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CN101318922B - Novel dipeptidyl peptidase restrainer, synthesizing process and uses thereof - Google Patents

Novel dipeptidyl peptidase restrainer, synthesizing process and uses thereof Download PDF

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CN101318922B
CN101318922B CN2007100417607A CN200710041760A CN101318922B CN 101318922 B CN101318922 B CN 101318922B CN 2007100417607 A CN2007100417607 A CN 2007100417607A CN 200710041760 A CN200710041760 A CN 200710041760A CN 101318922 B CN101318922 B CN 101318922B
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hydroxyl
hydrogen
cyanopyrolidine
glycyl
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CN101318922A (en
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陈慧茹
陈义朗
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Shanghai Sun Sail Pharmaceutical Science and Technology Co Ltd
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Abstract

The invention provides an inhibitor of dipeptidyl peptidase IV shown in formula (I). In the formula, R1 is hydrogen, chlorine, fluorine, bromine, hydroxide radical or alkoxy radical of C1-C6; R2 is hydrogen, fluorine, bromine or hydroxide radical; but R1 can not be the hydroxide or the alkoxy radical of C1-C6 when R2 is hydrogen; and R3 is hydrogen or fluorine. The compound can be used for treating or preventing diseases related with the dipeptidyl peptidase IV, such as diabetes mellitus, obesity and hyperlipoidemia. The invention also provides a method for preparing a compound shown in the formula (I), a preparation method of a pharmaceutically acceptable salt and a pharmaceutical composition thereof, and an application of the compound, the pharmaceutically acceptable salt and the pharmaceutical composition thereof in medicines used for treating or preventing the diseases related with the dipeptidyl peptidase IV.

Description

One class depeptidyl peptidase inhibitors, preparation method and use
Technical field
The present invention relates to a class novel dipeptidyl peptidase IV (Dipeptidyl peptidases, DPP-IV) inhibitor, its preparation method with and in preparation treatment DPP-IV relevant disease medicament, particularly preparation treatment diabetes, obesity, the application in the high blood cholesterol drug.
Background of invention
Diabetes are that a kind of carbohydrate, fat and protein metabolism that causes owing to hypoinsulinism or insulin resistant is unusual, and are one group of clinical syndrome of principal character with chronic hyperglycemia (fasting plasma glucose concentration is greater than 130mg/dL) and glycosuria.The hyperglycemia that continues can cause the generation of many complication, as retina, kidney, nervous system lesion and vascular complication, especially cardiovascular complication is the main threat that the diabetic subject is disabled, so the control blood glucose level in patients is for delaying or to block the generation of complication very important.At present, the medicine of treatment diabetes B mainly contains Regular Insulin, biguanides such as N1,N1-Dimethylbiguanide, sulphonyl urine class such as glimepiride, alpha-glucosidase inhibitor such as acarbose, how to be listed as class such as nateglinide, row ketone such as rosiglitazone.But these medicines all have significant side effects except that curative effect is limited, therefore press for new more effective, safer treatment diabetes medicament.
Glucagon-like-peptide-1 (GLP-1) is by alpha Cell of islet and enteron aisle L emiocytosis, and therefore the biosynthetic effect that has glucose dependency insulin secretion accelerating and increase Regular Insulin uses GLP-1 treatment diabetes to cause the very big interest of scientist.GLP-1 is except having the effect of the insulin secretion of promotion; also have physiological function [Trends Endocrinol Metab such as the generation that promotes beta cell hyperplasia, anti-beta cell apoptosis, glucagon suppression and glycogen, depress appetite, reduction gastrointestinal emptying speed, neuroprotective cell; 1999,10 (6): 229-235].GLP-1 contains 30 amino acid whose polypeptide, and glucose and fat can stimulate its release.These characteristics of GLP-1 make it become the ideal Remedies for diabetes.The GLP-1 continuous intravenous infusion can reduce diabetic subject's blood sugar, even still effective to the patient of sulfonylurea treatment failure, but single subcutaneous injection GLP-1 is invalid, and injection is satisfactory for result under continuous 6 peritheliums.The reason that produces this phenomenon is only several minutes GLP-1 transformation period in vivo, can be removed N end dipeptides, and lose insulin secretion accelerating activity [Expert Opin.Investing.Drugs by endogenous dipeptidyl peptidase (DPP-IV) degraded rapidly, 2004,13 (9): 1091-1102].DPP-IV extensively distributes in human body, is the main metabolic enzyme of GLP-1, is bringing into play important effect in regulation and control GLP-1 activity.Therefore the active compound that suppresses DPP-IV is the DPPIV inhibitor, can strengthen the effect of GLP-1 (intestines hypoglycemic element), is expected to become novel diabetes B medicine.
Existing document and patent disclosure many DPP-IV inhibitor [Current Medicinal Chemistry, 1999,6,311-327; Biochemistry1999,38,11597-11603; Expert Opin.Investing.Drugs, 2005,15 (10): 1387-1407; Expert Opin.Ther.Patents, 2003,13 (4): 499-510].WO00/34241 discloses to have DPP-IV and suppresses active N-replacement-2-cyanopyrrole compounds, its diamantane partly is single the replacement or simple alkyl replacement, US2003/0100563 discloses the beta-amino heterocyclic DPP-IV inhibitor that is used for the treatment of diabetes, WO03/057666 discloses Cyclopropanated 2-cyanopyrrole class DPP-IV inhibitor, US2004/0171848 discloses a series of 2-cyanopyrrole compounds that contain together with the phenylbenzene side chain, WO2005/095381 discloses 2 of a class new texture, 4-dioxy-3,4-dihydropyridine DPP-IV inhibitor.
Yet these compounds are satisfactory not enough to the inhibition of dipeptidyl peptidase in the prior art, so this area presses for the highly active depeptidyl peptidase inhibitors of exploitation, so that treat various and the relevant various diseases of dipeptidyl peptidase (DPP-IV).
Summary of the invention
The purpose of this invention is to provide class novel dipeptidyl peptidase IV (Dipeptidyl peptidases, DPP-IV) inhibitor, its preparation method and an application thereof.
A first aspect of the present invention provides the compound shown in a kind of formula (I), or its each optical isomer, each crystal formation, pharmaceutically acceptable inorganic or organic salt, hydrate or solvate:
Figure S07141760720070711D000021
In the formula, R 1Be hydrogen, chlorine, fluorine, bromine, hydroxyl or C 1-C 6Alkoxyl group;
R 2Be hydrogen, chlorine, fluorine, bromine or hydroxyl;
R 3Be hydrogen or fluorine;
And work as R 3During for hydrogen, R 1, R 2In at least one is a halogen.
In another preference, R 1Be chlorine or fluorine.
In another preference, R 2Be hydrogen or hydroxyl.
In another preference, R 3Be fluorine.
In another preference, described compound is selected from down group:
(2S)-and 1-[(3-fluoro-5-hydroxyl-1-adamantyl) glycyl]-2-Cyanopyrolidine (YF-4);
(2S, 4S)-1-[(3-fluoro-5-hydroxyl-1-adamantyl) glycyl]-4-fluoro-2-Cyanopyrolidine (YF-12);
(2S, 4S)-1-[(3-hydroxyl-1-adamantyl) glycyl]-4-fluoro-2-Cyanopyrolidine (YF-8);
(2S)-and 1-[(3-chloro-5-hydroxyl-1-adamantyl) glycyl]-2-Cyanopyrolidine (YF-3);
(2S, 4S)-1-[(3-chloro-5-hydroxyl-1-adamantyl) glycyl]-4-fluoro-2-Cyanopyrolidine (YF-9).
