CN101074238A - Heterocyclic boronic acid compounds - Google Patents
Heterocyclic boronic acid compounds Download PDFInfo
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- CN101074238A CN101074238A CN 200710098129 CN200710098129A CN101074238A CN 101074238 A CN101074238 A CN 101074238A CN 200710098129 CN200710098129 CN 200710098129 CN 200710098129 A CN200710098129 A CN 200710098129A CN 101074238 A CN101074238 A CN 101074238A
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Abstract
Dipeptidyl peptidase IV (DPP-IV)-inhibiting compounds are provided that have formula I: wherein n is 1 to 3; X is CH2; S; O; CF2 or C(CH3)2; Z is H; halogen; hydroxyl; (C1-6)alkoxy; (C1-12)alkyl; (C3-12) cy-cloalkyl; phenyl; or heteroaryl; where the phenyl and heteroaryl groups a re optionally mono- or independently plurisubstituted with R7; optionally, X to-gether with an adjacent ring carbon and Z form a fused cyclopropyl; and op-tionally, one of the bonds in the ring containing X is a double bond; and Cr i R ii, R1, R1, R3, R4 and R5 arc as described herein.
Description
The application is to be the application number on November 12nd, 2004 (the PCT application number: PCT/US2004/037820), denomination of invention divides an application for " heterocyclic boronic acid compounds " that is 200480037257.9 applying date.
Technical field
The present invention relates to boronic acid compounds and as the purposes of inhibitor of the amino pepx of cutting (post-proline/alanine cleaving amino-dipeptidase) behind proline(Pro)/L-Ala.The invention still further relates to the method for this inhibitor of using with treatment DPP relative disease.Therefore, the present invention has application in medical chemistry, pharmacology and medicine technology field.
Background technology
Dipeptidyl peptidase (DPP) is the serine protease family that belongs to the amino pepx group of cutting behind proline(Pro)/L-Ala.Though physiological role that can't best explain DPP, they are involved in the various disease states.For example, only catalysis is from the release of the proteinic N-end group dipeptides with the penultimate proline(Pro) of N end group or L-Ala for DPP-IV, and DPP-IV is considered to play an important role in impaired fasting glucose (IFG) (IFG) and diabetes.Particularly, DPP-IV relates to the control of glucose metabolism, and this is because its substrate comprises insulinotropin, hyperglycemic-glycogenolytic factor class peptide-1 (GLP-1) and gastrin inhibitory polypeptide (GIP), the deactivation by their two n terminal amino acids of removal of these materials.
The vivo medicine-feeding of the synthetic inhibitor of DPP-IV prevents the N-end degraded of GLP-1 and GIP, causes the more high plasma concentration of these hormones, the insulin secretion of increase and the glucose tolerance that improves thus.Therefore, this inhibitor is proposed to be used in treatment type ii diabetes patient, and type ii diabetes is a kind of glucose tolerance of reduction and disease of insulin resistant of being characterised in that.
Therefore, exist can be used for suppressing for example demand of the compound of DPP-IV of DPP.
Summary of the invention
The invention provides effective DPP inhibitor in the treatment disease, described disease can be regulated or normalizing by the inhibition of DPP.More specifically, the present invention relates to suppress borated heterogeneous ring compound and the derivative thereof of DPP-IV.
Embodiment
The invention provides the compound of formula I:
Comprise its whole enantiomers, diastereomer, solvate, hydrate and pharmacy acceptable salt, wherein:
N is 1-3;
X is CH
2, S, O, CF
2Or C (CH
3)
2
Z is H, halogen, hydroxyl, (C
1-6) alkoxyl group, (C
1-12) alkyl, (C
3-12) cycloalkyl, phenyl or heteroaryl; Wherein phenyl and heteroaryl are randomly used R
7Single replacement or polysubstituted independently;
R
7Be halogen, (C
1-10) alkyl, (C
1-10) alkoxyl group, (C
1-10) alkylamino, (C
1-10) dialkyl amido, phenmethyl, benzyloxy, hydroxyl (C
1-6) alkyl, methylol, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, N-azanol base, cyano group, carboxyl, kharophen, hydroxyl, sulfamyl, sulfonamido or formamyl;
Randomly, X and adjacent ring carbon and Z form the fused rings propyl group together; With
Randomly, a key being arranged in containing the ring of X is two keys;
R
1And R
2Independently or one be both hydrogen, boric acid protecting group or can be in the physiological pH value aqueous solution or be hydrolyzed to the group of hydroxyl in the biofluid; With
CR
iR
IiCan exist or not exist, and
Work as CR
iR
IiWhen existing, R
i, R
Ii, R
3, R
4And R
5Be selected from (aa) or (bb):
(aa): R
i, R
Ii, R
3And R
4Be hydrogen; And R
5Be hydrogen, (C
1-12) alkyl or (C
3-12) cycloalkyl;
(bb) R
i, R
Ii, R
3, R
4And R
5Be hydrogen independently, alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkylalkyl, bicyclic alkyl, tricyclic alkyl, alkyl-cycloalkyl, hydroxyalkyl, the hydroxyalkyl cycloalkyl, the hydroxyl cycloalkyl, the hydroxyl bicyclic alkyl, the hydroxyl tricyclic alkyl, the bicyclic alkyl alkyl, the alkyl bicyclic alkyl, alkyl-thio-alkyl, the arylalkyl alkylthio, cycloalkenyl group, aryl, aralkyl, heteroaryl, heteroarylalkyl, encircle the assorted alkyl-alkyl of assorted alkyl or ring, all randomly with the single replacement of following groups or polysubstituted independently: halogen, alkyl, multi-haloalkyl, alkoxyl group, halogenated alkoxy, many halogenated alkoxies, carbalkoxy, thiazolinyl, alkynyl, cycloalkyl, cycloalkylalkyl, multi-ring alkyl, heteroaryl amino, arylamino, the assorted alkyl of ring, the assorted alkyl-alkyl of ring, hydroxyl, hydroxyalkyl, nitro, cyano group, amino, substituted-amino, alkylamino, dialkyl amido, thiol, alkylthio, alkyl-carbonyl, acyl group, carbalkoxy, aminocarboxyl, the alkynyl aminocarboxyl, alkyl amino-carbonyl, the alkenyl amino carbonyl, alkyl carbonyl oxy, alkyl-carbonyl-amino, aryl-amino-carbonyl, alkyl sulfonyl amino, alkyl amino-carbonyl-amino, alkoxycarbonyl amido, alkyl sulphonyl, amino sulfinyl, amino-sulfonyl, alkyl sulphinyl, sulfonamido or alkylsulfonyl;
Or as an alternative,
Work as CR
iR
IiWhen not existing, R
3, R
4And R
5Be selected from (cc), (dd) or (ee):
(cc) R
3And R
4Be hydrogen and
R
5Be
A) hydrogen, prerequisite are when n is 1, X is CH
2R when being H with Z
5Not hydrogen;
B) (C
1-12) alkyl, (C
2-12) thiazolinyl, (C
2-12) alkynyl, (C
3-12) cycloalkyl or (C
3-12) cycloalkenyl group, wherein alkyl, thiazolinyl, alkynyl, cycloalkyl and cycloalkenyl group are randomly used R
6Single replace or polysubstituted independently, and wherein alkyl, thiazolinyl, alkynyl partly comprise line style or branched chain and can comprise circular part;
R
6Be (C
1-6) alkyl, (C
1-6) alkoxyl group, cycloalkyl, carboxyl, kharophen, cyano group, nitro, halogen, hydroxyl, hydroxyl (C
1-6) alkyl, methylol, trifluoromethyl, trifluoromethoxy, sulfamyl, sulfonamido, formamyl, aryl, heteroaryl, amino; Wherein aryl and heteroaryl are randomly used R
7Single replacement or polysubstituted independently, amino is randomly used R
8,-SOR
8,-SO
2R
8,-COR
8,-CO
2R
8,-CONHR
8,-CON (R
8)
2,-OR
8Or-S-R
8Single replacement or polysubstituted independently;
R
7Be halogen, (C
1-10) alkyl, (C
1-10) alkoxyl group, (C
1-10) alkylamino, (C
1-10) dialkyl amido, phenmethyl, benzyloxy, hydroxyl (C
1-6) alkyl, methylol, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, N-hydroxylamino, cyano group, carboxyl, kharophen, hydroxyl, sulfamyl, sulfonamido or formamyl;
R
8Be (C
1-10) alkyl, (C
2-10) thiazolinyl, (C
2-10) alkynyl, (C
3-10) cycloalkyl, (C
