Summary of the invention
Summary of the invention
The present invention relates to compound, it is that the inhibitor (" DP-IV inhibitor ") of dipeptidyl peptidase-IV enzyme and its are used for the treatment of or prevention and dipeptidyl peptidase-IV enzyme diseases associated such as diabetes, particularly type ii diabetes.The invention still further relates to the pharmaceutical composition that contains these compounds and these compounds and composition prevention or treat these and dipeptidyl peptidase-IV enzyme diseases associated in purposes.
Detailed description of the invention
The present invention relates to the compound of formula I:
Wherein: Ar is a phenyl, and it is unsubstituted or by 1-5 R5 replacement, wherein R5 is independently selected from:
(1) halogen,
(2) C
1-6Alkyl, it is linear or branched and is unsubstituted or is replaced by 1-5 halogen,
(3) OC
1-6Alkyl, its be linear or branched and be unsubstituted or replaced by 1-5 halogen and
(4)CN;
X is selected from:
(1) N and
(2)CR1;
Y is selected from:
(1) N and
(2)CR2;
Z is selected from:
(1) N and
(2)CR3;
R1, R2 and R3 are independently selected from:
(1) hydrogen,
(2)CN,
(3) C1-10 alkyl, it is linear or branched and is unsubstituted or is replaced by 1-5 halogen or phenyl, described phenyl is unsubstituted or by 1-5 substituting group replacement, described substituting group is independently selected from halogen, CN, OH, R4, OR4, NHSO2R4, SO2R4, CO2H and CO2C
1-6Alkyl, wherein said CO2C
1-6Alkyl is linear or branched,
(4) phenyl, it is unsubstituted or by 1-5 substituting group replacement, described substituting group is independently selected from halogen, CN, OH, R4, OR4, NHSO2R4, SO2R4, CO2H and CO2C
1-6Alkyl, wherein said CO2C
1-6Alkyl be linear or branched and
(5) 5-or 6-unit heterocycle, it can be saturated or undersaturated and comprise the heteroatoms that 1-4 is independently selected from N, S and O, described heterocycle is unsubstituted or is independently selected from oxo, OH, halogen, C by 1-3
1-6Alkyl and OC
1-6The substituting group of alkyl replaces, wherein said C
1-6Alkyl and OC
1-6Alkyl is linear or branched and optional by 1-5 halogen replacement;
R4 is C
1-6Alkyl, it is linear or branched and it is unsubstituted or is independently selected from halogen, CO2H and CO2C by 1-5
1-6The group of alkyl replaces, wherein said CO2C
1-6Alkyl is linear or branched;
And pharmacy acceptable salt and each diastereomer.
In the present invention, Ar is phenyl preferably, and it is unsubstituted or by 1-5 substituting group replacement, described substituting group is independently selected from:
(1) fluorine,
(2) bromine and
(3)CF3。
In the present invention, Ar more preferably is selected from:
(1) phenyl,
(2) 2-fluorophenyl,
(3) 3,4-difluorophenyls,
(4) 2,5-difluorophenyls,
(5) 2,4, the 5-trifluorophenyl,
(6) 2-fluoro-4-(trifluoromethyl) phenyl and
(7) the 4-bromo-2, the 5-difluorophenyl.
In the present invention, R1, R2 and R3 are preferably selected from:
(1) hydrogen and
(2) C
1-6Alkyl, it is linear or branched and it is unsubstituted or is replaced by phenyl or 1-5 fluorine.
In the present invention, R2 and R3 more preferably are selected from:
(1) hydrogen,
(2) methyl,
(3) ethyl,
(4)CF3,
(5)CH2CF3,
(6)CF2CF3,
(7) phenyl and
(8) benzyl.
In the present invention, R1 is more preferably hydrogen.
In the present invention, R2 and R3 are preferably selected from:
(1) hydrogen,
(2) C
1-6Alkyl, it is linear or branched and is unsubstituted or is replaced by 1-5 fluorine,
(3) phenyl, it is unsubstituted or is replaced by the substituting group that 1-3 is independently selected from fluorine, OCH3 and OCF3.
In the present invention, R2 and R3 more preferably are selected from:
(1) hydrogen,
(2) methyl,
(3) ethyl,
(4)CF3,
(5)CH2CF3,
(6)CF2CF3,
(7) phenyl,
(8) (4-methoxyl group) phenyl,
(9) (4-trifluoromethoxy) phenyl,
(10) the 4-fluorophenyl and
(11) 3,4-difluorophenyls and
(12) sec.-propyl.
In the present invention, preferably F, Br or CF3 of R5.