A second aspect of the present invention, a kind of pharmaceutical composition is provided, it contains acceptable vehicle or carrier on the pharmacology, and above-claimed cpd of the present invention or its each optical isomer, each crystal formation, pharmaceutically acceptable inorganic or organic salt, hydrate or solvate.
A third aspect of the present invention provides the purposes of above-claimed cpd of the present invention or its each optical isomer, each crystal formation, pharmaceutically acceptable inorganic or organic salt, hydrate or solvate, and they are used to prepare the DPP-IV inhibitor.
A fourth aspect of the present invention, the purposes of above-claimed cpd of the present invention or its each optical isomer, each crystal formation, pharmacy acceptable salt, hydrate or solvate is provided, and they are used to prepare the medicine of treatment, prevention and the alleviation disease relevant with DPP-IV.
In another preference, the described disease relevant with DPP-IV is selected from diabetes, obesity, hyperlipidemia.
A fifth aspect of the present invention provides the manufacture method of above-claimed cpd of the present invention or its each optical isomer, each crystal formation, pharmacy acceptable salt, hydrate or solvate, and wherein said method comprises the steps:
In inertia solution, under the alkaline condition, make compound shown in the reaction production of compound shown in compound shown in the formula (II) and the formula (III) (I),
Figure S07141760720070711D000041
In the formula, R 1Be hydrogen, chlorine, fluorine, bromine, hydroxyl or C 1-C 6Alkoxyl group;
R 2Be hydrogen, chlorine, fluorine, bromine or hydroxyl;
R 3Be hydrogen or fluorine;
And work as R 3During for hydrogen, R 1, R 2In at least one is a halogen.
In another preference, in described method various, R 1Be fluorine, R 2Be hydroxyl, R 3Be hydrogen.
In another preference, in described method various, R 1Be fluorine, R 2Be hydroxyl, R 3Be fluorine.
In another preference, in described method various, R 1Be hydroxyl, R 2Be hydrogen, R 3Be fluorine.
Embodiment
The inventor has screened a large amount of compounds through extensive and deep research, and discoverable type (I) compound has very high restraining effect to DPP-IV first, is particularly suitable as the inhibitor of DPP-IV.The inventor has finished the present invention on this basis.
Activeconstituents
" compound of the present invention " is meant the compound shown in the formula (I) herein.This term also comprises the various crystal formations of formula (I) compound, pharmaceutically acceptable inorganic or organic salt, hydrate or solvate.There are one or more unsymmetrical carbons in The compounds of this invention, so general formula (I) comprises the racemic modification thing, racemic mixture, single enantiomer, non-enantiomer mixture and single diastereomer.R on the pyrrole ring in the The compounds of this invention 3With cyano group can be cis, also can be trans.
" pharmacy acceptable salt " as used herein so long as pharmaceutically acceptable salt just there is no particular limitation, can enumerate the salt that forms with acid particularly, be fit to salifiable acid and include, but is not limited to mineral acids such as hydrochloric acid, Hydrogen bromide, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, acidic amino acids such as organic acid such as formic acid, acetate, propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, picric acid, methylsulfonic acid, Phenylsulfonic acid and aspartic acid, L-glutamic acid.
C 1-C 6Alkoxyl group, its alkyl can be C 1-C 6The straight or branched alkyl, can exemplify as methyl, ethyl, propyl group, sec.-propyl, cyclopropyl, cyclobutyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, neo-pentyl, tert-pentyl, the 1-methyl butyl, the 2-methyl-propyl, hexyl, isohexyl, the 1-methyl amyl, the 2-methyl amyl, the 3-methyl amyl, the 2-methyl butyl, 1, the 1-dimethylbutyl, 1, the 2-dimethylbutyl, 1, the 3-dimethylbutyl, 2, the 3-dimethylbutyl, 3, the 3-dimethylbutyl, the 1-ethyl-butyl, the 2-ethyl-butyl, 1,1,2-trimethylammonium propyl group, 1,2,2-trimethylammonium propyl group, 1-ethyl-1-methyl-propyl and 1-ethyl-2-methyl-propyl.In these groups, being preferably carbonatomss such as methyl, ethyl, propyl group, cyclopropyl, sec.-propyl, butyl is the individual alkyl of 1-4.
Compound title and structural formula representative in the compound shown in the formula of the present invention (I) are as follows:
Figure S07141760720070711D000051
Compound Title R 1 R 2 R 3
YF-1 (2S)-and 1-[(3-fluoro-1-adamantyl) glycyl]-the 2-Cyanopyrolidine F H H
YF-2 (2S)-and 1-[(3-chloro-1-adamantyl) glycyl]-the 2-Cyanopyrolidine Cl H H
YF-3 (2S)-and 1-[(3-chloro-5-hydroxyl-1-adamantyl) glycyl]-the 2-Cyanopyrolidine Cl OH H
YF-4 (2S)-and 1-[(3-fluoro-5-hydroxyl-1-adamantyl) glycyl]-the 2-Cyanopyrolidine F OH H
YF-5 (2S)-and 1-[(3-bromo-5-hydroxyl-1-adamantyl) glycyl]-the 2-Cyanopyrolidine Br OH H
YF-6 (2S)-and 1-[(3-methoxyl group-5-hydroxyl-1-adamantyl) glycyl]-the 2-Cyanopyrolidine 0CH 3 OH H
YF-7 (2S)-and 1-[(3,5-two chloro-1-adamantyls) glycyl]-the 2-Cyanopyrolidine Cl Cl H
YF-8 (2S, 4S)-1-[(3-hydroxyl-1-adamantyl) glycyl]-4-fluoro-2-Cyanopyrolidine OH H F
YF-9 (2S, 4S)-1-[(3-chloro-5-hydroxyl-1-adamantyl) glycyl]-4-fluoro-2-Cyanopyrolidine Cl OH F
YF-10 (2S, 4S)-1-[(3-fluoro-1-adamantyl) glycyl]-4-fluoro-2-Cyanopyrolidine F H F
YF-11 (2S, 4S)-1-[(3-chloro-1-adamantyl) glycyl]-4-fluorine 2-Cyanopyrolidine Cl H F
YF-12 (2S, 4S)-1-[(3-fluoro-5-hydroxyl-1-adamantyl) glycyl]-4-fluoro-2-Cyanopyrolidine F OH F
[0045]The preparation method
More specifically describe the preparation method of structural formula of the present invention (I) compound below, but these concrete grammars do not constitute any restriction to the present invention.Reaction conditions in addition, for example the amount of reactant, solvent, alkali, compound used therefor, temperature of reaction, reaction required time etc. are not limited to following explanation.
The compounds of this invention can also be chosen various synthetic methods that will describe in this manual or known in the art wantonly and combine and make easily, and such combination can be easy to carry out by those skilled in the art in the invention.
In preparation method of the present invention, each reaction in inert solvent, is carried out to solvent refluxing temperature (preferred room temperature～80 ℃) at 0 ℃ usually.Reaction times is generally 0.1 hour～and 60 hours, preferably be 0.5～48 hour.
In a preference, formula of the present invention (I) compound can prepare by following route I:
Route I
Figure S07141760720070711D000061
Wherein, a:SOCl 2, CCl 4, b:1-chloracetyl-2-cyanopyrrole, K 2CO 3, THF
Step 1.3-hydroxyl-1-adamantanamine hydrochloride 1[Synthetic Communications; 1988,18 (16): 1975-1978], in aprotic solvent, react high yield with chlorination reagent down and obtain 3-chloro-1-amantadine but exist in alkali.