5-10) cycloalkenyl group, phenmethyl, styroyl, aryl or heteroaryl; Wherein alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group randomly replace with aryl or heteroaryl list or are polysubstituted independently, and wherein aryl and heteroaryl are randomly used R
7Single replacement or polysubstituted independently;
C) optional and (C
3-10) Cycloalkylfused aryl or optional and (C
3-10) Cycloalkylfused heteroaryl; Wherein aryl and heteroaryl are randomly used R
7Single replacement or polysubstituted independently;
D) indanyl, 1,2,3,4-tetralyl, j are the (CH of 0-3
2)
jAdamantyl, or [2.2.1] or [3.1.1] bicyclic carbocyclic part comprise (4-amyl group dicyclo [2.2.2] suffering-1-yl) amine; Indanyl, 1,2,3 wherein, 4-tetralyl, (CH
2)
jAdamantyl and [2.2.1] or [3.1.1] bicyclic carbocyclic part are randomly used hydroxyl, (C
1-8) alkyl, (C
1-8) alkoxyl group, (C
1-8) alkanoyloxy or R
9R
10The single replacement of N-CO-O-or polysubstituted independently, wherein R
9And R
10Be (C independently
1-8) alkyl or phenyl, wherein alkyl and phenyl are randomly used (C
1-8) alkyl, (C
1-8) alkoxyl group, halogen or trifluoromethyl list replace or polysubstituted independently, perhaps R
9And R
10Be (C together
3-6) alkylidene group;
E) R
11(CH
2)
p-, R wherein
11Be 2-oxygen pyrrolidyl, (C
1-6) alkoxyl group, phenyl, phenoxy group, (C
1-8) cycloalkyl, [3.3.3] bicyclic carbocyclic part, pyridyl, naphthyl, cyclohexenyl or adamantyl, wherein 2-oxygen pyrrolidyl, (C
1-6) alkoxyl group, phenyl, pyridyl and naphthyl randomly use R
12The single replacement or two independently the replacement or three replacements independently; Wherein phenoxy group is randomly used (C
1-4) alkyl, (C
1-4) replacement of alkoxy or halogen list or two independently the replacement; And wherein [3.3.3] bicyclic carbocyclic part is randomly used (C
1-8) alkyl list replacement or polysubstituted independently; P is 0-3;
R
12Be halogen, trifluoromethyl, cyano group, nitro, (C
1-6) alkyl, (C
1-6) alkoxyl group, cycloalkyl, carboxyl, kharophen, hydroxyl, hydroxyl (C
1-6) alkyl, methylol, trifluoromethoxy, sulfamyl, formamyl, sulfonamido, alkyl sulphonyl, benzenesulfonyl, aryl, heteroaryl, wherein aryl and heteroaryl are randomly used R
7Single replacement or polysubstituted independently;
F) (R
13)
2CH (CH
2)
q-, R wherein
13It is phenyl; Wherein each phenyl is chosen wantonly independently and is used R
12The single replacement or two independently the replacement; Q is 0-3;
G) group of following formula:
R wherein
14And R
15Be hydrogen, (C independently
1-8) alkyl, (C
1-6) alkyl-carbonyl, (C
3-12) cycloalkyl ring, (C
3-12) cyclenes basic ring, phenmethyl, benzoyl, pyridine, pyrimidine, phenyl, phenyl amino-carbonyl, alkyl sulphonyl or benzenesulfonyl, wherein cycloalkyl ring is randomly used hydroxyl (C
1-6) alkyl replaces, and wherein phenmethyl, benzoyl, pyridine, pyrimidine, phenyl, phenyl amino-carbonyl, alkyl sulphonyl and benzenesulfonyl are randomly used R
12The single replacement or two independently the replacement; Perhaps R
14And R
15Form (C together
3-12) cycloalkyl ring; With r be 2-6;
H) group of following formula:
R wherein
16And R
17Be hydrogen, (C independently of one another
1-8) alkyl, (C
1-6) alkyl-carbonyl, two-(C
1-6) alkyl amino-carbonyl, phenmethyl, benzoyl, pyridine, pyrimidine, phenyl, phenyl amino carbonyl, alkyl sulphonyl or benzenesulfonyl, wherein phenmethyl, benzoyl, pyridine, pyrimidine, phenyl, phenyl amino carbonyl, alkyl sulphonyl and benzenesulfonyl are randomly used R
12The single replacement or two independently the replacement; Perhaps R
16And R
17Form (C together
3-12) cycloalkyl ring; With s be 1-6;
I) group of following formula:
R wherein
18And R
19Be hydrogen, (C independently
1-8) alkyl, (C
1-6) alkyl-carbonyl, two-(C
1-6) alkyl amino-carbonyl, phenmethyl, benzothiazole, benzoyl, pyridine, pyrimidine, phenyl, phenyl amino carbonyl, alkyl sulphonyl or benzenesulfonyl, wherein phenmethyl, benzoyl, benzothiazole, pyridine, pyrimidine, phenyl, phenyl amino carbonyl, alkyl sulphonyl and benzenesulfonyl are randomly used R
12The single replacement or two independently the replacement; Perhaps R
18And R
19Form (N, the C that contains nitrogen-atoms with N
3-12) heterocycloalkyl ring; Each t is 0-6 independently; With u be 0-3;
J) group of following formula:
(phenyl-CH
2-C (CH
3)
2-),
Wherein phenyl is randomly used R
12Single replacement or polysubstituted independently;
Or
K) group of following formula:
R wherein
21Be hydrogen, (C
1-8) alkyl, phenmethyl or phenyl, wherein phenmethyl and phenyl are randomly used R
12The single replacement or two independently replacement the on ring; Each t is 0-6 independently; U is 0-3; And
The key table that wherein contains wavy line shows binding site;
(dd) R
3, R
4And R
5Be hydrogen independently; alkyl; thiazolinyl; alkynyl; cycloalkyl; cycloalkylalkyl; bicyclic alkyl; tricyclic alkyl; alkyl-cycloalkyl; hydroxyalkyl; the hydroxyalkyl cycloalkyl; the hydroxyl cycloalkyl; the hydroxyl bicyclic alkyl; the hydroxyl tricyclic alkyl; the bicyclic alkyl alkyl; the alkyl bicyclic alkyl; alkyl-thio-alkyl; the arylalkyl alkylthio; cycloalkenyl group; aryl or aralkyl; all randomly with the single replacement of following groups or polysubstituted independently: halogen; alkyl; multi-haloalkyl; alkoxyl group; halogenated alkoxy; many halogenated alkoxies; carbalkoxy; thiazolinyl; alkynyl; cycloalkyl; cycloalkylalkyl; multi-ring alkyl; arylamino; hydroxyl; hydroxyalkyl; nitro; cyano group; amino; substituted-amino; alkylamino; dialkyl amido; thiol; alkylthio; alkyl-carbonyl; acyl group; carbalkoxy; aminocarboxyl; the alkynyl aminocarboxyl; alkyl amino-carbonyl; the alkenyl amino carbonyl; alkyl carbonyl oxy; alkyl-carbonyl-amino; aryl-amino-carbonyl; alkyl sulfonyl amino; alkyl amino-carbonyl-amino; alkoxycarbonyl amido; alkyl sulphonyl; amino sulfinyl; amino-sulfonyl; alkyl sulphinyl; sulfonamido or alkylsulfonyl; suppose that working as n is 1, X is CH
2, the ring that contains X is saturated, and Z, R
3And R
5When being H, R
4Be not the side chain of the alpha amino acid of nature existence, and suppose that working as n is 1, X is CH
2, the ring that contains X is saturated, and Z and R
5When being H, R
3And R
4It not all is methyl; Or
(ee) R
3Be hydrogen, R
4And R
5Form the 4-8 unit heterocycle of 3~7 carbon and 1 nitrogen with their institute's bonded atoms,
Wherein remove and N and R
4Heterocycle carbon atom outside the carbon that connects has formula-(CR
22R
23)
m-, wherein m is 2-6, R
22And R
23Be hydrogen, hydroxyl, alkoxyl group, alkyl, thiazolinyl, alkynyl, cycloalkyl, halogen, amino, substituted-amino, cycloalkylalkyl, cycloalkenyl group, aryl, aralkyl, heteroaryl, heteroarylalkyl, the assorted alkyl of ring, the assorted alkyl-alkyl of ring, alkyl-carbonyl-amino, aryl-amino-carbonyl, alkoxycarbonyl amido, aryloxy carbonyl amino, carbalkoxy, aryloxy carbonyl or alkyl amino-carbonyl amino independently; Randomly, described heterocycle have aryl, heteroaryl or with its condensed 3-7 unit cycloalkyl ring, suppose that working as n is 1, X is CH
2, the ring that contains X is saturated, and Z and R
3When being H, R
4And R
5Be not together-(CH
2)
2-or-(CH
2)
3-.
Formula I compound also comprises those materials that meet following condition: wherein X is CH
2The ring that contains X is saturated; CR
iR
IiThere is not R
1, R
2Be hydrogen; R
3, R
4And R
5Have aforementioned clause (cc) b) meaning that provides.In some such embodiments, R
5Be (C
1-12) alkyl or (C
3-12) cycloalkyl, include but not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexyl methyl, 1-cyclohexyl ethyl or adamantyl.
In some embodiments of formula I compound, X is CH
2The ring that contains X is saturated; CR
iR
IiThere is not R
1, R
2Be hydrogen; R
3, R
4And R
5Have aforementioned clause (cc) d) meaning that provides.