The present invention relates to the compound of formula II:
Wherein: Ar is a phenyl, and it is unsubstituted or by 1-5 R5 replacement, wherein R5 is independently selected from:
(1) halogen,
(2) C
1-6Alkyl, it is linear or branched and is unsubstituted or is replaced by 1-5 halogen,
(3) OC
1-6Alkyl, its be linear or branched and be unsubstituted or replaced by 1-5 halogen and
(4)CN;
X1 is selected from:
(1) N and
(2)CR1;
Y1 is selected from:
(1) N and
(2)CR2;
Z is selected from:
(1) N and
(2)CR3;
R1, R2 and R3 are independently selected from:
(1) hydrogen,
(2)CN,
(3) C1-10 alkyl, it is linear or branched and it is unsubstituted or is replaced by 1-5 halogen or phenyl, described phenyl is unsubstituted or by 1-5 substituting group replacement, described substituting group is independently selected from halogen, CN, OH, R4, OR4, NHSO2R4, SO2R4, CO2H and CO2C
1-6Alkyl, wherein said CO2C
1-6Alkyl is linear or branched,
(4) phenyl, it is unsubstituted or by 1-5 substituting group replacement, described substituting group is independently selected from halogen, CN, OH, R4, OR4, NHSO2R4, SO2R4, CO2H and CO2C
1-6Alkyl, wherein said CO2C
1-6Alkyl be linear or branched and
(5) 5-or 6-unit heterocycle, it can be saturated or undersaturated and comprise the heteroatoms that 1-4 is independently selected from N, S and O, described heterocycle is unsubstituted or is independently selected from oxo, OH, halogen, C by 1-3
1-6Alkyl and OC
1-6The substituting group of alkyl replaces, wherein said C
1-6Alkyl and OC
1-6Alkyl is linear or branched and optional by 1-5 halogen replacement;
R4 is C
1-6Alkyl, it is linear or branched and it is unsubstituted or is independently selected from halogen, CO2H and CO2C by 1-5
1-6The group of alkyl replaces, wherein said CO2C
1-6Alkyl is linear or branched;
And pharmacy acceptable salt and each diastereomer.
In the present invention, Ar is phenyl preferably, and it is unsubstituted or by 1-5 substituting group replacement, described substituting group is independently selected from:
(1) fluorine,
(2) bromine and
(3)CF3。
In the present invention, Ar more preferably is selected from:
(1) phenyl,
(2) 2-fluorophenyl,
(3) 3,4-difluorophenyls,
(4) 2,5-difluorophenyls,
(5) 2,4, the 5-trifluorophenyl,
(6) 2-fluoro-4-(trifluoromethyl) phenyl and
(7) the 4-bromo-2, the 5-difluorophenyl.
In the present invention, R1, R2 and R3 are preferably selected from:
(1) hydrogen and
(2) C
1-6Alkyl, it is linear or branched and it is unsubstituted or is replaced by phenyl or 1-5 fluorine.
In the present invention, R2 more preferably is selected from:
(1) hydrogen,
(2) methyl,
(3) ethyl,
(4)CF3,
(5)CH2CF3,
(6)CF2CF3,
(7) phenyl and
(8) benzyl.
In the present invention, preferably F, Br or CF3 of R5.
The present invention relates to the compound of formula III:
Wherein: Ar is a phenyl, and it is unsubstituted or by 1-5 R5 replacement, wherein R5 is independently selected from:
(1) halogen,
(2) C
1-6Alkyl, it is linear or branched and is unsubstituted or is replaced by 1-5 halogen,
(3) OC
1-6Alkyl, its be linear or branched and be unsubstituted or replaced by 1-5 halogen and
(4)CN;
X2 is selected from:
(1) N and
(2)CR1;
Y2 is selected from:
(1) N and
(2)CR2;
Z2 is selected from:
(1) N and
(2)CR3;
R1, R2 and R3 are independently selected from:
(1) hydrogen,
(2)CN,
(3) C1-10 alkyl, it is linear or branched and it is unsubstituted or is replaced by 1-5 halogen or phenyl, described phenyl is unsubstituted or by 1-5 substituting group replacement, described substituting group is independently selected from halogen, CN, OH, R4, OR4, NHSO2R4, SO2R4, CO2H and CO2C
1-6Alkyl, wherein said CO2C
1-6Alkyl is linear or branched,
(4) phenyl, it is unsubstituted or by 1-5 substituting group replacement, described substituting group is independently selected from halogen, CN, OH, R4, OR4, NHSO2R4, SO2R4, CO2H and CO2C
1-6Alkyl, wherein said CO2C
1-6Alkyl be linear or branched and
(5) 5-or 6-unit heterocycle, it can be saturated or undersaturated and comprise the heteroatoms that 1-4 is independently selected from N, S and O, described heterocycle is unsubstituted or is independently selected from oxo, OH, halogen, C by 1-3
1-6Alkyl and OC
1-6The substituting group of alkyl replaces, wherein said C
1-6Alkyl and OC
1-6Alkyl is linear or branched and optional by 1-5 halogen replacement;
R4 is C
1-6Alkyl, it is linear or branched and it is unsubstituted or is independently selected from halogen, CO2H and CO2C by 1-5
1-6The group of alkyl replaces, wherein said CO2C
1-6Alkyl is linear or branched;
And pharmacy acceptable salt and each diastereomer.
In the present invention, Ar is phenyl preferably, and it is unsubstituted or by 1-5 substituting group replacement, described substituting group is independently selected from:
(1) fluorine,
(2) bromine and
(3)CF3。
In the present invention, Ar more preferably is selected from:
(1) phenyl,
(2) 2-fluorophenyl,
(3) 3,4-difluorophenyls,
(4) 2,5-difluorophenyls,
(5) 2,4, the 5-trifluorophenyl,
(6) 2-fluoro-4-(trifluoromethyl) phenyl and
(7) the 4-bromo-2, the 5-difluorophenyl.
