suspending agent, and these reagents are as described above.Aseptic injection
Preparation can also be the Injectable sterile aqueouss in the acceptable diluent of nontoxic parenteral or solvent or Oil suspensions, example
Solution such as in 1,3 butylene glycol.
Other information about preparation refers to volume 5 of Comprehensive Medicinal Chemistry, and 25.2
Chapter (Corwin Hanschl；Chairman of Editorial Board), PergamonPress1990.
Can according to treated host and the difference of concrete route of administration, determine mix with one or more excipient with
Prepare the amount of ingle dose form active component.For example, for typically containing such as 0.5mg-2g to the preparation of oral administration in human
Activating agent and appropriate and convention amount excipient (accounting for the 5-98% of compositionss gross weight).In unit formulation general containing about
There is the active component of 1mg-500mg.Further information about route of administration and dosage regimen refers to Comprehensive
Volume 5 of Medicinal Chemistry, 25.3 chapters (Corwin Hansch；Chairman of Editorial Board),
Pergamon Press1990.
For treat or prevent purpose formula (I) compound dosage, should according to the property of disease and seriousness, animal or
The age of patient and sex and route of administration, the known principle according to medicine is changing.
When formula (I) compound is used based on treatment or prevention purpose, usually with daily dose in such as 0.001mg-
It is administered in the range of 100mg/kg body weight, can be administered with divided dose if needed.Generally, with during parenteral administration adopt compared with
Low dosage, such as when through intravenous administration, the general dosage using in such as 0.001mg-10mg/kg weight ranges.
The actual dosage for taking compound of series compound of the present invention should determine according to relevant situation by doctor,
These situations include the health of patient, the individual reaction of the route of administration of selection, age, body weight, patient to medicine,
Order of severity of patients symptomatic etc..
The compounds of this invention and the purposes of pharmaceutical composition
The feature of the pharmaceutical composition of the present invention is included listed by formula (I) or the compound shown in formula (II) or the present invention
Compound, and pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or combinations thereof.The present invention's
In compositionss, the amount of compound can effectively suppress the activity of phosphate, promote the development of gonad, prevents and treats sexual dysfunction
Disease.
The present invention compound or pharmaceutically acceptable compositionss " effective dose " or " effective dose " refer to process or
Mitigate the effective dose that one or more present invention are previously mentioned the severity of disease.The method according to the invention, compound and combination
Thing can be any dosage and any route of administration being efficiently used for the order of severity for processing or mitigating disease.Required standard
Situation according to patient is changed by true amount, and this depends on race, and age, the generic condition of patient, the order of severity are special
Factor, administering mode, etc..Compound or compositionss can with one or more other therapeutic agents administering drug combinations.
The general synthetic method of the compounds of this invention
Usually, compound of the invention can be prepared by method described in the invention, unless there are further
Explanation, wherein shown in the definition of substituent group such as formula (I) or formula (II).Following reaction scheme and embodiment are used for further lifting
Example explanation present disclosure.
Those skilled in the art will realize that：Chemical reaction described in the invention can be used to suitably prepare perhaps
Other compounds of many present invention, and the model in the present invention is considered as preparing other methods of the compound of the present invention
Within enclosing.For example, can successfully by those skilled in the art according to the synthesis of the compound of those non-illustrations of the invention
Completed by method of modifying, group is disturbed in such as appropriate protection, by using reagent known to other except described in the invention
, or reaction condition is made some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged
Ground is applied to the preparation of other compounds of the invention.
The embodiments described below, unless shown in terms of other that all of temperature is set to degree Celsius.Reagent is bought in business
Product supplier such as Ling Kai medicine, Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa
Chemical Company, not through being further purified during use, unless shown in terms of other.General reagent is from Shantou
Western Gansu Province chemical plant, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Companies, Qingdao is risen
Imperial chemical reagent company limited, and Haiyang Chemical Plant, Qingdao is commercially available.
Anhydrous tetrahydro furan is dried to obtain through metallic sodium backflow.Ethyl acetate, DMAC N,N' dimethyl acetamide and oil
Ether is to dry in advance to use through anhydrous sodium sulfate.