In other embodiment of formula I compound, X is CH
2The ring that contains X is saturated; CR
iR
IiThere is not R
1, R
2Be hydrogen; R
3, R
4And R
5Have aforementioned clause (cc) e) meaning that provides.
In some embodiment of formula I compound, X is CH
2The ring that contains X is saturated; CR
iR
IiThere is not R
1, R
2Be hydrogen; R
3, R
4And R
5Have aforementioned clause (cc) f) meaning that provides.
In some embodiments of formula I compound, X is CH
2The ring that contains X is saturated; CR
iR
IiThere is not R
1, R
2Be hydrogen; R
3, R
4And R
5Have aforementioned clause (cc) g) meaning that provides.
Formula I compound comprises those materials that meet following condition: wherein X is CH
2The ring that contains X is saturated; CR
iR
IiThere is not R
1, R
2Be hydrogen; R
3, R
4And R
5Have aforementioned clause (cc) h) meaning that provides.
Formula I compound, wherein X is CH
2The ring that contains X is saturated; CR
iR
IiThere is not R
1, R
2Be hydrogen; R
3, R
4And R
5Have aforementioned clause (cc) i) meaning that provides.
In some embodiments of formula I compound, X is CH
2The ring that contains X is saturated; CR
iR
IiThere is not R
1, R
2Be hydrogen; R
3, R
4And R
5Have aforementioned clause (cc) j) meaning that provides.
In some embodiments of formula I compound, X is CH
2The ring that contains X is saturated; CR
iR
IiThere is not R
1, R
2Be hydrogen; R
3, R
4And R
5Have aforementioned clause (cc) k) meaning that provides.
CR in formula I
iR
IiWhen not existing, preferred affiliated preparation of the present invention comprises the formula II compound with following linear alkyl tetramethyleneimine molecular formula:
In the embodiment of formula II, R
3, R
4And R
5(cc) that provides as above-mentioned formula I, (dd) and (ee) in definition, and R
1And R
2Be independently or together-OH ,-O
-M
+, M wherein
+Be positively charged ion, have the boric acid protecting group hydroxyl or can be in the physiological pH value aqueous solution or be hydrolyzed to the group of hydroxyl in the biofluid.
In these embodiments of formula II, R
5Can be alkyl, cycloalkyl, randomly single as mentioned above replacement or polysubstituted independently.
In some embodiments of formula II compound, R
3And R
4All be hydrogen.
In other embodiment of formula II, n is 1.
Also comprise the formula II compound that meets following condition: wherein X is CH
2The ring that contains X is saturated; R
1, R
2, R
3And R
4Be hydrogen; R
5Group with following formula:
R wherein
21Be hydrogen, (C
1-8) alkyl, phenmethyl or phenyl, wherein phenmethyl and phenyl are randomly used R
12The single replacement or two independently replacement the on ring; Each t is 0-6 independently; U is 0-3.In some such embodiments, R
5Have formula:
Work as CR
iR
IiWhen existing, preparation comprised the formula III compound under another of formula I was preferred:
R wherein
1And R
2Be independently or together-OH ,-O
-M
+, M wherein
+Be positively charged ion, have the boric acid protecting group hydroxyl or can be in the physiological pH value aqueous solution or be hydrolyzed to the group of hydroxyl in the biofluid; And, R
3, R
4, R
5, R
iAnd R
IiWith (aa) among the aforementioned formula I with identical (bb).
The invention still further relates to the method for preparing above-claimed cpd.Such as shown in hereinafter and in an embodiment description, by making cyclammonium (for example tetramethyleneimine or piperidines) and sec-BuLi/TMEDA reaction then and B (OCH
3)
3Reaction is providing the methyl-boron-dihydroxide ester derivative, thus preparation formula I and II compound, and wherein said cyclammonium is with for example due cares such as Boc-, Fmoc-, CBz-of standard blocking group.The acidolysis of methyl ester and 2N HCl provides boric acid intermediate 1.1 with the reaction of (+) pinine glycol, the go protection and the recrystallization of amino protecting group provide pinane diol ester 2 as the pure salt of isomery.
Intermediate 2 can be used for synthesizing series A and serial B compound.For example, 2 provide α-chloro-acid amide 3 with the N-acidylate of chloroacetyl chloride.Use Na
2CO
3Provide formula I compound 4 with cyclopentamine to 3 the processing and the hydrolysis of pinine glycol boric acid ester.As an alternative, thus utilizing EDAC/HOBT that intermediate 2 is combined with N-Boc-5-phenyl-Pro provides acid amides 5.Amino going protects the hydrolysis with boric acid ester that formula II compound 6 is provided.
By making suitable cyclammonium (tetramethyleneimine, piperidines and other cyclammonium) and sec-BuLi/B (OCH
3)
3Reaction and pass course A or B make the boric acid ester intermediate respectively with required chloride of acid or sour the combination, this synthetic schemes is suitable for preparing whole compound of the present invention.Suitable cyclammonium can be buied or be easy to by known program synthetic, for example, and at United States Patent (USP) 6,617,340,6,432,969,6,380,398,6,172,081,6,166,063,6,124,305,6,110,949,6,107,317,6,011, disclosed program in 155 and 6,395,767, the disclosed full content of these patents is incorporated this paper by reference into.
Therefore, the present invention provides the method for preparation I compound on the other hand:
By making the following formula active compound
With formula R
5-NH
2The amine combination, randomly make boric acid ester go protection, and reclaim the synthetic compound as free acid or as acid salt, wherein L is a leaving group.R
1, R
2, R
3, R
4, R
i, R
Ii, n, X and Z as defined herein.R wherein
3And R
4Be that hydrogen, L are halogen, the R that includes but not limited to Cl
5-NH
2The embodiment that is cyclopentamine is a preferred embodiment.
Compound of the present invention can also be prepared as the form of pharmacy acceptable salt, particularly comprises the acid salt of the salt of organic acid and mineral acid.The example of this salt comprises for example salt of formic acid, fumaric acid, acetate, propionic acid, oxyacetic acid, lactic acid, pyruvic acid, oxalic acid, succsinic acid, oxysuccinic acid, tartrate, citric acid, phenylformic acid, Whitfield's ointment etc. of organic acid.Suitable inorganic acid addition salt comprises the salt of hydrochloric acid, Hydrogen bromide, sulfuric acid and phosphoric acid etc.Pharmaceutically acceptable other example inorganic or organic acid addition salt is included in Journal of PharmaceuticalScience, listed pharmacy acceptable salt in 66,2 (1977), and this is known to those skilled in the art.
Acid salt can be used as the synthetic direct product of compound and obtains.In alternate embodiment, free alkali dissolves in the suitable solvent that contains suitable acid, thereby isolates salt by evaporating solvent or with other method separated salt and solvent.
Utilize method known to those skilled in the art, The compounds of this invention can form solvate with the standard low molecular weight solvent, comprises with water forming hydrate.
It should be understood that the present invention contains whole stereoisomer forms of the compound that requires, comprise enantiomer and diastereomer and racemoid.
Pharmaceutical composition
The pharmaceutical composition of the present invention that contains The compounds of this invention can prepare by traditional technology, and for example at Remington:The Science and Practise of Pharmacy, 19th Ed. is described in 1995.Said composition can show as conventional form, for example capsule, tablet, aerosol, solution, suspension or topical application thing (topical applications).
Compound of the present invention effectively suppresses DPP-IV in the wide region dosage range.For example, when the treatment grownup, every day, spendable dosage was the about 1000mg of about 0.05-, the about 500mg of preferably about 1-.Typical dosage is the about 500mg/ of about 10mg-days.When selecting treatment plan for the patient, beginning needs high dosage usually and reduce dosage when the patient's condition is controlled.Accurate dose will depend on target compound and the body weight of therapeutic goal thing and physician or animal doctor's the preference and the experience of the mode of administration, required treatment, form of medication, treatment.
Usually, The compounds of this invention is adjusted and is that presented in unit dosage form, every dosage unit comprise activeconstituents and the pharmaceutically acceptable carrier of the about 1000mg of about 0.05-.
Definition
With regard to the The compounds of this invention of " pure substantially " such as but not limited to regard to those compounds of formula VA and VB, this means a kind of isomer or other material, comprise whole enantiomers, diastereomer, solvate, hydrate and its pharmacy acceptable salt, represent the composition of 90wt% at least.In some embodiments, a kind of isomer is represented the composition of 98wt% at least.
Term " boric acid protecting group " is meant when being used for this paper that the reaction that is used to relate to other position of function of compound blocks or protect the group part of boric acid function simultaneously.Usually, boric acid OH group is protected as boric acid ester, and described boric acid ester is derived by alcohol; for example (+)-pinine glycol, tetramethyl ethylene ketone, 1,2-dicyclohexyl-ethylene glycol, 1,2; 2-diethanolamine, 1; ammediol, 2,3-butyleneglycol, di-isopropyl tartrate, 1,4-butyleneglycol, di-isopropyl ethylene glycol, (S; S; )-5,6-decanediol, 1,1; 2-triphenyl-1; 2-ethylene glycol, (2R, 3R)-1,4-dimethoxy-1; 1; 4,4-tetraphenyl-2,3-butyleneglycol, methyl alcohol, ethanol, Virahol, catechol or 1-butanols etc.It will be understood by those skilled in the art that only have monohydroxy alcohol for example methyl alcohol form and to have structure-B (OR)
2Diester, wherein R be from alcohol organic moiety (for example-B (OMe)
2).Comparatively speaking, glycol for example tetramethyl ethylene ketone form and to have-B (OR)
2Ring boric acid diester, wherein organic moiety (for example-C (Me)
2-C (Me)
2-) two oxygen of connection.
