CN101565429A - Inhibitors of dipeptidylpeptidase iv - Google Patents
Inhibitors of dipeptidylpeptidase iv Download PDFInfo
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- CN101565429A CN101565429A CNA2009101341712A CN200910134171A CN101565429A CN 101565429 A CN101565429 A CN 101565429A CN A2009101341712 A CNA2009101341712 A CN A2009101341712A CN 200910134171 A CN200910134171 A CN 200910134171A CN 101565429 A CN101565429 A CN 101565429A
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Abstract
The present invention relates to inhibitors of post-proline cleaving enzymes, such as inhibitors of dipeptidyl peptidase IV, as well as pharmaceutical compositions thereof, and methods for using such inhibitors. In particular, the inhibitors of the present invention are improved over those in the prior art by selection of particular classes of sidechains in the P1 and/or P2 position of the inhibitor that contain a carboxylic acid moiety. The compounds of the present invention can have a better therapeutic index, owing in part to reduced toxicity and/or improved specificity for the targeted protease.
Description
The application is dividing an application of following application: the applying date: on February 23rd, 2005; Application number: 200580011588.X (PCT/US2005/006128); Denomination of invention: the same.
Related application
The sequence number that the application submitted on February 23rd, 1 is that the sequence number submitted in 60/547,227 U.S. Provisional Application and on August 6th, 2004 is the rights and interests of 60/599,336 U.S. Provisional Application.The clause of these applications all is attached to herein by reference.
Background of invention
Proteolytic enzyme is for being enzyme single, the specificity peptide bond with protein cleavage.Proteolytic enzyme generally can be divided into four classes: Serine, mercaptan or cysteinyl, acid or aspartoyl and metalloprotease (Cuypers et al., J.Biol.Chem.257:7086 (1982)).Proteolytic enzyme all is essential concerning many biological activitys, as the formation and the dissolving of digestion, clot, duplicate and to external cell and organic immune response.The paraprotein hydrolysis is with human relevant with other mammiferous numerous disease state.In many examples, in treatment, to handle in the process of animal, the function of destroying one or more proteolytic ferments is useful.
The binding site of the peptide substrates of being made up of a series of " specific sub sites " passes the surface of enzyme.Term " specific sub site " be meant can with the interactional bag of the part of enzyme substrates (pocket) or other site.When the interaction of peptide and proteolytic enzyme was discussed, as Serine and L-Cysteine HCL Anhydrous etc., the application had used Schechter and Berger[(1967) Biochem.Biophys.Res.Commun.27:157-162)] nomenclature.The carboxylic terminal residue that produces from scission reaction begins, and the individual amino acids residue of substrate or inhibitor is called as P1, P2 etc. and the corresponding sublocus of enzyme is called as S1, S2 etc.The key that substrate splits is the amido linkage between the substrate P1-P1 '.Therefore, concerning cracked peptide Xaa1-Xaa2-Xaa3-Xaa4 between Xaa3 and Xaa4 residue, the Xaa3 residue is designated as the P1 residue and links to each other with the S1 sublocus of enzyme, and Xaa2 is designated as the P2 residue and links to each other with the S2 sublocus, or the like.
For example, DPP IV (DPIV) is a serine protease, and preferably, its cracking comprises the N-end dipeptides of the peptide chain of proline residue as the P1 position in position, inferior end.DPIV belongs to the relevant peptase of cytolemma, and is II type integral protein as most cells surface peptase, is fixed in the endochylema film by its signal sequence.In many differentiated Mammals epitheliums, endothelium and hematopoiesis (hematopoetic) cell and tissue, comprise that specificity is present in CD4
+Found DPIV in the lymph source of T cell surface.DPIV is accredited as white corpuscle differentiation marker CD26.
The invention summary
One aspect of the present invention provides proteinase inhibitor or its pharmaceutically acceptable salt with formula I structure,
Formula I
Wherein:
R
1Expression H, alkyl, alkoxyl group, thiazolinyl, alkynyl, amino, alkylamino, acyl amino, cyano group, sulfuryl amino, acyloxy, aryl, cycloalkyl, heterocyclic radical, heteroaryl or have the polypeptide chain of 1-8 amino-acid residue;
R
2Expression H, low alkyl group or aralkyl;
R
3And R
4Independent expression H, halogen or alkyl, or R
3And R
4Form 3-to 6-unit heterocycle with the carbon that connects them;
R
5Expression H, halogen, low alkyl group or aralkyl, preferred H or low alkyl group;
R
6The avtive spot residue reaction of expression and targeting proteins enzyme forms the functional group of covalency adducts;
R
7Expression H, aryl, alkyl, aralkyl, cycloalkyl, heterocyclic radical, heteroaryl, heteroaralkyl or have the polypeptide chain of 1-8 amino-acid residue;
L does not exist or L represent alkyl, thiazolinyl, alkynyl ,-(CH
2)
mO (CH
2)
m-,-(CH
2)
mNR
2(CH
2)
m-and-(CH
2)
mS (CH
2)
m-;
X does not exist or X represents-N (R
7)-,-O-or-S-;
Y does not exist or Y represents-C (=O)-,-C (=S)-or-SO
2-;
Independently be the integer of 0-10 at every turn when m occurs, be preferably the integer of 1-3; And
N is the integer of 1-6.
In certain preferred aspects, R
1Expression H or low alkyl group, R
3Be H and R
4Be low alkyl group, or R
3And R
4Form 5-unit ring with the carbon that connects them, and n is 2.
In other some embodiment preferred, R
1Expression H or low alkyl group, R
3Expression H, R
4Expression H or low alkyl group, R
5Expression H, and n is 2.
Do not exist at X, in some embodiment preferred of Y and L, R
1For having the polypeptide chain of 2-8 amino-acid residue, wherein proline(Pro) is the residue that directly links to each other with formula I high order end residue.In specific so embodiment, R
1For having the polypeptide chain of 2 amino-acid residues, wherein proline(Pro) is the residue that directly is connected with formula I high order end nitrogen.
In the embodiment on some, R
6Expression boric acid (boronic acid), CN ,-SO
2Z
1,-P (=O) Z
1,-P (=R
8) R
9R
10,-C (=NH) NH
2,-CH=NR
11Or-C (=O)-R
11, wherein:
R
8Be O or S;
R
9Expression N
3, SH
2, NH
2, NO
2Or OLR
12, and
R
10Expression low alkyl group, amino, OLR
12Or its pharmaceutically acceptable salt, or
R
9And R
10Form 5-to 8-unit heterocycle with the phosphorus that connects them;
R
11Expression H, alkyl, thiazolinyl, alkynyl, NH
2,-(CH
2)
p-R
12,-(CH
2)
q-OH ,-(CH
2)
q-O-alkyl ,-(CH
2)
q-O-thiazolinyl ,-(CH
2)
q-O-alkynyl ,-(CH
2)
q-O-(CH
2)
p-R
12,-(CH
2)
q-SH ,-(CH
2)
Q-The S-alkyl ,-(CH
2)
q-S-thiazolinyl ,-(CH
2)
q-S-alkynyl ,-(CH
2)
q-S-(CH
2)
p-R
12,-C (O) NH
2,-C (O) OR
13Or-C (Z
1) (Z
2) (Z
3);
R
12Expression H, alkyl, thiazolinyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl group or heterocyclic radical;
R
13Expression H, alkyl, thiazolinyl or LR
12
Z
1The expression halogen;
Z
2And Z
3Independent expression H or halogen;
When occurring at every turn, p independently is the integer of 0-8; And
When occurring at every turn, q independently is the integer of 1-8.
In certain preferred aspects, R
6Expression CN, CHO or C (=O) C (ZI) (Z
2) (Z
3), Z wherein
1Expression halogen, and Z
2And Z
3Expression H or halogen.In another embodiment, R
6Expression C (=O) C (Z
1) (Z
2) (Z
3), Z wherein
1Expression fluorine, and Z
2And Z
3Expression H or fluorine.
In certain preferred aspects, R
6Expression-B (Y
1) (Y
2) group, Y wherein
1And Y
2Independent be the group (promptly forming boric acid) of OH or form 5-to the 8-unit ring that hydrolyzable is a boric acid for OH or hydrolyzable with the boron atom that connects them.
Another aspect of the present invention relates to proteinase inhibitor or its pharmaceutically acceptable salt with formula II structure,
Formula II
Wherein:
R
1Expression H, alkyl, alkoxyl group, thiazolinyl, alkynyl, amino, alkylamino, acyl amino, cyano group, sulfuryl amino, acyloxy, aryl, cycloalkyl, heterocyclic radical, heteroaryl or have the polypeptide chain of 1-8 amino-acid residue;
R
2Expression H, low alkyl group or aralkyl;
R
3And R
4Independent expression H, halogen or alkyl, or R
3And R
4Form 3-to 6-unit heterocycle with the carbon that connects them;
R
5Expression H, halogen, low alkyl group or aralkyl, preferred H or low alkyl group;
R
6The avtive spot residue reaction of expression and targeting proteins enzyme forms the functional group of covalency adducts;
R
7The polypeptide chain of expression H, aryl, alkyl, aralkyl, cycloalkyl, heterocyclic radical, heteroaryl, heteroaralkyl or 1-8 amino-acid residue;
R
14Expression H, alkyl, alkoxyl group, thiazolinyl, alkynyl or the preferred H of aralkyl;
A does not exist or A represents-NHC (=NH)-, or R
14Form heterocycle with A with the nitrogen that is connected them;
L does not exist or L represent alkyl, thiazolinyl, alkynyl ,-(CH
2)
mO (CH
2)
m-,-(CH
2)
mNR
2(CH
2)
m-or-(CH
2)
mS (CH
2)
m-;
X does not exist or X represents-N (R
7)-,-O-or-S-;
Y does not exist or Y represents-C (=O)-,-C (=S)-or-SO
2-;
When occurring at every turn, m independently is the integer of 0-10; And
N is the integer of 1-6.
In certain preferred aspects, R
1Expression H or low alkyl group, R
3Be H and R
4Be low alkyl group, or R
3And R
4Form 5-unit ring with the carbon that connects them, and n is the integer of 1-4.
In other some embodiment preferred, R
1Expression H or low alkyl group, R
3Expression H, R
4Expression H or low alkyl group, R
5Expression H, and n is the integer of 1-4.
Therein in non-existent some embodiment preferred of X, Y and L, R
1For having the polypeptide chain of 2-8 amino-acid residue, wherein proline(Pro) is the residue that directly links to each other with formula II high order end residue.At some so in the embodiment, R
1For having the polypeptide chain of 2 amino-acid residues, wherein proline(Pro) is the residue that directly links to each other with formula II high order end nitrogen.
In certain embodiments, R
14Be H or alkyl.In some this class embodiment, A do not exist or A for-NHC (=NH)-.
In certain preferred aspects, R
14Be H, A does not exist, and n is 4.In other some embodiment, R
14Being H, A is-NHC (=NH)-, and n is 3.
In certain preferred aspects, A and R
14Form imidazole ring with the nitrogen that connects them, and n is 1.
In certain embodiments, R
6Expression boric acid ,-CN ,-SO
2Z
1,-P (=O) Z
1,-P (=R
8) R
9R
10,-C (=NH) NH
2,-CH=NR
11Or-C (=O)-R
11, wherein:
R
8Be O or S;
R
9Expression N
3, SH
2, NH
2, NO
2Or OLR
12, and
R
10Expression low alkyl group, amino, OLR
12Or its pharmaceutically acceptable salt, or
R
9And R
10Form 5-to 8-unit heterocycle with the phosphorus that connects them;
R
11Expression H, alkyl, thiazolinyl, alkynyl ,-NH
2,-(CH
2)
p-R
12,-(CH
2)
q-OH ,-(CH
2)
q-O-alkyl ,-(CH
2)
q-O-thiazolinyl ,-(CH
2)
q-O-alkynyl ,-(CH
2)
q-O-(CH
2)
p-R
12,-(CH
2)
q-SH ,-(CH
2)
q-S-alkyl ,-(CH
2)
q-S-thiazolinyl ,-(CH
2)
q-S-alkynyl ,-(CH
2)
q-S-(CH
2)
p-R
12,-C (O) NH
2,-C (O) OR
13Or-C (Z
1) (Z
2) (Z
3);
R
12Expression H, alkyl, thiazolinyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl group or heterocyclic radical;
R
13Expression H, alkyl, thiazolinyl or LR
12
Z
1The expression halogen;
Z
2And Z
3Independent expression H or halogen;
When occurring at every turn, p independently is the integer of 0-8; And
When occurring at every turn, q independently is the integer of 1-8.
In certain preferred aspects, R
6Expression CN, CHO or C (=O) C (Z1) (Z
2) (Z
3), Z wherein
1Expression halogen, and Z
2And Z
3Expression H or halogen.In another embodiment, R
6Expression C (=O) C (Z
1) (Z
2) (Z
3), Z wherein
1Expression fluorine, and Z
2And Z
3Expression H or fluorine.
In certain preferred aspects, R
6Expression-B (Y
1) (Y
2) group, Y wherein
1And Y
2Independent is that OH or hydrolyzable are the group of OH, or forms 5-to the 8-unit ring that hydrolyzable is a boric acid with the boron atom that connects them.
Another aspect of the present invention relates to proteinase inhibitor or its pharmaceutically acceptable salt of formula III,
Formula III
Wherein:
R
1Expression H, alkyl, alkoxyl group, thiazolinyl, alkynyl, amino, alkylamino, acyl amino, cyano group, sulfuryl amino, acyloxy, aryl, cycloalkyl, heterocyclic radical, heteroaryl or have the polypeptide chain of 1-8 amino-acid residue;
R
2Expression H, low alkyl group or aralkyl;
R
3And R
4Independent expression H, halogen or alkyl or R
3And R
4Form 3-to 6-unit heterocycle with the carbon that connects them;
R
5Expression H, halogen, low alkyl group or aralkyl, preferred H or low alkyl group;
R
6The avtive spot residue reaction of expression and targeting proteins enzyme forms the functional group of covalency adducts;
R
7Expression H, aryl, alkyl, aralkyl, cycloalkyl, heterocyclic radical, heteroaryl, heteroaralkyl or have the polypeptide chain of 1-8 amino-acid residue;
R
15For have the functional group of positive charge or negative charge, preferred amines or carboxylic acid in physiological pH;
L does not exist or L represent alkyl, thiazolinyl, alkynyl ,-(CH
2)
mO (CH
2)
m-,-(CH
2)
mNR
2(CH
2)
m-and-(CH
2)
mS (CH
2)
m-;
X does not exist or X represents-N (R
7)-,-O-or-S-;
Y does not exist or Y represents-C (=O)-,-C (=S)-or-SO
2-;
When occurring at every turn, m independently is the integer of 0-10; And
N is the integer of 1-6.
In certain preferred aspects, R
1Expression H or low alkyl group, R
3Be H and R
4Be low alkyl group, or R
3And R
4Form 5-unit ring with the carbon that connects them, and n is the integer of 1-4.
In other some embodiment preferred, R
1Expression H or low alkyl group, R
3Expression H, R
4Expression H or low alkyl group, R
5Expression H, and n is the integer of 1-4.
Therein in non-existent some embodiment preferred of X, Y and L, R
1For having the polypeptide chain of 2-8 amino-acid residue, wherein proline(Pro) is the residue that directly links to each other with formula II high order end residue.At some so in the embodiment, R
1For having the polypeptide chain of 2 amino-acid residues, wherein proline(Pro) is the residue that directly links to each other with formula II high order end nitrogen.
In certain preferred aspects, n is integer and the R of 1-4
15For have the functional group of positive charge or negative charge in physiological pH.In a more preferred embodiment, n is integer and the R of 1-4
15Be selected from amine, carboxylic acid, imidazoles and guanidine functional group.
In certain embodiments, R
6Expression boric acid ,-CN ,-SO
2Z
1,-P (=O) Z
1,-P (=R
8) R
9R
10,-C (=NH) NH
2,-CH=NR
11Or-C (=O)-R
11, wherein:
R
8Be O or S;
R
9Expression N
3, SH
2, NH
2, NO
2Or OLR
12, and
R
10Expression low alkyl group, amino, OLR
12Or its pharmaceutically acceptable salt, or
R
9And R
10Form 5-to 8-unit heterocycle with the phosphorus that connects them;
R
11Expression H, alkyl, thiazolinyl, alkynyl, NH
2,-(CH
2)
p-R
12,-(CH
2)
q-OH ,-(CH
2)
q-O-alkyl ,-(CH
2)
q-O-thiazolinyl ,-(CH
2)
q-O-alkynyl ,-(CH
2)
q-O-(CH
2)
p-R
12,-(CH
2)
q-SH ,-(CH
2)
q-S-alkyl ,-(CH
2)
q-S-thiazolinyl ,-(CH
2)
q-S-alkynyl ,-(CH
2)
q-S-(CH
2)
p-R
12,-C (O) NH
2,-C (O) OR
13Or-C (Z
1) (Z
2) (Z
3);
R
12Expression H, alkyl, thiazolinyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl group or heterocyclic radical;
R
13Expression H, alkyl, thiazolinyl or LR
12
Z
1The expression halogen;
Z
2And Z
3Independent expression H or halogen;
When occurring at every turn, p independently is the integer of 0-8; And
When occurring at every turn, q independently is the integer of 1-8.
In certain preferred aspects, R
6Expression CN, CHO or C (=O) C (Z
1) (Z
2) (Z
3), Z wherein
1The expression halogen, Z
2And Z
3Expression H or halogen.In another embodiment, R
6Expression C (=O) C (ZI) (Z
2) (Z
3), Z wherein
1The expression fluorine, Z
2And Z
3Expression H or fluorine.
In certain preferred aspects, R
6Expression-B (Y
1) (Y
2) group, Y wherein
1And Y
2Independent is that OH or hydrolyzable are the group of OH, or forms 5-to the 8-unit ring that hydrolyzable is a boric acid with the boron atom that connects them.