The solvent that is fit to above-mentioned reaction is tetracol phenixin, methylene dichloride, benzene, toluene, dimethyl formamide and chloroform, and suitable alkali is triethylamine and pyridine.Chlorination reagent can be thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, and temperature of reaction is the temperature that room temperature arrives solvent refluxing.
Step 2. is in organic solvent tetracol phenixin, methylene dichloride, benzene, toluene, dimethyl formamide, tetrahydrofuran (THF), dioxane, methyl tertiary butyl ether, compound 2 or compound 3[J.Chem.Soc.2000,122,466-473] under alkaline condition with (2S)-1-chloracetyl-2-cyanopyrrole [J.Med.Chem; 2003,46,2774-2789] reaction, obtain YF-1 and YF-2.
Temperature of reaction arrives in the scope of solvent refluxing temperature at 0 ℃, and optimum temps is 0～35 ℃.The alkali that uses of reaction is mineral alkalis such as organic bases such as triethylamine, pyridine or salt of wormwood, yellow soda ash, sodium hydroxide, potassium hydroxide, Potassium monofluoride, Sodium Fluoride.In reaction, add sodium iodide or potassiumiodide, with fast reaction speed.
Step 3. as required, YF-1 and YF-2 can be made into various crystal formations, pharmaceutically acceptable inorganic or organic salt, hydrate or solvate, and contain their pharmaceutical compositions as activeconstituents.
In another preference, formula of the present invention (I) compound can prepare by following route II:
Route II
Figure S07141760720070711D000071
Wherein, a:KMnO 4, 2%KOH; B:DPPA, BnOH, TEA, benzene; C:H 2/ Pd/C; D:1-chloracetyl-2-cyanopyrrole, K 2CO 3, THF
Adamantanecarboxylic acid compound 4～7[Chem Ber of step 1.3 replacement; 1962,95:667] in alkaline aqueous solution, oxidized 24～72 hours, be advisable in general 24 ± 2 hours, obtain the adamantanecarboxylic acid compound 8～11 that compound 5-hydroxyl-3-replaces.
The alkali that reaction is used is potassium hydroxide, sodium hydroxide, lithium hydroxide etc., and oxygenant is potassium permanganate, concentrated nitric acid, the vitriol oil etc., and 0～100 ℃ of the temperature of reaction, optimal temperature are 40～60 ℃.
Step 2. is in aprotic solvent such as tetracol phenixin, methylene dichloride, benzene, toluene, tetrahydrofuran (THF), dioxane, methyl tertiary butyl ether; adamantanecarboxylic acid compound 8～11 under alkaline condition with DPPA (two phenoxy group phosphoryl nitrine), benzylalcohol reflux; carry out rearrangement reaction, obtain 5-hydroxyl-3-replacement-(1-benzyloxycarbonyl amino)-1-adamantane compound 12～15.
Employed alkali is organic basess such as triethylamine or pyridine in the reaction.
Step 3. is in acetic acid, methyl alcohol, ethanol isopolarity protonic solvent; under 0～100 ℃ of temperature, 25 ± 5 ℃ of optimal temperatures; compound 12～15 is hydro-reduction under the catalysis of Pd/C or other metal catalyst such as nickel, rhodium, ruthenium etc.; slough the benzyloxy acyl group; obtain 5-hydroxyl-3-replacement-1-amantadine acetate 16～19, optimal solvent is an acetic acid.
Step 4. is in organic solvents such as tetracol phenixin, methylene dichloride, benzene, toluene, dimethyl formamide, tetrahydrofuran (THF), dioxane or methyl tertiary butyl ether; compound 16～19 under alkaline condition with (2S)-1-chloracetyl-2-cyanopyrrole is with mol ratio 1～10:1 reaction, obtains YF-3, YF-4, YF-5, YF-6.
Reacting optimum mol ratio is 2:1, temperature of reaction arrives in the scope of solvent refluxing temperature at 0 ℃, optimum temps is 0～35 ℃, the alkali that uses of reaction is mineral alkalis such as organic bases such as triethylamine, pyridine or salt of wormwood, yellow soda ash, sodium hydroxide, potassium hydroxide, Potassium monofluoride, Sodium Fluoride, in reaction, can add sodium iodide or potassiumiodide, with fast reaction speed.
Step 5. as required, YF-3, YF-4, YF-5, YF-6 can be made into various crystal formations, pharmaceutically acceptable inorganic or organic salt, hydrate or solvate, and contain their pharmaceutical compositions as activeconstituents.
In another preference, formula of the present invention (I) compound can prepare by following route (III):
Route III
Figure S07141760720070711D000081
Wherein, a:MeOH, dense H 2SO 4B SOCl 2And CCl 4C:KOH, 50%EtOH/H 2O; D:KMnO 4, 2%KOH; E:DPPA, BnOH, TEA, benzene; F:H 2/ Pd/C; G:1-chloracetyl-2-cyanopyrrole, K 2CO 3, THF
Step 1. is solvent with methyl alcohol, adds a small amount of sulfuric acid or thionyl chloride, and reflux can make carboxylate 20.
Step 2. compound 20 can obtain compound 21 with the chlorination reagent reaction in the presence of alkali in aprotic solvent.
The solvent that is suitable for above-mentioned reaction is tetracol phenixin, methylene dichloride, benzene, toluene, dimethyl formamide chloroform, the alkali that is fit to is triethylamine, pyridine, chlorination reagent can be thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, and temperature of reaction is in room temperature arrives the scope of solvent refluxing temperature.
Step 3. is in the polar solvent of Ru Shui, ethanol, dioxane, and hydrolysis compound 21 can obtain compound 22 under alkaline condition.
The alkali that is fit to is lithium hydroxide, potassium hydroxide or sodium hydroxide, and temperature of reaction is 0～100 ℃, and optimum temps is 30-50 ℃.
Step 4. is used and is prepared compound 12 similar methods and can make compound 23 by compound 22.
Step 5. is used and is prepared compound 16 similar methods and can make compound 24 by compound 23.
Step 6. use with prepare compound YF-3 similar methods can be by compound 24 and (2S)-1-chloracetyl-2-cyanopyrrole makes compound YF-7.
Step 7. as required, YF-7 can be made into various crystal formations, pharmaceutically acceptable inorganic or organic salt, hydrate or solvate, and contain their pharmaceutical compositions as activeconstituents.
In another preference, formula of the present invention (I) compound can prepare by following route IV:
Route IV
Figure S07141760720070711D000091
Wherein, Im represents imidazolyl; A: saturated NaHCO 3, Cbz-Cl, 5-10 ℃; B: imidazoles, SO 2Cl 2, CH 2Cl 2C:HF/TEA, CH 3COOEt, 60 ℃; D:KOH, EtOH; E:EDC, HOBT, CH 3CN; F:H 2/ Pd/C; G: chloroacetyl chloride, K 2CO 3, THF, TFAA; H:3,5 two replace adamantanamine hydrochloride, K 2CO 3, THF
Step 1. is made solvent with alkali aqueous solution, (4R)-and 4-hydroxyl-L-proline methyl ester [US20040171848] and benzyloxy acyl chloride be-5～50 ℃ of reactions, obtains compound 26.
The most suitable temperature of reaction is 5～10 ℃, and the alkali that reaction is fit to is salt of wormwood, yellow soda ash, sodium bicarbonate, sodium hydroxide, potassium hydroxide.