In the present invention, R1, R2 and R3 are preferably selected from:
(1) hydrogen and
(2) C
1-6Alkyl, its be linear or branched and its be unsubstituted or by phenyl or
1-5 fluorine replaces.
In the present invention, preferably F, Br or CF3 of R5.
Compound of the present invention can contain one or more asymmetric centers, and therefore can occur with the form of racemic modification and racemic mixture, single enantiomer, non-enantiomer mixture and each diastereomer.Compound of the present invention has an asymmetric center at the beta carbon place.
Depend on each substituent character in the molecule, can have other asymmetric center.Each such asymmetric center will generate two kinds of optical isomers independently, the present invention includes all possible optical isomer and non-enantiomer mixture and pure or partial-purified compound.The present invention includes all these isomeric form of these compounds.
Compounds more described herein contain olefinic double bond, except as otherwise noted, the present invention includes two kinds of geometrical isomers of E and Z.
Compounds more described herein can exist with the form of tautomer, and it has different hydrogen points of contact by following one or more pairs of keys to move.For example, ketone and enol form thereof are the keto-enol tautomerism bodies.
Each tautomer and composition thereof all is included in the compound of the present invention.
Passing through as known in the art carries out suitable improvement to method disclosed herein, can realize synthetic or their chromatographic separation of the independence of these diastereomers.The X-ray crystalline diffraction of the crystal intermediate by crystalline product or derivatize (if necessary, deriving with the reagent of the asymmetric center that contains known absolute configuration) can be determined their absolute stereo chemistry.
If necessary, can separate the racemic mixture of described compound, so that separate each enantiomer.Can separate by means commonly known in the art, for example the compound coupling of the racemic mixture of compound and enantiomeric pure to be to form non-enantiomer mixture, then separates each diastereomer by standard method such as fractionation crystallization or chromatography.Use the acid of enantiomeric pure or the coupled reaction of alkali to generate salt usually.Then, the cracking by the chirality residue that adds is converted into pure enantiomer with described non-enantiomer derivative.The racemic mixture of described compound can also directly separate by the chromatography of using chiral stationary phase, and this method is known in the art.
Perhaps, use the optically pure starting material or the reagent of configuration known, by means commonly known in the art, by the synthetic any enantiomorph that can obtain compound of stereoselectivity.
Term " pharmacy acceptable salt " is meant the salt that is made by pharmaceutically acceptable nontoxic alkali or acid (comprising inorganic or organic bases and inorganic or organic acid).The salt that derives from these mineral alkalis comprises salt such as aluminium, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganic salt, bivalent manganese, potassium, sodium, zinc.Particularly preferably be ammonium, calcium, magnesium, potassium and sodium salt.May there be more than a kind of crystalline structure in the salt of solid-state form, and can be with the form of hydrate.The salt that derives from pharmaceutically acceptable organic nontoxic alkali comprises the salt of following compound: primary, the second month in a season and tertiary amines, substitutional amine-group, comprise naturally occurring substitutional amine-group, cyclammonium and Zeo-karb, arginine for example, trimethyl-glycine, caffeine, choline, N, N '-dibenzyl-ethylenediamin, diethylamine, 2-diethylaminoethanol, the 2-dimethylaminoethanol, thanomin, quadrol, N-ethyl-morpholine, N-ethylpiperidine, glycosamine, glucosamine, Histidine, breathe out amine, Isopropylamine, Methionin, methylglucosamine, morpholine, piperazine, piperidines, the polyamines resin, PROCAINE HCL, PHARMA GRADE, purine, Theobromine, triethylamine, Trimethylamine 99, tripropyl amine, tromethane etc.
When compound of the present invention was alkalescence, salt can be made by pharmaceutically acceptable non-toxic acid, comprises mineral acid and organic acid.These acid comprise, acetate, Phenylsulfonic acid, phenylformic acid, camphorsulfonic acid, citric acid, ethyl sulfonic acid, fumaric acid, glyconic acid, L-glutamic acid, Hydrogen bromide, hydrochloric acid, hydroxyl second (base) sulfonic acid, lactic acid, toxilic acid, oxysuccinic acid, amygdalic acid, methylsulfonic acid, glactaric acid, nitric acid, pounce on acid, pantothenic acid, phosphoric acid, succsinic acid, sulfuric acid, tartrate, tosic acid etc.Particularly preferably be citric acid, Hydrogen bromide, hydrochloric acid, toxilic acid, phosphoric acid, sulfuric acid, fumaric acid and tartrate.
When being appreciated that the compound as volume type I in this article, it is meant and also comprises its pharmacy acceptable salt.