Proteinase inhibitor or its pharmaceutically acceptable salt that relate on the other hand more of the present invention with formula IV structure,
Formula IV
Wherein:
A is selected from the 4-8 unit heterocycle that comprises N and C α carbon;
Z is C or N;
W be selected from CN ,-CH=NR
5, with the functional group of targeting proteins enzyme active sites residue reaction,
R
1Be selected from peptide that amino-acid residue that C-end connects or amino acid analogue, C-end connect or peptide analogs, amino-blocking group,
R
2The substituting group of representing one or more A ring, each independently be selected from halogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, lower alkoxy, rudimentary hydroxyalkyl, low-grade alkoxy alkyl, carbonyl, thiocarbonyl, amino, acyl amino (acylamino), amido (amido), cyano group, nitro, azido-, sulfate group (sulfate), sulfonate group (sulfonate), sulfonamido (sulfonamido) ,-(CH
2)
m-R
7,-(CH
2)
m-OH ,-(CH
2)
m-O-low alkyl group ,-(CH
2)
m-O-low-grade alkenyl ,-(CH
2)
n-O-(CH
2)
m-R
7,-(CH
2)
m-SH ,-(CH
2)
m-S-low alkyl group ,-(CH
2)
m-S-low-grade alkenyl or-(CH
2)
n-S-(CH
2)
m-R
7, at least one R wherein
2Be selected from-OH, low alkyl group, lower alkoxy, rudimentary hydroxyalkyl and low-grade alkoxy alkyl, preferably at least one is low alkyl group (as methyl), lower alkoxy, rudimentary hydroxyalkyl (as methylol) and low-grade alkoxy alkyl;
Wherein Z is N, R
3Be hydrogen;
When Z is C, R
3Be selected from hydrogen, halogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, carbonyl, thiocarbonyl, amino, acyl amino, amido, cyano group, nitro, azido-, sulfate group, sulfonate group, sulfonamido ,-(CH
2)
m-R
7,-(CH
2)
m-OH ,-(CH
2)
m-O-low alkyl group ,-(CH
2)
m-O-low-grade alkenyl ,-(CH
2)
n-O-(CH
2)
m-R
7,-(CH
2)
m-SH ,-(CH
2)
m-S-low alkyl group ,-(CH
2)
m-S-low-grade alkenyl and-(CH
2)
n-S-(CH
2)
m-R
7
R
5Be selected from hydrogen, alkyl, thiazolinyl, alkynyl ,-C (X
1) (X
2) X
3,-(CH
2)
m-R
7,-(CH
2)
n-OH ,-(CH
2)
n-O-alkyl ,-(CH
2)
n-O-thiazolinyl ,-(CH
2)
n-O-alkynyl ,-(CH
2)
n-O-(CH
2)
m-R
7,-(CH
2)
n-SH ,-(CH
2)
n-S-alkyl ,-(CH
2)
n-S-thiazolinyl ,-(CH
2)
n-S-alkynyl ,-(CH
2)
n-S-(CH
2)
m-R
7,-C (O) C (O) NH
2With-C (O) C (O) OR
7';
R
6Be selected from hydrogen, halogen, alkyl, thiazolinyl, alkynyl, aryl ,-(CH
2)
m-R
7,-(CH
2)
m-OH ,-(CH
2)
m-O-alkyl ,-(CH
2)
m-O-thiazolinyl ,-(CH
2)
m-O-alkynyl ,-(CH
2)
m-O-(CH
2)
m-R
7,-(CH
2)
m-SH ,-(CH
2)
m-S-alkyl ,-(CH
2)
m-S-thiazolinyl ,-(CH
2)
m-S-alkynyl or-(CH
2)
m-S-(CH
2)
m-R
7,
Each R
7Independently be selected from aryl, aralkyl, cycloalkyl, cycloalkenyl group and heterocyclic radical;
Each R
7' independently be selected from hydrogen, alkyl, thiazolinyl, aryl, aralkyl, cycloalkyl, cycloalkenyl group and heterocyclic radical;
R
8And R
9Independently be selected from hydrogen, alkyl, thiazolinyl ,-(CH
2)
m-R
7,-C (=O)-alkyl ,-C (=O)-thiazolinyl ,-C (=O)-alkynyl and-C (=O)-(CH
2)
m-R
7Or
R
8And R
9Form the heterocycle that has 4-8 atom on the ring structure with the N atom that connects them;
R
50Be O or S;
R
51Be selected from N
3, SH, NH
2, NO
2And OR
7';
R
52Be selected from hydrogen, low alkyl group, amine or OR
7', or its pharmaceutically acceptable salt, or
R
51And R
52Form the heterocycle that has 5-8 atom on the ring structure with the P atom that connects them;
X
1Be halogen;
X
2And X
3Be selected from hydrogen and halogen separately;
Y
1And Y
2Independently be selected from the group that OH and hydrolyzable are OH, comprise wherein Y
1And Y
2By the continuous cyclic derivatives of ring that has 5-8 atom on the ring structure;
M be 0 or the 1-8 scope in integer; With
N is the integer in the 1-8 scope.
In above-mentioned some embodiment, proteinase inhibitor suppresses tool 50nm or lower K
iDPIV.
In certain embodiments, described inhibitor is oral effectively.
In certain embodiments, described inhibitor is at least 2 to the mankind's therapeutic index, in addition more preferably 5,10 or even 100, as regulating the therapeutic index of glucose metabolism.
Another aspect of the present invention provides and has comprised the medicinal compositions that pharmaceutical acceptable carrier and one or more topics are stated proteinase inhibitor or its pharmaceutically acceptable salt or its prodrug.
Another aspect of the present invention provides one or more topics to state purposes in inhibitor suppresses postproline cleavage enzyme in producing body the medicine.The medicine of the plasma concentration of the peptide hormone after for example, topic is stated inhibitor and be can be used for produce increasing one or more and handled by postproline cleavage enzyme (as DP-IV etc.).The medicine of example can be used for increasing the plasma concentration as this parahormones such as glucagon-like peptide, NPY, PPY, secretin, GLP-1, GLP-2 and GIP.
In certain preferred aspects, topic is stated inhibitor and be can be used for producing the medicine of regulating glucose metabolism, as is used for the treatment of the patient who suffers from type ii diabetes, insulin resistant, glucose intolerance, hyperglycemia, hypoglycemia, hyperinsulinemia, obesity, hyperlipidaemia or high ester gp mass formed by blood stasis.
The medicine that the packing that comprises following substances is provided on the other hand again of the present invention: one or more topics are stated the preparation of proteinase inhibitor; Optional pharmaceutical acceptable carrier; With the specification sheets of literal and/or graphic form, describe the purposes that suppresses postproline cleavage enzyme in the said preparation body, as be used to regulate glucose metabolism.
Described medicine through packing also can comprise as with proteinase inhibitor preparation formulated together or just and proteinase inhibitor, Regular Insulin and/or pancreotropic hormone drug packages preparation together.
Described medicine through packing also can comprise as the preparation formulated together with proteinase inhibitor, or just with proteinase inhibitor, M1 receptor antagonist, prolactin inhibitor, act on medicine, N1,N1-Dimethylbiguanide and/or the glucosidase inhibitor preparation packaging together of the ATP-dependency potassium channel of P-cell.
The invention still further relates to the treatment plan that gives based on short-term, reduce or alleviate the improved method of at least a aforementioned diseases for a long time.
The present invention also provides to serve as for a long time the basis adjusting and to change the method that comprises human vertebrate glucose and steatogenesis reaction.
Especially, compound of the present invention can be used for providing the method that following one or more situations is produced long lasting useful variation: therefore species provide diabetes, obesity and/or atherosclerotic effective methods of treatment susceptibility (reduction insulin resistant), blood insulin level, hyperinsulinemia, blood glucose levels, body fat storage capacity and the blood lipoprotein levels of the cell response of Regular Insulin.
The accompanying drawing summary
Fig. 1 has shown in 120 minutes in the restraining effect of three kinds of different dosage Lys-boroPro to DPIV.
Fig. 2 has shown in 120 minutes in the restraining effect of three kinds of different dosage Arg-boroPro to DPIV.
Detailed Description Of The Invention
I. general introduction
The present invention relates to postproline cleavage enzyme (PPCE) inhibitor, such as inhibitors of dipeptidyl IV, and the method for Pharmaceutical composition and this inhibitor of use. The prototype of these molecules has an acidic amino acid and with the electrophilic site of multiple side chain.
The significant feature of the compounds of this invention comprises: therapeutic index preferably, and part improves owing to its less toxicity and/or to the targeting proteins enzyme spcificity; Oral validity preferably; Shelf life prolongs; And/or acting duration prolongs (can keep such as single peroral dosage form effective more than 4 hours, even above 8,12 or 16 hours).
Compound of the present invention can be used as the part of the methods for the treatment of of numerous disease/illness, such as the disease/illness by the DPIV mediation. For example, topic is stated inhibitor and be can be used for raising GIP and GLP-1 activity, such as the half-life by those hormones of growth, part as the methods for the treatment of of regulating glucose level and/or metabolism, as reduce insulin resistance, treatment hyperglycemia, hyperinsulinemia, obesity, hyperlipidemia, hyperlipoprotememia (such as chylomicron, VLDL and LDL) and control agent fat more are commonly regulates the lipid storage, more generally be used for improving dysbolism, the particularly dysbolism relevant with diabetes, obesity and/or atherosclerotic.
Do not wish that by specific theory the compound that suppresses according to observations DPIV can be correlated with and be improved glucose-tolerant, although be not inevitable in the mechanism that relates to DPIV inhibition itself. In fact, similarly compound exhibits goes out the validity to the mouse that lacks the GLP-1 acceptor, shows that topic states method and might not comprise the mechanism of action that directly involves GLP-1 itself, although can not get rid of GLP-1 other acceptor may be arranged. But, consider relevantly with the DPIV inhibitory action, in preferred embodiments, topic is stated the medicine that method uses and is had 50.0nm or lower KiThe DPIV inhibitory action, more preferably 10.0 or lower, even more preferably 1.0,0.1 or even 0.01nM or lower. In fact, should consider K at the inhibitor of pmol even femto molar rangeiValue. Therefore, for simplicity, when this paper described active medicine, such as " DPIV inhibitor ", should understand this nomenclature was not in order to limit the present invention in the specific mechanism of action.
Some titled reference compound has long active duration. Correspondingly, in certain preferred aspects, after taking single dose, the amount of inhibitor can provide and suppress at least blood-serum P PCE (such as DPIV) level at least 50% in 4 hours in selected inhibitor and the prescription, even more preferably took behind the single dose at least 8 hours or even 12 or 16 hours.
For example, described method relates to the administration of DPIV inhibitor in certain embodiments, preferred predetermined time during 24 hours is to improve the effective dose administration of one or more abnormal indexs relevant with impaired glucose metabolism (such as GI, insulin resistance, hyperglycemia, hyperinsulinemia and I type and type ii diabetes).
In other embodiments, described method relates to the DPIV inhibitor to improve the effective dose administration of the abnormal index relevant with obesity. Adipocyte releasing hormone leptin, it is being transported to brain by blood, stimulates there the generation of GLP-1 by leptin receptor. GLP-1 produces satiety successively. Leading theory is that most overweight people's adipocyte may produce enough leptins, but leptin possibly can't normally make the leptin receptor work in the brain, thus the generation that can't stimulate GLP-1. Have a large amount of about using the GLP-1 preparation as the research of appetite inhibitor. Topic is stated the method for half-life that method provides the GLP-1 of the diseases related middle increase endogenous for the treatment of of obesity or exogenous adding.
Generally speaking, the invention provides the method and composition that changes the pharmacokinetics of multiple different polypeptide hormones by the proteolysis of one or more peptide hormones of suppressing to be caused by DPIV or other proteolytic activity. Metabolism is for regulating the key factor in the whole Equilibrium of peptide after the secretion, and other enzyme that relates in these processes can be according to topic and states the suitable target that pharmacology that method carries out is got involved.
For example, topic is stated the peptide that method can be used for increasing other proglucagon-derive, such as enteroglucagon (corresponding with PG 1-69), oxyntomodulin (PG 33-69), the relevant pancreatic polypeptide (GRPP of enteroglucagon, PG 1-30), get involved peptide (intervening peptide-2) (IP-2, PG 111-122 acid amides) and the half-life of glucagon-like peptide (glucagon-like peptide)-2 (GLP-2, PG 126-158).
For example, GLP-2 is by the key factor of conclusive evidence for inducing enteric epithelium to breed. As referring to (1996) PNAS 93:7911 such as Drucker. Topic is stated the part that method can be used as the damage for the treatment of intestinal tissue, inflammation or resection, as wherein needing to strengthen the growth of epithelium of intestinal mucosa and the treatment of reparation, as in treatment Crohn ' s disease or inflammatory bowel disease (IBD).
DPIV is also relevant with metabolism and the deactivation of somatotropin releasing factor (GHRF). GHRF is the member who comprises the homeopeptide class family of glucagons, secretin, vasoactive intestinal peptide (VIP), group different bright peptide (PHI), PACAP (PACAP), Gastric inhibitory polypeptide (GIP) and helodermin (Kubiak et al. (1994) Peptide Res 7:153). GHRF is secreted by hypothalamus, and stimulating growth hormone (GH) is the release of hypophysis in the past. Therefore, topic is stated method and be can be used for improving clinical treatment to some GHD children, and the adult is improved nutrition and changes the clinical treatment that health forms (muscle is to fat). Topic state method also can be used for for animals, as, the exploitation dairy produce of high yield and the lean meat poultry of high yield.
Equally, DPIV inhibitor of the present invention can be used for changing the plasma half-life of secretin, VIP, PHI, PACAP, GIP and/or helodermin. In addition, topic is stated the pharmacokinetics that method can be used for changing PYY and neuropeptide tyrosine, and PYY and neuropeptide tyrosine all are the members of pancreatic polypeptide family, and it is relevant that DPIV is considered to change with those peptides the process of mode of receptor-selectives.
In other embodiments, topic is stated inhibitor and be can be used for stimulating haemocyte to generate.
In other embodiments again, topic is stated growth or the vascularization that inhibitor can be used for suppressing mutant/tissue, as suppressing the cell proliferation relevant with growth and metastasis of tumours and the blood vessel generation of inhibition abnormality proliferation cell mass.
In other embodiments again, topic is stated inhibitor and be can be used for reducing immune response, as immunodepressant.
In other again embodiment, DPIV inhibitor of the present invention can be used for treating the CNS disease, such as apoplexy, tumour, ischaemic, Parkinson's, the loss of memory, anakusis, visual deprivation, antimigraine, brain damage, spinal cord injury, Alzheimer ' s disease and amyotrophic lateral sclerosis (having the CNS composition). In addition, the DPIV inhibitor can be used for treating the disease with more periphery character, comprises multiple sclerosis and diabetic neuropathy.
Another aspect of the present invention relates to Pharmaceutical composition, particularly DPIV inhibitor and their purposes in treating and/or preventing the disease that can improve by change peptide hormone Equilibrium thereof that topic is stated the postproline cleavage enzyme inhibitor. In preferred embodiments, described inhibitor has hypoglycemic and anti-diabetic activity, can be used for the illness for the treatment of take abnormal glucose metabolism (comprising storage) as feature. In special embodiment, the composition that topic is stated method can effectively be used as the pancreotropic hormone medicine or make the medicine of bringing into play the pancreotropic hormone effect such as the molecule of GLP-1. In this respect, some embodiment of the present composition can be used for treating and/or preventing various diseases, comprises following one or more: hyperlipidemia, hyperglycemia, obesity, GI, insulin resistance and diabetic complications.
Generally speaking, the inhibitor that topic is stated method is little molecule, as has the molecular weight less than 7500amu, preferably less than 5000amu, even is more preferably less than 2000 or even less than 1000 amu. In preferred embodiments, described inhibitor is oral effectively.
II. definition
Term " high affinity " refers to dissociation constant KDBe no more than the intermolecular strong affinity of 1 μ M. In the preferred embodiment, KDBe no more than 100nM, 10nM, 1nM, 100pM or even 10pM or lower. In the most preferred embodiment, two molecules can be covalently bound (KDBe essentially 0).
Term " boro-Ala " refers to that hydroxy-acid group (COOH) is by boric acid one acyl group (boronyl) group (B (OH)2) the alanine analog that replaces. Equally, term " boro-Pro " refers to that hydroxy-acid group (COOH) is by boric acid one carboxyl groups (B (OH)2) proline analogs that replaces. More at large, " boro-Xaa ", wherein Xaa is amino acid residue, refers to that hydroxy-acid group (COOH) is by group (B (OH)2) amino acid analogue that replaces.
Stating " patient " or " experimenter " that method is treated with topic can be the mankind or non-human main body.
Term " ED50" drug dose that refers to provide the physiology indication that makes 50% patient that clinical relevant improvement or variation occur is such as reducing etc. of the increase of glucose response, packed cell volume, gross tumor volume.
Term " IC50" refer to suppress 50% bioactive drug dose, as suppressing the amount of the required inhibitor of at least 50% DPIV (or other PPCE) activity in vivo.
Maybe can cause the stimulation that makes insulin synthesis or expression if a kind of compound can stimulate insulin synthesis or express, then it is called as and has " insulinotropic activity ".
Term " interaction " refers to comprise all Molecular interactions (such as biochemical, chemical or biophysical interaction), such as protein-protein, protein-nucleic acid, nucleic acid-nucleic acid, albumen-little molecule, nucleic acid-little molecule or little molecule-little Molecular interaction.
Term " LD50" be the drug dose of instigating 50% experimenter's death.
Term " prevention or therapeutic " is treated to generally acknowledges in the field, comprises that giving one or more topics of host states composition. If administration before not wishing symptom (such as disease or other undesirable state of host animal) clinical manifestation; then this is treated to prevention (being that its protection host defense is not wished the development of symptom); if do not wish administration after the symptom clinical manifestation, then this is treated to treatment (being that it is in order to reduce, alleviate or stablize present do not wish symptom or its side effect).
Term " prevention " is to generally acknowledge in the field, when being used for related symptoms, such as local recurrence (such as pain), such as the disease of cancer, such as complicated syndrome or other medical symptom of heart failure, be fine understanding in the art, comprise giving to reduce patient medical symptom frequency of disease development or delay the composition that symptom occurs with respect to the patient who does not accept composition. Therefore, the prevention of cancer comprises, for example, with respect to untreated control population, reduce to accept to detect the quantity of cancerous growths thing in the preventative-therapeutic patient colony and/or with respect to untreated control population, delay to detect in the patients receiving treatment colony appearance of cancerous growths thing, as give effective dose statistically or clinically. The prevention of inflammation comprises, as with respect to untreated control population, reduces the diagnosis number of times of inflammation in the colony that receives treatment, and/or with respect to untreated control population, the generation of inflammatory symptom in the colony that delays to receive treatment. The prevention of pain comprises, as with respect to untreated control population, reduces the pain degree of patient in the colony that receives treatment or delays the generation of patient's pain sensation.
Term " therapeutic index " refers to be defined as LD50/ED
50The drug therapy index.
The topic about treatment of compound such as DPIV inhibitor of the present invention is stated the amount that method " treatment effective dose " refers to compound in the preparation, when its a part of administration (animal as the therapeutic scheme required dosage, preferred human) time, clinical acceptable standard or cosmetic purpose according to treatment disease or illness, but mitigation symptoms, improve illness or delay the generation of illness, as to be applicable to approve the rational interests/risk-ratio of therapeutic treatment.
" single oral formulations dosage " is not less than EC for providing to produce50But be not higher than LD50The dosage of medication amount of drug serum concentration. Another method of weighing single oral formulations dosage is not less than IC at least for providing to be enough to produce50But be not higher than LD50The dosage of medication amount of drug serum concentration. In two kinds of balancing methods, single oral formulations dosage is preferably and can produces at least less than LD 5010% drug serum concentration, even more preferably at least less than medicine LD5050%, 75% or even 90%.
Aliphatic chain comprises alkyl, thiazolinyl and the alkynyl that defines below. The aliphatic straight chain is limited to the carbochain part of non-side chain. Term used herein " aliphatic group " refers to straight chain, side chain or ring-shaped fat hydro carbons group, comprises saturated and undersaturated aliphatic group, such as alkyl, alkenyl or alkynyl.
If alkyl refers to have the carbon number of appointment or be to be no more than the complete saturated side chain of 30 carbon atoms or the carbochain part of non-side chain when not specifying. For example, the alkyl of 1-8 carbon atom refers to such as methyl, ethyl, propyl group, butyl, amyl group, hexyl, heptyl and octyl group part, and the position isomer of these parts. The alkyl of 10-30 carbon atom comprises decyl, undecyl, dodecyl, tridecyl, myristyl, pentadecyl, cetyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl and tetracosyl. In preferred embodiments, the straight or branched alkyl has 30 or still less carbon atom (such as, C at its main chain1-C
30Straight chain, C3-C
30Side chain), more preferably 20 or carbon atom still less. Equally, preferred cycloalkyl has 3-10 carbon atom at its ring structure, more preferably has 5,6 or 7 carbon atoms at its ring structure.
In addition, the term that uses in whole specification, embodiment and claim " alkyl " (or " low alkyl group ") comprises " unsubstituted alkyl " and " substituted alkyl ", and the latter refers to have the substituent moieties that replaces the hydrogen on one or more hydrocarbon backbone c atoms. This substituting group can comprise; as, halogen, hydroxyl, carbonyl (such as carboxyl, alkoxy carbonyl, formoxyl or acyl group), thiocarbonyl (such as thioesters, thiacetate or thiocarboxylic), alkoxyl, phosphoryl, phosphate, phosphonate ester, phosphinate (phosphinate), amino, acylamino-, amidine (amidine), cyano group, nitro, sulfydryl, alkylthio group, sulfate group, sulfonate group, sulfamoyl, sulfonamido, sulfonyl, heterocyclic radical, aralkyl or aromatic series or heteroaromatic part. Should be appreciated that for those of skill in the art in this area, if suitable, can partly replace the substituting group on the hydrocarbon chain voluntarily. For example; the substituting group of substituted alkyl can comprise the replacement of following radicals and not replace form: amino, azido, imido grpup, amide groups, phosphoryl (comprising phosphonate ester and phosphinate), sulfonyl (comprising sulfuric ester, sulfonamido, sulfamoyl and sulphonic acid ester) and silicyl, and ethers (ethers), alkylthio group, carbonyl (comprising ketone, aldehyde, carboxylate and ester class) ,-CF3,-CN etc. The example of substituted alkyl is as described below. Cycloalkyl also can by the alkyl of alkyl, thiazolinyl, alkoxyl, alkylthio group, aminoalkyl, carbonyl-replacement ,-CF3,-the replacements such as CN.