Step 2. is made solvent with DMF or methylene dichloride under anhydrous condition, compound 26 is mixed with SULPHURYL CHLORIDE, imidazoles, is 0～50 ℃ in temperature, is preferably 20～25 ℃ of reactions 1～5 hour down, is preferably 2 hours, obtains compound 27.
Step 3. as 1, in 2-ethylene dichloride, ethyl acetate, toluene, the dimethyl formamide, is carried out the SN2 reaction with HF/TEA to the imidazoles alkylsulfonyl at polar aprotic solvent, obtains the fluoro product 28 of configuration reversal.
Temperature of reaction is 40 ℃ and arrives the solvent refluxing temperature that optimum temps is 70～80 ℃.
In addition, compound 26 and DAST react in inert solvent, also can a step make 28.
Step 4. in the polar solvent of Ru Shui, ethanol or dioxane, with lithium hydroxide, potassium hydroxide or sodium hydroxide hydrolysis compound 28, can obtain compound 29 in 30～50 ℃.
Step 5. is in dimethyl formamide or acetonitrile isopolarity aprotic solvent, with carbodiimide (EDC), N, N-dicyclohexylcarbodiimide (DCC) or block special condensing agent condensing agents such as (BOP) and make 29 reactions of I-hydroxybenzotriazole (HOBt) and compound form active ester, then and ammonia gas react, ammonia is separated the active ester of formation, obtains amide compound 30.
The temperature that reaction is fit to is 0～40 ℃, and optimal temperature is between 20～30 ℃.
Step 6. is in acetic acid, methyl alcohol, ethanol isopolarity protonic solvent; in 0～100 ℃ of temperature, be preferably under 25 ℃; make compound 30 hydro-reduction under the catalysis of Pd/C or other metal catalyst such as nickel, rhodium, ruthenium etc.; slough the benzyloxy acyl group and obtain 31; optimal solvent is an acetic acid, and optimal temperature is 10～25 ℃.
Step 7. makes compound 31 in ether solvents such as anhydrous tetrahydro furan, dioxane or methylene dichloride, chloroform, ethyl acetate, acetonitrile equal solvent, exist down in alkali, with chloroacetyl chloride 0～35 ℃ the reaction 1～10 hour after, filter, in filtrate, add trifluoroacetic anhydride again, in stirring at room 1～15 hour, obtain compound 32.
Step 8. is in organic solvent tetracol phenixin, methylene dichloride, benzene, toluene, dimethyl formamide, tetrahydrofuran (THF), dioxane, methyl tertiary butyl ether, compound 1,2,3,16,17 reacts with compound 32 under alkaline condition, obtains YF-8, YF-9, YF-10, YF-11, YF-12 respectively.
Temperature of reaction arrives between the solvent refluxing temperature at 0 ℃, optimum temps is 0～35 ℃, the alkali that uses of reaction is mineral alkalis such as organic bases such as triethylamine, pyridine or salt of wormwood, yellow soda ash, sodium hydroxide, potassium hydroxide, Potassium monofluoride, Sodium Fluoride, in reaction, add sodium iodide or potassiumiodide, with fast reaction speed.
Step 9. as required, YF-8, YF-9, YF-10, YF-11, YF-12 can be made into various crystal formations, pharmaceutically acceptable inorganic or organic salt, hydrate or solvate, and contain their pharmaceutical compositions as activeconstituents.
Pharmaceutical composition and application process
Because The compounds of this invention has excellent DPP-IV restraining effect, therefore The compounds of this invention and various crystal formation thereof, pharmaceutically acceptable inorganic or organic salt, hydrate or solvate, and to contain The compounds of this invention be that the pharmaceutical composition of main active ingredient can be used for treatment, prevention and alleviates the DPP-IV relative disease.According to prior art, The compounds of this invention can be used for treating diabetes B, obesity, hyperlipidemia.
Pharmaceutical composition of the present invention comprises on The compounds of this invention in the safety, significant quantity scope or its pharmacology acceptable vehicle or carrier on the acceptable salt and pharmacology.Wherein " safety, significant quantity " refers to: the amount of compound is enough to obviously improve the state of an illness, and is unlikely to produce severe side effect.Usually, pharmaceutical composition contains 1-1000mg The compounds of this invention/agent, and preferably 5-500mg The compounds of this invention/agent more preferably, contains 10-200mg The compounds of this invention/agent.
Acceptable salt can be made into various preparations on compound of the present invention and the pharmacology thereof, wherein comprises on The compounds of this invention in the safety, significant quantity scope or its pharmacology acceptable vehicle or carrier on the acceptable salt and pharmacology.Wherein " safety, significant quantity " refers to: the amount of compound is enough to obviously improve the state of an illness, and is unlikely to produce severe side effect.The safety of compound, significant quantity are determined according to particular cases such as age of treatment target, the state of an illness, the courses of treatment.
" acceptable vehicle or carrier on the pharmacology " refers to: one or more consistency solids or liquid filler or gelatinous mass, they are suitable for the people uses, and enough purity and enough low toxicity must be arranged." consistency " referred to herein as in the composition each component can and compound of the present invention and blending mutually between them, and the drug effect of not obvious reduction compound.On the pharmacology acceptable vehicle or carrier part example have Mierocrystalline cellulose and derivative (as Xylo-Mucine, ethyl cellulose sodium, cellulose ethanoate etc.) thereof, gelatin, talcum, solid lubricant (as stearic acid, Magnesium Stearate), calcium sulfate, vegetables oil (as soya-bean oil, sesame oil, peanut oil, olive wet goods), polyvalent alcohol (as propylene glycol, glycerine, N.F,USP MANNITOL, sorbyl alcohol etc.), emulsifying agent (as
Figure S07141760720070711D000121
), wetting agent (as sodium lauryl sulphate), tinting material, seasonings, stablizer, antioxidant, sanitas, apirogen water etc.
When using The compounds of this invention, can be oral, rectum, parenteral (intravenously, intramuscular or subcutaneous), topical.
The solid dosage that is used for oral administration comprises capsule, tablet, pill, powder and granule.In these solid dosages, active compound mixes with at least a conventional inert excipient (or carrier), as Trisodium Citrate or Lin Suanergai, or mixes with following compositions: (a) filler or expanding material, for example, starch, lactose, sucrose, glucose, N.F,USP MANNITOL and silicic acid; (b) tackiness agent, for example, Walocel MT 20.000PV, alginate, gelatin, Polyvinylpyrolidone (PVP), sucrose and gum arabic; (c) wetting Agent for Printing Inks, for example, glycerine; (d) disintegrating agent, for example, agar, lime carbonate, yam starch or tapioca (flour), alginic acid, some composition silicate and yellow soda ash; (e) retarding solvent, for example paraffin; (f) absorb accelerator, for example, quaternary ammonium compound; (g) wetting agent, for example hexadecanol and glyceryl monostearate; (h) sorbent material, for example, kaolin; (i) lubricant, for example, talcum, calcium stearate, Magnesium Stearate, solid polyethylene glycol, sodium lauryl sulphate, or its mixture.In capsule, tablet and the pill, formulation also can comprise buffer reagent.
Solid dosage such as tablet, sugar-pill, capsule, pill and granule can adopt dressing and the preparation of shell material, as casing and other material well known in the art.They can comprise opacifying agent, and, discharge in the mode that the release of active compound or compound can postpone in this composition certain part in digestive tube.The example of adoptable embedding component is polymeric material and Wax.In case of necessity, active compound also can with above-mentioned vehicle in one or more form microencapsulation form.
