CN104513188A - Cyano pyrrolidine derivative and preparation method and application thereof - Google Patents
Cyano pyrrolidine derivative and preparation method and application thereof Download PDFInfo
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- CN104513188A CN104513188A CN201410570639.3A CN201410570639A CN104513188A CN 104513188 A CN104513188 A CN 104513188A CN 201410570639 A CN201410570639 A CN 201410570639A CN 104513188 A CN104513188 A CN 104513188A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention discloses a kind of cyanopyrrole alkane derivative and its preparation method and application, shown in the derivant structure formula such as formula (I):
; Derivative cyanopyrrolidine moiety provided by the present invention can accurately be embedded in the P1 pocket of target proteins, and hydrophily cyano and the amino acid residue Ser630 of conserved region, which form covalent bond, facilitates the enhancing of inhibitor activity, to play the effect as dipeptidyl peptidase-IV enzyme inhibitor. Derivative of the present invention have the advantages that synthesis material be easy to get, be at low cost, is long-acting, is less toxic, targeting it is high, prevented and treated in preparation and have wide application space on the drug of dipeptidyl peptidase-IV enzyme related disease.
Description
Technical field
The present invention relates to Cyanopyrolidine technical field, more specifically, relate to a kind of cyanopyrrole alkane derivative and its preparation method and application.
Background technology
Diabetes are mainly divided into insulin-dependent diabetes mellitus (type 1 diabetes, IDDM) and non insulin dependent diabetes (diabetes B, NIDDM).Type 1 diabetes is because beta Cell of islet is impaired, causes level of insulin secretion to decline, and then causes the symptoms such as the poisoning and metabolism disorder of hyperglycemia, beta-keto acid.Diabetes B is then a kind of insulin resistance disease, and pathogenic factor is mainly due to insulin resistant.At present, the conventional medicament being used for the treatment of diabetes B mainly contains insulin secretion stimulators, euglycemic agent, alpha-glucosidase inhibitor etc., but all exists and can not maintain long-acting reduction hyperglycemia, hypofunction of islet beta cells lacked to magnetic target therapy and the deficiency such as side effect is large.
Research finds to input the secretion that ectogenic GLP-1 significantly can increase Regular Insulin to diabetes B patient, and, GLP-1 can also act on alpha Cell of islet, the secretion of glucagon suppression, suppress glycogen to export thus reduce fasting plasma glucose content, but GLP-1 can be decomposed into rapidly GLP-1 (9-36) NH of non-activity by dipeptidyl peptidase-IV enzyme in vivo
2with GLP-1 (9-37) NH
2, and remove through liver, kidney, the transformation period is only 1-2min, thus loss of activity.Studies have found that, the concentration of GLP-1 can be made to improve significantly to 15-20pmol/L from 5-6pmol/L by suppressing the activity of dipeptidyl peptidase-IV enzyme, visible by suppressing the activity of dipeptidyl peptidase-IV enzyme, effectively can extend the transformation period of GLP-1, increase the concentration of GLP-1, thus reach the object regulating blood sugar.At present, according to the basic physiological process of GLP-1, it is two kinds of therapy approach of target spot that investigator and diabetes scholar propose respectively with GLP-1: the first, using GLP-1 analogue as medicine, shows anti-high-blood-sugar function mainly through simulation strengthens the secretion enhancing of glucose dependent insulin and the secretion of incretin.Although natural GLP-1 analogue or agonist are effective to treatment diabetes B, its transformation period is short, must administrated by injection and expensive, and these all make it apply to be restricted, and the development difficulty of small molecules GLP-1 agonist is very big.
Another kind of approach suppresses the activity of dipeptidyl peptidase-IV enzyme in human body to reach the hydrolysis of GLP-1 in baffle by small molecules.At present, in world wide, existing multiple dipeptidyl peptidase-iv inhibitor listing, shows good result for the treatment of to diabetes B, but also comes with some shortcomings part.Such as report has Sitagliptin to there is the risk of initiation pancreatitis and Pancreatic ductal epitheliumization life; And Vildagliptin, Saxagliptin may can not abundant pump blood and cause heart failure because of heart; Sitagliptin and Vildagliptin may cause the risk of urinary system or respiratory system infection or headache to rise, and the bad patient of hepatic and renal function may cause hepatic and renal function decline.In addition, the price of DPP-IV inhibitor is high relative to traditional treatment medicine, is difficult to for more diabetic subject accepts extensively.
Summary of the invention
The object of the invention is for deficiency of the prior art, a kind of new cyanopyrrole alkane derivative is provided.
The present invention also provides preparation method and the application of said derivative, derivative of the present invention has the advantage that synthesis material is easy to get, cost is low, long-acting, low toxicity, targeting are high, and the medicine preparing prevention and therapy and dipeptidyl peptidase-IV enzyme relative disease has wide application space.