The number of carbon atom unless otherwise, otherwise " low alkyl group " used herein refers to aforesaid alkyl, but on its backbone structure, only have 1-10 carbon atom, more preferably 1-6 carbon atom is such as methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, sec-butyl and the tert-butyl group. Equally, " low-grade alkenyl " and " low-grade alkynyl " has similar chain length. In whole application, preferred alkyl is low alkyl group. In preferred embodiments, the alkyl substituent of this paper appointment is low alkyl group.
Term " alkylthio group " refers to be connected with the aforesaid alkyl of sulphur part. In preferred embodiments, " alkylthio group " part represents a kind of of following radicals :-(S)-alkyl ,-(S)-thiazolinyl ,-(S)-alkynyl and-(S)-(CH2)
m-R
1, wherein m and R1Such as following definition. Representational alkylthio group comprises methyl mercapto, ethylmercapto group etc.
If thiazolinyl refers to have when specifying the carbon number purpose or not limiting carbon atom number, be no more than any side chain of 26 carbon atoms or the unsaturated carbon chain part of non-side chain; And in part, have one or more pairs of keys. The example of the thiazolinyl of 6-26 carbon atom has hexenyl, heptenyl, octenyl, nonene base, decene base, undecenyl, dodecenyl succinic, tridecylene base, tetradecene base, 15 carbene bases, hexadecene base, heptadecene base, vaccenic acid base, 19 carbene bases, eicosylene base, heneicosene base, two dodecenyl succinic, tricosene base, tetracosa carbon thiazolinyl, can be various isomeric forms, wherein unsaturated bond can be in the approval position of part, and can be with respect to (Z) of two keys or (E) configuration.
Alkynyl refers to the hydrocarbon part in the thiazolinyl scope, but has one or more triple bonds in part.
Term " alkoxyl " refers to have the alkyl such as following definition of oxygen part. Representational alkoxyl comprises methoxyl group, ethyoxyl, propoxyl group, tert-butoxy etc. " ether " is that two hydrocarbon are covalently bound by oxygen. Therefore, the substituting group that makes alkyl become this alkyl of ether is or is similar to alkoxyl, for example can represent with one of following radicals :-O-alkyl ,-the O-thiazolinyl ,-the O-alkynyl ,-O-(CH2)
m-R
1, wherein m and R1Such as following definition.
Term " amine " and " amino " they are what generally acknowledge in the field, refer to the amine that do not replace and replace, such as the part that can be represented by following general formula:
R wherein3、R
5And R6Separately independent expression hydrogen, alkyl, thiazolinyl ,-(CH2)
m-R
1, or R3And R5Form the heterocycle that has 4-8 atom on the ring structure with the N atom that connects them; R1Expression thiazolinyl, aryl, cycloalkyl, cycloalkenyl group, heterocyclic radical or many cyclic groups (polycyclyl); And m be 0 or the 1-8 scope in integer. In preferred embodiments, R3Or R5Only have one to can be carbonyl, as, R3、R
5Do not form together imines with nitrogen. In addition preferred embodiment in, R3And R5(with optional R6) separately independent expression hydrogen, alkyl, thiazolinyl or-(CH2)
m-R
1 Therefore, term " alkylamine " refers to be connected with and replaces or the not as defined above amido of substituted alkyl, i.e. R3And R5At least one be alkyl. In certain embodiments, amino or alkylamine are alkaline, and the meaning is that it has pKa〉=7.00 conjugate acid is that the protonated form of these functional groups has with respect to water greater than about 7.00 pKa。
Term " carbonyl " is what generally acknowledge in the field, and comprising can be by the part of following general formula representative:
Wherein X is key or expression oxygen or sulphur, R7Expression hydrogen, alkyl, thiazolinyl ,-(CH2)
m-R
1Or pharmaceutically acceptable salt, R8Expression hydrogen, alkyl, thiazolinyl or-(CH2)
m-R
1, wherein m and R1Such as above-mentioned definition. Wherein X is oxygen and R7Or R8When being not hydrogen, this formula represents " ester group ". Wherein X is oxygen and R7Such as above-mentioned definition, this part is called carboxylic group, particularly R7During for hydrogen, this formula represents " carboxylic acid group ". Wherein X is oxygen and R8During for hydrogen, this formula represents " formic acid ester group ". Generally speaking, wherein the oxygen atom in the following formula is replaced formula by sulphur, and this formula represents " thiocarbonyl " group. Wherein X is sulphur and R7Or R8When being not hydrogen, this formula represents " thioesters " group. Wherein X is sulphur and R7During for hydrogen, this formula represents " thiocarboxylic acid " group. Wherein X is sulphur and R8During for hydrogen, this formula represents " thiocarboxylic " group. In addition, wherein X is key, and R7When being not hydrogen, following formula represents " ketone " group. Wherein X is key, and R7During for hydrogen, following formula represents " aldehyde " group.
Term " heterocyclic radical " or " heterocyclic group " refer to 3-to 10-ring structure, and more preferably 3-to 7-unit encircles, and its ring structure comprises 1-4 hetero atom. Heterocycle also can be many rings. Heterocyclic radical comprises, for example, thiophene, thianthrene, furans, pyrans, isobenzofuran, chromene, xanthenes, phenoxthine, pyrroles, imidazoles, pyrazoles, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, iso-indoles, indoles, indazole, purine, quinolizine, different quinoline woods, quinoline woods, phthalazines, naphthyridines (naphthyridine), quinoxaline, quinazoline, cinnolines, pteridine, carbazole, carboline, phenanthridines, acridine, pyrimidine, phenanthroline, azophenlyene, phenarsazine, phenthazine, furazan, phenoxazine, pyrrolidines, tetrahydrofuran (oxolane), tiacyclopentane (thiolane), oxazole, piperidines, piperazine, morpholine, lactone, lactams such as azetidinone and pyrrolidones, sultam class (sultams), sultone class (sultones) etc. Described heterocycle can be replaced by aforesaid substituting group in one or more positions, as halogen, alkyl, aralkyl, thiazolinyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfydryl, imido grpup, amide groups, phosphate, phosphonate ester, phosphinate, carbonyl, carboxyl, silicyl, sulfamoyl, sulfinyl, ether, alkylthio group, sulfonyl, ketone, aldehyde, ester, heterocyclic radical, aromatic series or heteroaromatic part ,-CF3,-CN etc.
Term " replacement " refers to the substituting group that comprises that all organic compounds are permissible. In a broad sense, described permissible substituting group includes the substituting group non-annularity of organic compounds and ring-type, side chain and non-side chain, carbocyclic ring and heterocycle, aromatic series and non-aromatic. Exemplary substituting group comprises above-described substituting group. To suitable organic compound, permissible substituting group can be one or more, identical or different. For the purposes of the present invention, hetero atom such as nitrogen can have hydrogen substituting group and/or the permissible substituting group of any organic compound described herein that can satisfy the hetero atom valence link. The present invention does not think to be limited by the permissible substituting group of organic compound by any way.
Term " alkyl " refers to by carbochain or is no more than the monovalent hydrocarbon part that 26 rings that are connected with the carbon atom of hydrogen atom form. This term comprises alkyl, cycloalkyl, thiazolinyl, alkynyl and aryl, is mixed with the group of saturated and unsaturated bond, carbocyclic ring, also comprises the assembly of these groups. It can be straight chain, side chain, ring structure or its assembly.
Term " alkylene " refers to the bivalent hydrocarbon radical part. Representational example comprises alkylidene, phenylene or cyclohexylidene. Preferably, described alkylene chain is complete chain saturated and/or that have 1-10 carbon atom.
Term " nitro " refers to-NO2 Term " halogen " refers to-F ,-Cl ,-Br or-I; Term " sulfydryl " refers to-SH; Term " hydroxyl " refers to-OH; Term " sulfonyl " refers to-SO2-。
Should be appreciated that " substituting group " or " substituted " comprises such implication: this substituting group be substituted atom and valence link that substituting group is allowed is consistent, and should replace the stable compound of generation, as can spontaneously not transforming such as effects such as rearrangement, cyclisation, eliminations.
Term " sulfamoyl " is what generally acknowledge in the field, and comprising can be by the part of following general formula representative:
R wherein3And R5Such as above-mentioned definition.
Term " sulfate group " is what generally acknowledge in the field, and comprising can be by the part of following general formula representative:
R wherein7Such as above-mentioned definition.
Term " sulfoamido (sulfonamide) " is what generally acknowledge in the field, and comprising can be by the part of following general formula representative:
R wherein3And R5Such as above-mentioned definition.
Term " sulfonate group " is what generally acknowledge in the field, and comprising can be by the part of following general formula representative:
R wherein7Be duplet, hydrogen, alkyl, cycloalkyl or aryl.
Term " sulfoxide group " or " sulfinyl " refer to can be by the part of following general formula representative:
R wherein12Be selected from hydrogen, alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aralkyl or aryl.
Can carry out similar replacement and generate the thiazolinyl of amino thiazolinyl, amino alkynyl, acylamino-thiazolinyl, acylamino-alkynyl, imino group thiazolinyl, imino group alkynyl, sulfo-thiazolinyl, sulfo-alkynyl, carbonyl substituted or the alkynyl of carbonyl substituted thiazolinyl and alkynyl group.
As used herein, the definition of various expression is such as alkyl, m, n etc., when it occurs once representing that it is independent of the definition in other places of same structure when above in any structure.
" little " substituting group is 10 or the substituting group of atom still less.
Term " amino acid residue " and " peptide residue " refer to not have on the carboxyl-amino acid or the peptide molecule of OH. Usually expression amino acid used herein and the abbreviation of blocking group are according to the recommendation of IUPAC-IUB Commission in Biochemical Nomenclature (see Biochemistry (1972) 11:1726-1732). For example, Met, Ile, Leu, Ala and Gly represent respectively methionine, isoleucine, leucine, alanine and glycine " residue ". Residue refers to derive from corresponding amino acid whose part except the H part on the part of the OH on the decarboxylate and the amino. Term " amino acid side chain " is for removing-CH (NH2) the outer amino acid moiety of COOH part, at " Peptides and Amino Acids " W. A.Benjamin Inc., New York and Amsterdam defines in 1966, the 2 and 33 pages such as K.D.Kopple. The example of this type of side chain of common amino acid is-CH2CH
2SCH
3(side chain of methionine) ,-CH2(CH
3)-CH
2CH
3(side chain of isoleucine) ,-CH2CH(CH
3)
2(leucic side chain) or H-(side chain of glycine).
In most of situation, used amino acid is at albumen or the naturally occurring naturally occurring amino acid of finding in this type of carbamic anabolic or catabolic product of amino and carboxyl that comprises in the present patent application. Specially suitable amino acid side chain comprises and is selected from following amino acid whose side chain: glycine, alanine, valine, cysteine, leucine, isoleucine, serine, threonine, methionine, glutamic acid, aspartic acid, glutamine, asparagine, lysine, arginine, proline, histidine, phenylalanine, tyrosine and tryptophan, and be amino acid and the amino acid analogue of peptidyl glycan bacterial cell wall fraction by conclusive evidence.
The term amino acid residue also comprises analog, derivative and the homologue of any specific amino acids of mentioning herein, and the amino acid derivativges of C-end or the protection of N-end (holding protected group to revise such as N-end or C-). For example, the present invention consider side chain wherein for lengthen or shorten still can be the purposes of amino acid analogue that cyclisation provides the amino acid analogue of carboxyl, amino or other reactivity precursor functional group and has the variation side chain of suitable functional group. For example, topic is stated mixture and can be comprised amino acid analogue such as cyano group alanine, canavanine, djenkolic acid, nor-leucine, 3-phosphoserine, homoserine, dihydroxy-phenylalanine, 5-hydroxytryptophan, 1-Methyl histidine, 3-Methyl histidine, diaminopimelic acid, ornithine or DAB. Other herein the suitable naturally occurring amino acid metabolite with side chain or precursor will be recognized by those skilled in the art, and within the scope of the present invention.
When amino acid whose structure allows stereoisomer form, also comprise this type of amino acid whose (D) and (L) stereoisomer. Amino acid herein and the configuration of amino acid residue are specified with suitable sign (D), (L) or (DL), and when not specifying configuration, and amino acid or residue can have (D), (L) or (DL) configuration. The structure that should note some compounds of the present invention comprises asymmetric carbon atom. Therefore should be appreciated that by this asymmetric isomers that forms and be also included within the scope of the present invention. Can synthesize by the isolation technics of classics with by solid control and obtain basically pure this isomers. For the application, unless explicitly point out opposite situation, the amino acid of name should be understood to include (D) and (L) stereoisomer.
Term " blocking group " refers to prevent that reactive functional from carrying out the substituting group of unwanted chemical reaction. The example of these blocking groups comprises the ester of carboxylic acid and boric acid, acetal and the ketal of ether, aldehyde and ketone of alcohol. For example, term " N-holds blocking group " or " amino-blocking group " refer to can be used in building-up process preventing that the N-of amino acid or peptide from holding the various amino-blocking groups that carry out unwanted reaction. The example of suitable group comprises acyl group blocking group such as formoxyl, dansyl (dansyl), acetyl group, benzoyl, trifluoroacetyl group, succinyl group and methoxy succinyl group; Aromatic series urethane (urethane) blocking group such as benzyloxy carbonyl carbonyl (Cbz); With aliphatic urethane blocking group such as tert-butoxycarbonyl (Boc) or 9-fluorenylmethyloxycarbonyl (Fmoc).
As mentioned above, specifically geometric isomer or stereoisomer form existence of some compound of the present invention. It is considered herein that all these compounds, comprise cis-and trans-isomers, R-S-enantiomter, diastereoisomer, (D)-isomers, (L)-isomers, its racemic mixture and other compound thereof are all within the scope of the invention. In substituting group such as alkyl, also can there be other asymmetric carbon atom. All these isomers and composition thereof all comprise within the scope of the invention. Given enantiomer is in preferred some embodiment therein, compound of the present invention can be enriched with＞60%,＞70%,＞80%, 90%,＞95% or even greater than 98% or 99% preferred enantiomter, respectively account for 50% racemic mixture from two kinds of enantiomters wherein different.
For example, if need the given enantiomer of the compounds of this invention, it can be derived by asymmetric syntheses or by chiral auxiliary and prepare, and wherein separating obtained non-enantiomer mixture and cracking auxiliary group obtain pure required enantiomter. Perhaps, wherein comprise basic functionality such as amino, or the molecule of acidic functionality such as carboxyl, available suitable optical activity acid or key prepare diastereoisomeric salt, then split formed diastereoisomer by fractional crystallization well known in the art or chromatographic process, then reclaim the pure enantiomter that obtains.
For the present invention, chemical element is according to CAS version, Handbook of Chemistry and Physics, and 67th Ed., 1986-87, the periodic table of elements of interior front cover is differentiated. Also for the present invention, term " hydrocarbon " base is intended to comprise all compounds that contains at least one hydrogen atom and a carbon atom. That broad sense, permissible compound comprise is can be substituted or unsubstituted acyclic and ring-type, side chain and non-side chain, carbocyclic ring and heterocycle, the organic compound of aromatic series and non-aromatic.
The compound of described tool " insulinotropic activity " refers to that it can stimulate or cause insulin synthesis or expression.
Should be appreciated that all general structures described here, with regard to suitable substituting group combination, be intended to cover those embodiments of chemical valence and stability permission.
III. the embodiment of example
(i). compound
Below compounds effective will be described in various manners.In each example, the variable in the formula is clearly defined respectively.Although the variable that is not defined in a formula can be by being defined with analogizing of the similar formula in other places definition, the definition of variable shall not be applied to the definition in another formula of change in formula.
In certain embodiments of the invention, titled reference compound has formula I structure
Formula I
Wherein
R
1Expression H, alkyl, alkoxyl group, thiazolinyl, alkynyl, amino, alkylamino, acyl amino, cyano group, sulfuryl amino, acyloxy, aryl, cycloalkyl, heterocyclic radical, heteroaryl or have the polypeptide chain of 1-8 amino-acid residue;
R
2Expression H, low alkyl group or aralkyl;
R
3And R
4Independent expression H, halogen or alkyl or R
3And R
4Form 3-to 6-unit heterocycle with the atom that connects them;
R
5Expression H, halogen, low alkyl group or aralkyl;
R
6The avtive spot residue reaction of expression and targeting proteins enzyme forms the functional group of covalency adducts;
R
7The polypeptide chain of expression H, aryl, alkyl, aralkyl, cycloalkyl, heterocyclic radical, heteroaryl, heteroaralkyl or 1-8 amino-acid residue;
L does not exist or L represent alkyl, thiazolinyl, alkynyl ,-(CH
2)
mO (CH
2)
m-,-(CH
2)
mNR
2(CH
2)
m-and-(CH
2)
mS (CH
2)
m-;
X does not exist or X represents-N (R
7)-,-O-or-S-;
Y does not exist or Y represents-C (=O)-,-C (=S)-or-SO
2-;
When occurring at every turn, m independently is the integer of 0-10; And
N is the integer of 1-6.
In certain preferred aspects, R
1Expression H or low alkyl group, R
3And R
4Form 5-unit ring with the atom that connects them, and n is 2.
In other some embodiment preferred, R
1Expression H or low alkyl group, expression H, R
4Expression H or low alkyl group, R
5Expression H, and n is 2.
In certain preferred aspects, R
1For having the polypeptide chain of 2-8 amino-acid residue, wherein proline(Pro) is the residue that directly links to each other.Most preferably, R
1For having the polypeptide chain of 2 amino-acid residues.
In above-mentioned some embodiment, R
6Expression cyano group, boric acid ,-SO
2Z
1,-P (=O) Z
1,-P (=R
8) R
9R
10,-C (=NH) NH
2,-CH=NR
11With-C (=O)-RI 1, wherein
R
8Expression O or S;
R
9Expression N
3, SH
2, NH
2, NO
2And OLR
12, and
R
10Expression low alkyl group, amino, OLR or its pharmaceutically acceptable salt, or
R
9And R
10Form 5-to 8-unit heterocycle with the phosphorus that connects them;
R
11Expression H, alkyl, thiazolinyl, alkynyl ,-(CH
2)
p-R
12,-(CH
2)
q-OH ,-(CH
2)
q-O-alkyl ,-(CH
2)
q-O-thiazolinyl ,-(CH
2)
q-O-alkynyl ,-(CH
2)
q-O-(CH
2)
p-R
12,-(CH
2)
q-SH ,-(CH
2)
q-S-alkyl ,-(CH
2)
q-S-thiazolinyl ,-(CH
2)
q-S-alkynyl ,-(CH
2)
q-S-(CH
2)
p-R
12,-C (O) C (O) NH
2,-C (O) C (O) OR
13Or-C (Z
1) (Z
2) (Z
3);
R
12Expression H, alkyl, thiazolinyl, aryl, cycloalkyl, cycloalkenyl group and heterocyclic radical;
R
13Expression H, alkyl, thiazolinyl and LR
12
Z
1The expression halogen;
Z
2And Z
3Independent expression H or halogen;
When occurring at every turn, p independently is the integer of 0-8; And
When occurring at every turn, q independently is the integer of 1-8.
In another embodiment, R
6Expression CN, CHO or C (=O) C (Z
1) (Z
2) (Z
3), Z wherein
1Expression halogen, and Z
2And Z
3Expression H or halogen.At some so in the embodiment, R
6Expression C (=O) C (Z
1) (Z
2) (Z
3), wherein Z ' expression fluorine, and Z
2And Z
3Expression H or fluorine.