The liquid dosage form that is used for oral administration comprises pharmaceutically acceptable emulsion, solution, suspension, syrup or tincture.Except the active ingredient beyond the region of objective existence, liquid dosage form can comprise the conventional inert diluent that adopts in this area, as water or other solvent, solubilizing agent and emulsifying agent, example is known, the mixture of ethanol, Virahol, ethyl-carbonate, ethyl acetate, propylene glycol, 1,3 butylene glycol, dimethyl formamide and oil, particularly Oleum Gossypii semen, peanut oil, maize germ, sweet oil, Viscotrol C and sesame oil or these materials etc.
Except these inert diluents, composition also can comprise auxiliary agent, as wetting agent, emulsifying agent and suspension agent, sweeting agent, the agent of tender flavor and spices.
Except the active ingredient beyond the region of objective existence, suspension can comprise suspension agent, for example, and the mixture of ethoxylation isooctadecane alcohol, polyoxyethylene sorbitol and Isosorbide Dinitrate, Microcrystalline Cellulose, aluminum methylate and agar or these materials etc.
The composition that is used for parenteral injection can comprise physiologically acceptable aseptic moisture or anhydrous solution, dispersion liquid, suspension or emulsion and be used for being dissolved into again the aseptic Injectable solution or the sterilized powder of dispersion liquid.Suitable moisture and nonaqueous carrier, thinner, solvent or vehicle comprise water, ethanol, polyvalent alcohol and suitable mixture thereof.
The formulation that is used for the The compounds of this invention of topical comprises ointment, powder, patch, propellant and inhalation.Activeconstituents under aseptic condition with physiologically acceptable carrier and any sanitas, buffer reagent, or the propelling agent that may need in case of necessity is mixed together.
The compounds of this invention can be individually dosed, perhaps with other pharmaceutically acceptable compound Combined Preparation.
When making pharmaceutical composition, it is the Mammals (as the people) that the The compounds of this invention of safe and effective amount is applicable to the needs treatment, the effective dosage of dosage for pharmaceutically thinking when wherein using, for the people of 60kg body weight, day dosage is generally 1～1000mg, preferred 20～500mg.Certainly, concrete dosage also should be considered factors such as route of administration, patient health situation, and these all are within the skilled practitioners skill.
Major advantage of the present invention comprises:
(1) The compounds of this invention has stronger inhibition activity to dipeptidyl peptidase (DPP-IV).
(2) The compounds of this invention is the novel dipeptidyl peptidase of a class (DPP-IV) inhibitor.
(3) the The compounds of this invention preparation method is simple, low cost of manufacture.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, usually according to normal condition, or the condition of advising according to manufacturer.Unless otherwise indicated, otherwise umber and per-cent are weight part and weight percent.
Among all embodiment, fusing point is measured with MEL-TEMP fusing point instrument, and thermometer is not proofreaied and correct; 1H-NMR Varian Mercury400 nuclear magnetic resonance analyser record, chemical shift is represented with δ (ppm); Separate and adopt silica gel, the undeclared 200-300 order that is, it is volume ratio that column chromatography and TLC detect the developping agent ratio.
Embodiment 1:(2S)-and 1-[(3-fluoro-1-adamantyl) glycyl]-2-Cyanopyrolidine (YF-1)
At room temperature; with 3-fluoro-1-adamantanamine hydrochloride (245mg; 1.45mmol), salt of wormwood (500mg; 3.6mmol) and tetrahydrofuran (THF) (15ml) add in the reaction flask together; start stirring, be added dropwise to (2S)-1-chloracetyl-2-cyanopyrrole (100mg, tetrahydrofuran solution 0.58mmol); dropwise, add sodium iodide (0.1g).Stirred reaction mixture 15h under the room temperature is with TLC (CH 2Cl 2/ MeOH=10:1) monitoring reaction.After question response is complete, cool off, filter out potash solid, the filtrate decompression solvent evaporated is directly carried out column chromatography, (developping agent: CH 2Cl 2/ MeOH=25:1) must yellow thick thing.The ether saturated solution that adds hydrogenchloride to the thick thing of yellow generates hydrochloride, obtains white solid (61mg, 12%) after the filtration.
Mp：190-200℃。 1H NMR(400MHz，CDCl 3)δ1.48-2.37(m，19H)，3.36-3.68(m，4H)，4.74-4.82(dd，1H)。
Embodiment 2:(2S)-and 1-[(3-chloro-1-adamantyl) glycyl]-2-Cyanopyrolidine (YF-2)
1.3-chloro-1-amantadine (compound 2)
(500mg 3mmol) is dissolved in the tetracol phenixin (20ml), and (0.5ml, 7.5mmol), stirring and refluxing 22h screws out solvent and gets thick thing (650mg, 100%) to add thionyl chloride with the 3-hydroxyadamantaneamine.Directly drop into next step reaction.
1H NMR(400MHz，CDCl 3)δ1.46-1.56(m，8H)，1.97-2.07(m，6H)，2.25(s，2H)。
2. glycyl (2S)-1-[(3-chloro-1-adamantyl)]-2-Cyanopyrolidine (YF-2)
With compound 2 (555mg, 3.0mmol) and (2S)-1-chloracetyl-2-cyanopyrrole (172mg, 1mmol) react by embodiment 1 method and handle white solid (54g, 5.6%).
Mp：134-138℃。 1H NMR(400MHz，CDCl 3)δ1.49-2.29(m，19H)，3.35-3.59(m，4H)，4.71-4.73(dd，1H)。
Embodiment 3:(2S)-and 1-[(3-chloro-5-hydroxyl-1-adamantyl) glycyl]-2-Cyanopyrolidine (YF-3)
1.3-chloro-5-hydroxyl-1-adamantanecarboxylic acid (compound 9)
With potassium permanganate (1.58g, 0.01mol) and KOH solution (2.0%, 50ml) add together in the bottle, under agitation, add in batches 3-chloro-1-adamantanecarboxylic acid (2g, 0.009mol), add finish after, be warming up to 50-60 ℃ of reaction 20h.Afterwards,, be adjusted to strongly-acid, add the sodium bisulfite solid with concentrated hydrochloric acid with the mixed solution cooling, become white up to mixed solution, cross filter solid, use ethyl acetate extraction filtrate, the extraction liquid anhydrous sodium sulfate drying, filter, be spin-dried for and be white solid compound 9 (900mg, 41%).
Mp：198-200℃。 1H NMR(400MHz，DMSO)δ1.48-1.66(m，11H)，2.11(s，2H)。
2.3-chloro-5-hydroxyl-(1-benzyloxy acyl group)-1-amantadine (compound 13)
With compound 9 (820mg, 3.56mmol), DPPA (1.2g, 0.93ml, 4.2mmol), triethylamine (430mg, 0.6mmol) and benzene (60ml) add together in the reaction flask, add benzylalcohol (1.4ml, 13.5mmol) backflow 12h behind the stirring and refluxing 1h.Screw out solvent, add the ethyl acetate dilution, with saturated sodium bicarbonate solution and saturated common salt water washing, tell the organic layer anhydrous sodium sulfate drying, filter, be spin-dried for, column chromatography gets white solid compound 13 (500mg, 51%).
1H NMR(400MHz，CDCl 3)δ1.49-1.51(m，2H)，1.65(s，4H)，1.82-1.91(m，5H)，2.23(s，2H)，2.40(s，1H)4.86(s，1H)，5.00(s，1H)7.26-7.32(m，5H)。
3.3-chloro-5-hydroxyl-1-amantadine acetate (compound 17)
(500g 1.49mmol) is dissolved in the Glacial acetic acid (25ml), adds Pd/C (100mg), logical hydrogen stirring at room 10h with compound 13.Filter Pd/C, steam acetate, add toluene and be spin-dried for and take unnecessary acetic acid solvent out of and get white solid compound 17 (420mg, 100%).