The present invention is realized by following technical scheme:
The invention provides a kind of cyanopyrrole alkane derivative, described cyanopyrrole alkane derivative structural formula is such as formula shown in (I):
Wherein,
R
1can be independently selected from:
(1) phenyl, it is unsubstituted or with 1-5 R
3replace,
(2) C
1-6straight chained alkyl, it is unsubstituted or uses one or more R
4replace,
(3) C
3-6cycloalkyl,
(4) heterocyclic aryl, it is substituted or unsubstituted heterocyclic aryl, or
(5) hydrogen
R
3can be independently selected from:
(1) halogen,
(2) C
1-3alkyl, it is unsubstituted or replaces with one or more halogen atom, or
(3) alkoxyl group
R
4can independently be selected from:
(1) halogen,
(2) hydroxyl,
(3) aromatic group, it is phenyl or heterocyclic aryl
Ar is the group independently with aromaticity, can independently be selected from:
(1) phenyl, it is unsubstituted or uses one or more R
2replace,
(2) xenyl, it is unsubstituted or uses one or more R
2replace,
(3) naphthyl, it is unsubstituted or uses one or more R
2replace,
(4) quinolyl, it is unsubstituted or uses one or more R
2replace,
(5) pyrimidyl, it is unsubstituted or uses one or more R
2replace,
(6) pyridyl, it is unsubstituted or uses one or more R
2replace
R
2can be independently selected from:
(1) halogen,
(2) C
1-3alkyl, it is unsubstituted or replaces with one or more halogen atom,
(3) alkoxyl group, it is unsubstituted or is replaced by one or more halogen atom,
(4) phenyl, it is unsubstituted or replaces with a halogen atom,
(5) heterocyclic radical, it is for containing nitrification or undersaturated heterocyclic radical containing 1 ~ 2 heteroatomic 5-or 6-unit independently selected from N and O.
Preferably, described Ar group can be independently selected from:
(1) phenyl, it is unsubstituted or with 1-5 R
3replace,
(2) heterocyclic aryl, it is substituted or unsubstituted heterocyclic aryl,
R
3can be independently selected from:
(1) halogen,
(2) C
1-3alkyl, it is unsubstituted or replaces with one or more halogen atom, or
(3) alkoxyl group;
R
1can be independently selected from:
(1) phenyl, it is unsubstituted or with 1-5 R
3replace,
(2) C
1-6straight chained alkyl, it is unsubstituted or uses one or more R
4replace, or
(3) naphthyl,
R
4can independently be selected from:
(1) halogen,
(2) hydroxyl.
More preferably, described Ar group can be independently selected from:
(1) phenyl, it is unsubstituted or with a R
3replace,
(2) pyridyl,
R
3can be independently selected from:
(1) halogen,
(2) C
1-3straight chained alkyl, it is unsubstituted or replaces with one or more halogen atom, or
(3) methoxyl group;
R
1can be independently selected from:
(1) phenyl, it is unsubstituted or with a R
3replace,
(2) C
1-3straight chained alkyl, it is unsubstituted or with a R
4replace, or
(3) naphthyl,
R
4for hydroxyl.
The preparation method of derivative provided by the present invention, its synthesis step is:
S1: successively salt of wormwood, potassiumiodide, (S)-1-(2-chloracetyl) tetramethyleneimine-2-formonitrile HCN to be added under condition of ice bath in tetrahydrofuran solution and to stir;
S2: at room temperature, by the compound dissolution of formula (II) in tetrahydrofuran solution;
S3: be slowly added dropwise in S1 gained solution by gained solution in S2 step, dropwises and reaction 2 hours under keeping condition of ice bath, react under being placed in room temperature after 2 hours again and reacts 24 hours;
S4: filter gained solution in S3 step, and use tetrahydrofuran solution washing leaching cake, collects filtrate, except desolventizing, after separation and purification, namely obtains cyanopyrrole alkane derivative;
Wherein, the structural formula of compound of formula (II) is:
The synthesis step of the compound of described formula (II) is as follows:
S1: first by R
1-Br halogenating agent is prepared into Grignard reagent;
S2: gained Grignard reagent in S1 and Ar-CN nitrile reagent are reacted in a heated condition, and with ammoniacal liquor and saturated ammonium chloride solution process;
S3: obtained processing gained solution in S2 by reduction reaction
Described (S)-1-(2-chloracetyl) tetramethyleneimine-2-formonitrile HCN synthesis step is as follows:
S1: L-PROLINE and chloroacetyl chloride are carried out substitution reaction, generates (S)-1-(chloracetyl) tetramethyleneimine-2-formic acid;
S2: S1 step is obtained product under the catalysis of N, N-dicyclohexylcarbodiimide and bicarbonate of ammonia generation acylation reaction obtains (S)-1-(chloracetyl) tetramethyleneimine-2-methane amide;
S3: dehydration reaction occurs under trifluoroacetic anhydride condition and generates (S)-1-(2-chloracetyl) tetramethyleneimine-2-formonitrile HCN.
Derivative provided by the invention be applied to the pharmaceutical composition preparing prevention and therapy and dipeptidyl peptidase-IV enzyme relative disease, wherein, described disease is diabetes B, obesity, hyperglycemia, lipid disorders syndromes or Alzheimer disease, described pharmaceutical composition also comprises and its pharmacy acceptable salt or carrier, is applied to pharmaceutical compositions also includes N1,N1-Dimethylbiguanide with derivative provided by the invention.
The term " alkyl " used in the present invention and other groups with prefix " alkane ", such as alkoxyl group and alkyloyl etc., refer to saturated hydrocarbyl that is straight or branched chain structure, except as otherwise noted.The example of alkyl comprises methyl, ethyl, propyl group, sec.-propyl etc.Such as, if specify concrete carbon atom number, C
3-C
8, term alkyl also comprises cycloalkyl, and the straight or branched-chain alkyl combined with cycloalkyl.When not indicating concrete carbon atom number, mean C
1-C
6.
Term used herein " cycloalkyl " refers to the saturated carbon ring group of the carbon atom with defined amount.The example of cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.Except as otherwise noted, cycloalkyl is often referred to monocycle.Except as otherwise noted, cycloalkyl is saturated.
Term used herein " alkoxyl group " refers to have the straight of concrete number of carbon atoms or branched-chain hydrocarbon oxide compound (such as C
1-10alkoxyl group), as methoxyl group, oxyethyl group, propoxy-, isopropoxy etc.