Understandable as those skilled in the art, be to be used for comprising fluorine, chlorine, bromine and iodine at this employed halo or halogen.Similarly, C1-8, when being defined in the C1 alkyl to determine to have the group of 1,2,3,4,5,6,7 or 8 carbon in linearity or branch arrangement, the C1 alkyl comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, amyl group, hexyl, heptyl and octyl group particularly like this.Equally, C0 is defined by existing direct covalent linkage in the C0 alkyl.A kind of group, it is called as and is substituted basic replacement independently and can be independently replaced by a plurality of these substituting groups.At this employed term " heterocyclic radical " is to be used for being included in following institute: 5-in the row scope or 6-unit member ring systems benzimidazolyl-, benzo
Alkyl, benzofuryl, benzopyrazoles base, diazosulfide base, benzotriazole base, benzothienyl, benzo
Di azoly, benzo
Azoles base, carbazyl, carbolinyl, chromanyl, cinnolines base, furyl, imidazolyl, indolinyl, indyl, indolazinyl, indazolyl, isobenzofuran-base, pseudoindoyl, isoquinolyl, isothiazolyl, different
Azoles base, naphthyridinyl,
Di azoly,
Azoles base, pyrazinyl, pyrazolyl, pyridopyridine base, pyridazinyl, pyridyl, pyrimidyl, pyrryl, quinazolyl, quinolyl, quinoxalinyl, tetrazyl, thiadiazolyl group, thiazolidyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-two
Alkyl, six hydrogen azepine bases, piperazinyl, piperidyl, pyrrolidyl, morpholinyl, thio-morpholinyl, dihydrobenzo imidazolyl, dihydro benzo furyl, dihydrobenzo thienyl, dihydrobenzo
Azoles base, dihydrofuran base, glyoxalidine base, indolinyl, dihydro are different
Azoles base, dihydro isothiazolyl, dihydro
Di azoly, dihydro
Azoles base, dihydro pyrazinyl, pyrazoline base, dihydropyridine base, dihydro-pyrimidin base, pyrrolin base, dihydroquinoline base, dihydro tetrazyl, thiodiazoline base, dihydro-thiazolyl, dihydro-thiophene base, dihydro triazolyl, dihydro azetidinyl, methylenedioxyphenyl formyl radical, tetrahydrofuran base, imidazolidine base, tetrahydro isoquinolyl and tetrahydro-thienyl.
The present invention illustrates the purposes at embodiment and compound disclosed herein.
Particular compound of the present invention is included in disclosed compound and pharmacy acceptable salt and each diastereomer in the following example.
Compound of the present invention is used for suppressing to comprise the described compound that gives significant quantity in the method for dipeptidyl peptidase-IV enzyme the patient of this inhibition of needs such as Mammals.
The present invention relates to the purposes of compound disclosed herein as the dipeptidyl peptidase-IV activity inhibitor.
Except that primate such as people, method of the present invention can be used for treating multiple other Mammals.For example, treatable Mammals includes but not limited to ox, sheep, goat, horse, dog, cat, cavy, rat or other ox, sheep, horse, dog, cat family, rodent or murine species.Yet this method can also be used for other species such as avian species (for example, chicken).
The invention still further relates to preparation and in humans and animals, be used to suppress the method for the medicine of dipeptidyl peptidase-IV enzymic activity, comprise compound of the present invention and pharmaceutical carrier or mixing diluents.
The treatment target of the inventive method normally needs to suppress the Mammals of dipeptidyl peptidase-IV enzymic activity, preferred people, sex.Term " treatment significant quantity " is meant the quantity of the The compounds of this invention of the biology that will cause tissue, system, animal or human looked for by researchist, animal doctor, attending doctor or other clinicist or medical response.
Be meant the product that comprises the special component that contains specific quantity at this employed term " composition ", and any directly or indirectly from the product of the combination of the special component of specific quantity.Term " pharmaceutical composition " is meant and comprises the inert component that contains activeconstituents, constitute carrier and the product of any product, it is directly or indirectly by any two or more composition mixing, complexing or gathering, or decompose, or obtain by the reaction or the interaction of other type of one or more compositions by one or more compositions.
Therefore, pharmaceutical composition of the present invention comprises any composition that mixes acquisition by compound of the present invention with pharmaceutically acceptable carrier.Term " pharmaceutically acceptable " is meant that carrier, thinner or vehicle must be compatible with other composition of preparation and the experimenter do not poisoned.
Term " gives compound " and/or " administration of compound " is construed as the prodrug that compound of the present invention or The compounds of this invention are provided to the individuality of needs treatment.
The compounds of this invention can prove by methods known in the art as the practicality of dipeptidyl peptidase-IV activity inhibitor.Suppress the following mensuration of constant.Use the continuous fluorescence assay method of band substrate Gly-Pro-AMC, it discharges fluorescence AMC leavings group by the DP-IV cracking.The kinetic parameter of describing this reaction is as follows: Km=50JAM; Kcat=75s-1; Kcat/Km=1.5x106M-1s-1.In the 100l total reaction volume, type reaction comprises about 50pM enzyme, 50 μ M Gly-Pro-AMC and damping fluid (100mM HEPES, pH 7.5,0.1mg/ml BSA).Use the excitation wavelength of 360nm and the emission wavelength of 460nm, the release of continuous monitoring AMC in 96 orifice plate photofluorometers.Under these conditions, under 25 ℃, in 30 minutes, generate about 0.8uM AMC.The enzyme that is used for these researchs is solubility (striding except the expansion of film district and tenuigenin) the people's albumen that generates in baculovirus expression system (Bac-To-Bac, Gibco BRL).The hydrolysis dynamics constant of finding Gly-Pro-AMC and GLP-1 conforms to the literature value of natural enzyme.In order to measure the dissociation constant of compound, in the reaction that contains enzyme and substrate (final DMSO concentration is 1%), add the solution of inhibitor in DMSO.All experiments all at room temperature use above-mentioned standard reaction condition to carry out.In order to measure dissociation constant (Ki), by non-linear regression with the speed of reaction match to the Michaelis-Menton equation of competitive inhibition.The error that dissociation constant is reproduced is typically less than twice.