Hereinafter reaction is usually to cover a drying tube under nitrogen or argon gas positive pressure or on anhydrous solvent (unless in terms of other
Show), reaction bulb all suitable rubber closures beyond the Great Wall, substrate are squeezed into by syringe.Glass drying oven is all dried.
Chromatographic column is to use silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.NMR (Nuclear Magnetic Resonance) spectrum with
CDC13Or DMSO-d6(report in units of ppm) for solvent, with TMS (0ppm) or chloroform (7.25ppm) as reference standard.
When there is multiplet, following abbreviation will be used：S (singlet, unimodal), d (doublet, bimodal), t
(triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of
Doublets, quartet), dt (doublet of triplets, double triplets).Coupling constant, is represented with hertz (Hz).
By outfit G1312A binary pumps and a G1316A TCC, (column temperature is maintained at 30 to Algorithm (MS) data
DEG C) Agilent6320 series LC-MS spectrogrph determining, G1329A automatic samplers and G1315B DAD detectors
It is applied to analyze, ESI sources are applied to LC-MS spectrogrphs.
Algorithm (MS) data are by being equipped with G1311A quaternary pump and G1316A TCC (column temperature is maintained at 30 DEG C)
Agilent6120 series LC-MS spectrogrph determining, G1329A automatic samplers and G1315D DAD detector applications
In analysis, ESI sources are applied to LC-MS spectrogrphs.
Both the above spectrogrph is provided with Agilent Zorbax SB-C18 posts, and specification is 2.1 × 30mm, 5 μm.Note
Beam product is determined by sample concentration；Flow velocity is 0.6mL/min；The peak value of HPLC is by 210nm and 254nm
UV-Vis wavelength is recording reading.Mobile phase be 0.1% formic acid acetonitrile solution (phase A) and 0.1% formic acid ultrapure water-soluble
Liquid (phase B).Condition of gradient elution is as shown in table 1：
Table 1
| Time (min) | A(CH3CN, 0.1%HCOOH) | B(H2O, 0.1%HCOOH) |
| 0-3 | 5-100 | 95-0 |
| 3-6 | 100 | 0 |
| 6-6.1 | 100-5 | 0-95 |
| 6.1-8 | 5 | 95 |
Compound purification is evaluated by Agilent1100 series of high efficiency liquid chromatograph (HPLC), and wherein UV is detected
At 210nm and 254nm, Zorbax SB-C18 posts, specification are 2.1 × 30mm, and 4 μm, 10 minutes, flow velocity was 0.6mL/min,
(0.1% aqueous formic acid) of (0.1% formic acid acetonitrile solution) of 5-95%, column temperature is maintained at 40 DEG C.
The step of following synthetic schemes describes to prepare the present invention and discloses compound.
Synthetic schemes 1
R1For defining described in formula, X is halogen, preferably bromine or iodine.
Compound formula (I) can be carried out substitution reaction and be obtained in the basic conditions by compound (A) and compound (B).
Wherein, alkali, may be, but not limited to, potassium carbonate, cesium carbonate etc.；The reaction is carried out in corresponding solvent, and solvent for use includes,
But it is not limited to acetone, N,N-dimethylformamide etc..
Synthetic schemes 2
X is halogen, preferably uses bromine；N is 2,3 or 4.
Step A1：Compound formula (III) can be replaced in the basic conditions by compound (A) and compound (C)
Reaction is obtained.Wherein, alkali, may be, but not limited to, potassium carbonate, cesium carbonate etc.；The reaction is carried out in corresponding solvent, used
Solvent includes, but are not limited to acetone, DMF etc..
Step A2：Compound formula (IV) can pass through compound (III) with sulfur trioxide pyridine complex in alkalescence condition
Lower reaction is obtained.Wherein, alkali, may be, but not limited to, pyridine etc.；The reaction is carried out in corresponding solvent, solvent for use bag
Include, but be not limited to pyridine etc..