Term used herein " aryl " refers to list containing carbon atom or polycyclic aromatic loop systems.Preferred aryl is the hexa-atomic aromatic ring systems of monocycle or dicyclo.Preferably phenyl and naphthyl.Most preferred is phenyl.
Term used herein " heterocyclic radical " refers to be selected from the heteroatomic saturated of O, S and N or unsaturated non-aromatic ring or loop systems containing at least one.The Non-limiting examples ground of heterocyclic radical comprises piperazinyl, morpholine base, pyrrolidyl etc.
Term used herein " halogen " refers to fluorine, chlorine, bromine and iodine.Generally be preferably fluorine and chlorine.Be most preferably fluorine.
Be to be understood that, the compounds of this invention being illustrated as formula (I) structure also should comprise its pharmacy acceptable salt, and when they are used as free cpds or its pharmacy acceptable salt or the precursor as other synthesis, also comprise acceptable salt in non-pharmaceutical.
Compound of the present invention can be given with the form of pharmacy acceptable salt or episome.Term " pharmacy acceptable salt " means by pharmaceutically acceptable atoxic acid or alkali, comprise prepared by inorganic or organic acid or inorganic or organic bases salt.Be included in the salt of the basic cpd in term " pharmacy acceptable salt ", refer to the non-toxic salt of the compounds of this invention usually prepared by free alkali and atoxic inorganic or organic acid reaction.The exemplary salt of the compounds of this invention comprises without limitation: hydrochloride, bromide, vitriol, phosphoric acid salt, borate, acetate, tartrate, sulfonate, tosilate, hydroxynaphthoic acid salt, lactic acid salt, malate, maleate, succinate, Clavulanate, salicylate etc.
Compound of the present invention can give, for preventing, improving, control or treat the disease relevant to dipeptidyl peptidase-IV separately or with the form of combination.Compound of the present invention combines with the form of combination that give should than giving more effective with single form.This combination gives can in mode sequentially, also can be simultaneously or occurs with the form of compound formulation.The medicine given with compound combination of the present invention should comprise without limitation and is selected from following medicine:
(1) other dipeptidyl peptidase-iv inhibitor, such as sitagliptin, vildagliptin etc.;
(2) GLP-1 agonist, such as Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37], Exenatide etc.;
(3) other antidiabetic drug, comprises sulfonylurea such as tolbutamide, biguanides such as N1,N1-Dimethylbiguanide, glitazone such as rosiglitazone, alpha-glucosidase inhibitor such as acarbose and the α-glucose protein inhibitor such as Da Gelie that cotransports clean etc.;
(4) lipid regulating agent, such as hydroxy-3-methylglutaryl CoA reductase inhibitor as atorvastatin, affect the medicine of cholesterol and triacylglycerol metabolism as clofibrate;
(5) diuretic(s), such as hydrochlorothiazide etc.;
(6) antihypertensive drug, such as ACE inhibitor is if enalapril, angiotensin II receptor antagonists are if valsartan, sodium channel inhibitor are if Quinidine or procainamide, potassium channel antagonists are if amiodarone or sematilide, beta-blocker are as general naphthalene Nore or betaxolol, and calcium channel blocker is as nifedipine, Odizem, verapamil etc.;
(7) antiphlogiston, such as acetylsalicylic acid, acetylsalicylic acid, Acetanilide, Phenacetin, Tacote, Phenylbutazone, indomethacin and cox 2 inhibitor are as celecoxib etc.;
(8) antiviral, such as anti-AIDS drug is as Oseltamivir, zidovudine etc.;
(9) treat alzheimer medicine, such as AChEI is if tacrine, E2020 and other classes are as accounted for Mei Nuolin, memantine etc.;
(10) antitumor drug;
(11) cholesterol lowering medication, such as clofibrate, gemfibrozil, alufibrate etc.; Or
(12) hormone medicine.
The medicine combined with the compounds of this invention is not limited to those medicines described above, also should comprise not yet listing or other the effective medicines in the above cited disease of grinding.
When compound of the present invention and one or more other drugs combinationally use, the combination containing the compounds of this invention should be preferred.
Preferably, in the composition of described pharmaceutical composition except the cyanopyrrole alkane derivative described in formula (I), also N1,N1-Dimethylbiguanide is comprised.
Compound of the present invention can by oral, non-bowel, and the mode such as spraying, nose, sublingual or local gives.Correspondingly, compound of the present invention can form pharmaceutically acceptable formulation, to be effectively applied to patient separately or with the pharmaceutically acceptable carrier of the non-toxic of routine, vehicle and auxiliary agent etc.
Pharmaceutical composition of the present invention can exist with unit dosage expediently, and can form corresponding formulation in pharmaceutically acceptable any mode, and the method such as can known by pharmaceutical field is prepared.
The medicinal compositions comprising the compounds of this invention can give in oral mode, such as, give with forms such as tablet, capsule, lozenge, granule, syrup, suspensoids.Medicinal compositions for orally using can be prepared according to any known technology of medicinal compositions preparation field.And in order to make these preparations be easier to be easily accepted by the patient, usually following reagent can be added in this medicinal compositions: sweeting agent, sweetener, tinting material, sanitas etc.
Tablet should adopt the atoxic pharmaceutically acceptable vehicle being suitable for preparing tablet to be prepared, and these vehicle can be selected from: inert diluent is calcium carbonate, magnesiumcarbonate, sodium carbonate, calcium phosphate, sodium phosphate, lactose such as; Disintegrating agent, such as starch, Lalgine; Tackiness agent, such as starch, gel and arabic acid; Lubricant, such as Magnesium Stearate, stearic acid and talcum powder etc.Tablet can be non-dressing or dressing, and the tablet of dressing can be used for the disintegration and the absorption that postpone medicine.Existing general technology can be adopted to carry out dressing.