In certain preferred aspects, R
6Expression-B (Y
1) (Y
2) group, Y wherein
1And Y
2Independent be the group (that is, forming boric acid) of OH or form 5-to the 8-unit ring that hydrolyzable is a boric acid for OH or hydrolyzable with the boron atom that connects them.
In certain preferred aspects, R
3And R
4Form 5-unit ring with the atom that connects them, it is selected from following group and replaces by one or more: hydroxyl, low alkyl group (as methyl), low-grade alkenyl, low-grade alkynyl, lower alkoxy, rudimentary hydroxyalkyl (as methylol) and low-grade alkoxy alkyl.
In a more preferred embodiment, described substituted radical is selected from low alkyl group, rudimentary hydroxyalkyl and low-grade alkoxy alkyl.In preferred this type of embodiment, described substituted radical is substituted in the 5-position of ring ring.
In other preferred embodiment, described substituted radical is a hydroxyl, and it preferably is substituted in the 4-position of ring.
In certain embodiments, contain R
3And R
45-unit ring on substituting group be selected from low alkyl group (as methyl), hydroxyl, rudimentary hydroxyalkyl (as, methylol) and low-grade alkoxy alkyl.In this type of the embodiment, described substituted radical has and R at some
6The stereochemistry relation of cis.This stereochemistry relation is particularly advantageous to the 4-or the substituent again compound of 5-position tool of the 5-unit ring that has just discussed the front.
The structure of example comprises
In certain embodiments of the invention, titled reference compound or its pharmaceutically acceptable salt have formula II structure
Formula II
Wherein:
R
1Expression H, alkyl, alkoxyl group, thiazolinyl, alkynyl, amino, alkylamino, acyl amino, cyano group, sulfuryl amino, acyloxy, aryl, cycloalkyl, heterocyclic radical, heteroaryl or have the polypeptide chain of 1-8 amino-acid residue;
R
2Expression H, low alkyl group or aralkyl;
R
3And R
4Independent expression H, halogen or alkyl or R
3And R
4Form 3-to 6-unit heterocycle with the carbon that connects them;
R
5Expression H, halogen, low alkyl group or aralkyl, preferred H or low alkyl group;
R
6Expression is reacted the functional group that forms the covalency adducts with targeting proteins enzyme active sites residue;
R
7Expression H, aryl, alkyl, aralkyl, cycloalkyl, heterocyclic radical, heteroaryl, heteroaralkyl or have the polypeptide chain of 1-8 amino-acid residue;
R
14Expression H, alkyl, alkoxyl group, thiazolinyl, alkynyl or aralkyl, preferred H;
A does not exist or A represents-NHC (=NH)-, or R
14Form heterocycle with A with the nitrogen that is connected them;
L does not exist or L represents alkyl, thiazolinyl, alkynyl, (CH
2)
mO (CH
2)
m,-(CH
2)
mNR
2(CH
2)
m-and-(CH
2)
mS (CH
2)
m-;
X does not exist or X represents-N (R
7)-,-O-or-S-;
Y does not exist or Y represents-C (=O)-,-C (=S)-or-SO
2-;
When occurring at every turn, m independently is the integer of 0-10; And
N is the integer of 1-6.
In certain preferred aspects, R
1Expression H or low alkyl group, R
3And R
4Form 5-unit ring with the carbon that connects them, and n is the integer of 1-4.
In certain preferred aspects, R
14Be H, A does not exist, and n is 4.In some other embodiments, R
14Being H, A is-NHC (=NH)-, and n is 3.
In certain preferred aspects, A goose R
14Form imidazole ring with the nitrogen that connects them, and n is 1.
In certain embodiments, R
6Expression boric acid, CN ,-SO
2Z
1,-P (=O) Z
1,-P (=R
8) R
9R
10,-C (=NH) NH
2,-CH=NR
11Or-C (=O)-R
11, wherein
R
8O or S;
R
9Expression N
3, SH
2, NH
2, NO
2Or OLR
12And
R
10Expression low alkyl group, amino, OLR
12Or its pharmaceutically acceptable salt, or
R
9And R
10Form 5-to 8-unit heterocycle with the phosphorus that connects them;
R
11Expression H, alkyl, thiazolinyl, alkynyl, NH
2,-(CH
2)
p-R
12,-(CH
2)
q-OH ,-(CH
2)
q-O-alkyl ,-(CH
2)
q-O-thiazolinyl ,-(CH
2)
q-O-alkynyl ,-(CH
2)
q-O-(CH
2)
p-R
12,-(CH
2)
qSH ,-(CH
2)
q-S-alkyl ,-(CH
2)
q-S-thiazolinyl ,-(CH
2)
q-S-alkynyl ,-(CH
2)
q-S-(CH
2)
p-R
12,-C (O) NH
2,-C (O) O
13Or C (Z
1) (Z
2) (Z
3);
R
12Expression H, alkyl, thiazolinyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl group or heterocyclic radical;
R
13Expression H, alkyl, thiazolinyl or LR
12
Z
1The expression halogen;
Z
2And Z
3Independent expression H or halogen;
When occurring at every turn, p independently is the integer of 0-8; And
When occurring at every turn, q independently is the integer of 1-8.
In certain preferred aspects, R
6Expression CN, CHO or C (=O) C (Z
1) (Z
2) (Z
3), Z wherein
1The expression halogen, Z
2And Z
3Expression H or halogen.In another embodiment, R
6Expression C (=O) C (Z
1) (Z
2) (Z
3), Z wherein
1The expression fluorine, Z
2And Z
3Expression H or fluorine.
In certain preferred aspects, R
6Expression-B (Y
1) (Y
2) group, Y wherein
1And Y
2Independent is that OH or hydrolyzable are the group of OH, or forms 5-to the 8-unit ring that hydrolyzable is a boric acid with the boron atom that connects them.
In certain preferred aspects, R
3And R
4Form 5-unit ring with the atom that connects them, it is by one or more following group substituted hydroxy, low alkyl group (as methyl), low-grade alkenyl, low-grade alkynyl, lower alkoxy, rudimentary hydroxyalkyl (as methylol) and low-grade alkoxy alkyls of being selected from.
In a more preferred embodiment, described substituted radical is selected from low alkyl group, rudimentary hydroxyalkyl and low-grade alkoxy alkyl.In preferred this type of embodiment, described substituted radical is substituted in the 5-position of ring.
In other preferred embodiment, described substituted radical is a hydroxyl, and it preferably is substituted in the 4-position of ring.
In certain embodiments, contain R
3And R
45-unit ring on substituted radical be selected from low alkyl group (as methyl), hydroxyl, rudimentary hydroxyalkyl (as, methylol) and low-grade alkoxy alkyl. in some preferred this type of embodiment, described substituted radical and R
6Stereochemistry relation with cis.This stereochemistry relation to the front just mentioned to have substituent compound in the ring 4-of 5-unit or 5-position be particularly advantageous.
The structure of example comprises
In certain embodiments of the invention, titled reference compound or its pharmaceutically acceptable salt have the formula III structure
Wherein:
R
1Expression H, alkyl, alkoxyl group, thiazolinyl, alkynyl, amino, alkylamino, acyl amino, cyano group, sulfuryl amino, acyloxy, aryl, cycloalkyl, heterocyclic radical, heteroaryl or have the polypeptide chain of 1-8 amino-acid residue;
R
2Expression H, low alkyl group or aralkyl;
R
3And R
4Independent expression H, halogen or alkyl or R
3And R
4Form 3-to 6-unit heterocycle with the carbon that connects them;
R
5Expression H, halogen, low alkyl group or aralkyl, preferred H or low alkyl group;
R
6The avtive spot residue reaction of expression and targeting proteins enzyme forms the functional group of covalency adducts;
R
7Expression H, aryl, alkyl, aralkyl, cycloalkyl, heterocyclic radical, heteroaryl, heteroaralkyl or have the polypeptide chain of 1-8 amino-acid residue;
R
15For have the functional group of positive charge or negative charge, preferred amines or carboxylic acid in physiological pH;
L does not exist or L represent alkyl, thiazolinyl, alkynyl ,-(CH
2)
mO (CH
2)
m-,-(CH
2)
mNR
2(CH
2)
m-and-(CH
2)
mS (CH
2)
m-;
X does not exist or X represents-N (R
7)-,-O-or-S-;
Y does not exist or Y represents-C (=O)-,-C (=S)-or-SO
2-;
When occurring at every turn, m independently is the integer of 0-10; And
N is the integer of 1-6.
In certain preferred aspects, R
1Expression H or low alkyl group, R
3Be H, and R
4Be low alkyl group, or R
3And R
4Form 5-unit ring with the carbon that connects them, and n is the integer of 1-4.
In certain preferred aspects, n is the integer of 1-4, R
15For have the functional group of positive charge or negative charge in physiological pH.In a more preferred embodiment, n is the integer of 1-4, R
15Be selected from amine, carboxylic acid, imidazoles or guanidine functional group.
In certain embodiments, R
6Expression boric acid, CN ,-SO
2Z
1,-P (=O) Z
1,-P (=R
8) R
9R
10,-C (=NH) NH
2,-CH=NR
11Or-C (=O)-R
11, wherein
R
8Be O or S;
R
9Expression N
3, SH
2, NH
2, NO
2Or OLR
12, and
R
10Expression low alkyl group, amino, OLR
12Or its pharmaceutically acceptable salt, or
R
9And R
10Form 5-to 8-unit heterocycle with the phosphorus that connects them;
R
11Expression H, alkyl, thiazolinyl, alkynyl, NH
2,-(CH
2)
p-R
12,-(CH
2)
q-OH ,-(CH
2)
q-O-alkyl ,-(CH
2)
q-O-thiazolinyl ,-(CH
2)
q-O-alkynyl ,-(CH
2)
q-O-(CH
2)
p-R
12,-(CH
2)
q-SH ,-(CH
2)
q-S-alkyl ,-(CH
2)
q-S-thiazolinyl ,-(CH
2)
q-S-alkynyl ,-(CH
2)
q-S-(CH
2)
p-R
12,-C (O) NH
2,-C (O) OR
13Or-C (Z
1) (Z
2) (Z
3);
R
12Expression H, alkyl, thiazolinyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl group or heterocyclic radical;
R
13Expression H, alkyl, thiazolinyl or LR
12
Z
1The expression halogen;
Z
2And Z
3Independent expression H or halogen;
When occurring at every turn, p independently is the integer of 0-8; And
When occurring at every turn, q independently is the integer of 1-8.
In certain preferred aspects, R
6Expression CN, CHO or C (=O) C (Z
1) (Z
2) (Z
3), Z wherein
1The expression halogen, Z
2And Z
3Expression H or halogen.In another embodiment, R represents C (=O) C (Z
1) (Z
2) (Z
3), Z wherein
1The expression fluorine, Z
2And Z
3Expression H or fluorine.
In certain preferred aspects, R
6Tabular form-B (Y
1) (Y
2) group, Y wherein
1And Y
2Independent be the group of OH or form 5-to the 8-unit ring that hydrolyzable is a boric acid for OH or hydrolyzable with the boron atom that connects them.
In certain preferred aspects, R
3And R
4Form by one or more 5-unit rings that are selected from following group replacement with the atom that connects them: hydroxyl, low alkyl group (as methyl), low-grade alkenyl, low-grade alkynyl, lower alkoxy, rudimentary hydroxyalkyl (as methylol) and low-grade alkoxy alkyl.
In a more preferred embodiment, described substituted radical is selected from low alkyl group, rudimentary hydroxyalkyl and low-grade alkoxy alkyl.In preferred this type of embodiment, described substituted radical is substituted in the 5-position of ring.
In other preferred embodiment, described substituted radical is a hydroxyl, and it preferably is substituted in the 4-position of ring.
In certain embodiments, contain R
3And R
45-unit ring on substituted radical be selected from low alkyl group (as methyl), hydroxyl, rudimentary hydroxyalkyl (as, methylol) and low-grade alkoxy alkyl.In some preferred this type of embodiment, described substituted radical and R
6Stereochemistry relation with cis.This stereochemistry relation to the front just mentioned to have substituent compound in the ring 4-of 5-unit or 5-position be particularly advantageous.
Another aspect of the present invention relates to inhibitor or its pharmaceutically acceptable salt of tool formula IV structure:
Formula IV
Wherein
A is selected from the 4-8 unit heterocycle that comprises N and C α carbon;
Z is C or N;
W is selected from CN ,-CH=NR
5, with the functional group of targeting proteins enzyme active sites residue reaction,
R
1Be selected from peptide that amino-acid residue that C-end connects or amino acid analogue, C-end connect or peptide analogs, amino-blocking group,
R
2The substituting group of representing one or more A ring, each independently be selected from halogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, lower alkoxy, rudimentary hydroxyalkyl, low-grade alkoxy alkyl, carbonyl, thiocarbonyl, amino, acyl amino, amido, cyano group, nitro, azido-, sulfate group, sulfonate group, sulfonamido ,-(CH
2)
m-R ,-(CH
2)
m-OH ,-(CH
2)
m-O-low alkyl group ,-(CH
2)
m-O-low-grade alkenyl ,-(CH
2)
n-O-(CH
2)
m-R
7,-(CH
2)
m-SH ,-(CH
2)
m-S-low alkyl group ,-(CH
2)
m-S-low-grade alkenyl or-(CH
2)
n-S-(CH
2)
m-R
7, at least one R wherein
2Be selected from-OH, low alkyl group, lower alkoxy, rudimentary hydroxyalkyl and low-grade alkoxy alkyl, preferably at least one R
2Be low alkyl group (as methyl), lower alkoxy, rudimentary hydroxyalkyl (as methylol) and low-grade alkoxy alkyl;
When Z is N, R
3Be hydrogen;
When Z is C, R
3Be selected from hydrogen, halogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, carbonyl, thiocarbonyl, amino, acyl amino, amido, cyano group, nitro, azido-, sulfate group, sulfonate group, sulfonamido ,-(CH
2)
m-R
7,-(CH
2)
m-OH ,-(CH
2)
m-O-low alkyl group ,-(CH
2)
m-O-low-grade alkenyl ,-(CH
2)
n-O-(CH
2)
m-R
7,-(CH
2)
m-SH ,-(CH
2)
m-S-low alkyl group ,-(CH
2)
m-S-low-grade alkenyl and-(CH
2)
n-S-(CH
2)
m-R
7
R
5Be selected from hydrogen, alkyl, thiazolinyl, alkynyl ,-C (X
1) (X
2) X
3,-(CH
2)
m-R
7,-(CH
2)
n-OH ,-(CH
2)
n-O-alkyl ,-(CH
2)
n-O-thiazolinyl ,-(CH
2)
n-O-alkynyl ,-(CH
2) O-(CH
2)
m-R
7,-(CH
2)
n-SH ,-(CH
2)
n-S-alkyl ,-(CH
2)
n-S-thiazolinyl ,-(CH
2)
n-S-alkynyl ,-(CH
2)
n-S-(CH
2)
m-R
7,-C (O) C (O) NH
With-C (O) C (O) OR
7';
R
6Be selected from hydrogen, halogen, alkyl, thiazolinyl, alkynyl, aryl ,-(CH
2)
m-R
7,-(CH
2)
m-OH ,-(CH
2)
m-O-alkyl ,-(CH
2)
m-O-thiazolinyl ,-(CH
2)
m-O-alkynyl ,-(CH
2)
m-O-(CH
2)
m-R
7,-(CH
2)
m-SH ,-(CH
2)
m-S-alkyl ,-(CH
2)
m-S-thiazolinyl ,-(CH
2)
m-S-alkynyl or-(CH
2)
m-S-(CH
2)
m-R
7,
Each R
7Independently be selected from aryl, aralkyl, cycloalkyl, cycloalkenyl group and send out heterocyclic radical;
Each R
7' independently be selected from hydrogen, alkyl, thiazolinyl, aryl, aralkyl, cycloalkyl, cycloalkenyl group and heterocyclic radical; R
8And R
9Independently be selected from hydrogen, alkyl, thiazolinyl ,-(CH
2)
m-R
7,-C (=O)-alkyl ,-C (=O)-thiazolinyl ,-C (=O)-alkynyl and-C (=O)-(CH
2)
m-R
7Or
R
8And R
9Form the heterocycle that has 4-8 atom on the ring structure with the N atom that connects them;
R
50Be O or S; R
51Be selected from N
3, SH, NH
2, NO
2And OR
7';
R
52Be selected from hydrogen, low alkyl group, amine or OR
7' or its pharmaceutically acceptable salt, or
R
51And R
52Form the heterocycle that has 5-8 atom on the ring structure with the P atom that connects them;
X
1Be halogen;
X
2And X
3Be selected from hydrogen and halogen separately;
Y
1And Y
2Independently be selected from the group that OH and hydrolyzable are OH, comprise wherein Y
1And Y
2By the continuous derivative of ring that 5-8 atom arranged on the ring structure;
M be 0 or the 1-8 scope in integer; And
N is the integer in the 1-8 scope.
In certain embodiments, W is selected from CN and B (Y
1) (Y
2).In certain preferred aspects, A is a 5-unit ring, and Z is C, W B (Y
1) (Y
2).In a more preferred embodiment, Z has the absolute steric configuration of L-proline(Pro).
In certain embodiments, A is a 5-unit ring, and Z is C, and R is selected from hydroxyl, low alkyl group, low-grade alkenyl, low-grade alkynyl, lower alkoxy, rudimentary hydroxyalkyl and low-grade alkoxy alkyl.In some preferred this type of embodiment, R
2Be selected from rudimentary hydroxyalkyl and low-grade alkoxy alkyl.In preferred this type of embodiment, W is in the 5-position of ring.
In certain embodiments, A is a 5-unit ring, and Z is C, and W is selected from hydroxyl, low alkyl group (as methyl), rudimentary hydroxyalkyl (as methylol) and low-grade alkoxy alkyl.In some preferred this type of embodiment, Z has the absolute steric configuration of L-proline(Pro), is the R of low alkyl group, rudimentary hydroxyalkyl and low-grade alkoxy alkyl
25-position at ring is the R of hydroxyl
24-position at ring.In preferred this type of embodiment, R
2The stereochemistry that has cis with W concerns.
Another aspect of the present invention relates to inhibitor or its pharmaceutically acceptable salt with formula V structure
Formula V
Wherein
R
1Be selected from peptide that amino-acid residue that C-end connects or amino acid analogue, C-end connect or peptide analogs,
R
2The substituting group of representing one or more A ring, each independently be selected from halogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, lower alkoxy, rudimentary hydroxyalkyl, low-grade alkoxy alkyl, carbonyl, thiocarbonyl, amino, acyl amino, amido, cyano group, nitro, azido-, sulfate group, sulfonate group, sulfonamido ,-(CH
2)
m-R
7,-(CH
2)
m-OH ,-(CH
2)
m-O-low alkyl group ,-(CH
2)
m-O-low-grade alkenyl ,-(CH
2)
n-O-(CH
2)
m-R
7,-(CH
2)
m-SH ,-(CH
2)
m-S-low alkyl group ,-(CH
2)
m-S-low-grade alkenyl or-(CH
2)
n-S-(CH
2)
m-R
7, at least one R wherein
2Be selected from-OH, low alkyl group (as methyl), lower alkoxy, rudimentary hydroxyalkyl (as methylol) and low-grade alkoxy alkyl, preferably at least one R
2Be low alkyl group, lower alkoxy, rudimentary hydroxyalkyl and low-grade alkoxy alkyl;
R
6Be selected from hydrogen, halogen, alkyl, thiazolinyl, alkynyl, aryl ,-(CH
2)
m-R
7,-(CH
2)
m-OH ,-(CH
2)
m-O-alkyl ,-(CH
2)
m-O-thiazolinyl ,-(CH
2)
m-O-alkynyl ,-(CH
2)
m-O-(CH
2)
mR
7,-(CH
2)
m-SH ,-(CH
2)
m-S-alkyl ,-(CH
2)
m-S-thiazolinyl ,-(CH
2)
m-S-alkynyl ,-(CH
2)
m-S-(CH
2)
m-R
7,
R
7Be selected from aryl, cycloalkyl, cycloalkenyl group and heterocyclic radical;
R
8And R
9Independently be selected from hydrogen, alkyl, thiazolinyl ,-(CH
2)
m-R
7,-C (=O)-alkyl ,-C (=O)-thiazolinyl ,-C (=O)-alkynyl and-C (=O)-(CH
2)
m-R
7Or
R
8And R
9Form the heterocycle that has 4-8 atom on the ring structure with the N atom that connects them;
Y
1And Y
2Independently be selected from the group that OH and hydrolyzable are OH, comprise wherein Y
1And Y
2By the continuous cyclic derivatives of ring that has 5-8 atom on the ring structure;
M be 0 or the 1-8 scope in integer; And
N is the integer in the 1-8 scope.