Synthetic schemes 3
Work as R1For NaOS (=O)2During O- glucopyranosyls, compound (D) is with sulfur trioxide pyridine complex in alkaline bar
Substitution reaction is carried out under part, is carried out post processing with saturated sodium bicarbonate solution and is obtained compound (I).Wherein alkali, Ke Yishi, but not
It is limited to pyridine etc.；The reaction is carried out in corresponding solvent, and solvent for use includes, but are not limited to pyridine etc..
The following examples can be so that the present invention will be further described, however, these embodiments are should not be used as to this
The restriction of bright scope.
Embodiment
Intermediate 5,7- dihydroxy -2- (4- methoxyphenyls) -8- (3- methyl but-2-ene -1- bases) -3- (((2S, 3R,
4R, 5R, 6S) -3,4,5- trihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -4H- chromene -4- ketone
The first step) 5,7- dihydroxy -2- (4- methoxyphenyls) -8- (3- methyl but-2-ene -1- bases) -3- (((2S, 3R,
4R, 5R, 6S) -3,4,5- trihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -4H- chromene -4- ketone
Icariin (10g) and 1,4 beta-glucanase (10g) are added (pH in the buffer solution of 500mL sodium acetates and hydrochloric acid
=5.0, EtOH/H2O=30/70, V/V), reactant mixture is stirred 5 hours at 50 DEG C, concentrating under reduced pressure.Residue is added
2000mL water is simultaneously stirred 30 minutes, adds ethyl acetate extraction (50mL × 3), is merged organic faciess, is washed with saturated nacl aqueous solution
Wash (30mL), anhydrous sodium sulfate drying.Organic faciess concentrating under reduced pressure, after residue with Ethyl acetate recrystallization, obtains yellow solid mark
Topic compound (6g, yield 79%, HPLC:98%).
MS(ESI,pos.ion)m/z:515.2[M+H]+.
1 5- hydroxyl -2- (4- methoxyphenyls) -8- of embodiment (3- methyl but-2-ene -1- bases) -7- (2- morpholine ethoxies
Base) -3- (((2S, 3R, 4R, 5R, 6S) -3,4,5- trihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -4H- chromene -4-
Ketone
The first step) 5- hydroxyl -2- (4- methoxyphenyls) -8- (3- methyl but-2-ene -1- bases) -7- (2- morpholine ethoxies
Base) -3- (((2S, 3R, 4R, 5R, 6S) -3,4,5- trihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -4H- chromene -4-
Ketone
By 5,7- dihydroxy -2- (4- methoxyphenyls) -8- (3- methyl but-2-ene -1- bases) -3- (((2S, 3R, 4R,
5R, 6S) -3,4,5- trihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -4H- chromenes -4- ketone (180mg, 0.35mmol)
Acetone soln (10mL) is dissolved in 4- (2- bromoethyls) morpholine (58mg, 0.39mmol), be subsequently adding Anhydrous potassium carbonate
(54mg, 0.39mmol), reactant mixture heated overnight at reflux under nitrogen protection, concentrating under reduced pressure.Add ethyl acetate extraction
(40mL × 3), merge organic faciess, wash (30mL), anhydrous sodium sulfate drying, concentrating under reduced pressure with saturated nacl aqueous solution.Residual
Thing silica gel chromatography (ethyl acetate:Petroleum ether=1:1), yellow solid title compound (100mg, yield are obtained:
46%, HPLC:90%).
MS(ESI,pos.ion)m/z:628.2[M+H]+；
1H NMR(400MHz,CDCl3):δ 7.87 (d, J=8.8Hz, 2H), 7.12 (d, J=8.8Hz, 2H), 6.58 (s,
1H), 5.27 (s, 1H), 4.923 (t, J=4.2Hz, 1H), 4.68 (d, J=4.8Hz, 1H), 4.59 (d, J=6.4Hz, 1H),
4.22 (t, J=11.2Hz, 2H), 3.99-3.97 (m, 1H), 3.85 (s, 3H), 3.60-3.56 (m, 5H), 3.50-3.43 (m,
5H), 3.11-3.08 (m, 2H), 2.73 (t, J=11.2Hz, 2H), 1.69 (s, 3H), 1.62 (s, 3H).