Can also present in a capsule for oral preparation, such as can hard gelatin capsule (to be mixed with inert diluent by activeconstituents and make) or present with the form of soft gelatin capsule (making by directly active ingredient being dissolved in fluid).
Compound of the present invention can also present with the form of syrup, wherein can sweeting agent comprise glycerine, propylene glycol, Sorbitol Powder etc.This formulation can also contain tinting material, sanitas, flavouring agent and seasonings etc.
Meanwhile, compound of the present invention or its medicinal compositions can also give with formulations such as injection, suppository, emulsion, suspensoid, paste.The present invention includes but be not limited to give mode above.
The medicine that derivative of the present invention prepares, except being applied to treatment people, can also treat other Mammals.
Molecular docking method is as one of method most important in structure-based drug design, huge success is achieved in medicinal design, the present invention uses molecular docking software to carry out molecular Docking Study, the display of docking result, derivative of the present invention and dipeptidyl peptidase-IV enzyme have and dock marking value preferably, its marking value, also higher than existing DPP-IV inhibitor, illustrates that derivative of the present invention has the activity of excellent suppression dipeptidyl peptidase-IV.
Especially, by synthesizing the compound 5 that obtains to the present invention and target proteins binding site analyzes rear discovery, compound 5 can be combined with target proteins significantly, wherein cyanopyrrolidine moiety is filled in the P1 pocket of binding site, and hydrophilic cyano group then forms covalent bonds with the Sauerstoffatom on amino-acid residue Ser630.And this cyano group can with the hydrogen evolution hydrogen bond on the imidazoleimines of near-end amino-acid residue His740 end; Biaryl moiety then forms a large hydrophobic field, and occupies the P2 pocket of dipeptidyl peptidase-IV enzyme; Carbonyl on ethanoyl then forms two hydrogen bonded with the residue A rg125 terminal amino group on target and imido grpup, substantially increases the tightness that it is combined with target enzyme.
The present invention have studied by quasi-medicated property the possibility that derivative becomes medicine, result is visible, and all synthesis obtain derivative all to be had good class medicine and beat part value, especially, C-1, C-2, C-5 and C-6 compounds medicine marking value is high, has the very high possibility becoming medicine.
The present invention has carried out safety evaluation to synthetic compound, using teratogenesis, mutagenesis, pungency toxicity and reproducibility toxicity as Drug safety assessment factor, found that derivative nontoxicity provided by the invention or have very little toxicity meets the standard of security medicinal design.
Compared with prior art, the present invention has the following advantages and beneficial effect:
1. derivative synthetic route provided by the invention is simple, and raw material is easy to get.
2. derivative targeting provided by the invention is high, and molecular docking marking value is high, is a class good cyanopyrrole alkane derivative dipeptidyl peptidase-IV enzyme inhibitors.
3. derivative safety evaluation score value provided by the invention is high, is a kind of low toxicity or nontoxic suppression dipeptidyl peptidase-IV enzyme inhibitors.
4. derivatives class property of medicine score value provided by the invention is high, possess the prospect becoming the medicine preparing prevention and therapy and dipeptidyl peptidase-IV enzyme relative disease, the diseases such as treatment and prevention diabetes B, obesity, hyperglycemia, lipid disorders syndromes or Alzheimer disease possess great application space.
Accompanying drawing explanation
Fig. 1 C-5 compound and target binding site schematic diagram.
The crystalline diffraction structural representation of Fig. 2 C-5 compound and target proteins.
Embodiment
The present invention is further described below in conjunction with specific embodiment.Unless stated otherwise, the present invention adopts reagent, equipment and method are conventional commercial reagent, equipment and the conventional method used of the art.
Embodiment 1: the synthesis of compd A-1:
L-PROLINE 3.0g, tetrahydrofuran (THF) 30mL, chloroacetyl chloride 2.5mL and 2 zeolite is added successively, reacting by heating 10min in reaction vessel.The process (methylene dichloride: methyl alcohol=20:1) that reacts completely is monitored through thin layer chromatography.After reaction terminates, be cooled to room temperature, above-mentioned solution dripped the N be dissolved in 10mL methylene dichloride, N-dicyclohexylcarbodiimide 2.14g.Drip and finish, add bicarbonate of ammonia 5.0g, and continue to stir 1h, period reacts completely (chloroform: methyl alcohol=20:1) through thin layer chromatography monitoring.Continue slowly to drip trifluoroacetic anhydride 1.28mL in above-mentioned gained solution.Drip and finish, remove cryosel bath, and in stirred at ambient temperature 2h, period reacts completely (chloroform: methyl alcohol=20:1) through TLC monitoring.After reaction terminates, add saturated sodium bicarbonate aqueous solution and be adjusted to pH 8 ~ 9, and stir 30min.Add 20mL ethyl acetate to extract, and be separated organic layer.Aqueous layer with ethyl acetate (10mL × 2) extracts again, and with 20mL saturated common salt solution washing merge organic layer.Through anhydrous sodium sulfate drying, filter, and remove solvent under reduced pressure.Enriched material normal hexane recrystallization, obtains (S)-1-(2-chloracetyl) tetramethyleneimine-2-formonitrile HCN of 0.78g, yield 75.5%, and compound structure is confirmed with known structure by nuclear-magnetism contrast.