Especially, the compound of the following example has the activity that suppresses the dipeptidyl peptidase-IV enzyme in above-mentioned test, and IC50 is less than about 1uM usually.This result shows the intrinsic activity of described compound as the dipeptidyl peptidase-IV activity inhibitor.
Dipeptidyl peptidase-IV enzyme (DP-IV) relates to the cell surface protein of various biological function.It has tissue distribution (intestines, kidney, liver, pancreas, placenta, thymus gland, spleen, epithelial cell, blood vessel endothelium, lymph and medullary cell, serum) widely, and different tissues and cell type expression level.DP-IV is confirmed as t cell activation mark CD26, and it can be at immunoregulatory in a large number, the endocrine and neurologic peptide of external cracking.This shows the latent effect in the various diseases process of this peptase in human body or other species.
Therefore, compound of the present invention can be used for the method for the prevention or the treatment of following disease, obstacle and illness.
Type ii diabetes and relative disease: now definite fully, incretin GLP-1 and GIP are in vivo by the DP-IV rapid deactivation.To the defective mouse of DP-IV (~/~) and just clinical trial phase show: DP-IV suppresses to have increased the Css of GLP-1 and GIP, causes glucose tolerance to improve.Similar with GLP-1 and GIP, other relates to the glycoregulatory hyperglycemic-glycogenolytic factor of grape family peptide equally by DP-IV (for example, PACAP, hyperglycemic-glycogenolytic factor) inactivation.
These peptides can also be worked in glucose homeostasis by the deactivation of DP-IV.
Therefore, DP-IV inhibitor of the present invention can be used for treating type ii diabetes and is used for the treatment of and prevents the common many illnesss followed of type ii diabetes, comprises metabolic syndrome X, reactive hypoglycemia and diabetic hyperlipemia.Obesity hereinafter described is often to find to follow the another kind of symptom of type ii diabetes, and it has response to the treatment of compound of the present invention.
Following disease, obstacle is relevant with type ii diabetes with illness, therefore can be by treating with compounds for treating of the present invention, control or prevention in some cases: (1) hyperglycemia, (2) low dextrose tolerance, (3) insulin resistance, (4) obesity, (5) lipoid dyscrasias, (6) hyperlipemia, (7) hyperlipidaemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (11) high LDL level, (12) atherosclerosis and sequela thereof, (13) vascular restenosis, (14) irritable bowel syndrome, (15) enteritis comprises Crohn disease and ulcerative colitis, (16) other inflammation, (17) pancreatitis, (18) abdominal fatness, (19) neurodegenerative disease, (20) retinopathy, (21) ephrosis, (22) neuropathy, (23) X syndromes, (24) hyperandrogenism (polycystic ovary syndrome) and other have the disease of insulin resistance.
Obesity: the DP-IV inhibitor can be used for treatment of obesity.This is based on observed GLP-1 and the GLP-2 restraining effect to food intake and stomach emptying.The exogenous GLP-1 of giving of human body can significantly reduce food intake and slow down stomach emptying (Am.J.Physiol.277, R910-R916 (1999)).The ICV administration of rat and mouse being carried out GLP-1 has profound influence (Nature Medicine 2,1254-1258 (1996)) to food intake equally.In the GLP-1R mouse, do not observe this feed and suppress, show that these are used as by brain GLP-1 acceptor to regulate.Similar with GLP-1, GLP-2 is regulated by DP-IV also may.
Be similar to the observed effect with GLP-1, the ICV administration of GLP-2 suppresses food intake (Nature Medicine 6,802-807 (2000)) equally.
Growth hormone deficiency: based on hypothesis is that the peptide that somatotropin releasing factor (GRF)-a kind of stimulating growth hormone discharges from prepituitary gland-in vivo by DP-IV enzymatic lysis (WO 00/56297), DP-IV suppresses to can be used for treating growth hormone deficiency.It is the evidence of endogenous substrate that following column data provides GRF: (1) GRF generates inactivation product GRF[3-44 in the effective cracking of external quilt] (BBA 1122,147-153 (1992)); (2) GRF is degraded into GRF[3-44 fast in blood plasma]; This is stoped by DP-IV inhibitor diprotin A; And (3) find GRF[3-44 in the blood plasma of people GRF transgenic pig] (J.Clin.Invest.83,1533-1540 (1989)).Therefore, the DP-IV inhibitor can be used for the short indication of secreting the same range as that agent assert of tethelin.