2 5- hydroxyl -2- (4- methoxyphenyls) -8- of embodiment (3- methyl but-2-ene -1- bases) -7- (the own oxygen of 6- morpholines
Base) -3- (((2S, 3R, 4R, 5R, 6S) -3,4,5- trihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -4H- chromene -4-
Ketone
The first step) 7- ((6- bromine hexyls) oxygen) -5- hydroxyl -2- (4- methoxyphenyls) -8- (3- methyl but-2-ene -1-
Base) -3- (((2S, 3R, 4R, 5R, 6S) -3,4,5- trihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -4H- chromene -4-
Ketone
By 5,7- dihydroxy -2- (4- methoxyphenyls) -8- (3- methyl but-2-ene -1- bases) -3- (((2S, 3R, 4R,
5R, 6S) -3,4,5- trihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -4H- chromenes -4- ketone (200mg, 0.389mmol)
Dry acetone soln (20mL) is dissolved in 1,6- dibromo-hexanes (285mg, 1.2mmol), be subsequently adding Anhydrous potassium carbonate
(108mg, 0.79mmol), reactant mixture heated overnight at reflux under nitrogen protection, concentrating under reduced pressure.Add ethyl acetate extraction
(40mL × 3), merge organic faciess, wash (30mL), anhydrous sodium sulfate drying, concentrating under reduced pressure with saturated nacl aqueous solution.Residual
Thing silica gel chromatography (ethyl acetate:Petroleum ether=1:1), title compound as yellow oil (166mg, yield are obtained:
63%).
MS(ESI,pos.ion)m/z:678.2[M+H]+.
Second step) 5- hydroxyl -2- (4- methoxyphenyls) -8- (3- methyl but-2-ene -1- bases) -7- ((the own oxygen of 6- morpholines
Base) -3- (((2S, 3R, 4R, 5R, 6S) -3,4,5- trihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -4H- chromene -4-
Ketone
By 7- ((6- bromine hexyls) oxygen) -5- hydroxyl -2- (4- methoxyphenyls) -8- (3- methyl but-2-ene -1- bases) -- 3-
(((2S, 3R, 4R, 5R, 6S) -3,4,5- trihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -4H- chromene -4- ketone
(166mg, 0.245mmol) and morpholine (0.15mL, 1.0mmol) are dissolved in anhydrous tetrahydrofuran solution (10mL), reaction mixing
Thing was heated to reflux liquid, concentrating under reduced pressure under nitrogen protection.10mL water quenchings are added to go out reaction, be extracted with ethyl acetate (40mL ×
3), merge organic faciess, (30mL), anhydrous sodium sulfate drying, concentrating under reduced pressure is washed with saturated nacl aqueous solution.Residue silica gel
Column chromatography purification (ethyl acetate:Petroleum ether=1:1), yellow solid title compound (75mg, yield are obtained:45%,
HPLC:95%).
MS(ESI,pos.ion)m/z:684.2[M+H]+；
1H NMR(400MHz,DMSO-d6):δ 12.66 (s, 1H), 7.87 (d, J=8.8Hz, 2H), 7.14 (d, J=
9.2Hz, 2H), 5.27 (d, J=1.6Hz, 1H), 5.14 (t, J=2.4Hz, 1H), 5.01 (d, J=4.2Hz, 1H), 4.76 (d,
J=5.2Hz, 1H), 4.71 (d, J=6.0Hz, 1H), 4.13 (t, J=12.2Hz, 2H), 4.01-3.97 (m, 1H), 3.95-
3.91(m,1H),3.86(s,3H),3.50-3.46(m,3H),3.13-3.06(m,4H),1.80-1.78(m,2H),1.69(s,
3H),1.63(s,3H),1.50-1.47(m,2H),1.38-1.35(m,2H),1.26-1.21(m,1H).