Embodiment 2: the synthesis of compd B-1:
2.0g 4-bromofluorobenzene, 0.3g magnesium chips and 10mL tetrahydrofuran (THF) is added successively in reaction vessel, vigorous stirring at 45 ~ 50 DEG C of temperature, use constant pressure funnel in above-mentioned solution, slowly add the 0.51g cyanobenzene solution be dissolved in 10mL tetrahydrofuran (THF), finish, heat up, and in stirred under reflux temperature 4h, react completely (ethyl acetate: sherwood oil=1:4) through thin layer chromatography monitoring.After reacting completely, continue reaction solution to stir at 0 DEG C and be slowly added dropwise in the mixing solutions of 15mL ammoniacal liquor and 15mL saturated ammonium chloride, dripping and finish, add 30mL ethyl acetate and extract, and be separated organic layer.Aqueous layer with ethyl acetate (15mL × 2) extracts again, and with the organic layer that 20mL saturated common salt solution washing merges, through anhydrous sodium sulfate drying, filters, and concentrating under reduced pressure, obtain bolarious residual oil thing.In above-mentioned remaining enriched material, add 10mL methyl alcohol, and be cooled to-5.DEG C keep temperature lower than at-5 DEG C, with stir under add 0.2g sodium borohydride successively, stirring is spent the night, through thin layer chromatography monitoring react completely (ethyl acetate: sherwood oil=1:1).After reaction terminates, except desolventizing, be separated organic layer.Aqueous layer with ethyl acetate (10mL × 2) extracts again, and with 10mL saturated common salt solution washing merge organic layer.Through anhydrous sodium sulfate drying, filter, and remove ethyl acetate solvent under reduced pressure, obtain yellow resistates.Resistates, through column chromatography purification, obtains product, productive rate 27%, and compound structure is confirmed with known structure by nuclear-magnetism contrast.
The preparation of embodiment 3 ~ embodiment 12 compound is with reference to the preparation method in embodiment 2, and its structure, starting raw material and productive rate are in table 1, and compound (B-1) ~ (B-12) compound structure is confirmed with known structure by nuclear-magnetism contrast.
Table 1. (B-1) ~ (B-12) compound structure, starting raw material and ultimate yield
Embodiment 14: the synthesis of Compound C-1:
In three-necked flask, add 0.4g salt of wormwood, 0.005g potassiumiodide, 0.4g L-benzene glycinol and 6.0mL tetrahydrofuran (THF) successively, and be cooled to less than 0 DEG C with cryosel bath.Then 0.5g A-1 compound is dissolved in 2.0mL tetrahydrofuran (THF), and is slowly added dropwise in above-mentioned solution, then with the inwall of 1.0mL tetrahydrofuran (THF) washing dropping funnel.Temperature is kept to continue stirring reaction 2h at 0 DEG C.Remove cryosel bath, and react 24h under room temperature, period reacts completely (methylene dichloride: methyl alcohol=8:1) through thin layer chromatography monitoring.After reaction terminates, filter, and with 1.0mL tetrahydrofuran (THF) washing leaching cake, collect filtrate.Remove solvent under reduced pressure, enriched material, through column chromatography purification, obtains the flaxen oily resistates of 0.7g, yield 88.4%.ESI-MS，m/z:296(M+Na+)，274(M+H+)
Embodiment 15: the synthesis of Compound C-2
Method, with embodiment 14, replaces L-benzene glycinol unlike with B-1, obtains white to flaxen pulverulent solids, yield 50.0%.m.p.119.2-120.3；℃
-0.917(c 1.00g·100mL-1,CHCl3)；ESI-MS，m/z:342.1606(M+Na+)，320.1774(M+H+)。1H NMR(DMSO-d6,500Hz)δppm:2.04-2.10(m,2H),2.16(m,1H),2.25(m,1H),2.54(brs,1H,),3.18-3.22(m,2H),3.34(s,2H),4.75(t,1H),4.89(s,1H,),7.21(t,2H,J＝7Hz),7.31(t,4H),7.43(d,4H,J＝9Hz)。
Embodiment 16: the synthesis of Compound C-3
Method, with embodiment 14, replaces L-benzene glycinol unlike with B-2, obtains white solid, yield 49.1%.m.p.126.4-127.3；℃
-0.375(c 1.00g·100mL-1,CHCl3)；ESI-MS,m/z:338.1670(M+Na+),360.1441(M+H+)。1H NMR(DMSO-d6,500Hz)δppm:1.91-1.99(m,2H),2.09-2.13(m,1H),2.50(m,1H),2.71(brs,1H),3.20-3.27(m,2H),3.33(s,2H),4.75(t,1H),4.91(s,1H),7.11-7.15(d,4H,J＝8Hz),7.41-7.45(m,5H)。
Embodiment 17: the synthesis of Compound C-4
Method, with embodiment 14, replaces L-benzene glycinol unlike with B-3, obtains white to faint yellow solid.m.p.84.0-85.5；℃