Damage of intestines: result of study shows glucagon-like-peptide-2 (GLP-2), the possible endogenous substrate of a kind of DP-IV, can show the trophicity effect to enteric epithelium, this result of study explanation uses the DP-IV inhibitor can potentially be used for the treatment of damage of intestines (Regulatory Peptides 90,27-32 (2000)).
The administration of GLP-2 causes rodent small intestine weight to increase, and has weakened the damage of intestines in the rodent model of colitis and enteritis.
Immunosuppression: based on the effectiveness of DP-IV inhibitor in the research of the DP-IV enzyme in the processing of relevant t cell activation and chemokine and the disease body inner model, DP-IV suppresses to can be used for regulating immunne response.
DP-IV identification in CD26, a kind of cell surface marker thing of immune cell activated.The expression of CD26 is regulated by the differentiation and the state of activation of immunocyte.It is generally acknowledged that CD26 plays co stimulatory molecule in the external model of t cell activation.Many chemokines contain proline(Pro) in position second from the bottom, estimation may be to prevent that them from being degraded by non-specific aminopeptidase.Many the proof at the external DP-IV of being subjected in these processed.In some situations (RANTES, LD78-beta, MDC, eotaxin, SDF-lalpha), cracking causes the change activity of chemotaxis and signal test.(RANTES) in some cases, receptor-selective might as well as if be changed.In the cell in vitro culture system, identified many n terminal truncations form of some chemokines, comprise the prediction product of DP-IV hydrolysis.
In transplanting and arthritic animal model, the DP-IV inhibitor has proved effective immunosuppressor.Prodipine (Pro Pro-phenylbenzene-phosphonic acid ester), the irreversible inhibitor of a kind of DP-IV is proved to be the survival of rats 7 to 17 (Transplantation63,1495-1500 (1997)) that makes the dirty allograft of diplocardia.The DP-IV inhibitor has carried out test and show rear solid end swelling in this model in collagen protein and alkyl diamine inductive rat arthritis statistical significance weakens that (Int.J.Immunopharmacology 19,15-24 (1997), Immunopharmacology 40,21-26 (1998)).DP-IV comprises in rheumatoid arthritis, multiple sclerosis, Exophthalmus goiter and the struma lymphomatosa it being (Immunology Today 20, the 367-375 (1999)) that raises at some autoimmune diseases.
HIV infection: DP-IV suppresses can be used for treatment or prevention HIV infects or AIDS, because many chemokines that inhibition HIV cell enters are potential substrates (ImmunologyToday 20,367-375 (1999)) of DP-IV.In the situation of SDF-1 α, cracking has reduced antiviral activity (PNAS 95,6331-6 (1998)).
Therefore, wish that stablizing SDF-1 α by inhibition DP-IV reduces the HIV infection.
Hemopoietic: because DP-IV may relate to hemopoietic, so DP-IV suppresses can be used for treatment or prevention hemopoietic.In the mouse model that the neutrophilic leukocyte that endoxan brings out reduces, DP-IV inhibitor (Val-Boro-Pro) stimulates hemopoietic (WO99/56753).
Neuronal disease: because the relevant peptide of many and various neurone processes external by the DP-IV cracking, so the DP-IV inhibition can be used for treating or preventing various neuronal diseases or mental disorder.Therefore, the DP-IV inhibitor has the treatment benefit in the treatment neuronal disease.
Endomorphin-2, beta-caseins morphine peptide and P material are at the external substrate that all is proved to be DP-IV.In all situations, external cracking is that efficient is very high, the about 106M-ls-1 of kcat/Km or bigger.In the analgesia electric shock skip test model of rat, the DP-IV inhibitor shows significant effect, the existence of this effect and exogenous endomorphin-2 irrelevant (Brain Research, 815,278-286 (1999)).
Tumour is invaded and shifted: DP-IV suppresses can be used for treatment or prophylaxis of tumours is invaded and shifted, because at normal cell in malignant phenotype's conversion process, increase or minimizing (J.Exp.Med.190,301-305 (1999)) that several exopeptidases (comprising DP-IV) are expressed have been observed.These proteic rises or downward modulation be tissue and cell type-specific seemingly.For example, on t cell lymphoma, T cell acute lymphoblastic leukemia, cell-derived thyroid carcinoma, rodent cancer and mammary cancer, observe CD26/DP-IV and expressed increase.Therefore, the DP-IV inhibitor can be used for treating these cancers.
Benign prostatauxe: DP-IV suppresses to can be used for treating benign prostatauxe, because observe active increase (Eur.J.Clin.Chem.Clin.Biochem 30,333-338 (1992)) of DP-IV in BPH patient's prostata tissue.
Motility of sperm/male contraception: because in seminal fluid, prostate gland, prostate gland deutero-have very high-caliber DP-IV activity to the important organoid of motility of sperm, so DP-IV suppresses to can be used for changing motility of sperm and be used for male contraception (Eur.J.Clin.Chem.Clin.Biochem30,333-338 (1992)).
Gingivitis: because in the research relevant with the periodontopathy severity of gum seam fluid, find the DP-IV activity, so DP-IV suppresses to can be used for treating gingivitis (Arch.Oral Biol.37,167-173 (1992)) with some.