Term " N protecting group " or " N protection " are meant N-end or amino those groups that to avoid undesirable reaction of protection that are used for protecting amino acid or peptide during building-up process when being used for this paper.N-end protecting group commonly used is at T.W.Greene, P.G.Wuts's " Protective Groups In Organic Synthesis, 3rd Ed. " (JohnWiley ﹠amp; Sons, New York (1999)) open in, the document is incorporated this paper by reference into.The N protecting group comprises acyl group for example formyl radical, ethanoyl, propionyl, valeryl, tertiary butyl ethanoyl, 2-chloracetyl, 2-acetyl bromide, trifluoroacetyl group, tribromo-acetyl base, phthalyl, ortho-nitrophenyl oxygen base acetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzene formacyl, 4-benzoyl bromide, 4-nitro benzoyl etc.; Alkylsulfonyl is benzenesulfonyl, p-toluenesulfonyl etc. for example; Carbamate forms for example benzyloxycarbonyl of group, to the chlorine benzyloxycarbonyl, to methoxyl group benzyloxy base carbonyl, to the nitro benzyloxycarbonyl, 2-nitro benzyloxycarbonyl, to the bromo-benzyloxy-carbonyl, 3,4-dimethoxy benzyloxycarbonyl, 3,5-dimethoxy benzyloxycarbonyl, 2,4-dimethoxy benzyloxycarbonyl, 4-methoxyl group benzyloxy base carbonyl, 2-nitro-4,5-dimethoxy benzyloxycarbonyl, 3,4,5-trimethoxy benzyloxycarbonyl, 1-(p-biphenyl)-1-methyl ethoxy carbonyl, α, alpha-alpha-dimethyl-3,5-dimethoxy benzyloxycarbonyl, benzhydryloxycarbonyl, tert-butoxycarbonyl, the di-isopropyl methoxycarbonyl, isopropoxy carbonyl, ethoxy carbonyl, methoxycarbonyl, allyloxy carbonyl, 2,2,2 ,-trichlorine ethoxy carbonyl, carbobenzoxy, 4-nitro carbobenzoxy, fluorenyl-9-methoxycarbonyl, encircle penta oxygen carbonyl, the Buddha's warrior attendant carbalkoxy, hexamethylene oxygen carbonyl, thiophenyl carbonyl etc.; Alkyl is phenmethyl, trityl, benzyloxymethyl etc. and silyl trimethyl silyl etc. for example for example.Preferred N-protected base is formyl radical, ethanoyl, benzoyl, valeryl, tertiary butyl ethanoyl, benzenesulfonyl, phenmethyl, 9-fluorenylmethyloxycarbonyl (Fmoc), tertbutyloxycarbonyl (Boc) and carbobenzoxy-(Cbz) (Cbz).
Term " alkyl " or " (C
1-12) alkyl " line style of (1-12 used herein is meant each in 1,2,3,4,5,6,7,8,9,10,11 and 12) the individual carbon atom that refers to have 1-12 alone or in combination or branched chain and can comprise circular part; such as but not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl, n-pentyl, 2-methyl butyl, 3-methyl butyl, n-hexyl, 4-methyl amyl, neo-pentyl, 2,2-dimethyl propyl etc.
Term " (C
1-10) alkyl ", " (C
1-8) alkyl " and " (C
1-6) alkyl " refer to have respectively the line style of 1-10,1-8 or 1-6 carbon atom or branched chain alone or in combination and can comprise circular part; such as but not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl, n-pentyl, 2-methyl butyl, 3-methyl butyl, n-hexyl, 4-methyl amyl, neo-pentyl, 2,2-dimethyl propyl etc.
Term " (C
1-4) alkyl " refer to have the line style of 1-4 carbon atom or branched chain alone or in combination and can comprise circular part, such as but not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl etc.
Term " (C
2-12) thiazolinyl " and " (C
2-10) thiazolinyl " refer to have respectively the line style of 2-12 or 2-10 carbon atom and at least one two key or branching, aliphatic unsaturated hydrocarbon alone or in combination, such as but not limited to vinyl, propenyl, allyl group, pseudoallyl, n-butene base, positive pentenyl, n-hexylene base etc.
Term " (C
2-12) alkynyl " and " (C
2-10) alkynyl " refer to have respectively 2-12 or 2-10 carbon atom and at least one triple-linked aliphatic unsaturated hydrocarbon alone or in combination, for example include but not limited to-C ≡ CH ,-C ≡ C-CH
3,-CH
2C ≡ CH ,-CH
2-CH
2-C ≡ CH ,-CH (CH
3) C ≡ CH etc.
Term " (C
3-12) cycloalkyl " and " (C
3-10) cycloalkyl " be meant one or more saturated cyclic hydrocarbons that have 3-12 or 3-10 carbon atom respectively, such as but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl etc.
Term " (C
5-10) cycloalkenyl group " be meant one or more cyclic hydrocarbon that have 5-10 carbon atom and have at least one two key, such as but not limited to cyclopentenyl, cyclohexenyl etc.
Term " ring alkylidene group " is meant single bonded " cycloalkyl " that has connection at two different carbon atoms places.
Term " (C
1-6) alkyl amino-carbonyl " and " two-(C
1-6) alkyl amino-carbonyl " be meant to have 1-6 carbon atom and connect NC (=O) straight or branched.Typical alkyl includes but not limited to methyl, ethyl, propyl group, sec.-propyl, normal-butyl, the tertiary butyl, isobutyl-, amyl group, hexyl etc.
Term " (C
1-6) alkyl-carbonyl " be meant to have 1-6 carbon atom and connect C (=O) line style or branched chain and cyclic hydrocarbon radical.Typical alkyl includes but not limited to methyl, ethyl, propyl group, sec.-propyl, normal-butyl, the tertiary butyl, isobutyl-, amyl group, hexyl etc.
Term (C
3-8) naphthene base carbonyl is meant to have 3-8 carbon atom and connect C (=O) cyclic hydrocarbon radical.Typical cycloalkyl includes but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.
Term " (C
1-10) alkoxyl group ", " (C
1-8) alkoxyl group " and " (C
1-6) alkoxyl group " refer to be connected to " O " of alkyl alone or in combination, have the line style of 1-10, a 1-8 or 1-6 carbon atom or branched chain respectively and can comprise circular part.The example of line style alkoxyl group includes but not limited to methoxyl group, oxyethyl group, propoxy-, butoxy, pentyloxy, hexyloxy etc.The example of branched alkoxy includes but not limited to isopropoxy, sec-butoxy, tert.-butoxy, isopentyloxy, different hexyloxy etc.The example of cycloalkyloxy includes but not limited to encircle propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc.
Term " aryloxy " is meant the aryl that connects O.
Term " alkyloyl " is meant the alkyl that connects carbonyl separately or as the part of other group.
Term " alkylidene group " is meant the single bonded alkyl that has connection at two different carbon atoms places.
Term " alkenylene " is meant the single bonded thiazolinyl that has connection at two different carbon atoms places.
Term " alkynylene " is meant the single bonded alkynyl that has connection at two different carbon atoms places.
Term " aryl " is meant monocycle, dicyclo or the three ring carbocyclic ring aromatic nucleus systems that have 6-14 carbon atom at circular part.The example of aryl includes but not limited to phenyl, naphthyl, xenyl, anthryl, camomile cyclic group etc.Aryl can also comprise and comprises 1,2,3, the partial hydrogenation derivative of the carbocyclic ring system of 4-tetrahydrochysene-naphthyl, indanyl etc.
The example of " aryl " includes but not limited to phenyl, xenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), anthryl (1-anthryl, 2-anthryl, 3-anthryl) etc.
Term " aryl alkenyl " and " aromatic yl polysulfide yl " are meant above-mentioned thiazolinyl and the alkynyl with aryl substituent separately or as the part of other group.
Term " halogen " and " halogen " are meant chlorine, fluorine, bromine or iodine.
Term " alkylamino ", " arylamino " or " aryl-alkyl amino " comprise any abovementioned alkyl, the aryl or aralkyl that connects nitrogen-atoms separately or as the part of other group.
Term " substituted-amino " is meant amino with one or two substituting group replacement separately or as the part of other group when being used for this paper, substituting group can be identical or different, for example alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, the assorted alkyl of ring, the assorted alkyl-alkyl of ring, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl or alkylthio.These substituting groups can also replace with above-mentioned any group.
Term " alkylthio ", " arylthio " or " aromatic alkylthio " comprise any abovementioned alkyl, aralkyl or the aryl that connects sulphur atom separately or as the part of other group.