-0.334(c 1.00g·100mL-1,CHCl3)；ESI-MS,m/z:378.1425(M+Na+),356.1572(M+H+)。1H NMR(DMSO-d6,500Hz)δppm:1.90-1.99(m,2H),2.08-2.12(m,2H),2.80(brs,1H),3.22-3.36,3.41-3.51(m,2H),3.36(s,2H),4.76(t,1H),5.20(s,1H),7.12-7.16(dd,4H,J＝9Hz),7.23(t,1H,J＝7.5Hz),7.31(m,1H),7.37-7.42(m,1H),7.65-7.70(m,1H)。
Embodiment 18: the synthesis of Compound C-5
Method, with embodiment 14, replaces L-benzene glycinol unlike with B-4, obtains white solid, yield 61.2%.m.p.95.4-97.2；℃
-0.250(c 1.00g·100mL-1,CHCl3)；ESI-MS,m/z:356.0989(M+H+),378.0670(M+Na+)。1H NMR(DMSO-d6,500Hz)δppm:1.90-1.97(m,2H),2.09-2.13(m,1H),2.50(m,1H),2.69(brs,1H),3.20-3.25(m,2H),3.33(s,2H),4.70(m,1H),4.89(s,1H),7.12(t,2H),7.21(t,2H),7.31(t,2H),7.74(m,2H)。
Embodiment 19: the synthesis of Compound C-6
Method, with embodiment 14, replaces L-benzene glycinol unlike with B-5, obtains white solid, yield 24.8%.m.p.108.5-109.1；℃
-0.192(c 1.00g·100mL-1,CHCl3)；ESI-MS,m/z:343.1351(M+Na+),321.1197(M+H+)。1H NMR(DMSO-d6,500Hz)δppm:1.88-1.20(m,2H),2.10-2.14(m,1H),2.18-2.19(m,1H),3.10(brs,1H),3.25,3.40(m,2H),3.34(s,2H),4.75(q,1H),4.95(s,1H),7.20-7.24(m,1H),7.29-7.32(t,4H,J＝7.5Hz),7.38-7.42(m,1H),7.44-7.45(d,1H,J＝8Hz),7.72-7.76(t,1H,J＝8Hz),7.49-7.85(d,1H,J＝5Hz)。
Embodiment 20: the synthesis of Compound C-7
Method, with embodiment 14, replaces L-benzene glycinol unlike with B-6, obtains white solid, yield 68.0%.m.p.155.2-156.7；℃
-0.700(c 1.00g·100mL-1,CHCl
3)；ESI-MS,m/z:424.1621(M+Na+),402.1371(M+H+)。1H NMR(DMSO-d6,500Hz)δppm:1.87-1.98(m,2H),2.07-2.18(m,4H),2.50(m,1H),2.76(brs,1H),3.21-3.25(m,2H),3.34(s,2H),4.74-4.78(m,1H),4.95(s,1H),7.11-7.13(d,2H,J＝9Hz),7.28-7.31(dd,2H,J＝9Hz),7.62-7.67(m,4H)。
Embodiment 21: the synthesis of Compound C-8
Method, with embodiment 14, replaces L-benzene glycinol unlike with B-7, obtains 0.80g white solid, yield 75.1%.m.p.82.2-84.6；℃
-0.275(c 1.00g·100mL-1,CHCl3)；ESI-MS,m/z:390.1612(M+Na+),368.1820(M+H+)。1H NMR(DMSO-d6,500Hz)δppm:1.88-1.98(m,2H),2.09-2.13(m,1H),2.50(m,1H),2.62(brs,1H),3.23,3.38(m,2H),3.34(s,2H),3.71(s,3H),4.76(t,1H),4.83(s,1Hl),6.86(d,2H,J＝8.5Hz),7.10(t,2H,J＝9Hz),7.27-7.31(m,2H),7.39-7.44(m,2H)。
Embodiment 22: the synthesis of Compound C-9
Method, with embodiment 14, replaces L-benzene glycinol unlike with B-8, obtains white solid, yield 67.7%.m.p.116.2-119.4；℃
-0.183(c 1.00g·100mL-1,CHCl3)；ESI-MS,m/z:356.0989(M+Na+),378.0670(M+H+)。1H NMR(DMSO-d6,500Hz)δppm:1.90-1.97(m,2H),2.09-2.13(m,1H),2.50(m,1H),2.69(brs,1H),3.20-3.25(m,2H),3.33(s,2H),4.70(m,1H),4.89(s,1H),7.12(t,2H,J＝9Hz),7.21(t,2H,J＝8Hz,7.5Hz),7.31(t,2H,J＝8.5Hz,8Hz),7.74(m,2H)。
Embodiment 23: the synthesis of Compound C-10
Method, with embodiment 14, replaces L-benzene glycinol unlike with B-9, obtains white solid, yield 76.4%.m.p.161.5-165.9；℃
-0.692(c 1.00g·100mL-1,CHCl3)；ESI-MS,m/z:460.1607(M+Na+),438.1734(M+H+)。1H NMR(DMSO-d6,500Hz)δppm:1.87-1.97(m,2H),2.08-2.12(m,1H),2.52(m,1H),2.86(brs,1H),3.21-3.25,3.35-3.38(m,2H),3.34(s,2H),4.75(t,1H),5.2(s,1H),7.47-7.57(m,4H),7.68-7.74(dd,4H,8.5Hz),7.85-7.87(d,1H,J＝7.5Hz),7.90-7.92(d,1H,J＝8Hz),7.99-8.02(d,1H,J＝7.5Hz)。
Embodiment 24: the synthesis of Compound C-11
Method, with embodiment 14, replaces L-benzene glycinol unlike with B-10, obtains white solid, yield 72.0%.m.p.128.1-130.4；℃
-0.744(c 1.00g·100mL-1,CHCl3)；ESI-MS,m/z:410.1658(M+Na+)。1H NMR(DMSO-d6,500Hz)δppm:1.87-1.94(m,2H),2.08-2.13(m,1H),2.50(m,1H),2.83(brs,1H),3.22-3.53,3.35-3.38(m,2H),3.36(s,2H),4.75-4.78(q,1H),5.07(s,1H),7.12-7.16(t,4H),7.46-7.53(m,4H),7.84-7.87(t, 1H,J＝8Hz,6.5Hz),7.90-7.91(d,1H,J＝7.5Hz),7.95-7.97(d,1H,J＝7Hz)。
Embodiment 25: the synthesis of Compound C-12
Method, with embodiment 14, replaces L-benzene glycinol unlike with B-11, obtains faint yellow solid, yield 34.3%.m.p.74.5-76.7；℃
-0.658(c 1.00g·100mL-1,CHCl3)；ESI-MS,m/z:356.0989(M+Na+),378.0670(M+H+)。1H NMR(DMSO-d6,500Hz)δppm:1.90-1.97(m,2H),2.09-2.13(m,1H),2.50(m,1H),2.69(brs,1H),3.20-3.25(m,2H),3.33(s,2H),4.70(m,1H),4.89(s,1H),7.12(t,2H,J＝9Hz),7.21(t,2H,J＝8Hz,7.5Hz),7.31(t,2H,J＝8.5Hz),7.74(m,2H)。
Embodiment 26: the synthesis of Compound C-13
Method, with embodiment 14, unlike replacing the preparation of L-benzene glycinol with B-12, obtains white solid, yield 35.0%.m.p.99.8-103.5。℃