Osteoporosis: because gip receptor is present in the scleroblast, so DP-IV suppresses can be used for treatment or preventing osteoporosis disease.
Compound of the present invention can be used for the treatment of or prevent one or more following illness or diseases: (1) hyperglycemia, (2) low dextrose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disease, (6) hyperlipemia, (7) hyperlipidaemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (11) high LDL level, (12) atherosclerosis and sequela thereof, (13) vascular restenosis, (14) irritable bowel syndrome, (15) inflammatory bowel comprises Crohn disease and ulcerative colitis, (16) other inflammatory conditions, (17) pancreatitis, (18) abdominal fatness, (19) neurodegenerative disease, (20) retinopathy, (21) ephrosis, (22) neuropathy, (23) X syndromes, (24) ovarian hyperandrogenism (polycystic ovary syndrome), (25) type ii diabetes, (26) tethelin defective, (27) neutropenia, (28) neuronal disease, (29) metastases, (30) benign prostatauxe, (32) gingivitis, (33) hypertension, (34) osteoporosis, and other can be by suppressing the illness that DP-IV treats.
Compound of the present invention can also be used from the method for the prevention of above-mentioned disease, obstacle and illness or treatment with other medicament one.
Compound of the present invention can be used in combination with one or more other medicines, described one or more other medicines are used for the treatment of, prevent, suppress or improve compound or effective disease of other medicines possibility or the illness of formula I, and the combination of wherein said medicine is more safer or more effective than drug alone.These other medicines can be by compound while or the administration successively of a kind of approach and its common employed quantity and formula I.When the compound of formula I and one or more other medicines used simultaneously, the preferred unit forms of pharmaceutical compositions contained the compound of these other medicines and formula I.Yet described combination therapy can also comprise wherein with the compound of formula I and the therapy of one or more other medicines administration in the different staggered courses of treatment.Also consider the time, can use than separately compound of the present invention and other activeconstituents of lower dosage during medication separately with one or more other activeconstituents drug combinations.Therefore, except that the compound of formula I, pharmaceutical composition of the present invention comprises those that contain one or more other activeconstituentss.
Can with the compound drug combination of formula I and respectively administration or in same medicinal compositions the example of other activeconstituents of administration include, but are not limited to: (a) other DPP IV (DP-IV) inhibitor; (b) insulin sensitizer comprises (i) PPARy agonist for example glitazone (for example troglitazone, U-721017E, englitazone, MCC-555, rosiglitazone etc.) and other RPAR part, comprise the PPARaJy dual agonists, KRP297 and PPARoc agonist Fenofibric Acid derivative (gemfibrozil, clofibrate, fenofibrate and bezafibrate) for example for example, (ii) for example N1,N1-Dimethylbiguanide and phenformin and (iii) Protein Tyrosine Phosphatases-1B (PTP-1B) inhibitor of biguanides; (c) Regular Insulin or insulin-mimickers; (d) for example tolbutamide and Glipizide, meglitinide of sulfonylurea and other insulin secretagogue agent, and related substance; (e) alpha-glucosidase inhibitor (for example acarbose); (f) glucagon receptor antagonist those disclosed in WO 98/04528, WO 99/01423, WO 00/39088 and WO 00/69810 for example; (g) GLP-1, GLP-1 stand-in and GLP-1 receptor stimulant those disclosed in WO00/42026 and WO/59887 for example; (h) GIP and GIP stand-in those disclosed in WO 00/58360 for example, and gip receptor agonist; (i) PACAP, PACAP stand-in and PACAP acceptor 3 agonists those disclosed in WO 01/23420 for example; (j) cholesterol decline reagent, (i) HMG-CoA reductase inhibitor (lovastatin for example, Simvastatin, Pravastatin, Fluvastatin, Zarator, upright his spit of fland of cutting down, itavastatin, superstatin, and other his spit of fland), (ii) sequestrant (QUESTRAN, the dialkyl aminoalkyl derivative of colestipol and crosslinked dextran), (iii) nicotinic alcohol, nicotinic acid or its salt, (iv) PPAR alfa agonists Fenofibric Acid derivative (gemfibrozil for example, clofibrate, fenofibrate and bezafibrate), (v) PPARon/ dual agonists, KRP-297 for example, (vi) cholesterol absorption inhibitor, for example beta Sitosterol and ezetimibe, (vii) acyl CoA: chole-sterol acyltransferase inhibitor, avasimibe for example, (viii) antioxidant, for example probucol; (k) PPAR8 agonist, for example those disclosed in WO 97/28149; (l) for example Phenfluoramine, dexfenfluramine, phentermine, sibutramine, orlistat, neuropeptide Y 5 inhibitor and 33 adrenergic receptor agonists of anti-obesity compound; (m) ileal bile acid transfer protein inhibitor; (n) be for example Asprin, nonsteroidal anti-inflammatory drug, glucocorticosteroid, sulfasalazine and cyclo-oxygenase 2 selective depressants of the designed medicine of inflammatory conditions.