Term " acyl group " itself or be meant the organic group that is connected to carbonyl as the part of other group; The example of acyl group comprises any group that is bonded to carbonyl, as alkyloyl, enoyl-, aroyl, aralkanoyl, 4-hetaroylpyrazol, cycloalkanes acyl group, the assorted alkyloyl of ring etc.
Statement " the a-amino acid side chain of Cun Zaiing naturally " is meant the part (side chain) that is bonded to alpha-amino group carbon in the following a-amino acid that exists naturally: glycine, L-Ala, 2-aminobutyric acid, Xie Ansuan, leucine, Isoleucine, Terleu, Serine, Threonine, halfcystine, l-asparagine, aspartic acid, glutamine, L-glutamic acid, phenylalanine, Histidine, tryptophane, tyrosine, phenylglycocoll, Methionin, methionine(Met) and arginine.These amino acid whose side chains are known in the art.For example the side chain of the a-amino acid of L-Ala is a methyl; The side chain of phenylalanine is a phenmethyl; The side chain of Terleu is the tertiary butyl.
Term " multi-haloalkyl " is meant and comprises 2-9, preferred 2-5 halogenic substituent for example above defined " alkyl " of F or Cl, preferably F substituting group, for example CF
3CH
2, CF
3Or CF
3CF
2CH
2
Term " many halogenated alkoxies " is meant and comprises 2-9, preferred 2-5 halogenic substituent for example above defined " alkoxyl group " or " alkyl oxygen " base of F or Cl, preferably F substituting group, for example CF
3CH
2O, CF
3O or CF
3CF
2CH
2O.
Term " polycyclic " and " many ring " are meant two or more rings (for example assorted alkyl of cycloalkyl, cycloalkenyl group, aryl, heteroaryl and/or ring), two shared two or more carbon atoms of adjacent ring wherein, and for example ring is " condensing " ring.The fused rings that connects by non-adjacent atom is also referred to as " bridge joint " ring.Each ring of polycyclic can use above described substituting group to replace, for example halogen, alkyl, aralkyl, thiazolinyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfydryl, imino-, amido, phosphonic acid ester, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, alkylsulfonyl, ketone, aldehyde, ester, heterocyclic radical, aromatics or heteroaromatic moiety, trifluoromethyl, cyano group etc.
Embodiment
In conjunction with non-limiting example hereinafter the present invention is described in further detail.
Embodiment 1
(2R)-and boroPro-(1S, 2S, 3R, 5S)-pinane diol ester, hydrochloride (2) synthetic
Under nitrogen atmosphere, N-Boc-tetramethyleneimine (20g, 117mmol, 1 eq) and dried THF (60mL) packed in the round-bottomed flask of flame oven dry that magnetic stirring bar is housed.With this limpid colourless solution be cooled to-78 ℃ and with time of 30 minutes slowly adding s-BuLi solution (the 1.4M solution of 100ml in the hexanaphthene, 140mmol).Stirred bright orange solution 3 hours down at-78 ℃, then (39ml 350mmol) handles, and removes cooling bath and clear colorless solution is slowly warm to 0 ℃ afterwards with B (OMe) 3.When reaching 0 ℃, (~2mL) cancellation reaction warmly is extracted into (250ml) among the 2N NaOH then to room temperature, with other EtOAc (150mL) backwash with less water.Is that pH3 is then with EtOAc extraction (3 * 120mL) by adding 2N HCl with aqueous phase as acidified.Organic extract is combined and at Na
2SO
4Last dry and concentrate with produce the free boric acid of sticky white solid (22.08g, 103mmol), productive rate 88%.Do not carry out single step purification, this boric acid is dissolved in the t-butyl methyl ether (150mL), (17.5g 103mmol) also continues to stir at room temperature to add (+)-pinine glycol.After 18 hours, remove ether and with column chromatography (silica gel, purifying (+)-pinine glycol boric acid ester of 1: 3 hexane/EtOAc) is to produce limpid heavy-gravity oily matter (26.84g, 76.8mmol, 76% productive rate, Rf=0.6, adopt 2: 1 hexane/ethyl acetate eluents, through I
2And/or PMA dyeing back is visual).By being dissolved in oily matter in the dry ether, in ice bath, being cooled to 0 ℃ of removal of finishing the Boc protecting group, HCl (g) is bubbled enters in this solution also to continue 10 minutes.After 2 hours, occur white precipitate and vacuum in the flask and remove ether and excessive HCl to produce the racemize HCl salt of white solid.The crystallization of required isomer is with to separate implementation process as follows: this HCL salt is dissolved in the methylene dichloride (250mL) of trace simultaneously slowly heating to help to produce homogeneous solution, then continue to stir 8 hours to produce fluffy white precipitate, collect this precipitation by vacuum filtration, be dissolved in after the drying micro-2-propyl alcohol (~200mL), simultaneously mild heat is up to evenly.This alcoholic solution is stirred a whole night, collect the white precipitate that is produced, thereby produce the isomer pure 1 of white solid state by vacuum filtration.(7.0g, 27mmol, 23% productive rate).
1H?NMR(400MHz,D
2O)δ4.28(d,J=8.0Hz,1H),3.06(m,3H),2.18(m,1H),1.96(m,2H),1.78(m,3H),1.62(m,2H),1.21(s,3H),1.05(m,5H),0.84(d,J=12Hz,2H),0.71(s,2H),0.62(s,3H)。
Embodiment 2
Synthesizing of series A compound: (2R)-1-(2-cyclopentyl amino-ethanoyl)-boroPro-OH (4)
Step 1:(2R)-and 1-(2-chloracetyl)-boroPro-(1S, 2S, 3R, 5S)-pinane diol ester (3A).
At N
2Down (12.34mL 155.2mmol) joins to be dissolved in and does CH with chloroacetyl chloride in protection
2Cl
2(200mL) and be cooled to 0 ℃ 2 (36.7g is in solution 129.3mmol).Lentamente with the 4-methylmorpholine (42.4mL 182mmol) joins in this solution producing limpid bright orange solution fully, this solution by warm to room temperature.After 30 minutes this solution is cooled to once more 0 ℃ and add the HCl solution of 200mL 0.2N, orange layer is separated, and is dry and concentrate producing garnet oily matter, and this oily matter is point (2: 1 hexane/EtOAc, a R after by TLC
f=0.22, through I
2And/or PMA dyeing back is visual) and be used for next step and be not further purified.
1H?NMR(400MHz,CDCl
3)δ0.80(s,3H),1.25(m,1H),1.26(s,3H),1.42(s,3H),1.75-1.96(m,4H),1.98-2.10(m,3H),2.12-2.20(m,1H),2.29-2.35(m,1H),3.12-3.16(m,1H),3.47-3.53(m,1H),3.58-3.63(m,1H),3.97-4.05(q,2H),4.30-4.32(d,1H)。
Step 2:(2R)-and 1-(2-cyclopentyl amino-ethanoyl)-boroPro-(1S, 2S, 3R, 5S)-pinane diol ester (3B).
With compound 3A be dissolved in do THF (~150mL) in, then add K
2CO
3(35g) and be cooled to 0 ℃, add afterwards cyclopentamine (21.93g, 258mmol).Then that reaction mixture is warm to room temperature and stir a whole night.TLC shows that all raw materials all are consumed.Mixture filters, uses CH by C salt (celite) and silica pad
2Cl
2Middle 5%MeOH (200mL) washing also concentrates, and produces thickness bright orange solid.Red sticky solid is dissolved in CH
2Cl
2(150mL), add Et again
2O (~200mL) and stir this solution a whole night.Filter then the emulsus produced and with cold EtOAc (2 * 60mL) and hexane (2 * 50mL) washing precipitations, drying with the 3B that produces fluffy white solid (28.92g, 120.5mmol).Concentrate the female filtrate of garnet and carry out above-mentioned recrystallization process with the secondary product that obtains 3B (6.17g, 25.7mmol), obtained 73% the comprehensive overall yield of 3B (35.09g, 93.8mmol).R
f=0.45 (CH
2C1
2Middle 10%MeOH).
1H?NMR(400MHz,CDC1
3)δ4.18(d,1H),3.95(d,J=16Hz,1H),3.6(d,J=16Hz,1H),3.46(m,3H),2.74(m,1H),2.36(m,1H),2.16(m,2H),2.04(m,4H),1.90(s,1H),1.74(m,6H),1.61(s,1H),1.46(m,2H),1.34(s,3H),1.30(s,3H),0.88(s,3H)。
Step 3:(2R)-1-(2-cyclopentyl amino-ethanoyl)-boroPro-OH (4)
(13.37g 109.5mmol) joins H with hexane (200mL) and phenyl-boron dihydroxide
23B among the O (40.59g, (200mL, adding 2N HCl adjustment pH is 2) and this two-phase mixture of high degree of agitation in solution 108.5mmol).Regularly remove hexane layer and replace, in 24 hours, carry out 6 times with neohexane.Water layer is separated and be applied to Dowex50-X2-100 ion exchange column (H
+Type), the water wash-out is neutral up to elutriant.With aqueous ammonium hydroxide (2wt%) wash-out, the then suitable cut of freeze-drying, thereby produce white crystalline solid 4 (23.91g, 99.6mmol), productive rate is 92%.4TFA salt
1H NMR (400MHz, D
2O) δ 3.88 (dd, J=8.0Hz, 2H), 3.54 (m, 1H), 3.42 (m, 1H), 3.28 (m, 1H), 2.96 (m, 1H), 1.96 (m, 4H), 1.85 (m, 2H), 1.63 (m, 7H); MS (ESI) m/z 223 (M+H-H
2O)
+
Embodiment 3
1-(2-cyclopropyl amino-ethanoyl)-tetramethyleneimine-(2R)-boric acid (A2) synthetic:
Utilize suitable raw material to prepare title compound according to the program of embodiment 2.