-0.050(c 1.00g·100mL-1,CHCl3)；ESI-MS,m/z:356.0989(M+Na+),378.0670(M+H+)。1H NMR(DMSO-d6,500Hz)δppm:1.90-1.97(m,2H),2.09-2.13(m,1H),2.50(m,1H),2.69(brs,1H),3.20-3.25(m,2H),3.33(s,2H),4.70(m,1H),4.89(s,1H),7.12(t,2H,J＝9Hz),7.21(t,2H,J＝8Hz,7.5Hz),7.31(t,2H,J＝8.5Hz,8Hz),7.74(m,2H)。
Table 2 is for synthesizing structure and the yield of the compound obtained in embodiment 14 ~ embodiment 26:
Table 2. (C-1) ~ (C-13) compound structure and yield
Fig. 1 is the binding site schematic diagram that C-5 compound is combined with target proteins, Fig. 2 is the crystalline diffraction structural representation of C-5 compound and target proteins, wherein target proteins derives from Protein Data Bank (PDB code:3W2T), rear discovery is analyzed to it, C-5 compound can be combined with target proteins significantly, wherein cyanopyrrolidine moiety is filled in the P1 pocket of binding site, and hydrophilic cyano group then forms covalent bonds with the Sauerstoffatom on amino-acid residue Ser630.And this cyano group can with the hydrogen evolution hydrogen bond on the imidazoleimines of near-end amino-acid residue His740 end; Biaryl moiety then forms a large hydrophobic field, and occupies the P2 pocket of dipeptidyl peptidase-IV enzyme; Carbonyl on ethanoyl then forms two hydrogen bonded with the residue A rg125 terminal amino group on target and imido grpup, substantially increases the tightness that it is combined with target enzyme.
Embodiment 27: the present invention uses molecular docking software Molegro Virtual Dock (Vertion 5.5) to carry out molecular Docking Study, the docking marking value obtained refers to table 3, wherein target proteins derives from Protein Data Bank (PDB code:3W2T), first wife's volume recombination small molecules LF7 (Vildagliptin) selected by object of reference, and LF7 structure is
containing the Cyanopyrolidine skeleton identical with series compound P1 part of the present invention.The display of docking result, derivative of the present invention and dipeptidyl peptidase-IV enzyme have and better dock marking value, illustrate that derivative of the present invention can suppress the activity of dipeptidyl peptidase-IV.
The marking value that table 3. derivative of the present invention docks with target proteins
Embodiment 28: the present invention carries out quasi-medicated property assessment to described derivative, by quasi-medicated property parameter, class medicine Principles (fat water partition coefficients LogP is not more than 5, molecular weight MW is not more than 500, hydrogen donor number nOHNH is no more than 5, hydrogen acceptor nON number no more than 10) is as determining whether molecule has the important parameter of quasi-medicated property, key nRotb can be reversed in addition, molecule availability be also affect molecule can the important factor of patent medicine.The present invention utilizes webpage www.molinspiration.com and formula %ABS=109-0.693TPSA (Zhao et al, Pharm Res, 19:1446-1457 (2002)) to carry out detecting and assessing to it.
Table 4 is that every quasi-medicated property parameter of carrying out according to derivative of the present invention comments value, result shows, and derivative of the present invention has good class medicine marking value, especially, C-1, C-2, C-5 and C-6 compounds medicine marking value is high, possess prepare medicine greatly can application space.
Table 4
Embodiment 29: the safety evaluation of derivative of the present invention:
Using teratogenesis, mutagenesis, pungency toxicity and the reproducibility toxicity important factor as Drug safety assessment, choosing the derivative obtained synthesized by the present invention utilizes webpage www.organic-chemistry.org to carry out difference detecting and assessing to it, result is as shown in table 5, as can be seen from Table 5, the equal nontoxicity of the compound chosen or have very little toxicity, meets the standard of security medicinal design.
Table 5
Embodiment 30: the Macrogol 4000 taking the C-5 compound of 50mg, the Microcrystalline Cellulose of 150mg, the Xylo-Mucine of 12mg and 2mg, first C-5 compound, Microcrystalline Cellulose and Xylo-Mucine are mixed, and then said mixture is lubricated with Macrogol 4000, and tabletted.