In certain embodiments, have B (Y
1) (Y
2) carbon have the absolute steric configuration of L-proline(Pro).In some preferred this type of embodiment, R
2Be selected from hydroxyl, low alkyl group, rudimentary hydroxyalkyl and low-grade alkoxy alkyl.In preferred this type of embodiment, be low alkyl group (as methyl), rudimentary hydroxyalkyl (as methylol) and low-grade alkoxy alkyl R
2In the 5-position of ring, or be the R of hydroxyl
24-position at ring.In most preferred this type of embodiment, R
2With B (Y
1) (Y
2) have a stereochemistry relation of cis.
The compound of example comprises:
Another aspect of the present invention relates to compound or its pharmaceutically acceptable salt of tool formula VI structure
Formula VI
Wherein
A is the 3-8 unit heterocycle that comprises N and C α carbon;
W is the functional group that generates the covalency adducts with the reaction of targeting proteins avtive spot residue;
R
1Be selected from amino acid or peptide or its analogue and the amido protecting group of hydrogen, the connection of C-end;
R
2The substituting group of representing one or more A ring, each independently be selected from halogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, lower alkoxy, rudimentary hydroxyalkyl, low-grade alkoxy alkyl, carbonyl, thiocarbonyl, amino, acyl amino, amido, cyano group, nitro, azido-, sulfate group, sulfonate group, sulfonamido ,-(CH
2)
m-R
6,-(CH
2)
m-OH ,-(CH
2)
m-O-low alkyl group ,-(CH
2)
m-O-low-grade alkenyl ,-(CH
2)
n-O-(CH
2)
m-R
6,-(CH
2)
m-SH ,-(CH
2)
m-S-low alkyl group ,-(CH
2)
m-S-low-grade alkenyl and-(CH
2)
n-S-(CH
2)
m-R
6, at least one R wherein
2Be selected from-OH, low alkyl group, lower alkoxy, rudimentary hydroxyalkyl and low-grade alkoxy alkyl, preferably at least one R
2Be low alkyl group (as methyl), lower alkoxy (as, rudimentary methylol), rudimentary hydroxyalkyl and low-grade alkoxy alkyl;
R
3aThe electron pair conjugated substituting group that is selected from hydrogen and does not provide with nitrogen.
There is not R
3bOr R
3bFor the electron pair conjugated substituting group that does not provide with nitrogen, as low alkyl group;
R
4aAnd R
4bIndependently be selected from hydrogen, low alkyl group, assorted alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, alkoxyl group, carboxyl, carbamyl, carbonyl and cyano group, condition is R
4aAnd R
4bAll be hydrogen or for hydrogen;
R
4cBe selected from halogen, amine, alkyl, assorted alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, alkoxyl group, carboxyl, carbamyl, carbonyl and cyano group;
Each R
6Independently be selected from aryl, aralkyl, cycloalkyl, cycloalkenyl group and heterocyclic radical;
Z be 0 or the 1-3 scope in integer;
M be 0 or the 1-8 scope in integer; And
N is the integer in the 1-8 scope.
In certain embodiments, W is selected from CN and B (Y
1) (Y
2), Y wherein
1And Y
2Separate or for OH or hydrolyzable are the group of OH, comprise wherein Y
1And Y
2By the continuous cyclic derivatives of ring that 5-8 atom arranged on the ring structure.In certain preferred aspects, A is a 5-unit ring, and W is B (Y
1) (Y
2).In a more preferred embodiment, C α has the absolute steric configuration of L-proline(Pro).
In certain embodiments, A is a 5-unit ring, and W is selected from hydroxyl, low alkyl group, low-grade alkenyl, low-grade alkynyl, lower alkoxy, rudimentary hydroxyalkyl and low-grade alkoxy alkyl.In some preferred this type of embodiment, R
2Be selected from low alkyl group (as methyl), rudimentary hydroxyalkyl (as methylol) and low-grade alkoxy alkyl.In preferred this type of embodiment, R
25-position at ring.
In certain embodiments, A is a 5-unit ring, R
2Be selected from hydroxyl, hydroxyl, low alkyl group, rudimentary hydroxyalkyl and low-grade alkoxy alkyl.In some preferred this type of embodiment, C α has the absolute steric configuration of L-proline(Pro), and is the R of low alkyl group (as methyl), rudimentary hydroxyalkyl (as methylol) and low-grade alkoxy alkyl
2The ring the 5-position or be the R of hydroxyl
24-position at ring.In preferred this type of embodiment, R
2The stereochemistry that has cis with W concerns.
Another aspect of the present invention relates to compound or its pharmaceutically acceptable salt of tool formula VII structure
Formula VII
Wherein
R
1, R
2, R
3a, R
3b, R
4a, R
4b, R
4cWith W such as above-mentioned definition to formula VI, and p is the integer of 1-3.In certain preferred aspects, p is 1, R
3aAnd R
3bAll be hydrogen.
In certain embodiments, W is selected from CN and B (Y
1) (Y
2), Y wherein
1And Y
2Separate or for OH or hydrolyzable are the group of OH, comprise wherein Y
1And Y
2By the continuous cyclic derivatives of ring that 5-8 atom arranged on the ring structure.In certain preferred aspects, W is B (Y
1) (Y
2).In a more preferred embodiment, the carbon that has a W has the absolute steric configuration of L-proline(Pro).
In certain embodiments, R
2Be selected from hydroxyl, low alkyl group, low-grade alkenyl, low-grade alkynyl, lower alkoxy, rudimentary hydroxyalkyl and low-grade alkoxy alkyl.In certain preferred aspects, R
2Be selected from rudimentary hydroxyalkyl (as methylol) and low-grade alkoxy alkyl.In preferred this type of embodiment, p is 1 and R
25-position at ring.
In certain embodiments, R
2Be selected from hydroxyl, low alkyl group, rudimentary hydroxyalkyl and low-grade alkoxy alkyl.In some preferred this type of embodiment, p is 1, and the carbon that has W has the absolute steric configuration of L-proline(Pro), and is the R of low alkyl group (as methyl), rudimentary hydroxyalkyl (as methylol) and low-grade alkoxy alkyl
2The ring the 5-position or be hydroxyl R
24-position at ring.In preferred this type of embodiment, R
2The stereochemistry that has cis with W concerns.
Compound or its pharmaceutically acceptable salt that relates to tool formula VIII structure more on the other hand of the present invention:
Formula VIII
Wherein
A is the 3-8-unit heterocycle that comprises N and C α carbon;
B is 3-8 ring or C
7-14Fused bicyclic or three ring ring systems;
W and the reaction of targeting proteins enzyme active sites residue generate the functional group of covalency adducts, for example-CN ,-CH=NR
5,
R
1Be selected from amino acid or peptide or its analogue and the amido protecting group of hydrogen, the connection of C-end;
R
2The substituting group of representing one or more A ring, each independently be selected from halogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, lower alkoxy, rudimentary hydroxyalkyl, low-grade alkoxy alkyl, carbonyl (as carboxyl, ester, manthanoate or ketone), thiocarbonyl (as thioesters, thioacetate or thiocarboxylic), amino, acyl amino, amido, cyano group, nitro, azido-, sulfate group, sulfonate group, sulfonamido ,-(CH
2)
m-R
6,-(CH
2)
m-OH ,-(CH
2)
m-O-low alkyl group ,-(CH
2)
m-O-low-grade alkenyl ,-(CH
2)
n-O-(CH
2)
m-R
6,-(CH
2)
m-SH ,-(CH
2)
m-S-low alkyl group ,-(CH
2)
m-S-low-grade alkenyl and-(CH
2)
nS-(CH
2)
m-R
6, at least one R wherein
2Be selected from-OH, low alkyl group, lower alkoxy, rudimentary hydroxyalkyl and low-grade alkoxy alkyl, preferably at least one R
2Be low alkyl group (as methyl), lower alkoxy (as methylol), rudimentary hydroxyalkyl and low-grade alkoxy alkyl;
R
3bDo not exist or R
3bExpression does not connect thereon substituting group with the electron pair conjugated of nitrogen, as low alkyl group;
R
5Be selected from hydrogen, alkyl, thiazolinyl, alkynyl ,-C (X
1) (X
2) X
3,-(CH
2)
m-R
6,-(CH
2)
n-OH ,-(CH
2)
n-O-alkyl ,-(CH
2)
n-O-thiazolinyl ,-(CH
2)
n-O-alkynyl ,-(CH
2)
n-O-(CH
2)
m-R
6,-(CH
2)
n-SH ,-(CH
2)
n-S-alkyl ,-(CH
2)
n-S-thiazolinyl ,-(CH
2)
n-S-alkynyl ,-(CH
2)
n-S-(CH
2)
m-R
6,-C (O) C (O) NH
2With-C (O) C (O) OR
7
Each R
6Independently be selected from aryl, aralkyl, cycloalkyl, cycloalkenyl group and heterocyclic radical;
Each R
7Independently be selected from hydrogen, alkyl, thiazolinyl, aryl, aralkyl, cycloalkyl, cycloalkenyl group and heterocycle;
Y
1And Y
2Separate, be selected from-OH or hydrolyzable are the group of hydroxyl, comprise wherein Y
1And Y
2By the continuous cyclic derivatives (as tetramethyl ethylene ketone (pinacol) or analogue) of ring that 5-8 atom arranged on the ring structure;
R
50Be O or S;
R
51Be selected from N
3, SH
2, NH
2, NO
2Or-OR
7
R
52Expression hydrogen, low alkyl group, amine ,-OR
7Or its pharmaceutically acceptable salt, or R
51And R
52Form the heterocycle that has 5-8 atom on the ring structure with the phosphorus atom that connects them;
X
1The expression halogen;
X
2And X
3Independently be selected from hydrogen and halogen;
M be 0 or the 1-8 scope in integer; And
N is the integer in the 1-8 scope.
In certain embodiments, W is selected from CN and B (Y
1) (Y
2), Y wherein
1And Y
2Separate or for OH or hydrolyzable are the group of OH, comprise Y
1And Y
2By the continuous cyclic derivatives of ring that 5-8 atom arranged on the ring structure.In certain preferred aspects, A is a 5-unit ring, W B (Y
1) (Y
2).In a more preferred embodiment, C α has the absolute steric configuration of L-proline(Pro).
In certain embodiments, A is a 5-unit ring, and R is selected from hydroxyl, low alkyl group, low-grade alkenyl, low-grade alkynyl, lower alkoxy, rudimentary hydroxyalkyl and low-grade alkoxy alkyl.In some preferred this type of embodiment, R
2Be selected from rudimentary hydroxyalkyl (methylol) and low-grade alkoxy alkyl.In preferred this type of embodiment, R
25-position at ring.
In certain embodiments, A is a 5-unit ring, R
2Be selected from hydroxyl, low alkyl group, rudimentary hydroxyalkyl and low-grade alkoxy alkyl.In some preferred this type of embodiment, C α has the absolute steric configuration of L-proline(Pro), and is the R of low alkyl group (as methyl), rudimentary hydroxyalkyl (as methylol) and low-grade alkoxy alkyl
2The ring the 5-position or be the R of hydroxyl
24-position at ring.In preferred this type of embodiment, R
2The stereochemistry that has cis with W concerns.
Another aspect of the present invention relates to compound or its pharmaceutically acceptable salt of tool formula IX structure:
Formula IX
Wherein
B, R
1, R
2, R
3bWith W such as above-mentioned definition to formula VIII, p is the integer of 1-3.In certain preferred aspects, p is 1, R
3bBe hydrogen.
In certain embodiments, W is selected from CN and B (Y
1) (Y
2), Y wherein
1And Y
2Separate or for OH or hydrolyzable are the group of OH, comprise wherein Y
1And Y
2By the continuous cyclic derivatives of ring that 5-8 atom arranged on the ring structure.In certain preferred aspects, W is B (Y
1) (Y
2).In a more preferred embodiment, the carbon that has a W has the absolute steric configuration of L-proline(Pro).
In certain embodiments, R
2Be selected from hydroxyl, low alkyl group, low-grade alkenyl, low-grade alkynyl, lower alkoxy, rudimentary hydroxyalkyl and low-grade alkoxy alkyl.In some preferred this type of embodiment, R
2Be selected from rudimentary hydroxyalkyl (as methylol) and low-grade alkoxy alkyl.In preferred this type of embodiment, R
25-position at ring.
In certain embodiments, R
2Be selected from hydroxyl, low alkyl group, rudimentary hydroxyalkyl and low-grade alkoxy alkyl.In some preferred this type of embodiment, p is 1, and the carbon that has W has the absolute steric configuration of L-proline(Pro), and is the R of hydroxyl
2The ring the 4-position, or be low alkyl group (as methyl), rudimentary hydroxyalkyl (as methylol) and low-grade alkoxy alkyl at R
25-position at ring.In preferred this type of embodiment, R
2The stereochemistry that has cis with W concerns.
Another aspect of the present invention relates to compound or its pharmaceutically acceptable salt of tool formula X structure:
Formula X
Wherein
A is the 4-8 unit heterocycle that comprises N and C α carbon;
W is the functional group of reacting with targeting proteins enzyme active sites residue, for example-CN ,-CH=NR
5,
R
1Peptide or peptide analogs that expression C-end connects, it is the substrate of activating enzyme;
R
2The substituting group of representing one or more A ring, each independently be selected from halogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, lower alkoxy, rudimentary hydroxyalkyl, low-grade alkoxy alkyl, carbonyl, thiocarbonyl, amino, acyl amino, amido, cyano group, nitro, azido-, sulfate group, sulfonate group, sulfonamido ,-(CH
2)
m-R
6,-(CH
2)
m-OH ,-(CH
2)
m-O-low alkyl group ,-(CH
2)
m-O-low-grade alkenyl ,-(CH
2)
n-O-(CH
2)
m-R
6,-(CH
2)
m-SH ,-(CH
2)
m-S-low alkyl group ,-(CH
2)
m-S-low-grade alkenyl ,-(CH
2)
n-S-(CH
2)
m-R
6, at least one R wherein
2Be selected from-OH, low alkyl group, lower alkoxy, rudimentary hydroxyalkyl and low-grade alkoxy alkyl, preferably at least one R
2Be low alkyl group (as methyl), lower alkoxy (as, methylol), rudimentary hydroxyalkyl and low-grade alkoxy alkyl;
Each R
3The electron pair conjugated substituting group that independently is selected from hydrogen and does not provide with nitrogen is as low alkyl group;
R
4Be selected from hydrogen and small molecules hydrophobic grouping, as halogen, low alkyl group, low-grade alkenyl or low-grade alkynyl;
R
5Be selected from hydrogen, alkyl, thiazolinyl, alkynyl ,-C (X
1) (X
2) X
3,-(CH
2)
m-R
6,-(CH
2)
n-OH ,-(CH
2)
n-O-alkyl ,-(CH
2)
n-O-thiazolinyl ,-(CH
2)
n-O-alkynyl ,-(CH
2)
n-O-(CH
2)
m-R
6,-(CH
2)
n-SH ,-(CH
2)
n-S-alkyl ,-(CH
2)
n-S-thiazolinyl ,-(CH
2)
n-S-alkynyl ,-(CH
2)
n-S-(CH
2)
m-R
6,-C (O) C (O) NH
2,-C (O) C (O) OR
7
R
6Represent when occurring to replace or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl group or heterocycle at every turn;
R
7Represent hydrogen or replacement or unsubstituted alkyl, thiazolinyl, aryl, aralkyl, cycloalkyl, cycloalkenyl group or heterocycle when occurring at every turn; With
Y
1And Y
2For being that OH or hydrolyzable are the group of hydroxyl independently or together, comprise wherein Y
1And Y
2By the continuous cyclic derivatives (as pinacol or analogue) of ring that 5-8 atom arranged on the ring structure;
R
50Be O or S;
R
51Be selected from N
3, SH
2, NH
2, NO
2With-OR
7
R
52Be selected from hydrogen, low alkyl group, amine ,-OR or its pharmaceutically acceptable salt; Or
R
51And R
52Form the heterocycle that has 5-8 atom on the ring structure with the phosphorus atom that connects them;
X
1Be halogen;
X
2And X
3Independently be selected from hydrogen and halogen;
M be 0 or the 1-8 scope in integer; And
N is the integer in the 1-8 scope.
In certain embodiments, W is selected from CN and B (Y
1) (Y
2).In certain preferred aspects, A is a 5-unit ring, and W is B (Y
1) (Y
2).In a more preferred embodiment, C α has the absolute steric configuration of L-proline(Pro).
In certain embodiments, A is a 5-unit ring, and Z is C, R
2Be selected from hydroxyl, low alkyl group, low-grade alkenyl, low-grade alkynyl, lower alkoxy, rudimentary hydroxyalkyl and low-grade alkoxy alkyl.In some preferred this type of embodiment, R
2Be selected from rudimentary hydroxyalkyl (as methylol) and low-grade alkoxy alkyl.In preferred this type of embodiment, R
25-position at ring.
In certain embodiments, A is a 5-unit ring, R
2Be selected from hydroxyl, low alkyl group, rudimentary hydroxyalkyl and low-grade alkoxy alkyl.In some preferred this type of embodiment, C α has the absolute steric configuration of L-proline(Pro), for hydroxyl R
2In the 4-position of ring, or be the R of low alkyl group, rudimentary hydroxyalkyl and low-grade alkoxy alkyl
25-position at ring.In preferred this type of embodiment, R and W have the stereochemistry relation of cis.
One aspect of the present invention relates to compound or its pharmaceutically acceptable salt of formula XI:
Formula XI
Wherein
L do not exist or L for-XC (O)-;
R
1Be selected from H, low alkyl group, lower acyl, rudimentary aralkyl, rudimentary aroyl, rudimentary 4-hetaroylpyrazol, carbocylic radical (carbocyclyl), aryl and ArSO
2-;
R
2The substituting group of representing one or more A ring, each independently be selected from halogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, lower alkoxy, rudimentary hydroxyalkyl, low-grade alkoxy alkyl, carbonyl, thiocarbonyl, amino, acyl amino, amido, cyano group, nitro, azido-, sulfate group, sulfonate group, sulfonamido ,-(CH
2)
m-R
6,-(CH
2)
m-OH ,-(CH
2)
m-O-low alkyl group ,-(CH
2)
m-O-low-grade alkenyl ,-(CH
2)
n-O-(CH
2)
m-R
6,-(CH
2)
m-SH ,-(CH
2)
m-S-low alkyl group ,-(CH
2)
m-S-low-grade alkenyl ,-(CH
2)
n-S-(CH
2)
m-R
6, at least one R wherein
2Be selected from-OH, low alkyl group, lower alkoxy, rudimentary hydroxyalkyl and low-grade alkoxy alkyl, preferably at least one R
2Be low alkyl group (as methyl), lower alkoxy (as, methylol), rudimentary hydroxyalkyl and low-grade alkoxy alkyl;
R
3Be selected from hydrogen, low alkyl group, rudimentary hydroxyalkyl, rudimentary alkylthio and rudimentary aralkyl;
R
4Be selected from H and low alkyl group, or R
1And R
4Be phthaloyl together, thereby form ring;
R
6When occurring, expression replaces or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl group or heterocycle at every turn;
W is selected from B (Y
1) (Y
2) and CN;
Y
1And Y
2Independently be selected from the group that OH or hydrolyzable are OH, or form 5-to the 8-unit ring that hydrolyzable is OH with the boron atom that connects them;
X is selected from O and NH.