3 7- of embodiment (2- (dimethylamino ethoxy) -5- hydroxyl -2- (4- methoxyphenyls) -8- (3- methyl butyl-
2- alkene -1- bases) -3- (((2S, 3R, 4R, 5R, 6S) -3,4,5- trihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -4H-
Chromene -4- ketone
The first step) 7- (2- (dimethylamino ethoxy) -5- hydroxyl -2- (4- methoxyphenyls) -8- (3- methyl butyl- 2-
Alkene -1- bases) -3- (((2S, 3R, 4R, 5R, 6S) -3,4,5- trihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -4H- colors
Alkene -4- ketone
By 5,7- dihydroxy -2- (4- methoxyphenyls) -8- (3- methyl but-2-ene-yl) -3- (((2S, 3R, 4R, 5R,
6S) -3,4,5- trihydroxies -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -4H- chromenes -4- ketone (500mg, 0.97mmol) and 2-
Chloro- N, N- dimethylethylamine hydrochloride (154mg, 1.07mmol) are dissolved in acetone soln (20mL), are subsequently adding Anhydrous potassium carbonate
(148mg, 1.07mmol), reactant mixture heated overnight at reflux under nitrogen protection, concentrating under reduced pressure.10mL water is added, second is used
Acetoacetic ester extracts (20mL × 3), merges organic faciess, is washed with saturated nacl aqueous solution (30mL), anhydrous sodium sulfate drying, reduces pressure
Concentration.Residue silica gel chromatography (dichloromethane:Methanol=8:1), yellow solid title compound is obtained
(100mg, yield:16.7%, HPLC:99%).
MS(ESI,pos.ion)m/z:586.2[M+H]+；
1H NMR(400MHz,DMSO-d6):δ 12.69 (s, 1H), 7.90 (d, J=6.8Hz, 2H), 7.16 (d, J=
6.8Hz,2H),6.33(s,1H),5.30(s,1H),5.05(s,1H),5.19(s,1H),4.80(s,1H),4.30(s,2H),
4.03(s,1H),3.90(s,3H),3.17-3.15(m,2H),2.92(s,2H),2.42(s,6H),1.65(s,3H),1.72
(s,3H).
4 2- of embodiment ((5- hydroxyl -2- (4- methoxyphenyls) -8- (3- methyl but-2-ene -1- bases) -4- oxo -3-
(((2S, 3R, 4R, 5R, 6S) -3,4,5- trihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -4H- chromene -4- ketone -7-
Base) oxygen) ethyl sulfonic acid sodium
The first step) 5- hydroxyl -7- (2- hydroxy ethoxies) -2- (4- methoxyphenyls) -8- (3- methyl but-2-ene -1- bases) -
3- (((2S, 3R, 4R, 5R, 6S) -3,4,5- trihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -4H- chromene -4- ketone
By 5,7- dihydroxy -2- (4- methoxyphenyls) -8- (3- methyl but-2-ene-yl) -3- (((2S, 3R, 4R, 5R,
6S) -3,4,5- trihydroxies -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -4H- chromenes -4- ketone (300mg, 0.58mmol) and 2-
Bromoethanol (72mg, 0.64mmol) is dissolved in acetone soln (20mL), is subsequently adding Anhydrous potassium carbonate (148mg, 1.07mmol), instead
Answer mixture heated overnight at reflux under nitrogen protection, concentrating under reduced pressure.10mL water is added, (20mL × 3) are extracted with ethyl acetate,
Merge organic faciess, (30mL), anhydrous sodium sulfate drying, concentrating under reduced pressure is washed with saturated nacl aqueous solution.Residue silicagel column
Chromatogram purification (ethyl acetate:Methanol=15:1), yellow solid title compound (100mg, yield are obtained:30%).
MS(ESI,pos.ion)m/z:559.2[M+H]+
Second step) 2- ((5- hydroxyl -2- (4- methoxyphenyls) -8- (3- methyl but-2-ene -1- bases) -4- oxo -3-
(((2S, 3R, 4R, 5R, 6S) -3,4,5- trihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -7 base of -4H- chromene -4- ketone)
Oxygen) ethyl sulfonic acid sodium
By 5- hydroxyl -7- (2- hydroxy ethoxies) -2- (4- methoxyphenyls) -8- (3- methyl but-2-ene -1- bases) -3-
(((2S, 3R, 4R, 5R, 6S) -3,4,5- trihydroxy -6- methyl tetrahydrochysene -2H- pyrans -2- bases) oxygen) -4H- chromene -4- ketone
(100mg, 0.19mmol) and sulfur trioxide pyridine complex (240mg, 1.6mmol) are dissolved in pyridine (5mL), reactant mixture
Be stirred overnight under nitrogen protection, the reactant liquor pH value of saturated sodium bicarbonate solution regulation system 6.5～7, sucking filtration, filtrate
Concentrating under reduced pressure.Residue ethyl alcohol recrystallization, obtains yellow solid title compound (25mg, yield:20%, HPLC:
97%).