Claims (10)
1. a cyanopyrrole alkane derivative, is characterized in that, described cyanopyrrole alkane derivative structural formula as
Shown in formula (I):
Wherein:
R
1can be independently selected from:
(1) phenyl, it is unsubstituted or with 1-5 R
3replace,
(2) C
1-6straight chained alkyl, it is unsubstituted or uses one or more R
4replace,
(3) C
3-6cycloalkyl,
(4) heterocyclic aryl, it is substituted or unsubstituted heterocyclic aryl, or
(5) hydrogen
R
3can be independently selected from:
(1) halogen,
(2) C
1-3alkyl, it is unsubstituted or replaces with one or more halogen atom, or
(3) alkoxyl group
R
4can independently be selected from:
(1) halogen,
(2) hydroxyl,
(3) aromatic group, it is phenyl or heterocyclic aryl
Ar is the group independently with aromaticity, can independently be selected from:
(1) phenyl, it is unsubstituted or uses one or more R
2replace,
(2) xenyl, it is unsubstituted or uses one or more R
2replace,
(3) naphthyl, it is unsubstituted or uses one or more R
2replace,
(4) quinolyl, it is unsubstituted or uses one or more R
2replace,
(5) pyrimidyl, it is unsubstituted or uses one or more R
2replace,
(6) pyridyl, it is unsubstituted or uses one or more R
2replace
R
2can be independently selected from:
(1) halogen,
(2) C
1-3alkyl, it is unsubstituted or replaces with one or more halogen atom,
(3) alkoxyl group, it is unsubstituted or is replaced by one or more halogen atom,
(4) phenyl, it is unsubstituted or replaces with a halogen atom,
(5) heterocyclic radical, it is for containing nitrification or undersaturated heterocyclic radical containing 1 ~ 2 heteroatomic 5-or 6-unit independently selected from N and O.
2. derivative as claimed in claim 1, is characterized in that, described Ar group can be independently selected from:
(1) phenyl, it is unsubstituted or with 1 ~ 5 R
3replace,
(2) heterocyclic aryl, it is substituted or unsubstituted heterocyclic aryl,
R
3can be independently selected from:
(1) halogen,
(2) C
1-3alkyl, it is unsubstituted or replaces with one or more halogen atom, or
(3) alkoxyl group;
R
1can be independently selected from:
(1) phenyl, it is unsubstituted or with 1-5 R
3replace,
(2) C
1-6straight chained alkyl, it is unsubstituted or uses one or more R
4replace, or
(3) naphthyl,
R
4can independently be selected from:
(1) halogen,
(2) hydroxyl.
3. derivative as claimed in claim 1 or 2, is characterized in that, described Ar group can be independently selected from:
(1) phenyl, it is unsubstituted or with a R
3replace,
(2) pyridyl,
R
3can be independently selected from:
(1) halogen,
(2) C
1-3straight chained alkyl, it is unsubstituted or replaces with one or more halogen atom, or
(3) methoxyl group;
R
1can be independently selected from:
(1) phenyl, it is unsubstituted or with a R
3replace,
(2) C
1-3straight chained alkyl, it is unsubstituted or with a R
4replace, or
(3) naphthyl,
R
4for hydroxyl.
4. the preparation method of the derivative as described in claim 1,2 or 3, is characterized in that, described synthesis step is:
S1: successively salt of wormwood, potassiumiodide, (S)-1-(2-chloracetyl) tetramethyleneimine-2-formonitrile HCN to be added under condition of ice bath in tetrahydrofuran solution and to stir;
S2: at room temperature, by the compound dissolution of formula (II) in tetrahydrofuran solution;
S3: be slowly added dropwise in S1 gained solution by gained solution in S2 step, dropwises and reaction 2 hours under keeping condition of ice bath, react under being placed in room temperature after 2 hours again and reacts 24 hours;
S4: filter gained solution in S3 step, and use tetrahydrofuran solution washing leaching cake, collects filtrate, except desolventizing, after separation and purification, namely obtains cyanopyrrole alkane derivative;
Wherein, the structural formula of compound of formula (II) is:
5. the preparation method of derivative as claimed in claim 4, it is characterized in that, the synthesis step of the compound of described formula (II) is as follows:
S1: first by R
1-Br halogenating agent is prepared into Grignard reagent;
S2: gained Grignard reagent in S1 and Ar-CN nitrile reagent are reacted in a heated condition, and with ammoniacal liquor and saturated ammonium chloride solution process;
S3: gained solution in S2 is obtained by reduction reaction
6. the preparation method of derivative as claimed in claim 4, it is characterized in that, described (S)-1-(2-chloracetyl) tetramethyleneimine-2-formonitrile HCN synthesis step is as follows:
S1: L-PROLINE and chloroacetyl chloride are carried out substitution reaction, generates (S)-1-(chloracetyl) tetramethyleneimine-2-formic acid;
S2: S1 step is obtained product under the catalysis of N, N-dicyclohexylcarbodiimide and bicarbonate of ammonia generation acylation reaction obtains (S)-1-(chloracetyl) tetramethyleneimine-2-methane amide;
S3: dehydration reaction occurs under trifluoroacetic anhydride condition and generates (S)-1-(2-chloracetyl) tetramethyleneimine-2-formonitrile HCN.
7. the application of the derivative described in claim 1,2 or 3, is characterized in that, is applied to the pharmaceutical composition preparing prevention and therapy and dipeptidyl peptidase-IV enzyme relative disease.
8. apply as claimed in claim 7, it is characterized in that, described disease is diabetes B, obesity, hyperglycemia, lipid disorders syndromes or Alzheimer disease.
9. apply as claimed in claim 7, it is characterized in that, described pharmaceutical composition also comprises and its pharmacy acceptable salt or carrier.
10. apply as claimed in claim 7, it is characterized in that, the composition of described pharmaceutical composition also comprises N1,N1-Dimethylbiguanide.
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| CN115322129A (en) * | 2022-08-29 | 2022-11-11 | 湖北科技学院 | Dicyano pyrrolidine derivative and preparation method and application thereof |
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