1H?NMR(D
2O)δ4.08(dd,J=12Hz,2H),3.54(m,1H),3.38(m,1H),3.07(m,1H),2.26(m,1H),2.09(m,2H),1.94(m,1H),1.71(m,1H),0.88(s,4H);MS(ESI)m/z?195.13(MH
+-H
2O)。
Embodiment 4
1-[2-(3-hydroxyl-diamantane-1-base amino)-ethanoyl]-tetramethyleneimine-(2R)-boric acid (A3) synthetic:
Utilize suitable raw material to prepare title compound according to the program of embodiment 2.
1H?NMR(D
2O)δ3.94(d,J=8Hz,2H),3.54(m,1H),3.40(m,1H),3.09(m,1H),2.41(s,2H),2.09(m,3H),1.93(m,2H),1.87(m,7H),1.71(m,6H),1.56(m,2H);MS(ESI)m/z305.21(MH
+-H
2O)。
Embodiment 5
1-(5R-phenyl-tetramethyleneimine-2S-carbonyl)-tetramethyleneimine-(2R)-boric acid (6) synthetic:
Step 1:N-Boc-5-phenyl Pro-(2R)-boroPro-(1S, 2S, 3R, 5S)-pinane diol ester (5):
With EDAC (174mg, 0.91mmol) and HOBt (105mg, 0.775) join and do CH
2Cl
2In ice-cooled (0 ℃) solution of N-Boc-5-phenyl-Pro-OH (0.84mmol) in.Down stirred this reactant 15 minutes at 0 ℃, add 2 then (200mg, 0.7mmol) and N-methylmorpholine (0.25mL, 2.1mmol) that this reactant is slowly warm to room temperature, lasting 8 hours of reaction.Add NaHCO then
3(10mL) with the cancellation linked reaction, be extracted among the EtOAc (2 * 15mL), with salt solution (15mL) washing, then at NaSO
4Last dry, concentrate and through column chromatography be further purified (silica gel, with EtOAc gradient elution in the hexane, 30-50%), thereby produce pale solid 5 (320mg, 0.62mmol, 88%).
Step 2:1-(5R-phenyl-tetramethyleneimine-2S-carbonyl)-tetramethyleneimine-(2R)-boric acid (6) synthetic:
(320mg, ice-cooled (0 ℃) solution 0.62mmol) is saturated and stirred 1 hour to make 5 in the dry ether with dried HCl (g).Concentrate this solution then to produce the thickness white solid under vacuum, this solid is attracted to H
2O (10mL, adding 2N HCl, to adjust pH be 2) and hexane (10mL) and phenyl-boron dihydroxide (74mg, 0.62mmol) in, this two-phase mixture of high degree of agitation.Regularly remove hexane layer and replace, in 24 hours, carry out 6 times with neohexane.Water layer is separated and be applied to Dowex 50-X2-100 ion exchange column (H
+Type), the water wash-out is neutral up to elutriant.With aqueous ammonium hydroxide (2wt%) wash-out, the then suitable cut of freeze-drying, thereby produce amorphous white solid free boric acid B1 (76mg, 0.26mmol).
1H?NMR(D
2O)δ7.46(m,5H),3.65(m,1H),3.44(m,1H),3.04(m,1H),2.54(m,1H),2.38(m,2H),2.20(m,1H),2.06(m,2H),1.86(m,1H),1.66(m,1H);MS(ESI)m/z?271(MH
+-H
2O)。
Embodiment 6
1-(piperidines-2S-carbonyl)-tetramethyleneimine-(2R)-boric acid (B2) synthetic:
Utilize suitable raw material to prepare title compound according to the program of embodiment 5.
1H?NMR(D
2O)δ4.07(m,1H),3.61(m,1H),3.34(m,2H),2.94(m,2H),2.16(m,1H),2.03(m,2H),1.87(m,3H),1.56(m,4H);MS(ESI)m/z?209(MH
+-H
2O)。
Embodiment 7
1-(2,3-dihydro 1-H-indoles-2S-carbonyl)-tetramethyleneimine-(2R)-boric acid (B3) synthetic:
Utilize suitable raw material to prepare title compound according to the program of embodiment 5.
1H?NMR(D
2O)δ4.54(m,1H),3.73(m,1H),3.58(m,1H),3.34(m,1H),2.48(m,1H),2.37(m,1H),2.06(m,3H),1.83(m,3H),1.58(m,4H),1.32(m,4H);MS(ESI)m/z?249(MH
+-H
2O)。
Embodiment 8
1-(4S-phenyl-tetramethyleneimine-2S-carbonyl)-tetramethyleneimine-(2R)-boric acid (B4) synthetic:
Utilize suitable raw material to prepare title compound according to the program of embodiment 5.
1H?NMR(D
2O)δ7.34(d,J=13Hz,2H),7.27(m,3H),4.79(m,1H),3.83(m,1H),3.59(m,1H),3.34(m,2H),3.06(m,1H),2.53(m,2H),2.08(m,2H)1.77(m,1H),1.64(m,1H);MS(ESI)m/z?271(MH
+-H
2O)。
Embodiment 9
Synthesizing of series C compound: (2R)-1-[(2S, 4S)-4-amino-tetramethyleneimine-2-carbonyl]-boroPro-OH (15)
Step 1:(2R)-1-[(2S, 4S)-1-tertbutyloxycarbonyl-4-benzyloxycarbonyl amino-tetramethyleneimine-2-carbonyl]-boroPro-(1S, 2S, 3R, 5S)-pinane diol ester (13)
Utilize (2S, 4S)-(628mg 2.2mmol) substitutes azetidine-1 to Fmoc-4-amino-1-boc-tetramethyleneimine-2-carboxylic acid, and the 2-dicarboxylic acid 1-tert-butyl ester is implemented above-mentioned synthetic 11 experimental program.Obtain the compound 13 of limpid colorless oil, be used for next step and be not further purified.
Step 2:(2R)-1-[(2S, 4S)-1-tertbutyloxycarbonyl-4-amino-tetramethyleneimine-2-carbonyl]-boroPro-(1S, 2S, 3R, 5S)-pinane diol ester (14)
Diethylamine (5mL) is once added in 13 the solution of solution D CM (10mL) and at room temperature stir the colourless solution a whole night that is produced.With the reactant evaporate to dryness and add other DCM, then evaporate to dryness once more.(silica gel is with 2.5-5%MeOH gradient elution among the DCM, through I by the column chromatography purifying for the oily matter that is produced
2And/or PMA dyeing back is visual), thus limpid colorless oil 14 produced, and productive rate is 48% in whole steps 2.
Step 3:(2R)-1-[(2S, 4S)-4-amino-tetramethyleneimine-2-carbonyl]-boroPro-OH (15)
To in synthetic compound 12, go protection and the esterolytic above-mentioned experimental program of pinine glycol boric acid to be applied to 14 by N-Boc.Obtain white solid compound 15.15TFA salt
1H NMR (500MHz, D
2O) δ 4.42 (dd, 1H), 3.87 (m, 1H), 3.5 (dd, 1H), 3.28 (m, 2H), 3.07 (m, 1H), 2.73 (m, 1H), 2.64 (m, 1H), 1.86 (m, 1H), 1.72 (br m, 2H), 1.55 (br m, 2H), 1.34 (m, 2H) .MS m/z (rel intensity) 228 (M+1) (55), 210 (M+1-H
2O) (95).
Embodiment 10
Synthesizing of series D compound: (2R)-1-[(2S)-4-methyl sulphonyl-piperazine-2-carbonyl]-boroPro-OH (19)
Step 1:(2R)-1-[(2S)-1-tertbutyloxycarbonyl-4-benzyloxycarbonyl-piperazine-2-carbonyl]-boroPro-(1S, 2S, 3R, 5S)-pinane diol ester (16)
(1g 2.6mmol) substitutes azetidine-1, and the 2-dicarboxylic acid 1-tert-butyl ester is implemented above-mentioned synthetic 11 experimental program to utilize (2S)-N-1-Boc-N-4-Cbz-2-piperazine carboxylic acid.(690mg, 1.5mmol), productive rate is 57% to obtain buttery compound 16 behind the silica gel column chromatography purifying.MS m/z (rel intensity) 618 (M+23)
+(17), 596 (M+1)
+(100), 496 (38).