Mp：230-240℃。 1H NMR(400MHz，DMSO)δ1.37-1.72(m，13H)，2.07(s，1H)，5.74(s，2H)。
4. glycyl (2S)-1-[(3-chloro-5-hydroxyl-1-adamantyl)]-2-Cyanopyrolidine (YF-3)
With compound 17 (120mg, 0.46mmol) and (2S)-(52mg 0.30mmol) reacts by embodiment 1 method and handles to such an extent that white solid is compound YF-3 (42g, 27%) 1-chloracetyl-2-cyanopyrrole.
Mp：200-205℃。 1H NMR(400MHz，CDCl 3)δ1.23-2.31(m，18H)，3.35-3.61(m，4H)，4.74-4.85(dd，1H)。
Embodiment 4:(2S)-and 1-[(3-fluoro-5-hydroxyl-1-adamantyl) glycyl]-2-Cyanopyrolidine (YF-4)
With compound 16[J.Chem.Soc; 2000,122,466-473] (161mg, 0.87mmol) and (2S)-(100mg 0.58mmol) reacts by embodiment 1 method and handles to such an extent that white solid is compound YF-4 (43mg, 20%) 1-chloracetyl-2-cyanopyrrole.
Mp：220-223℃。 1H NMR(400MHz，CDCl 3)δ1.43-2.40(m，18H)，3.34-3.60(m，4H)，4.71-4.77(dd，1H)。
Embodiment 5:(2S)-and 1-[(3-bromo-5-hydroxyl-1-adamantyl) glycyl]-2-Cyanopyrolidine (YF-5)
With compound 18 (410mg, 1.34mmol) and (2S)-(182mg 1mmol) reacts by embodiment 1 method and handles to such an extent that white solid is compound YF-5 (42mg, 7.5%) 1-chloracetyl-2-cyanopyrrole.
Mp：148-153℃ 1H NMR(300MHz，CDCl 3)δ1.49-1.67(m，11H)，1.95(s，3H)，2.39(s，1H)，2.04-2.34(m，5H)，3.33-3.66(m，4H)，4.72-4.86(m，1H)。
Embodiment 6:(2S)-and 1-[(3-methoxyl group-5-hydroxyl-1-adamantyl) glycyl]-2-Cyanopyrolidine (YF-6)
With compound 19 (272mg, 1.38mmol) and (2S)-(172.5mg 1mmol) reacts by embodiment 1 method and handles to such an extent that white solid is compound YF-6 (66mg, 20%) 1-chloracetyl-2-cyanopyrrole.
Mp：167-175℃。 1H NMR(400MHz，CDCl 3)δ1.43-1.80(m，14H)，2.10-2.31(m，4H)，2.39(s，1H)，3.25(s，1H)，3.38-3.62(m，4H)，4.75-4.77(m，1H)。
Embodiment 7:(2S)-and 1-[(3,5-two chloro-1-adamantyls) glycyl]-2-Cyanopyrolidine (YF-7)
1.5-hydroxyl-3-chloro-1-adamantanecarboxylic acid methyl esters (compound 20)
With compound 9 (1.7g, 7.4mmol), methyl alcohol (60ml) and the vitriol oil (0.2ml) add in the reaction flask stirring and refluxing 8h together.Screw out solvent, add the methylene dichloride dilution, use saturated sodium bicarbonate successively, the saturated nacl aqueous solution washing, the organic layer anhydrous sodium sulfate drying, filtration, be spin-dried for thick thing (2.6g, 98%).
2.3,5-two chloro-1-adamantanecarboxylic acid methyl esters (compound 21)
(2.6g 0.01mol) is dissolved in the methylene dichloride (60ml), adds thionyl chloride (2ml) stirring and refluxing 14h with compound 20.Screw out solvent and get oily matter (2.75g, 98%).Directly drop into next step reaction.
3.3,5-two chloro-1-adamantanecarboxylic acids (compound 22)
(3.6g 0.014mol) is dissolved in 50% the aqueous ethanolic solution (50ml), adds solid potassium hydroxide (852mg with starting compound 21,0.015mol) be warming up to 40 ℃ and stir 10h, cooling solution, thin up, with the 2NHCl acidifying is PH=2, filter white solid (1.8g, 56%).
4.3,5-two chloro-(1-benzyloxy acyl group)-1-amantadine (compound 23)
With compound 22 (1.8g, 0.007mol), DPPA (1.88ml, 0.0087mol), triethylamine (1.2ml, 0.0084mol) and benzene (120ml) add together in the reaction flask, add benzylalcohol (2.75ml, 0.0266mol) backflow 12h behind the stirring and refluxing 1h.The cooling back screws out solvent, adds the ethyl acetate dilution, and with saturated sodium bicarbonate solution and saturated nacl aqueous solution washing, the organic layer anhydrous sodium sulfate drying filters, and is spin-dried for successively, and column chromatography gets white solid (1.2g, 50%).(eluent: sherwood oil: ethyl acetate=2:1)
1H NMR(400MHz，CDCl 3)δ1.56-2.09(m，10H)，2.28-2.35(m，4H)，4.74(s，1H)，5.04(s，2H)，7.25-7.41(m，5H)。
5.3,5-two chloro-1-amantadine acetate (compound 24)
(1.2g 0.0036mol) is dissolved in the acetate (30ml), adds Pd/C (322mg), logical hydrogen stirring at room 2h with compound 23.Filter, be spin-dried for filtrate, add dilution with toluene, screw out viscous material (1g, 78%).
6. (2S)-1-[(3,5-two chloro-1-adamantyls) glycyl]-2-Cyanopyrolidine (YF-7)
With compound 24 (200mg, 0.71mmol) and (2S)-(60.7mg 0.48mmol) reacts by embodiment 1 method and handles to such an extent that white solid is compound YF-7 (36mg, 29%) 1-chloracetyl-2-cyanopyrrole.
Mp：155-160℃ 1H NMR(400MHz，CDCl 3)δ1.51-2.32(m，18H)，3.35-3.62(m，4H)，4.75-4.76(dd，1H)。
Embodiment 8:(2S, 4S)-1-[(3-hydroxyl-1-adamantyl) glycyl]-4-fluorine 2-Cyanopyrolidine (YF-8)
1. (4R)-carbobenzoxy-(Cbz)-4-hydroxyl-L-proline methyl ester (compound 26)
(5.0g 27.7mmol) is dissolved in saturated NaHCO with (4R)-4-hydroxyl-L-proline methyl ester 3Solution (150ml), 5-10 ℃ of ice bath cooling, the adding chloroformic acid benzyl ester (6.0g, 6ml), stirring at room 4h, TLC detection reaction process (CH 2Cl 2/ CH 3OH=15/1).Use the extracted with diethyl ether reaction solution, with saturated NaCl washing, anhydrous sodium sulfate drying filters, and is spin-dried for, and column chromatography gets weak yellow liquid (7.75g, 100%) (eluent: petrol ether/ethyl acetate=4/1).