In certain embodiments, W is B (Y
1) (Y
2).In certain preferred aspects, R
2Be selected from hydroxyl, low alkyl group, low-grade alkenyl, low-grade alkynyl, lower alkoxy, rudimentary hydroxyalkyl and low-grade alkoxy alkyl.In preferred this type of embodiment, R
2Be selected from rudimentary hydroxyalkyl and low-grade alkoxy alkyl.In preferred this type of embodiment, R is in the 5-position of ring.
In certain embodiments, R
2Be selected from hydroxyl, low alkyl group, rudimentary hydroxyalkyl and low-grade alkoxy alkyl.In some preferred this type of embodiment, C α has the absolute steric configuration of L-proline(Pro), is the R of hydroxyl
24-position at ring is the R of low alkyl group, rudimentary hydroxyalkyl and low-grade alkoxy alkyl
25-position at ring.In preferred this type of embodiment, R
2The stereochemistry that has cis with W concerns.
In certain preferred aspects, to state inhibitor be tool 10nm or lower to DPIV restraining effect K to topic
iThe DPIV inhibitor, 1.0nm or lower more preferably, even more preferably 0.1 or even 0.01nM or lower.In fact, should consider K
iValue is at the inhibitor of pmol even femto molar range.
Generally speaking, the inhibitor that topic is stated method is a small molecules, is no more than 7500amu as molecular weight, preferably is no more than 5000amu, even more preferably no more than 2000amu with even above 1000amu.In preferred embodiments, described inhibitor is oral effectively.
Another aspect of the present invention relates to the medicinal compositions of depeptidyl peptidase inhibitors, particularly inhibitor and they and is treating and/or preventing the disease that can improve by self balance that changes peptide hormone.In preferred embodiments, described inhibitor has hypoglycemic and anti-diabetic activity, and can be used for treatment is the illness of feature with abnormal glucose metabolism (comprising storage).In special embodiment, the composition that topic is stated method can effectively be used as the pancreotropic hormone medicine or make the medicine of bringing into play the pancreotropic hormone effect as the molecule of GLP-1.In this respect, some embodiment of the present composition can be used for treating and/or preventing multiple disease, comprises following one or more: hyperlipidaemia, hyperglycemia, obesity, glucose intolerance, insulin resistant and diabetic complications.
For example, described in certain embodiments method comprises and gives inhibitor, preferably the interval to be scheduled in 24 hours gives with the significant quantity that can improve one or more abnormal indexs relevant with glucose metabolism obstacle (as glucose intolerance, insulin resistant, hyperglycemia, hyperinsulinemia and type ii diabetes).The significant quantity of described inhibitor can be about 0.01,0.1,1,10,30,50,70,100,150,200,500 or 1000mg/kg.
The (ii) activation of .GLP-1 effect (Agonism)
In certain embodiments, state in topic that effective inhibitors has the lowering blood glucose level in the method, alleviate obesity, alleviate the ability that glucose tolerance reduces, suppresses hepatic glucose regeneration and blood fat reducing level and suppresses aldose reductase.Therefore they can be effective to prevent and/or treat hyperglycemia, obesity, hyperlipidaemia, diabetic complication (comprising retinopathy, ephrosis, DPN, cataract, coronary heart disease and arteriosclerosis), also can be effective to obesity relevant hypertension and osteoporosis.
Diabetes are that the hyperglycemia that causes with relative or absolute minimizing, insulin sensitivity reduction or insulin resistant by insulin secretion is the disease of feature.This sick M ﹠ M causes with complication nerve because of blood vessel, kidney.Oral glucose tolerance test is the clinical trial that is used for diagnosing diabetes.In oral glucose tolerance test, evaluate patient is to the physiologic response of glucose load or attack (challenge).After taking in glucose, the physiologic response that evaluate patient is attacked glucose.Usually, this finishes by the glucose level (glucose concn in patient's blood plasma, serum or the whole blood) of measuring the patient at several preset time points.
In one embodiment, the present invention relates to activate the method for GLP-1 effect.According to determining that the GLP-1 abnormal shape (GLP-1 (7-37) and GLP-1 (7-36)) that derives from the preceding proglucagon (preproglucagon) in intestines and the hindbrain has insulinotropic activity, promptly they can regulate glucose metabolism.DPIV divides described abnormal shape makes the peptide inactivation.Therefore, in certain embodiments, inhibitor of the present invention can activate (agonize) insulinotropic activity by the Degradation of intervening biological activity GLP-1 peptide.
(iii). the activation of the effect of other peptide hormone
In another embodiment, topic is stated the activity that medicine can be used for activating (agonize) (as simulation or reinforcement) peptide hormone such as GLP-2, GIP and NPY.
In order to further specify, the present invention relates to activate the method for GLP-2 effect.According to determining that GLP-2 is for promoting the growth nutrition of gastrointestinal tissue.It is feature that the effect of GLP-2 is quickened with the growth of small intestine especially, therefore is referred to herein as " intestines nutrition (intestinotrophic) " effect.Known DPIV can be cracked into GLP-2 the active peptide of lifeless matter.Therefore, in one embodiment, thereby the degraded that the restraining effect of DPIV is intervened GLP-2 is increased plasma half-life of this hormone.
In other embodiments again, topic is stated the transformation period that method can be used for increasing other proglucagon derived peptide, as the pancreatic polypeptide (GRPP) of enteroglucagon, oxyntomodulin, enteroglucagon-relevant and/or get involved peptide (IP-2).For example, enteroglucagon has been proved to be and can have caused intestinal mucosa propagation and can suppress peristole, therefore can be used as the medicine of digestive tract diseases, has therefore caused the present invention.
Therefore, one aspect of the present invention relates to inhibitor and promotes the gastrointestinal tissue particularly growth of small intestine and the therapeutics and the associated uses of propagation.For example, topic is stated the part that method can be used as the therapy of the damage of treatment intestinal tissue, inflammation or surgical blanking, strengthens the growth of epithelium of intestinal mucosa and the tissue of reparation as needs.
About small intestine, this growth can be used easily with respect to the increase of not treating control group small intestine quality and length and measure.Topic is stated inhibitor the effect of small intestine is shown that also folliculus adds the increase of fine hair axle (crypt plus villus axis) height.This activity is called " intestines nutrition " activity herein.The effect that topic is stated method also can be detected by the increase of crypt cell propagation and/or the apoptosis decrease of small intestine epithelium tissue.It should be noted that most that these cytosiies are relevant with jejunum, comprise the jejunum in distally, Lin Jin jejunum particularly is also in the jejunum in distally.When with described compounds for treating (or through gene engineering expression himself time), tangible small intestine weight increases if experimental animal demonstrates, folliculus adds that the fine hair axle highly increases or crypt cell propagation increases or small intestine epithelium histocyte apoptosis reduces, and then this compound is considered to have " intestines trophism ".United States Patent (USP) 5,834 has described being applicable to the model that detects this stomach and intestine growth in 428.
Generally speaking, the patient that can benefit from the enhancing of increase of small intestine quality and consequent mucous membrane of small intestine function states the candidate of method treatment for topic.The specific illness that can be treated comprises various forms of sprues, comprises the sprue that causes because of the toxic reaction to α-gliadin in the wheat, and its a large amount of losses with intestinal villus (villae) are feature; Because of inflammation cause to become flat with the part of intestinal villus be the ceylon sore mouth of feature; Significantly be reduced to the hypogammaglobulinemic sprue of feature with height of naps, it occurs in having common variable immunodeficiency or hypogammaglobulinemic patient usually.Described treatment can be observed fine hair morphology by the intestines examination of living tissue, by the biological activity assessment of dietetic alimentation, increases or by monitoring the effect of described treatment with the improvement of these disease related symptom by weight in patients.Other available topic state the illness of method treatment or available topic state method effectively the illness of prevention comprise radiation enteritis, communicable or metainfective (post-infectious) enteritis, local enteritis (regional enteritis) (Crohn ' s disease), by poisoning or injury of small intestine that other chemotherapeutics causes and patient with short bowel syndrome.
More at large, the present invention relates to treat the method for digestive tract diseases.Term " digestive tube " is meant the pipeline that food passes through, and comprises stomach and intestines.Term " digestive tract diseases " is meant the unusual of the matter of gastrointestinal mucosal or amount, and it comprises as ulcer or inflammatory diseases; Congenital or acquired character Disorder of Digestion and A orption comprises malabsorption syndrome; Lose the disease that causes by the intestinal mucosal barrier effect; And PLG.Ulcer disease comprises as stomach ulcer, duodenal ulcer, small intestinal ulcer, colonic ulcer and rectal ulcer.Inflammatory diseases comprises as esophagitis, gastritis, duodenitis, enteritis, colitis, Crohn ' s disease, rectitis, Behcet gastro-enteritis, disease, radiation enteritis, radiation colitis, radiation rectitis, enteritis and drug enteritis (medicamentosa).Malabsorption syndrome comprises primary malabsorption syndrome such as disaccharides-lytic enzyme defective, glucose-galactose malabsorption, fructose malabsorption; The Secondary cases malabsorption syndrome, as the obstacle that causes by gastrointestinal mucosal atrophy in intravenous injection parenteral alimentation or the elemental diet, disease that causes by the excision and the shunting of small intestine such as short bowel syndrome, retrotarsal fold syndrome; With the indigestion malabsorption syndrome, as the disease that causes by the stomach excision,, as dumping syndrome.
Term " medicine of digestive tract diseases " is meant the medicine of prevention or treatment digestive tract diseases, it comprises, as the medicine of the medicine of the medicine of treatment digestive tract ulcer, treatment inflammatory digestive tract diseases, the atrophy of treatment gastrointestinal mucosal disappear, treat the medicine of digestive tube wound, the medicine that improves tract function comprises the medicine that recovers the mucosal barrier effect and improves and digest and the medicine of absorptive function.Ulcer comprises that peptide ulceration and corrosion and acute ulcer are acute mucosal lesion.
Because topic is stated the propagation that method can promote intestinal mucosa, therefore can be used for treating and preventing to digest and absorb the pathology illness of defective, be mucosal atrophy treatment and prevention, or the digestive tube tissue development is bad and the treatment of the minimizing of these tissues that surgical excision causes and the improvement of digestion and absorptive function.In addition, topic is stated method section and is used for the pathology treatment of conditions that caused by inflammatory diseases such as enteritis, Crohn ' s disease and ulcerative colitis, can be used for also that the postoperative tract function reduces as the treatment of dumping syndrome and duodenal ulcer merge that peristole suppresses and food from stomach fast to the treatment of jejunum transfer.In addition, enteroglucagon section is effective to the promotion treatment of surgery infringement and improves tract function.Therefore, the present invention also provides the medicine of treatment gastrointestinal mucosal atrophy, treats the medicine of digestive tube wound and comprises the medicine that improve tract function of enteroglucagon as main component.
And inhibitor of the present invention section is used to change the plasma half-life of secretin, VIP, PHI, PACAP, GIP and/or helodermin.In addition, topic is stated the pharmacokinetics that method can be used for changing peptide YY and neuropeptide tyrosine, and peptide YY and neuropeptide tyrosine all are the members of pancreatic polypeptide family, because DPIV is considered to relevant with the course of processing of those peptides in the mode of change receptor-selective.
Neuropeptide tyrosine (NPY) is considered to regulate the effect of vascular smooth muscle tensity and blood pressure regulation.NPY also can reduce cardiac contractility.
NPY is the most effective appetite stimulator (Wilding et al., (1992) J still
Endocrinology132:299-302).The ingestion of food that maincenter brings out (appetite stimulation) effect is mainly receptor-mediated by NPY Y1, can cause that body fat stores increase and obesity (Stanleyet al., (1989)
Physiology and Behavior46:173-177).
According to the present invention, the method for treatment apositia comprises that the inhibitor that gives host patient's significant quantity stores to stimulate appetite and to increase body fat, thereby from alleviating the symptom of apositia in essence.
Treat hypotensive method and comprise the inhibitor of the present invention that gives host patient's significant quantity with adjusting vasoconstriction and increase blood pressure, thereby from alleviating hypotensive symptom in essence.
DPIV is also relevant with the metabolism and the deactivation of growth factor releasing hormone (GHRF).GHRF is for comprising glucagon, secretin, vasoactive intestinal peptide (VIP), peptide histidine isoleucine (PHI), pituitary adenylate cyclase activating peptide (PACAP), Gastric inhibitory polypeptide (GIP) and helodermin (Kubiak etal. (1994)
Peptide Res7:153) the member in interior homeopeptide class family.The secretion of GHRF hypothalamus, stimulating growth hormone (GH) is from adenohypophyseal release.Therefore, topic is stated method and be can be used for improving clinical treatment to some growth hormone deficiency children, and the adult is improved nutrition and changes the clinical treatment that health is formed (muscle is to fat).Topic state method also can be used for for animals, as, the exploitation milk preparation of high yield and the lean meat poultry of high yield.
(iv). the mensuration of insulinotropic activity
When selecting to be applicable to that topic is stated the compound of method, should note compound pancreotropic hormone character can by provide to zooblast this compound or to animal inject this compound and detect respectively immunoreactive insulin (IRI) in medium or the release of animal circulating system determine.The existence of IRI can detect by the radioimmunoassay of using special detection Regular Insulin.
The db/db mouse is the mouse that heredity is fat and the diabetes kind is.Along with the development of its obesity, the db/db mouse produces hyperglycemia and hyperinsulinemia, therefore can be used as the model of fat diabetes B (NIDDM).The db/db mouse can be bought and obtain, as from JacksonLaboratories (Bar Harbor, Me.).In the embodiment of example, the treatment plan of mouse comprise every animal quantitatively give inhibitor or reference substance after for some time as (60 minutes), gather sinus blood sample under the eye socket.Any mensuration blood sugar of available several routine techniquess, as use glucose meter.Compare group and the glucose level that gives the animal of inhibitor.
Also can then in ND or type ii diabetes experimenter, detect the metabolic fate of exogenous GLP-1 and the effect of candidate inhibitor.For example, use high pressure liquid chromatography (HPLC), specificity radioimmunoassay (RIAs) and enzyme-linked immunosorbent assay (LISA) be can unite and complete biological activity GLP-1 and meta-bolites thereof detected.Referring to, as, Deacon etal. (1995)
Diabetes44:1126-1131.For example, give GLP-1 after, available NH
2Directed RIA or the ELISA of-end detects complete peptide, and concentration difference between these mensuration and COOH-terminal specific RIA can be used to determine NH
2The meta-bolites of-end brachymemma.
During the unrestraint agent, subcutaneous GLP-1 degrades rapidly in the time dependent mode, is formed on HPLC and goes up the meta-bolites that comes out and have same immunocompetence feature with GLP-I (9-36) acid amides wash-out.For example, subcutaneously give diabetic subject (n=8) after GLP-130 minute, described meta-bolites accounts for the 88.5+1.9% that the blood plasma immunoreactivity that detected by COOH-end RIA increases, and is higher than the level (78.4+3.2% that detects in the health volunteer; N=8; P＜0.05).Referring to Deacon et al.,
Supra.Venoclysis GLP-1 is degraded in a large number also.
(v). Combined Preparation
Another aspect of the present invention provides wherein one or more medicines with the conjoint therapy of proteinase inhibitor administration.The individuality that this conjoint therapy can quantitatively give in the therapy by simultaneously, in succession or separately becomes to assign to finish.
In one embodiment, inhibitor and Regular Insulin or the medication combined administration of other pancreotropic hormone, as GLP-1, peptide hormone, the gene therapy vector (gene therapy vector) of medicine and peptide hormone ectopic expression as described in maybe can causing as GLP-2, GIP or NPY.In certain embodiments, described medicine or peptide hormone can be modification naturally occurring or the synthetic peptide hormone, and wherein one or more amino acid are coupled with or remove or are substituted.
In another exemplary embodiment, the topic state inhibitor can with M1 acceptor inhibitor Combined Preparation.The cholinomimetic thing is effective Regular Insulin release regulator, and it works by M-ChR.In addition, thus the use of this type of medicine can have the additional benefit that the reducing cholesterol level increases the HDL level.Suitable muscarinic receptor antagonist comprises the active material of direct or indirect retardance mAChR.Preferably to M1 acceptor tool this type of material (or use to promote this type of optionally to measure) optionally.
Non-limiting instance comprises quaternary amine (as methantheline (methantheline), Rinovagos and Propanthelinium), tertiary amine (as Wyovin and Scopolamine) and Tricyclic amine (as telenzepine).Preferred pirenzepine and epoxytropine tropate.Other suitable muscarinic receptor antagonist comprises Benzatropine (can buy from Merck, commodity are called COGENTIN), (the HHSID hydrochloride is disclosed in Lambrecht et al. (1989) to six hydrogen-sila-Dienidol
Trends in Pharmacol.Sci.10 (Suppl): 60); (+/-)-3-quinuclidinyl xanthenes-9-carboxylicesters half oxalate (QNX-half oxalate; Birdsall et al., Trends in Pharmacol.Sci.4:459,1983); Telenzepine dihydrochloride (Coruzzi et al. (1989)
Arch.Int.Pharmacodvn.Ther.302:232); With Kawashima et al. (1990)
Gen.Pharmacol21:17) and coromegine.The dosage of this type of muscarinic receptor antagonist generally can be optimised as mentioned above.Whether under the situation of lipid metabolism obstacle, the dosage optimization is necessary, regularly irrelevant with reference to lipid metabolism responsiveness window with administration.
From regulating the angle of Regular Insulin and lipid metabolism and reduction aforementioned obstacles, topic is stated inhibitor and also can be acted synergistically with prolactin inhibitor such as d2 dopamine agonist (as bromocriptine).Therefore, topic is stated method and can be comprised and this type of prolactin inhibitor Combined Preparation that resembles the inhibiting ergot of prolactin (ergo) alkaloid and the inhibiting dopamine agonist of prolactin.The example of suitable compound comprises 2-bromo-α-ergocristine; 6-methyl-8-β-carbonyl benzyloxy (carbobenzyloxy) amino-ethyl-10-α-ergoline; 8-amido ergoline; 6-methyl-8-α-(N-acyl group) amino-9-ergoline; 6-methyl-8-α-(N-phenylacetyl) amino-9-ergoline; ergocornine; 9, the 10-DHO180; the ergoline that D-2-halo-6-alkyl-8-replaces; D-2-bromo-6-methyl-8-cyano methyl ergoline; carbidopa; benserazide and other dopa decarboxylase inhibitor; the L-DOPA; Dopamine HCL and non-toxic salt thereof.
The used inhibitor of the present invention also can with the medication combined use that acts on beta cell ATP-dependency potassium channel, as Glyburide, Glipizide, gliclazide and AG-EE 623ZW.Described inhibitor also can be easily and other oral pharmaceutical combined utilization, as N1,N1-Dimethylbiguanide and related compound or glucosidase inhibitor, as acarbose.
(vi). medicinal compositions
The inhibitor of describing preparation as this paper can the various forms administration, depend on the disease patient that treated with age, symptom and body weight, this is well-known in the art.For example, be used for oral medicine and can be made into tablet, capsule, granule, powder or syrup; Or the compound that is used for parenteral admin can be made into injection (intravenous injection, intramuscular injection or subcutaneous injection), instillation (drop infusion preparations) or suppository.The compound that is used for the eye mucosa administration can be made into eye drops or eye ointment.These preparations can be prepared by ordinary method, if necessary, activeconstituents can be mixed with any conventional additives, as vehicle, tackiness agent, disintegrating agent, lubricant, corrigent (corrigent), solubilizing agent, suspending agent, emulsifying agent or Drug coating.Although dosage depend on the patient symptom, age and body weight, treat or the formulation of prophylactic character and seriousness, route of administration and medicine, but in general, recommending the adult patient per daily dose is the compound of 0.01-2000mg, and this can single dose or broken dose administration.