Step 2:(2R)-1-[(2S)-1-tertbutyloxycarbonyl-piperazine-2-carbonyl]-boroPro-(1S, 2S, 3R, 5S)-pinane diol ester (17)
Pd/C (40mg) is added the middle compound 16 of MeOH (6mL), and (314mg is in solution 0.53mmol).At H
2Stirred this mixture 2 hours under the atmosphere.When reaction is finished, plough (plough of Celite) with its filtration by C salt.Under reduced pressure remove solvent, the oily residue is used for next step and is not further purified.MS m/z (rel intensity) 462 (M+1)
+(100), 406 (12), 362 (11).
Step 3:(2R)-1-[(2S)-1-tertbutyloxycarbonyl-4-methyl sulphonyl-piperazine-2-carbonyl]-boroPro-(1S, 2S, 3R, 5S)-pinane diol ester (18)
(204 μ L, 1.9mmol) (72 μ L 0.93mmol) join the CH that is cooled to 0 ℃ successively with the methyl sulphonyl muriate with N-methylmorpholine
2Cl
2(214mg is in solution 0.46mmol) for compound 17 (5mL).Reaction mixture is warm to room temperature and stirred 3 hours.Use CH then
2Cl
2(6mL) and water (6mL) dilution.Separate organic phase and at MgSO
4Last dry.After the filtration, under reduced pressure remove solvent.The oily residue utilizes the EtOAc/ hexane to come purifying as eluent by column chromatography (silica gel).(112mg, 0.21mmol), productive rate is 45% to obtain compound 18.MS m/z (rel intensity) 562 (M+23)
+(14), 540 (M+1) (100), 388 (75).
Step 4:(2R)-1-[(2S)-4-methyl sulphonyl-piperazine-2-carbonyl]-boroPro-OH (19)
Will be in synthetic compound 12 N-Boc go protection and the esterolytic above-mentioned experimental program of pinine glycol boric acid be applied to 18 (112mg, 0.21mg).(32mg, 0.11mmol), productive rate is 53% to obtain compound 19.19TEA salt
1H NMR (500MHz, D
2O) δ 4.32 (dd, J=11.0,3.5Hz, 1H), 4.05 (m, 1H), 3.93 (m, 1H), 3.77 (m, 1H), 3.60 (ddd, J=10.5,8.0,2.5Hz, 1H), 3.47 (ddd, J=12.5,3.0,3.0,1H), 3.35 (m, 2H), 3.16 (m, 2H), 3.02 (dd, J=13.8,11.3Hz, 1H), 2.93 (s, 3H), 1.96 (m, 2H), 1.81 (m, 1H), 1.72 (m, 1H), 1.56 (m, 1H) .MS m/z (rel intensity) 575 (12), 328 (M+23)
+(6), 288 (M-17) (100).
Embodiment 11
Utilize method described above, the compound in the preparation table also utilizes liquid chromatography-mass spectrography (LC-MS) to characterize.
Though for those skilled in the art make and utilize the present invention and fully describe in detail and for example understand the present invention, but it will be readily apparent to one skilled in the art that to make variously substitutes, revises and improve and do not depart from the spirit and scope of claim.
All patents and publication by reference and this paper is incorporated on same degree ground into, promptly each publication all specifically and is individually indicated by reference and is incorporated into.
Term that uses and statement only are used for describing and are not restriction, use this term and statement and do not mean that any Equivalent or its part of getting rid of show and the feature of describing, but should be realized that, can in the desired scope of the invention, make various modifications.Therefore, it should be understood that, though specifically disclose the present invention by embodiment preferred and optional feature, but those skilled in the art can make amendment and change notion herein, and this modifications and variations are considered to be within the scope of the invention that is defined by the following claims.
In addition, when describing feature of the present invention and characteristic, it will be understood by those skilled in the art that thus and also describe the present invention according to any individual element or the subgroup of Markush family element according to Markush family.For example, if X is described as being selected from bromine, chlorine and iodine, then fully describing claim and the X that X is a bromine is the claim of bromine and chlorine.
Claims (3)
1. the pyrrolidine compound of formula I:
Comprise its whole enantiomers, diastereomer, solvate, hydrate and pharmacy acceptable salt, wherein:
N is 1-3;
X is CH
2, S, O, CF
2Or C (CH
3)
2
Z is H, halogen, hydroxyl, (C
1-6) alkoxyl group, (C
1-12) alkyl, (C
3-12) cycloalkyl, phenyl or heteroaryl; Wherein phenyl and heteroaryl are randomly used R
7Single replacement or polysubstituted independently;
R
7Be halogen, (C
1-10) alkyl, (C
1-10) alkoxyl group, (C
1-10) alkylamino, (C
1-10) dialkyl amido, phenmethyl, benzyloxy, hydroxyl (C
1-6) alkyl, methylol, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, N-azanol base, cyano group, carboxyl, kharophen, hydroxyl, sulfamyl, sulfonamido or formamyl;
Randomly, X and adjacent ring carbon and Z form the fused rings propyl group together; With
Randomly, a key being arranged in containing the ring of X is two keys;
R
1And R
2Independently or one be both hydrogen, boric acid protecting group or can be in the physiological pH value aqueous solution or be hydrolyzed to the group of hydroxyl in the biofluid; With
CR
iR
IiCan exist or not exist, and
Work as CR
iR
IiWhen existing, R
i, R
Ii, R
3, R
4And R
5Be selected from (aa) or (bb):
(aa): R
i, R
Ii, R
3And R
4Be hydrogen; And R
5Be hydrogen, (C
1-12) alkyl or (C
3-12) cycloalkyl;
(bb) R
i, R
Ii, R
3, R
4And R
5Be hydrogen independently, alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkylalkyl, bicyclic alkyl, tricyclic alkyl, alkyl-cycloalkyl, hydroxyalkyl, the hydroxyalkyl cycloalkyl, the hydroxyl cycloalkyl, the hydroxyl bicyclic alkyl, the hydroxyl tricyclic alkyl, the bicyclic alkyl alkyl, the alkyl bicyclic alkyl, alkyl-thio-alkyl, the arylalkyl alkylthio, cycloalkenyl group, aryl, aralkyl, heteroaryl, heteroarylalkyl, encircle the assorted alkyl-alkyl of assorted alkyl or ring, all randomly with the single replacement of following groups or polysubstituted independently: halogen, alkyl, multi-haloalkyl, alkoxyl group, halogenated alkoxy, many halogenated alkoxies, carbalkoxy, thiazolinyl, alkynyl, cycloalkyl, cycloalkylalkyl, multi-ring alkyl, heteroaryl amino, arylamino, the assorted alkyl of ring, the assorted alkyl-alkyl of ring, hydroxyl, hydroxyalkyl, nitro, cyano group, amino, substituted-amino, alkylamino, dialkyl amido, thiol, alkylthio, alkyl-carbonyl, acyl group, carbalkoxy, aminocarboxyl, the alkynyl aminocarboxyl, alkyl amino-carbonyl, the alkenyl amino carbonyl, alkyl carbonyl oxy, alkyl-carbonyl-amino, aryl-amino-carbonyl, alkyl sulfonyl amino, alkyl amino-carbonyl-amino, alkoxycarbonyl amido, alkyl sulphonyl, amino sulfinyl, amino-sulfonyl, alkyl sulphinyl, sulfonamido or alkylsulfonyl;
Or as an alternative,
Work as CR
iR
IiWhen not existing, R
3, R
4And R
5Be selected from (cc), (dd) or (ee):
(cc) R
3And R
4Be hydrogen and
R
5Be
A) hydrogen, prerequisite are when n is 1, X is CH
2R when being H with Z
5Not hydrogen;
B) (C
1-12) alkyl, (C
2-12) thiazolinyl, (C
2-12) alkynyl, (C
3-12) cycloalkyl or (C
3-12) cycloalkenyl group, wherein alkyl, thiazolinyl, alkynyl, cycloalkyl and cycloalkenyl group are randomly used R
6Single replace or polysubstituted independently, and wherein alkyl, thiazolinyl, alkynyl partly comprise line style or branched chain and can comprise circular part;
R
6Be (C
1-6) alkyl, (C
1-6) alkoxyl group, cycloalkyl, carboxyl, kharophen, cyano group, nitro, halogen, hydroxyl, hydroxyl (C
1-6) alkyl, methylol, trifluoromethyl, trifluoromethoxy, sulfamyl, sulfonamido, formamyl, aryl, heteroaryl, amino; Wherein aryl and heteroaryl are randomly used R
7Single replacement or polysubstituted independently, amino is randomly used R
8,-SOR
8,-SO
2R
8,-COR
8,-CO
2R
8,-CONHR
8,-CON (R
8)
2,-OR
8Or-S-R
8Single replacement or polysubstituted independently;
R
7Be halogen, (C
1-10) alkyl, (C
1-10) alkoxyl group, (C