1H-NMR(300MHz，CDCl 3)δ7.36-7.26(5H，m)，5.23-5.05(3H，m)，4.53-4.47(2H，m)，3.76-3.55(5H，m)，2.30-2.05(1H，m)。
2. (4R)-1-carbobenzoxy-(Cbz)-4-imidazoles alkylsulfonyl-L-proline methyl ester (compound 27)
(2.00g 7.2mmol) is dissolved in the methylene dichloride (50ml) ,-20 ℃ of stirrings, drips SO with compound 26 2Cl 2(1.08g 8.0mmol), finishes, add in batches imidazoles (544mg, 8.0mmol).Be warming up to stirring at room 2h, TLC detection reaction process (petrol ether/ethyl acetate=2/1).Add water stratification, tell organic layer, the water layer dichloromethane extraction merges organic phase, and with the saturated sodium-chloride washing, anhydrous sodium sulfate drying filters, and is spin-dried for, and gets yellow liquid (2.62g, 70%).
3. (4S)-1-carbobenzoxy-(Cbz)-4-fluoro-L-proline methyl ester (compound 28)
(1.8g 6.4mmol) is dissolved in ethyl acetate (50ml), and (0.45ml 20mmol), heats up 60 ℃ and stirs 4h, heats up 70 ℃ again and reacts 12h to add HF/TEA with compound 27.TLC detection reaction process (petrol ether/ethyl acetate=1/1).Add water stratification, tell organic layer, the water layer ethyl acetate extraction, saturated sodium-chloride washs, anhydrous sodium sulfate drying, be spin-dried for yellow liquid (620mg, 62%).
1H-NMR(400MHz，CDCl 3)δ7.34-7.26(5H，m)，5.19-5.03(2H，m)，4.51-4.32(2H，m)，4.01-3.93(1H，m)，3.72-3.68(2H，m)，3.61-3.52(1H，s)，2.71-2.62(1H，m)，2.43-2.37(1H，m)
4. (4S)-1-carbobenzoxy-(Cbz)-4-fluoro-L-proline(Pro) (compound 29)
(620mg 2.2mmol) is dissolved in 50% aqueous ethanolic solution (30ml), and (140mg 2.5mmol), is warming up to 40 ℃ and stirs 10h to add potassium hydroxide with compound 28.TLC tracking monitor (petrol ether/ethyl acetate=2/1).Cooling, thin up is used extracted with diethyl ether, the water layer hcl acidifying PH=2 of 2N.Use the dichloromethane extraction water layer, with saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, filter be spin-dried for yellow liquid (560mg, 94%).
1H-NMR(400MHz，CDCl 3)δ10.73(1H，s)，7.38-7.26(5H，m)，5.29-5.13(2H，m)，4.58-4.48(1H，m)，4.41-4.40(1H，m)，4.05-3.96(1H，m)，3.79-3.71(1H，m)，2.76-2.68(1H，m)，2.53-2.49(1H，m)
5. (4S)-1-carbobenzoxy-(Cbz)-4-fluoro-L-prolineamide (compound 30)
With compound 29 (560mg 2.07mmol) is dissolved in the acetonitrile (30ml), is cooled to 0 ℃, add HOBT (338mg, 2.5mmol) and EDC (480mg, 2.5mmol), stirring at room 14h, TLC detects (petrol ether/ethyl acetate=1/4).With the frozen water cooling, add strong aqua (1ml), stir 20min, be warming up to stirring at room 20min.Add acetonitrile, the elimination insolubles, filtrate is spin-dried for, and crosses chromatography column and gets yellow liquid (380mg, 68%) (eluent: petrol ether/ethyl acetate=1/4).
1H-NMR(400MHz，CDCl 3)δ7.31-7.26(5H，s)，6.75-6.39(2H，m)，5.16-5.07(2H，m)，4.36(2H，s)，3.92(1H，s)，3.67(1H，s)，2.57-2.49(2H，m)
6. (4S)-4-fluoro-L-prolineamide (compound 31)
(380mg 1.6mmol) is dissolved in methyl alcohol (50ml), adds Pd/C (76mg), feeds hydrogen, stirring at room 4h with compound 30.TLC detects (CH 2Cl 2/ CH 3OH=6/1).Filter, be spin-dried for, cross chromatography column (eluent: CH 2Cl 2/ CH 3OH=6/1) get compound 31 (100mg, 53%).
1H-NMR(400MHz，DMSO)δ7.46-7.12(2H，s)4.41-4.36(1H，m)，3.55-3.46(1H，dd)，3.21-3.15(1H，dt)，2.89-2.85(1H，dd)，2.57-2.49(2H，m)，1.95-1.89(1H，m)
7. (2S, 4S)-1-chloracetyl-4-fluoro-2-cyanopyrrole (compound 32)
With salt of wormwood (2.6g, 18.8mmol) and anhydrous tetrahydrofuran solution (60ml) add in the reaction flask, stir, (5-10 ℃) is added dropwise to chloroacetyl chloride (1.2g under ice-water bath, 0.88ml, 10mmol), finish, add compound 31 (627mg 3.72mmol), is warming up to stirring at room 2h in batches.Filter, filtrate is used anhydrous sodium sulfate drying, filters, and filtrate (5～10 ℃) under ice-water bath adds trifluoroacetic anhydride (2ml), stirring at room 5h.Screw out solvent, add the ethyl acetate dilution, be spin-dried for (so operating three times) again, the solution that is spin-dried for dilutes with ethyl acetate, with the sodium hydrogen carbonate solution washing, tell organic layer, the water layer ethyl acetate extraction, merge organic layer, use anhydrous sodium sulfate drying, filter, be spin-dried for, cross chromatography column (eluent: sherwood oil: ethyl acetate=1:2) yellow solid (710mg, 100%).
Mp：118-126℃。 1H NMR(300MHz，CDCl 3)δ2.31-2.76(m，2H)，3.81-4.29(m，4H)，4.93-5.05(dd，1H)，5.36-5.55(dd，1H)。
8. (2S, 4S)-1-[(3-hydroxyl-1-adamantyl) glycyl]-4-fluorine 2-Cyanopyrolidine (YF-8)
With 3-hydroxyl-1-amantadine (145mg, 0.87mmol), salt of wormwood (200mg, 1.2mmol) and tetrahydrofuran (THF) (15ml) add in the reaction flask together, be added dropwise to compound 32 (55mg, 0.30mmol) tetrahydrofuran solution, dropwise, add sodium iodide (50mg), reaction mixture is at stirring at room 20h.By embodiment 1 method handle white solid compound YF-8 (43mg, 42%).
Mp：128-133℃。 1H NMR(300MHz，CDCl 3)δ1.48-1.87(m，15H)，2.26-2.66，3.34-3.60(m，4H)，4.92-5.50(dd，2H)。
Embodiment 9:(2S, 4S)-1-[(3-hydroxyl-5-chloro-1-adamantyl) glycyl]-4-fluoro-2-Cyanopyrolidine (YF-9)
With compound 17 (300mg, 1.15mmol) with compound 32 (100mg, 0.52mmol) react by embodiment 8 methods and handle white solid compound YF-9 (24mg, 10%).Mp:225-232 ℃ (decomposition).