From given patient's treatment validity, the amount that produces the most effective result's accurate administration time and/or inhibitor depends on activity, pharmacokinetics and the bioavailability of specific compound, patient's physiological condition (comprise age, sex, disease type and stage, comprehensive physical integrity, to the reactivity of given formulation and the type of pharmacotherapy), route of administration etc.But above-mentioned guilding principle can be used as the basis of fine tuning treatment plan, as determining the Best Times and/or the dosage of administration, this need by monitored patient and regulate dosage and/or normal experiment that the time is formed just.
Term " pharmacy is acceptable " is meant in reliable medical range of value, is applicable to organize with the human and animal to contact and do not have over-drastic toxicity, pungency, anaphylaxis or other problem or complication, the part with rational interests/risk-ratio, material, composition and/or formulation.
Term " pharmaceutical acceptable carrier " is meant the acceptable material of pharmacy, composition or carrier, as liquid or solid weighting agent, thinner, vehicle, solvent or cover material.Every kind of carrier is compatible with other composition of preparation and must be " acceptable " to the patient on the harmless meaning.Some examples that can be used as the material of pharmaceutical acceptable carrier comprise: (1) carbohydrate, as lactose, dextrose plus saccharose; (2) starch based is as W-Gum and potato starch; (3) Mierocrystalline cellulose and derivative thereof are as Xylo-Mucine, ethyl cellulose and rhodia; (4) tragacanth gum powder (powdered tragacanth); (5) Fructus Hordei Germinatus; (6) gelatin; (7) talcum powder; (8) vehicle is as theobroma oil and beeswax bolt (suppository waxes); (9) grease is as peanut oil, oleum gossypii seminis, Thistle oil, sesame oil, sweet oil, Semen Maydis oil and soybean oil; (10) glycols is as propylene glycol; (11) polyvalent alcohol is as glycerine, sorbyl alcohol, N.F,USP MANNITOL and polyoxyethylene glycol; (12) ester class is as ethyl oleate and Laurate ethyl; (13) agar; (14) buffer reagent is as magnesium hydroxide and aluminium hydroxide; (15) Lalgine; (16) no heat source water; (17) isotonic saline solution; (18) Ringer ' s solution; (19) ethanol; (20) phosphate buffered saline buffer; (21) but other is used for the nontoxic compatibility material of pharmaceutical preparation.In certain embodiments, medicinal compositions of the present invention is non-to hot, and promptly the patient to administration can not cause that tangible temperature raises.
Term " pharmaceutically acceptable salt " is meant relevant nontoxic, the mineral acid and the organic acid addition salt of described inhibitor.These salt can the final separation of described inhibitor and purifying prepares period in position or separately with the inhibitor of purifying with free alkali form and suitable organic or inorganic acid-respons, separate the salt of formation then and prepare.Representational salt comprises hydrobromate, hydrochloride, vitriol, bisulfate, phosphoric acid salt, nitrate, acetate, valerate, oleate, palmitate, stearate, month silicate, benzoate, lactic acid salt, phosphoric acid salt, tosylate, Citrate trianion, maleate, fumarate, succinate, tartrate, naphthoate (naphthylate), mesylate, gluceptate, lactobionate and lauryl sulfonate etc.(referring to, Berge et al. (1977) " Pharmaceutical Salts " for example, J Pliarni.Sci.66:1-19).
In other example, the inhibitor that is effective to the inventive method can comprise one or more acidic functionalities, therefore can accept alkali with pharmacy and form pharmaceutically acceptable salt.In these examples, term " pharmaceutically acceptable salt " is meant the relevant nontoxic mineral alkali and the organic bases additive salt of inhibitor.Equally, these salt can the final separation of described inhibitor and purifying prepares period in position or separately with the inhibitor of purifying with free acid form and suitable alkali, can accept oxyhydroxide, carbonate or the supercarbonate of metallic cation as pharmacy, can accept organic primary, second month in a season or reactive tertiary amine with ammoniacal liquor or with pharmacy and prepare.Representational alkaline or alkaline-earth salts comprises lithium, sodium, potassium, calcium, magnesium and aluminium salt etc.The representational organic amino that is used to form base addition salt comprise ethylamine, diethylamide, quadrol, thanomin, diethanolamine, piperazine etc. (referring to, for example, Berge et al., supra).
As described in wetting agent, emulsifying agent and lubricant also can be present in as Sodium Lauryl Sulphate BP/USP and Magnesium Stearate ethyl tinting material, releasing agent (release agents), Drug coating, sweeting agent, seasonings and flavouring agent, sanitas and antioxidant in the composition.
The example that pharmacy can be accepted antioxidant comprises: (1) water soluble antioxidant, as xitix, cysteine hydrochloride, weight sodium sulfate, Sodium Metabisulfite, S-WAT etc.; (2) oil-soluble inhibitor is as ascorbyl palmitate, butylated hydroxy anisole (BHA) (BHA), Yoshinox BHT (BHT), Yelkin TTS, Tenox PG, alpha-tocopherol etc.; (3) metal chelator is as citric acid, ethylenediamine tetraacetic acid (EDTA) (EDTA), sorbyl alcohol, tartrate, phosphoric acid etc.
Being used for preparation of the present invention comprises and is suitable for oral, nose administration, topical (comprising oral cavity and hypogloeeis), rectal administration, vagina administration, aerosol and/or parenteral admin.Described formulation can exist with unit dosage form easily, can be by well-known method preparation in the pharmaceutical field.The amount that can mix the activeconstituents that forms single formulation with solid support material will be according to the host who is treated and specific administering mode and is different.Generally speaking, the amount that can mix the activeconstituents that forms single formulation with solid support material is the amount of the described compound that can produce result of treatment.Usually, in 100%, the scope of this amount is the activeconstituents of 1%-99%, is preferably 5%-70%, most preferably is 10%-30%.
Preparing these preparations or method for compositions comprises inhibitor and carrier and chooses any one kind of them or multiple ancillary component mixes.Generally speaking, by part and liquid vehicle or finely disseminated solid carrier or both are evenly closely combined, then, three words make product shaping if desired, make preparation.
Be suitable for oral preparation and can be capsule, cachet, pill, tablet, the lozenge (substrate of use features good taste, be generally sucrose and gum arabic or Tragacanth), powder, granule, or solution or the suspensoid in water-based or non-aqueous liquid, or be oil-in-water or water-in-oil liquid emulsion, or be elixir or syrup, or be that pastille (adopts the inertia substrate, as gelatin and glycerine, or sucrose and gum arabic) and/or mouth wash shua etc., the inhibitor of each self-contained predetermined amount is as activeconstituents.The all right bolus of compound, electuary (electuary) or paste (paste) form administration.
At oral dosage form (capsule, tablet, pill, coated tablet (dragees), powder.Granules etc.) in, activeconstituents and one or more pharmaceutical acceptable carriers such as Trisodium Citrate or calcium phosphate and/or following any composition mix: (1) weighting agent or supplement, as starch, lactose, sucrose, glucose, N.F,USP MANNITOL and/or silicic acid; (2) tackiness agent is as carboxymethyl cellulose, Lalgine, gelatin, polyvinylpyrrolidone, sucrose and/or gum arabic; (3) wetting agent is as glycerine; (4) disintegrating agent is as agar-agar, lime carbonate, potato or tapioca (flour), Lalgine, some silicate and yellow soda ash; (5) solution retarding agent (solution retarding agents) is as paraffin oil; (6) absorption enhancer is as quaternary ammonium compounds; (7) wetting agent is as ethanol and glyceryl monostearate; (8) absorption agent is as kaolin and wilkinite; (9) lubricant is as talcum powder, calcium stearate, Magnesium Stearate, solid polyethylene glycol, Sodium Lauryl Sulphate BP/USP and composition thereof; (10) tinting material.Under the situation of capsule, tablet and pill, described medicinal compositions also can comprise buffer reagent.In with soft or hard filled capsules as vehicle such as lactose (lactose) or lactose (milk sugars) ethyl high molecular weight polyethylene glycols, also the solids composition of available similar type is as weighting agent.
Tablet can be chosen wantonly and one or more ancillary components compacting or molded and prepare.Compressed tablets useful binders (as gelatin or Vltra tears), lubricant, inert diluent, sanitas, disintegrating agent (primojel or croscarmellose sodium), tensio-active agent or dispersion agent preparation.Molded tablet can be by making with Powdered peptide or the mold pressing in suitable machine of plan peptide (peptidomimetic) that inert liquid diluent is got wet.
Tablet and other solid dosage can be chosen wantonly by indentation (scored) or dressing and shell as coated tablet, capsule, pill and granule, as known dressing in enteric coating and the other medicines formulation art.They also can be made into the formulation that makes activeconstituents slowly-releasing or controlled release can be provided, as the Vltra tears that adopts various ratios is to provide required release profiles, other polymeric matrix, liposome and/or microballoon.They can be sterilized, and for example dissolve in the disinfectant of the sterilization solids composition form of aqua sterilisa or some other sterilization injection media with bacterium reservation filter or adding at once before use.These compositions also can choose wantonly comprise opalizer and only or preferably at the optional composition of gi tract privileged site with the delayed mode release of active ingredients.The example of available embedding composition comprises polymer and beeswax.If suitable, activeconstituents also can be the micro-capsule form with one or more above-mentioned vehicle.
Oral liquid dosage form comprises that pharmacy can accept emulsion, microemulsion, solution, suspensoid, syrup and elixir.Except that activeconstituents, liquid dosage form also can comprise inert diluent such as water or other solvent, solubilizing agent and emulsifying agent such as ethanol, Virahol, ethyl-carbonate ethyl acetate, phenylcarbinol, peruscabin, propylene glycol, 1,3 butylene glycol, grease (particularly oleum gossypii seminis, peanut oil, Semen Maydis oil, embryo oil, sweet oil, Viscotrol C and sesame oil), glycerine, tetrahydrofuran (THF) alcohol, polyoxyethylene glycol and sorbitan fatty acid esters and composition thereof commonly used in this area.
Except that inert diluent, oral dosage form also can comprise assistant agent such as wetting agent, emulsifying agent and suspending agent, sweeting agent, seasonings, tinting material, flavouring agent and sanitas.
Except that activity inhibitor, suspensoid can comprise suspending agent, as different hard ester alcohol, polyoxyethylene sorbitol and sorbitan ester, Microcrystalline Cellulose, aluminium hydroxide (aluminummetahydroxide), wilkinite, agar-agar and Tragacanth of ethoxyquin and composition thereof.
The preparation of rectum or vagina administration can be suppository, it can mix by nonirritant excipient that one or more inhibitor and one or more are suitable or carrier and prepare, described nonirritant excipient or carrier comprise, as theobroma oil, polyoxyethylene glycol, suppository with beeswax or salicylate, it at room temperature is solid-state, be liquid under body temperature, therefore can in rectum or vaginal canal, dissolve and discharge activeconstituents.
The preparation that is suitable for vagina administration also comprises vaginal suppository, tampon (tampons), emulsifiable paste, gelifying agent, paste, foam or the sprays that comprises known carrier in suitable this area.
The part of inhibitor or subcutaneous administration formulation comprise powder, sprays, ointment, paste, emulsifiable paste, lotion, gelifying agent, solution, patch (patches) and inhalation.Activeconstituents can be under aseptic condition with pharmaceutical acceptable carrier with need and any sanitas, buffer reagent or propellant mixing.
Except that inhibitor, ointment, paste, emulsifiable paste and gelifying agent can comprise vehicle, newborn animal tallow or vegetation fat, grease, beeswax, paraffin, starch, Tragacanth, derivatived cellulose, polyoxyethylene glycol, silicone, wilkinite, silicic acid, talcum powder and zinc oxide or its mixture.
Except that inhibitor, powder and sprays can comprise vehicle, as the mixture of lactose, talcum powder, silicic acid, aluminium hydroxide, Calucium Silicate powder and polyamide powder or these materials.Sprays also can comprise propelling agent commonly used, does not replace hydrocarbon such as butane and propane as chlorine hydrofluoric ether and volatility.
Inhibitor also can aerosol (aerosol) form administration.Aqueous aerosol, Liposomal formulation or solid particulate by the preparation inclusion compound are finished administration.Available non-water (as the fluorocarbon propelling agent) suspensoid.Preferred sound wave (Sonic) atomizer is because they can make drug exposure minimize in the situation of the shear force that causes degradation.
Usually, aqueous aerosol is by the aqueous solution of medicine or suspension can accept carrier with conventional pharmaceutical and stablizer prepares.Described carrier and stablizer be according to the needs of specific compound and different, but generally include nonionic surface active agent (Tweens, pluoronics or polyoxyethylene glycol), nontoxic protein such as serum albumin, sorbitan ester, oleic acid, Yelkin TTS, amino acid such as glycine, buffer reagent, salt, sugar or sugar alcohol.Aerosol is prepared by isotonic solution usually.
Transdermal patch has more advantage, and its may command inhibitor is to the release of health.Medicine can be dissolved in or be scattered in suitable medium and prepare this type of formulation.Available absorption enhancer increases the percutaneous flow of inhibitor.Can be by rate controlling membranes being provided or in polymeric matrix or gel, disperseing to intend the speed that peptide is controlled this flow.
Ophthalmic preparation, ophthalmic ointment, powder, solution etc. are also within the scope of the invention.
The medicinal compositions of the present invention that is suitable for parenteral admin comprises one or more inhibitor and one or more pharmacy can be accepted sterile isotonic aqueous or non-aqueous solution, dispersion liquid, suspension or emulsion or can be restored sterilized powder as aseptic injectable solution or dispersion liquid before using, and it can comprise antioxidant, buffer reagent, bacteriostatic agent, make preparation and the isoosmotic solute of recipient's blood, suspending agent or thickening material in advance at once.
The suitable water or the examples of non-aqueous carriers that can be used for medicinal compositions of the present invention comprise water, ethanol, polyvalent alcohol (as glycerine, propylene glycol, polyoxyethylene glycol etc.) and suitable mixture, vegetables oil such as sweet oil and injectable organosilane ester such as ethyl oleate.Can be by adopting coating material such as Yelkin TTS, by keeping the required particle diameter of dispersion and using tensio-active agent to keep suitable flowability.
These compositions also can comprise assistant agent such as sanitas, wetting agent, emulsifying agent and dispersion agent.Can wait and guarantee to prevent action of microorganisms by antiseptic-germicide and anti-mycotic agent such as parabens (paraben), trichloro-butyl alcohol, phenol Sorbic Acid.Also may need to comprise isotonic agent in the composition, as sugar, sodium-chlor etc.In addition, also can be by adding the absorption that the reagent that can postpone to absorb such as aluminum monostearate and gelatin prolong the injectable pharmaceutical dosage form.
In some cases, in order to prolong drug effect, need slow down from the absorption of the medicine of subcutaneous or intramuscular injection.This can realize by using the crystal liquid suspension or having weak water miscible amorphous material.This moment, the uptake rate of medicine depended on its dissolution rate, thereby depended on grain size and crystal formation.Perhaps, absorb can be by with medicine dissolution or be suspended in the oiliness carrier and realize in the delay of parenteral dosage forms.
Can be by inhibitor matrix being made biodegradable polymer (as polylactide-Polycolide) micro-capsule prepares injection bank formulation (Injectable depot forms).According to medicine and polymer ratio, and the character of used particular polymers, the may command drug release rate.The example of other biodegradable polymer comprises poly-(ortho ester) and poly-(acid anhydride).The bank injection formulations also can liposome or the microemulsion compatible with bodily tissue prepare by medicine is wrapped into.
When inhibitor of the present invention gives the human and animal as medicine, can give inhibitor itself or as the medicinal compositions administration, described medicinal compositions comprises, as active ingredient and the pharmaceutical acceptable carrier of 0.1-99.5% (more preferably 0.5-90%).
This pharmaceutical preparation Orally-administrable, parenteral admin, topical or rectal administration.They are naturally to be fit to the form administration of route of administration separately.For example, they are with tablet or Capsule form administration; By injection, inhalation, eye lotions, ointment, suppository, infusion solution administration; By lotion or ointment topical; With by the suppository rectal administration.The preferred oral administration.
Term " parenteral admin " and " parenteral introduction " be meant in intestines and local topical administering mode, be generally administrated by injection, include but not limited to the injection down of injection under intravenous injection, subcutaneous injection, the epidermis, intra-articular injection, capsule, arachnoid membrane injection intraspinal injection and breastbone inner injection and infusion down.
Term " whole body administration ", " general administration ", " peripherally administered " and " periphery administration " are meant part, medicine or other material except that directly entering the central nervous system external administration, so that it enters patient's whole body and participates in metabolism and other similar procedure, as subcutaneous administration.
In order to treat disease, these inhibitor can suitable route of administration give the mankind or other animal, that described route of administration comprises is oral, nose administration is as comprising orally administering and sublingual administration with (intracisternally) administration and topical in sprays, rectal administration, vagina administration, administered parenterally, the brain pond as with powder, ointment or drops.
No matter select which kind of route of administration, the known ordinary method of all available those skilled in the art of described inhibitor is made pharmacy with suitable hydrated form and/or medicinal compositions of the present invention and can be accepted formulation.
In order to obtain, can effectively reach required result of treatment and to the amount of the nontoxic activeconstituents of patient, the actual dose level of activeconstituents can be various in the medicinal compositions of the present invention for particular patient, composition and administering mode.
IV. embodiment
Now described the present invention generally, will be more readily understood the present invention with reference to the following examples, the following examples only are some aspects of embodiment in order to demonstrate the invention, rather than in order to limit the present invention.
Embodiment 1:DPIV suppresses to measure
The preparation of inhibitor solution: it is in 2 the solution (0.01N HCl), so that the concentration of solution is 1mg/10 μ L that the 3-5mg inhibitor is dissolved in pH.Then the sample of 10 these solution of μ L is joined 990 μ L pH and be in 8 the damping fluid (0.1M HEPES, 0.14M NaCl), gained solution is standing over night at room temperature.
The preparation of enzyme solution: be 8 damping fluid dilution with the DPIV (concentration is 2.5 μ M) of 20 μ L with 40mL pH.
The preparation of substrate solution: with 2.0mg L-alanyl-L-proline(Pro)-nitro N-anilide is dissolved in 20mL pH is 8 damping fluid.
The enzyme solution of 250 μ L is joined among hole #B1-#H1, the #A2-#H2 and #A3-#H3 of 96 hole flat boards, is that 8 damping fluid replaces enzyme solution and add 250 μ L pH among the #A1 of hole.Be that 8 damping fluid joins (from hole #A5-#H5) in the post 5 then with 90 μ LpH.
By in #A5, adding inhibitor solution it is carried out 1: 10 dilution then,, shift 10 these solution of μ L to #B5 from #A5 then gained solution thorough mixing.Solution thorough mixing among the #B5 is shifted 10 these solution of μ L to #C5 from #B5 then.Solution thorough mixing among the #C5 is shifted 10 these solution of μ L to #D5 from #C5 then.Solution thorough mixing among the #D5 is shifted 10 these solution of μ L to #E5 from #D5 then.Solution thorough mixing among the #E5 is shifted 10 these solution of μ L to #F5 from #E5 then.Solution thorough mixing among the #F5 is shifted 10 these solution of μ L to #G5 from #F5 then.Solution thorough mixing among the #G5 is shifted this solution of 10uL to #H5 from #G5 then.
For H row, branch test solutions such as 30 μ l are transferred to #H3 from #H5, then with gained content thorough mixing.Repeat similar operation G, F, E, D, C, B and A row successively.With flat board jolting 5 minutes on dull and stereotyped jolting device, then flat board was at room temperature hatched 5 minutes more then.
After flat board is hatched, in each hole except that the #A1 of hole, add 30 μ L substrates.With flat board jolting 5 minutes on dull and stereotyped jolting device, then flat board was at room temperature hatched 25 minutes then.Read absorbancy immediately at the 410nm wavelength then.
Use above-mentioned assay method, record the IC of Glu-boroAla
50When pH 8 72nM, the IC of Glu-boroPro
50Be 2.4 μ M, the IC of Glu-boroEtg
50Be 49nM.