1-10) alkylamino, (C
1-10) dialkyl amido, phenmethyl, benzyloxy, hydroxyl (C
1-6) alkyl, methylol, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, N-hydroxylamino, cyano group, carboxyl, kharophen, hydroxyl, sulfamyl, sulfonamido or formamyl;
R
8Be (C
1-10) alkyl, (C
2-10) thiazolinyl, (C
2-10) alkynyl, (C
3-10) cycloalkyl, (C
5-10) cycloalkenyl group, phenmethyl, styroyl, aryl or heteroaryl; Wherein alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group randomly replace with aryl or heteroaryl list or are polysubstituted independently, and wherein aryl and heteroaryl are randomly used R
7Single replacement or polysubstituted independently;
C) optional and (C
3-10) Cycloalkylfused aryl or optional and (C
3-10) Cycloalkylfused heteroaryl; Wherein aryl and heteroaryl are randomly used R
7Single replacement or polysubstituted independently;
D) indanyl, 1,2,3,4-tetralyl, j are the (CH of 0-3
2)
jAdamantyl, or [2.2.1] or [3.1.1] bicyclic carbocyclic part comprise (4-amyl group dicyclo [2.2.2] suffering-1-yl) amine; Indanyl, 1,2,3 wherein, 4-tetralyl, (CH
2)
jAdamantyl and [2.2.1] or [3.1.1] bicyclic carbocyclic part are randomly used hydroxyl, (C
1-8) alkyl, (C
1-8) alkoxyl group, (C
1-8) alkanoyloxy or R
9R
10The single replacement of N-CO-O-or polysubstituted independently, wherein R
9And R
10Be (C independently
1-8) alkyl or phenyl, wherein alkyl and phenyl are randomly used (C
1-8) alkyl, (C
1-8) alkoxyl group, halogen or trifluoromethyl list replace or polysubstituted independently, perhaps R
9And R
10Be (C together
3-6) alkylidene group;
E) R
11(CH
2)
p-, R wherein
11Be 2-oxygen pyrrolidyl, (C
1-6) alkoxyl group, phenyl, phenoxy group, (C
1-8) cycloalkyl, [3.3.3] bicyclic carbocyclic part, pyridyl, naphthyl, cyclohexenyl or adamantyl, wherein 2-oxygen pyrrolidyl, (C
1-6) alkoxyl group, phenyl, pyridyl and naphthyl randomly use R
12The single replacement or two independently the replacement or three replacements independently; Wherein phenoxy group is randomly used (C
1-4) alkyl, (C
1-4) replacement of alkoxy or halogen list or two independently the replacement; And wherein [3.3.3] bicyclic carbocyclic part is randomly used (C
1-8) alkyl list replacement or polysubstituted independently; P is 0-3:
R
12Be halogen, trifluoromethyl, cyano group, nitro, (C
1-6) alkyl, (C
1-6) alkoxyl group, cycloalkyl, carboxyl, kharophen, hydroxyl, hydroxyl (C
1-6) alkyl, methylol, trifluoromethoxy, sulfamyl, formamyl, sulfonamido, alkyl sulphonyl, benzenesulfonyl, aryl, heteroaryl, wherein aryl and heteroaryl are randomly used R
7Single replacement or polysubstituted independently;
F) (R
13)
2CH (CH
2)
q-, R wherein
13It is phenyl; Wherein each phenyl is chosen wantonly independently and is used R
12The single replacement or two independently the replacement; Q is 0-3;
G) group of following formula:
R wherein
14And R
15Be hydrogen, (C independently
1-8) alkyl, (C
1-6) alkyl-carbonyl, (C
3-12) cycloalkyl ring, (C
3-12) cyclenes basic ring, phenmethyl, benzoyl, pyridine, pyrimidine, phenyl, phenyl amino-carbonyl, alkyl sulphonyl or benzenesulfonyl, wherein cycloalkyl ring is randomly used hydroxyl (C
1-6) alkyl replaces, and wherein phenmethyl, benzoyl, pyridine, pyrimidine, phenyl, phenyl amino-carbonyl, alkyl sulphonyl and benzenesulfonyl are randomly used R
12The single replacement or two independently the replacement; Perhaps R
14And R
15Form (C together
3-12) cycloalkyl ring; With r be 2-6;
H) group of following formula:
R wherein
16And R
17Be hydrogen, (C independently of one another
1-8) alkyl, (C
1-6) alkyl-carbonyl, two-(C
1-6) alkyl amino-carbonyl, phenmethyl, benzoyl, pyridine, pyrimidine, phenyl, phenyl amino carbonyl, alkyl sulphonyl or benzenesulfonyl, wherein phenmethyl, benzoyl, pyridine, pyrimidine, phenyl, phenyl amino carbonyl, alkyl sulphonyl and benzenesulfonyl are randomly used R
12The single replacement or two independently the replacement; Perhaps R
16And R
17Form (C together
3-12) cycloalkyl ring; With s be 1-6;
I) group of following formula:
R wherein
18And R
19Be hydrogen, (C independently
1-8) alkyl, (C
1-6) alkyl-carbonyl, two-(C
1-6) alkyl amino-carbonyl, phenmethyl, benzothiazole, benzoyl, pyridine, pyrimidine, phenyl, phenyl amino carbonyl, alkyl sulphonyl or benzenesulfonyl, wherein phenmethyl, benzoyl, benzothiazole, pyridine, pyrimidine, phenyl, phenyl amino carbonyl, alkyl sulphonyl and benzenesulfonyl are randomly used R
12The single replacement or two independently the replacement; Perhaps R
18And R
19Form (N, the C that contains nitrogen-atoms with N
3-12) heterocycloalkyl ring; Each t is 0-6 independently; With u be 0-3;
J) group of following formula:
(phenyl-CH
2-C (CH
3)
2-),
Wherein phenyl is randomly used R
12Single replacement or polysubstituted independently;
Or
K) group of following formula:
R wherein
21Be hydrogen, (C
1-8) alkyl, phenmethyl or phenyl, wherein phenmethyl and phenyl are randomly used R
12The single replacement or two independently replacement the on ring; Each t is 0-6 independently; U is 0-3; And
The key table that wherein contains wavy line shows binding site;
(dd) R
3, R
4And R
5Be hydrogen independently; alkyl; thiazolinyl; alkynyl; cycloalkyl; cycloalkylalkyl; bicyclic alkyl; tricyclic alkyl; alkyl-cycloalkyl; hydroxyalkyl; the hydroxyalkyl cycloalkyl; the hydroxyl cycloalkyl; the hydroxyl bicyclic alkyl; the hydroxyl tricyclic alkyl; the bicyclic alkyl alkyl; the alkyl bicyclic alkyl; alkyl-thio-alkyl; the arylalkyl alkylthio; cycloalkenyl group; aryl or aralkyl; all randomly with the single replacement of following groups or polysubstituted independently: halogen; alkyl; multi-haloalkyl; alkoxyl group; halogenated alkoxy; many halogenated alkoxies; carbalkoxy; thiazolinyl; alkynyl; cycloalkyl; cycloalkylalkyl; multi-ring alkyl; arylamino; hydroxyl; hydroxyalkyl; nitro; cyano group; amino; substituted-amino; alkylamino; dialkyl amido; thiol; alkylthio; alkyl-carbonyl; acyl group; carbalkoxy; aminocarboxyl; the alkynyl aminocarboxyl; alkyl amino-carbonyl; the alkenyl amino carbonyl; alkyl carbonyl oxy; alkyl-carbonyl-amino; aryl-amino-carbonyl; alkyl sulfonyl amino; alkyl amino-carbonyl-amino; alkoxycarbonyl amido; alkyl sulphonyl; amino sulfinyl; amino-sulfonyl; alkyl sulphinyl; sulfonamido or alkylsulfonyl; suppose that working as n is 1, X is CH
2, the ring that contains X is saturated, and Z, R
3And R
5When being H, R
4Be not the side chain of the alpha amino acid of nature existence, and suppose that working as n is 1, X is CH
2, the ring that contains X is saturated, and Z and R
5When being H, R
3And R
4It not all is methyl; Or
(ee) R
3Be hydrogen, R
4And R
5Form the 4-8 unit heterocycle of 3~7 carbon and 1 nitrogen with their institute's bonded atoms,
Wherein remove and N and R
4Heterocycle carbon atom outside the carbon that connects has formula-(CR
22R
23)
m-, wherein m is 2-6, R
22And R
23Be hydrogen, hydroxyl, alkoxyl group, alkyl, thiazolinyl, alkynyl, cycloalkyl, halogen, amino, substituted-amino, cycloalkylalkyl, cycloalkenyl group, aryl, aralkyl, heteroaryl, heteroarylalkyl, the assorted alkyl of ring, the assorted alkyl-alkyl of ring, alkyl-carbonyl-amino, aryl-amino-carbonyl, alkoxycarbonyl amido, aryloxy carbonyl amino, carbalkoxy, aryloxy carbonyl or alkyl amino-carbonyl amino independently; Randomly, described heterocycle have aryl, heteroaryl or with its condensed 3-7 unit cycloalkyl ring, suppose that working as n is 1, X is CH
2, the ring that contains X is saturated, and Z and R
3When being H, R
4And R
5Be not together-(CH
2)
2-or-(CH
2)
3-.
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