MS(ESI,pos.ion)m/z:661.1[M+H]+；
1H NMR (400MHz, DMSO-d6):δ 12.63 (s, 1H), 7.87 (d, J=7.2Hz, 2H), 7.13 (d, J=
8.8Hz, 2H), 6.56 (s, 1H), 5.27 (s, 1H), 5.16 (t, J=6.4,1H), 4.96 (d, J=4.8Hz, 1H), 4.88 (t,
J=11.2Hz, 3H), 4.71 (d, J=4.8Hz, 1H), 4.63 (d, J=6.4Hz, 2H), 4.14-4.12 (m, 2H), 3.99 (s,
1H), 3.85 (s, 3H), 4.08 (t, J=6.4Hz, 2H), 3.95 (t, J=6.4Hz, 2H), 3.10-3.07 (m, 1H), 1.69
(s,3H),1.62(s,3H).
5 ((2R, 3S, 4S, 5R, 6S) -3,4,5- trihydroxy -6- ((5- hydroxyl -2- (4- methoxyphenyls) -8- of embodiment
(3- methyl but-2-ene -1- bases) -4- oxo -3- (((2S, 3R, 4R, 5R, 6S) -3,4,5- trihydroxy -6- methyl tetrahydrochysene -2H-
Pyrans -2- bases) oxygen) -4H- chromene -7- bases) oxygen) tetrahydrochysene -2H- pyrans -2- bases) novalgin
The first step) ((2R, 3S, 4S, 5R, 6S) -3,4,5- trihydroxy -6- ((5- hydroxyl -2- (4- methoxyphenyls) -8-
(3- methyl but-2-ene -1- bases) -4- oxo -3- (((2S, 3R, 4R, 5R, 6S) -3,4,5- trihydroxy -6- methyl tetrahydrochysene -2H-
Pyrans -2- bases) oxygen) -4H- chromene -7- bases) oxygen) tetrahydrochysene -2H- pyrans -2- bases) novalgin
Icariin (500mg, 0.74mmol) and sulfur trioxide pyridine complex (890mg, 5.9mmol) are dissolved in pyridine
In (10mL), reactant mixture is stirred overnight under nitrogen protection, pH of the reactant liquor with saturated sodium bicarbonate solution regulation system
Value 6.5～7, sucking filtration, filtrate reduced in volume.Residue ethyl alcohol recrystallization, obtains yellow solid title compound
(120mg, yield:22%, HPLC:95%).
MS(ESI,pos.ion)m/z:779.2[M+H]+；
1H NMR(400MHz,DMSO-d6):δ 0.79 (d, J=6.0Hz, 3H), 1.60 (s, 3H), 1.69 (s, 3H),
3.86 (s, 3H), 5.06 (d, J=5.2Hz, 1H), 5.13 (t, J=7.0Hz, 1H), 5.29 (d, J=1.6Hz, 1H), 6.64
(s, 1H), 7.14 (d, J=9.2Hz, 2H), 7.91 (d, J=9.2Hz, 2H), 12.57 (s, 1H), 3.10 4.08 (m, 16H),
5.67-5.69(m,2H).