Embodiment 2:L-Ala-[5-(HOCH
2)-2-boroPro] (I) synthetic
Illustrate L-Ala-[5-(HOCH in the scheme 1
2)-2-boroPro's is synthetic:
Reagent and condition: i) Boc
2O, NaH, THF, room temperature, 94%; Ii) LiBH
4, THF ,-10 ℃, 87%; Iii) DHP, TsOH, CH
2Cl
2, 96%; Iv) LiTMP, B (OMe)
3, THF, adds HCl then by-78 ℃; V) H
2/ Pt-C, EtOAc; Vi) (+)-pinine glycol (Pinanediol), Et
2O is 60% through three step productive rates; Vii) 4N HCl dioxane solution, 60%; Viii) N-Boc-L-boroAla-OH, HATU, DIPEA, DMF, 0 ℃-room temperature, 76%; Ix) BCl
3, CH
2Cl
2,-78 ℃, 50%.
Scheme 1
From commercially available pyrrole-2-aldehyde 1, via nine steps, synthetic L-Ala-[5-(HOCH
2)-2-boroPro] (I), total recovery is 17%.At first, tetrahydrofuran solution deprotonation with pyrrole-2-aldehyde 1 usefulness sodium hydride, obtain N-Boc-pyrrole-2-aldehyde 2 with the tert-Butyl dicarbonate reaction then and (see Tietze, Deng .Synthesis of N-protected2-hydroxymethylpyrroles and transformation into acyclic oligomers.Synthesis (1996), 7:851-857).Reduction reaction takes place with lithium borohydride at-10 ℃ and obtains methylol compound 3 in aldehyde 2.Methylol with THP trtrahydropyranyl radical protection compound 3 generates THP ether 4 then.Per step is used flash chromatography on silica gel method purifying, and the overall yield in first three step is 78%.Shielded pyrroles (is seen Kell y with LiTMP (being produced in THF at-78 ℃ by n-Butyl Lithium and tetramethyl piperidine) deprotonation; et al.The efficient synthesis and simpleresolution of a prolineboronate ester suitable for enzyme-inhibitionstudies.Tetrahedron (1993); 49 (5): 1009-16); with trimethyl borate quencher reaction, add HCl hydrolysis trimethyl borate then and obtain boric acid 5.Need not to be further purified, the ethyl acetate solution hydrogenation of compound 5 usefulness 5%Pt/C obtains tetramethyleneimine-2-boric acid 6.The ethereal solution of crude product 6 and 1.05 equivalent (+)-pinine glycols at room temperature stirs, and obtaining shielded 7, three step of 5-methylol boroPro pinane diol ester yield with flash chromatography on silica gel method purifying then is 60%.Remove tert-butoxycarbonyl (Boc) with the dioxane solution of 4NHCl and obtain midbody compound 8, productive rate is 94%.With compound 8 in the presence of HATU and DIPEA with the N-Boc-L-Ala-OH coupling, use BCl then
3With Boc and pinane blocking group deprotection, obtain target dipeptides boric acid ester I, last two step yields are 38%.
Embodiment 3:L-Ala-5-Me-boroPro's (II) is synthetic
Illustrate the synthetic of L-Ala-5-Me-boroPro in the scheme 2:
Reagent and condition: i:Boc
2O, NEt
3, DMAP, CH
2Cl
2, 93%; Ii:s-BuLi, TMEDA, (i-PrO)
3B, THF, adds NaOH then by-78 ℃; Iii:(+)-and pinine glycol, Et
2O, two step yields are 74%; The dioxane solution of iv:4N HCl, 88%; V:N-Boc-L-boroAla-OH, HATU, DIPEA, DMF, 0 ℃-room temperature, 85%; Vi:BCl
3, CH
2Cl
2,-78 ℃, 70%.
Scheme 2
From commercially available 2-crassitude synthetic L-Ala-5-Me-boroPro (II) shown in scheme 2.At first, 2-crassitude and tert-Butyl dicarbonate are reacted in the presence of triethylamine and DMAP, obtain N-Boc-tetramethyleneimine 1.With the THF-TMEDA solution of s-BuLi (2.2 equivalent) (see Gibson, etc.A Practical Synthesis ofL-Valyl-pyrrolidine-(2R)-boronic acid：Efficient Recycling of the CostlyChiral Auxiliary(+)-Pinanediol。Organic Process Research ﹠amp; Development (2002), 6 (6): 814-816.) at-78 ℃ of C-lithiumation things that obtain the N-Boc-tetramethyleneimine, then with triisopropyl boric acid ester quencher reaction.Then with after the HCl processing, crude product boric acid is protected with (+)-pinine glycol with NaOH.Behind flash chromatography on silica gel method purifying, the productive rate that obtains pure 2, two steps of boric acid ester compound is 51%.Remove tert-butoxycarbonyl (Boc) with the dioxane solution of 4N HCl and obtain intermediate 5-methyl boroPro pinane diol ester 3.With compound 3 and N-Boc-L-Ala-OH coupling in the presence of HATU and DIPEA, use BCl then
3Remove Boc and pinane blocking group and obtain target dipeptides boric acid ester II, last two step yields are 60%.
Embodiment 4:L-Ala-cis-boroHyp (III) and Ala-be trans-boroHyp (IV) synthetic
Illustrate in the scheme 3 L-Ala-cis-boroHyp and Ala-trans-boroHyp synthetic.
Reagent and condition: i:s-BuLi, TMEDA, (i-PrO)
3B, THF, adds NaOH then by-78 ℃; Ii:(+)-and pinine glycol, Et
2O, 51%; The dioxane solution of iii:4N HCl, 90-93%; Iv:N-Boc-L-boroAla-OH, HATU, DIPEA, DMF, 0 ℃-room temperature, 80-85%; V:BCl
3, CH
2Cl
2,-78 ℃, 50-55%; Vi:DEAD, Ph
3P, p-NO
2-PhCO
2H, THF, 67%; Vii:LiOH, THF-H
2O, 93%.
Scheme 3
From N-(tert-butoxycarbonyl)-(S)-(+)-3-pyrrolidinol (pyrrolidinol) with synthetic L-Ala-cis-boroHyp (III) of the method for example the scheme 3 and L-Ala-trans-boroHyp (IV).At first, the C-lithium that carries out the N-Boc-3-hydroxyl pyrrolidine with the THF-TMEDA solution of s-BuLi (2.2 equivalent) (see Gibson, etc., above-cited) connects, then with triisopropyl boric acid ester quencher reaction.Then with after the HCl processing, obtain cis-2 with NaOH, the dibasic adducts of 4-is as main diastereomer.With (+)-pinine glycol protection boric acid, obtain pure boric acid ester compound 1a from the ethyl acetate crystallization then, the productive rate in two steps is 51%.(see Hodges by the Mitsunobu reaction, Deng .Stereoelectronic Effects on Collagen Stability:TheDichotomy of 4-Fluoroproline Diastereomers.J.Am.Chem.Soc. (2003), 125 (31): 9262-3) the C-4 position atom of 1a is carried out configuration conversion and obtain 4 (R)-boroHyp derivative 1b, productive rate is 62%.The tert-butoxycarbonyl of removing among 1a or the 1b with the dioxane solution of 4N HCl (Boc) obtains cis-boroHyp pinane diol ester 2a or trans-boroHyp pinane diol ester 2b.
BCl is used in compound 2a or 2b and N-Boc-L-Ala-OH coupling in the presence of HATU and DIPEA then
3Remove Boc and pinane blocking group and obtain target dipeptides boric acid ester III or IV, last two step productive rates are 40-45%.
Embodiment 5:DPIV restraining effect is measured
The compound for preparing among the embodiment 2-4 is tested with the assay method of describing among the embodiment 1.
L-Ala-[5-(HOCH
2)-2-boroPro] at the IC of pH 2
50Be 21.92nM, at the IC of pH8
50Be 12.88 μ M.
L-Ala-5-Me-boroPro is at the IC of pH 2
50Be 11.04nM, at the IC of pH8
50Be 15.41 μ M.
L-Ala-cis-boroHyp is at the IC of pH 2
50Be 2.95nM, at the IC of pH 8
50Be 5.44 μ M.
L-Ala-is trans-and boroHyp is at the IC of pH 2
50Be the IC of 31.13nM at pH 8
50Be 64.29 μ M.
According to above-mentioned data, can determine that for hydroxylated boroPro-type inhibitor hydroxyl is preferably in the cis position of boric acid part (or its precursor).And according to these results, those skilled in the art can be by on the proline(Pro) ring of modifying at boric acid, preferably in the 4-position of ring and/or preferably add hydroxyl in the cis position of boric acid base group (or its precursor), thereby modifies U.S. Patent No. 6,803,357; The U. S. application Nos.10/496 that on May 25th, 2004 submitted to, 706 and 10/496,627; With the U.S. Provisional Application No.60/584 that submitted on July 1st, 2004, disclosed compound in 581, its full content is attached to herein by reference.
Also to L-Ala-[5-(HOCH
2)-2-boroPro] carried out test to determine its restraining effect to dipeptidyl peptidase 8 and 9 (DP8 and DP9).This measures identical with the method for description among the embodiment 1, only replaces DPIV with DP8 or DP9.At the pH value of test, L-Ala-[5-(HOCH
2)-2-boroPro] IC
50Greater than 70 μ M.
Embodiment 6: to the selectivity of dipeptidyl peptidase abnormal shape (Isoforms)
Determine the IC of the several compounds of the present invention with the method for describing among the embodiment 1
50Value.What carry out in this embodiment, is mensuration to DPIV and DP9.Calculate the IC of each test compound
50Value is so that determine its selectivity to the DPIV abnormal shape.In the mensuration process, under same pH, detect IC
50Value.
| Compound | DPIV IC 50(nM) | DP9 IC 50(nM) | The DP9/DPIV ratio |
| L-Ala-[5-(HOCH 2)-2-boroPro] | 40 | 2.80x10 7 | 700,000 |
| Arg-boroPro | 2 | 824 | 412 |
| Glu-boroPro | 3 | 20 | 6.67 |
| Asp-boroAla | 796800 | 5x10 6 | 6.28 |
| Arg-boroAla | 8 | 23 | 2.88 |
| Arg- |
10 | 7 | 0.70 |
Although the selectivity that all shows DPIV except all compounds of Arg-boroEtGly is better than DP9 (and supposition is better than similar DP8), the methylolated boroPro compound of 5-has high selectivity to DPIV.According to these data, can be expected on the proline(Pro) that boric acid modifies and add that the part that comprises hydroxyl, alkyl or hydroxyalkyl will produce the higher optionally inhibitor of DPIV tool.And this type of group is preferably in the cis position of boroPro boric acid base group (or its precursor).Correspondingly, the preferred compound of the present invention is better than it to inhibiting at least 10 times of DP8 and/or DP9 to the restraining effect of DPIV, preferably at least 100 times, promptly suppresses the IC of DPIV
50At least be lower than the IC that suppresses DP8 and/or DP9
50At least 10 times (or 100 times).
According to these results, those skilled in the art have higher optionally inhibitor in order to obtain to DPIV, can be by adding the part that comprises hydroxyl, alkoxyl group, alkyl or hydroxyalkyl on the proline(Pro) of modifying at boric acid, preferably add the part that comprises alkoxyl group, alkyl or hydroxyalkyl or add hydroxylic moiety in the 4-position in the cis position of boric acid base group (or its precursor) or in the 5-position, thereby modify U.S. Patent No. 6,803,357; The U. S. application Nos.10/496 that on May 25th, 2004 submitted to, 706 and 10/496,627; With the U.S. Provisional Application No.60/584 that submitted on July 1st, 2004, disclosed compound in 581, its full content is attached to herein by reference
IV. be equal to embodiment
Those skilled in the art only just will appreciate that with normal experiment maybe can determine the specific many embodiments that are equal to that can embodiment of the present invention described herein.This type of is equal to embodiment and is included in the following claim.
All the above-mentioned reference quoted and publication are attached to herein by reference at this.
Claims (14)
1. compound or its pharmaceutically acceptable salt of a tool formula IV structure:
Formula IV
Wherein
A is selected from the 4-8 unit heterocycle that comprises N and C α carbon;
Z is C or N;
W be selected from CN ,-CH=NR
5, with the functional group of targeting proteins enzyme active sites residue reaction,
R
1Be selected from peptide that amino-acid residue that C-end connects or amino acid analogue, C-end connect or peptide analogs, amino-blocking group,
R
2The substituting group of representing one or more ring A, each independently be selected from halogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, lower alkoxy, rudimentary hydroxyalkyl, low-grade alkoxy alkyl, carbonyl, thiocarbonyl, amino, acyl amino, amido, cyano group, nitro, azido-, sulfate group, sulfonate group, sulfonamido ,-(CH
2)
m-R
7,-(CH
2)
m-OH ,-(CH
2)
m-O-low alkyl group ,-(CH
2)
m-O-low-grade alkenyl ,-(CH
2)
n-O-(CH
2)
m-R
7,-(CH
2)
m-SH ,-(CH
2)
m-S-low alkyl group ,-(CH
2)
m-S-low-grade alkenyl or-(CH
2)
n-S-(CH
2)
m-R
7, at least one R wherein
2Be selected from-OH, low alkyl group, lower alkoxy, rudimentary hydroxyalkyl and low-grade alkoxy alkyl;
When Z is N, R
3Be hydrogen;
When Z is C, R
3Be selected from hydrogen, halogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, carbonyl, thiocarbonyl, amino, acyl amino, amido, cyano group, nitro, azido-, sulfate group, sulfonate group, sulfonamido ,-(CH
2)
m-R
7,-(CH
2)
m-OH ,-(CH
2)
m-O-low alkyl group ,-(CH
2)
m-O-low-grade alkenyl ,-(CH
2)
n-O-(CH
2)
m-R
7,-(CH
2)
m-SH ,-(CH
2)
m-S-low alkyl group ,-(CH
2)
m-S-low-grade alkenyl and-(CH
2)
n-S (CH
2)
m-R
7
R
5Be selected from hydrogen, alkyl, thiazolinyl, alkynyl ,-C (X
1) (X
2) X
3,-(CH
2)
m-R
7,-(CH
2)
n-OH ,-(CH
2)
n-O-alkyl ,-(CH
2)
n-O-thiazolinyl ,-(CH
2)
n-O-alkynyl ,-(CH
2)
n-O-(CH
2)
m-R
7,-(CH
2)
n-SH ,-(CH
2)
n-S-alkyl ,-(CH
2)
n-S-thiazolinyl ,-(CH
2)
n-S-alkynyl ,-(CH
2)
n-S-(CH
2)
m-R
7,-C (O) C (O) NH
2With-C (O) C (O) OR
7';
R
6Be selected from hydrogen, halogen, alkyl, thiazolinyl, alkynyl, aryl ,-(CH
2)
m-R
7,-(CH
2)
m-OH ,-(CH
2)
m-O-alkyl ,-(CH
2)
m-O-thiazolinyl ,-(CH
2)
m-O-alkynyl ,-(CH
2)
m-O-(CH
2)
mR
7,-(CH
2)
m-SH ,-(CH
2)
m-S-alkyl ,-(CH
2)
m-S-thiazolinyl ,-(CH
2)
m-S-alkynyl or-(CH
2)
m-S-(CH
2)
m-R
7,
Each R
7Independently be selected from aryl, aralkyl, cycloalkyl, cycloalkenyl group and heterocyclic radical;
Each R
7' independently be selected from hydrogen, alkyl, thiazolinyl, aryl, aralkyl, cycloalkyl, cycloalkenyl group and heterocyclic radical;
R
8And R
9Independently be selected from hydrogen, alkyl, thiazolinyl ,-(CH
2)
m-R
7,-C (=O)-alkyl ,-C (=O)-thiazolinyl ,-C (=O)-alkynyl and-C (=O)-(CH
2)
m-R
7Or
R
8And R
9Form the heterocycle that has 4-8 atom on the ring structure with the N atom that connects them;
R
50Be O or S;
R
51Be selected from N
3, SH, NH
2, NO
2And OR
7';
R
52Be selected from hydrogen, low alkyl group, amine, OR
7', or its pharmaceutically acceptable salt, or
R
51And R
52Form the heterocycle that has 5-8 atom on the ring structure with the P atom that connects them;
X
1Be halogen;
X
2And X
3Be selected from hydrogen and halogen separately;
Y
1And Y
2Independently be selected from the group that OH and hydrolyzable are OH, comprise wherein Y
1And Y
2By the continuous cyclic derivatives of ring that has 5-8 atom on the ring structure;
M be 0 or the 1-8 scope in integer; And
N is the integer in the 1-8 scope.
2. the compound of claim 1, wherein said compound is a proteinase inhibitor.
3. the inhibitor of claim 2, wherein said proteinase inhibitor is with 50nm or lower K
iSuppress DPP IV (DPIV).
4. each compound among the claim 1-3 is effective when oral.
5. medicinal compositions, described composition comprise among pharmaceutical acceptable carrier and the claim 1-4 each compound or its pharmaceutically acceptable salt or its prodrug.
6. the purposes of each compound in produce suppressing the medicine of postproline cleavage enzyme among the claim 1-4.
7. the purposes of claim 6, wherein said compound increases the plasma concentration of peptide hormone, and described peptide hormone is selected from glucagon-like peptide, NPY, PPY, secretin, GLP-1, GLP-2 and GIP.
8. each compound is being produced the purposes of regulating in the glucose metabolism medicine among the claim 1-4.
9. the purposes of claim 8 is used to regulate the patient's who suffers from type ii diabetes, insulin resistant, glucose intolerance, hyperglycemia, hypoglycemia, hyperinsulinemia, obesity, hyperlipidaemia or hyperlipoproteinemia glucose metabolism.
10. method that suppresses the postproline cleavage enzyme proteolytic activity, described method comprise enzyme are contacted with each compound among the claim 1-4.
Require the preparation of each compound among the 1-4 and describe the specification sheets that uses described preparation to suppress postproline cleavage enzyme 11. a packaged pharmaceuticals, described pharmaceutical pack contain right.
Require the preparation of each compound among the 1-4 and describe the specification sheets that uses described preparation to regulate glucose metabolism 12. a packaged pharmaceuticals, described pharmaceutical pack contain right.
13. the packaged pharmaceuticals of claim 12, wherein said compound and Regular Insulin and/or pancreotropic hormone medicine are formulated together or packaging together.
14. the packaged pharmaceuticals of claim 12, wherein said compound and M1 receptor antagonist, prolactin inhibitor, medicine, N1,N1-Dimethylbiguanide and/or the glucosidase inhibitor of ATP-dependency potassium channel that acts on beta cell are formulated together or packaging together.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US54722704P | 2004-02-23 | 2004-02-23 | |
| US60/547227 | 2004-02-23 | ||
| US60/599336 | 2004-08-06 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200580011588XA Division CN1942182B (en) | 2004-02-23 | 2005-02-23 | Inhibitors of dipeptidylpeptidase IV for regulating glucose metabolism |
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| Publication Number | Publication Date |
|---|---|
| CN101565429A true CN101565429A (en) | 2009-10-28 |
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|---|---|---|---|---|
| CN102203130A (en) * | 2010-08-06 | 2011-09-28 | 浙江贝达药业有限公司 | Glp-1 derivative and application thereof |
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|---|---|---|---|---|
| DK716188D0 (en) * | 1988-12-22 | 1988-12-22 | Ferrosan As | QUINOXAL COMPOUNDS, THEIR PREPARATION AND USE |
| WO1999021008A1 (en) * | 1997-10-23 | 1999-04-29 | Pharmaprint, Inc. | Pharmaceutical grade garlic |
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| CN102203130A (en) * | 2010-08-06 | 2011-09-28 | 浙江贝达药业有限公司 | Glp-1 derivative and application thereof |
| CN102203130B (en) * | 2010-08-06 | 2014-06-25 | 贝达药业股份有限公司 | Glp-1 derivative and application thereof |
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|---|---|
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| CN1942182A (en) | 2007-04-04 |
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