1H NMR(400MHz，CDCl 3)δ1.52-1.69(m，10H)，1.96(s，3H)，2.28-2.74(m，4H)，3.40-3.97(m，4H)，4.95-5.19(dd，1H)，5.28-5.50(dd，1H)。
Embodiment 10:(2S, 4S)-1-[(3-fluoro-1-adamantyl) glycyl]-4-fluoro-2-Cyanopyrolidine (YF-10)
With 3-fluoro-1-adamantanamine hydrochloride (160mg, 0.78mmol) with compound 32 (100mg, 0.52mmol) react by embodiment 8 methods and handle white solid compound YF-10 (94mg, 46%).Mp：165-175℃。
1H NMR(400MHz，CDCl 3)δ1.47-1.87(m，13H)，2.23-2.73(m，4H)，3.34-3.97(m，4H)，4.91-5.10(dd，1H)，5.27-5.49(dd，1H)。
Embodiment 11:(2S, 4S)-1-[(3-chloro-1-adamantyl) glycyl]-4-fluorine 2-Cyanopyrolidine (YF-11)
With compound 2 (350mg, 1.5mmol) with compound 32 (100mg, 0.52mmol) react by embodiment 8 methods and handle white solid compound YF-11 (42mg, 7%).Mp：140-145℃。
1H NMR(400MHz，CDCl 3)δ1.52-2.08(m，13H)，2.23-2.73(m，4H)，3.34-3.95(m，4H)，4.92-5.10(dd，1H)，5.27-5.49(dd，1H)。
Embodiment 12:(2S, 4S)-1-[(3-fluoro-1-adamantyl) glycyl]-4-fluorine 2-Cyanopyrolidine (YF-12)
With compound 16 (161mg, 0.87mmol) with compound 32 (100mg, 0.52mmol) react by embodiment 8 methods and handle white solid compound YF-12 (42mg, 7%).Mp：140-145℃。
1H NMR(400MHz，CDCl 3)δ1.52-2.08(m，13H)，2.23-2.73(m，4H)，3.34-3.95(m，4H)，4.92-5.10(dd，1H)，5.27-5.49(dd，1H)。
Embodiment 13.DPP-IV suppresses determination of activity
DPP-IV suppresses determination of activity can carry out with ordinary method.DPP-IV expresses and purified pure enzyme the K of pure enzyme for using baculovirus expression system m, K CatAll conform to, show that the pure enzyme of DPP-IV that expression and purification obtains is normal fully on zymologic property with bibliographical information.Reaction system is carried out in the damping fluid of PH7.5, and enzyme reaction substrate is L-Ala-proline(Pro)-7-amino-4-methylcoumarin (Ala-Pro-AMC).
DPP-IV degradable substrate A la-Pro-AMC generates product A MC, and AMC is produced the emission light of 460nm by the ultraviolet excitation of 355nm.Measure the activity of DPP-IV in the speed of the rising of 460nm place fluorescent value by dynamic measurement AMC.
With test-compound, enzyme and reaction buffer mixing, incubate 15min in advance at 37 ℃, add substrate and start reaction, METHOD FOR CONTINUOUS DETERMINATION 460nm fluorescent value 5min.The blank group do not add substrate is set simultaneously, substitutes the solvent control group and the LAF-237[Bioorg.Med.Chem.Lett. of test-compound with DMS0,2005,15,4770-4773] positive controls.The final volume that responds is 100ul.Each concentration of each sample is established 3 multiple holes.
At first calculate unit time fluorescence intensity in the enzyme initial velocity phase increment (unit: RFU/sec), represent the initial velocity of enzyme with this, the active percentage ratio of each concentration group of calculation sample then, formula is as follows:
Figure S07141760720070711D000211
V wherein SampleThe initial velocity of each concentration group of expression sample, v DMSOThe initial velocity of expression DMSO group
Logarithmic value with concentration is mapped to active percentage ratio, adopts non-linear regression to calculate then and fits curve, calculates the IC50 value.
The molecular structural formula of representative compounds of the present invention and the biological activity test of part of compounds the results are shown in Table 1.
Table 1 part of compounds of the present invention suppresses active to DPP-IV
Figure S07141760720070711D000212
Figure S07141760720070711D000221
Wherein LAF-237 proposes as correlated prior art, by the compound of the present invention as can be seen of the data in the table 1 the inhibition activity of DPP-IV obviously is better than DPP-IV, especially the DPP-IV of YF-1, YF-4, YF-12 inhibition specific activity LAF-237 is strong 2～5 times, therefore, The compounds of this invention has more excellent biological activity with respect to existing medicine.
Embodiment 13 pharmaceutical compositions
Compound YF-12 20g
Starch 140g
Microcrystalline Cellulose 60g
According to a conventional method, after the pharmaceutical composition of embodiment 13 gained mixed, the common gelatine capsule of packing into obtained 1000 capsules.
By similar approach, make the capsule that contains compound YF-8 or YF-4 respectively.
Embodiment 14: the preparation of capsule
Compound YF-12 50g
Starch 400g
Microcrystalline Cellulose 200g
According to a conventional method, after the pharmaceutical composition of embodiment 14 gained mixed, the common gelatine capsule of packing into obtained 1000 capsules.
By similar approach, make the capsule that contains compound YF-4 or YF-8 respectively.
All quote in this application as a reference at all documents that the present invention mentions, just quoted as a reference separately as each piece document.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims institute restricted portion equally.

Claims (10)

1. the compound shown in the formula (I), or its pharmaceutically acceptable inorganic or organic salt:
Figure FSB00000160727900011
In the formula, R 1Be chlorine, fluorine, bromine or hydroxyl;
R 2Be hydrogen or hydroxyl;
R 3Be hydrogen or fluorine;
And work as R 3During for hydrogen, R 1, R 2In at least one is a halogen.
2. compound as claimed in claim 1 is characterized in that R 1Be chlorine or fluorine.
3. compound as claimed in claim 1 is characterized in that R 2Be hydroxyl.
4. compound as claimed in claim 1 is characterized in that R 3Be fluorine.
5. compound as claimed in claim 1 is characterized in that, described compound is selected from down group:
(2S)-and 1-[(3-fluoro-5-hydroxyl-1-adamantyl) glycyl]-the 2-Cyanopyrolidine;
(2S, 4S)-1-[(3-fluoro-5-hydroxyl-1-adamantyl) glycyl]-4-fluoro-2-Cyanopyrolidine;
(2S, 4S)-1-[(3-hydroxyl-1-adamantyl) glycyl]-4-fluoro-2-Cyanopyrolidine;
(2S)-and 1-[(3-chloro-5-hydroxyl-1-adamantyl) glycyl]-the 2-Cyanopyrolidine;
(2S, 4S)-1-[(3-chloro-5-hydroxyl-1-adamantyl) glycyl]-4-fluoro-2-Cyanopyrolidine.
6. a pharmaceutical composition is characterized in that, it contains acceptable vehicle or carrier on the pharmacology, and the described compound of claim 1 or its pharmaceutically acceptable inorganic or organic salt.
7. the purposes of the pharmaceutically acceptable inorganic or organic salt of the described compound of claim 1 or its is characterized in that being used to prepare DPP IV is the DPP-IV inhibitor.
8. the purposes of the described compound of claim 1 or its pharmacy acceptable salt is characterized in that, being used to prepare treatment, prevention and alleviation is the medicine of the relevant disease of DPP-IV with DPP IV.
9. purposes as claimed in claim 8 is characterized in that, the described disease relevant with DPP IV is selected from diabetes, obesity, hyperlipidemia.
10. the method for compound shown in the preparation formula (I) is characterized in that described method comprises the steps:
In inertia solution, under the alkaline condition, make compound shown in the reaction production of compound shown in compound shown in the formula (II) and the formula (III) (I),
Figure FSB00000160727900021
In the formula, R 1Be chlorine, fluorine, bromine or hydroxyl;
R 2Be hydrogen or hydroxyl;
R 3Be hydrogen or fluorine;
And work as R 3During for hydrogen, R 1, R 2In at least one is a halogen.
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