Biological assessment
Inhibitory activity of the test case the compounds of this invention to phosphodiesterase 3A and 5A (PDE3A, 5A)
Detected using the HTRF test kits of Cisbio companies.Respectively by test compound and the (purchase of PDE3A or PDE5A enzymes
In BD companies) suitable concentration (5 μM) is diluted to reaction buffer, in 384 orifice plates, 5 μ L detection samples are then added, then
The PDE3A or PDE5A of 20 μ L is added, the substrate cGMP of 10 μ L is subsequently adding, sealing is sealed with TopSeal-A, be incubated 1 at 37 DEG C
The HTRF detectable (cGMP-d2 and Ab-cryptate) of 12.5 μ L after individual hour, is added per hole, then uses TopSeal-A384
Sealing is sealed, 1 hour is incubated at normal temperatures, is detected with the HTRF modules of PHERAstarPLUS (BMG).Use following public affairs
Formula calculates suppression ratio, as a result see the table below.
% suppression ratio=(1- test samples activity/gross activity) * 100
Conclusion：By the structural modification to icariin, the compounds of this invention compare icariin PDE5A enzymes are had bright
Aobvious inhibitory activity, while have good selectivity to PDE5A.
Finally it should be noted that also other modes are used for implementing the present invention.Correspondingly, embodiments of the invention are
To illustratively illustrate, but be not limited to content described in the invention, it is also possible to be made within the scope of the present invention
Modification or the equivalents that is added in the claims.All publications or patent cited in the present invention all will be used as this
Bright list of references.
Claims (6)
1. a kind of compound, which is the compound shown in formula (II), or the pharmaceutically acceptable salt of compound shown in formula (II)：
Wherein,
R1For C2-C6Heterocyclic radical C1-C6Alkyl, C1-C4Aminoalkyl, NaOS (=O)2O- glucopyranosyls or NaOS (=O)2-
(CH2) n-, wherein described C2-C6Heterocyclic radical C1-C6Alkyl, C1-C4Aminoalkyl and NaOS (=O)2O-(CH2) n- independently appoints
Selection of land is by H, C1-C3Alkyl, amino, halogen or C1-C3One or more substituent groups in alkoxyl are replaced；With
N is 2,3 or 4.
2. compound according to claim 1, wherein,
R1For morpholinyl ethyl, 2- methyl morpholine base ethyls, 3- methyl morpholine base ethyls, morpholinyl methyl, morpholinyl propyl,
Quinoline base butyl, morpholinyl amyl group, morpholinyl hexyl, piperidinoethyl, piperidino methyl, piperazinyl, pyrrolidinylmethyl,
Pyrrolidinyl ethyl, pyrrolidinylpropyl, NaOS (=O)2O- glucopyranosyls, NaOS (=O)2O-(CH2)2-, NaOS (=
O)2O-(CH2)3-, NaOS (=O)2O-(CH2)4-, dimethylaminoethyl, amino-ethyl or dimethylamino-propyl.
3. the structure according to claim 1, selected from the compound of one of,
Or said structure pharmaceutically acceptable salt.
4. a kind of pharmaceutical composition, comprising the compound described in claim 1, and its pharmaceutically acceptable adjuvant.
5. the compound described in a kind of claim 1 or the pharmaceutical composition described in claim 4 are preparing suppression phosphate
Purposes in the medicine of activity.
6. the compound described in a kind of claim 1 or the pharmaceutical composition described in claim 4 are used for protecting, locating in preparation
Purposes in reason, medicaments for treating sexual disorder.
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| WO2009003631A1 (en) * | 2007-07-03 | 2009-01-08 | Indena S.P.A. | Combinations of vasoactive substances with estrogens and their use in the treatment of female sexual dysfunctions |
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| WO2005004858A1 (en) * | 2003-07-11 | 2005-01-20 | Indena S.P.A. | Combinations of vasoactive agents, their use in the pharmaceutical and cosmetic field, and formulations containing them |
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| WO2009003631A1 (en) * | 2007-07-03 | 2009-01-08 | Indena S.P.A. | Combinations of vasoactive substances with estrogens and their use in the treatment of female sexual dysfunctions |
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Address after: 523808 No.1, Gongye North Road, Songshanhu Park, Dongguan City, Guangdong Province Patentee after: Guangdong Dongyangguang Pharmaceutical Co.,Ltd. Address before: 523808 No. 1 Industrial North Road, Songshan Industrial Park, Songshan, Guangdong, Dongguan, Hubei Patentee before: SUNSHINE LAKE PHARMA Co.,Ltd. |