Aforesaid combination comprises compound of the present invention and not only a kind of combination of other active compound, also comprises the combination of compound of the present invention and two or more other active compounds.Non-limitative example comprises the combination of formula I compound and two or more active compounds, and described two or more active compounds are selected from biguanides, sulfonylurea, HMG-CoA reductase inhibitor, RPAR agonist, PTP-1B inhibitor, other DP-IV inhibitor and anti-obesity compound.
Equally, compound of the present invention can make up with other medicines, and described other medicines are used for the treatment of/prevent/and suppress or improve employed disease of The compounds of this invention or illness.These other medicines can be by a kind of approach and its common employed quantity and compound of the present invention while or administration successively.When compound of the present invention and one or more other medicines use simultaneously, preferably except that compound of the present invention, also contain the pharmaceutical composition of these other medicines.Therefore, except that compound of the present invention, pharmaceutical composition of the present invention comprises those that also contain one or more other activeconstituentss.
The weight ratio of the The compounds of this invention and second active ingredient can change and will depend on the effective dose of each component.Usually, the effective dose of every kind of active principle will be used.
Therefore, for example, when compound of the present invention and other medicines are united when using, the weight ratio of compound of the present invention and other medicines usually will be about 1000: in about 1: 1000 scope of 1-, preferably about 200: in about 1: 200 scope of 1-.The drug combination of compound of the present invention and other activeconstituents usually also within above-mentioned scope, but in each case, should use the effective dose of every kind of activeconstituents.
In these drug combinations, compound of the present invention and other promoting agent can separate administration or administrations simultaneously.In addition, can with a kind of composition before giving other medicines, during or administration afterwards.
Compound of the present invention can be by oral, parenteral (for example, intramuscular, intraperitoneal, intravenously, ICV, intracisternal injection or transfusion, subcutaneous injection or implantation), by sucking spraying, nasal cavity, vagina, rectum, hypogloeeis or topical approach, can be separately or be mixed with the suitable dose unit formulation of the conventional nontoxic pharmaceutically acceptable carrier, adjuvant and the vehicle that are appropriate to every kind of route of administration together.Except that treating warm-blooded animal such as mouse, rat, horse, ox, sheep, dog, cat, monkey etc., compound of the present invention can be used for human body effectively.
Be used for the pharmaceutical composition of The compounds of this invention administration and can be easily exist, and can be prepared by the known any method of pharmacy field with the form of unit dosage.All methods all comprise the step that activeconstituents and the carrier that constitutes one or more auxiliary agents are mixed.Usually, by with activeconstituents with liquid vehicle or subdivided solids carrier or both are all even closely mixes, then if desired, make required system type, can prepare described pharmaceutical composition like this.In described pharmaceutical composition, the amount of described active target compound is enough to the course of disease of disease or illness are produced desired result.Be meant the product that comprises the special component that contains concrete quantity at this employed term " composition ", and any directly or indirectly from the product of the combination of the special component of concrete quantity.
The pharmaceutical composition that contains described activeconstituents can be to be suitable for oral form, for example tablet, lozenge, lozenge, moisture or contain oil suspension, and dispersible powder or granula, emulsion, form hard or soft capsule or syrup or elixir exist.Oral compositions can be prepared according to any method of pharmaceutical compositions known in the art, and these compositions can contain one or more and are selected from the reagent of sweeting agent, seasonings, tinting material and sanitas so that exquisite and good to eat preparation are provided pharmaceutically.Tablet contains and is suitable for preparing the activeconstituents of the nontoxic pharmaceutically acceptable vehicle fusion of tablet.These vehicle for example can be inert diluent such as lime carbonate, yellow soda ash, lactose, calcium phosphate or sodium phosphate; Granulating agent and disintegrating agent such as W-Gum or alginic acid; Tackiness agent such as starch, gelatin or gum arabic; And lubricant such as Magnesium Stearate, stearic acid or talcum powder.These tablets can be not dressing or carry out dressing postponing disintegration and the absorption in gi tract with known technology, and therefore in a long period, provide a kind of continuous action.For example, can use time-delay material for example glyceryl monostearate or distearin.They can also use U.S. Patent number 4,256,108; 4,160,452 and 4,265, the technology described in 874 is carried out dressing, to be formed for the osmotic therapeutic tablets of sustained release.
Oral preparations can also be a hard capsule, and wherein activeconstituents mixes with inert solid diluent such as lime carbonate, calcium phosphate or kaolin, perhaps can be soft capsule, wherein activeconstituents and water or oily medium such as peanut oil, whiteruss or mixed with olive oil.
Aqueous suspension contains and the mixed with excipients active substance together that is suitable for preparing aqueous suspension.These vehicle are suspension agents, for example Xylo-Mucine, methylcellulose gum, Vltra tears, sodium alginate, polyethylene-pyrrolidone, tragacanth gum and gum arabic; Dispersion agent or wetting agent can be naturally occurring phosphatide, Yelkin TTS for example, or the condensation product of alkylene oxide and lipid acid, polyoxyethylene stearic acid ester for example, or the condensation product of oxyethane and long-chain fat family alcohol, heptadecaethylene oxycetanol for example, or oxyethane and derive from lipid acid and the condensation product of hexitol partial ester, polyoxyethylene sorbitol monoleate for example, or oxyethane and derive from lipid acid and the condensation product of the partial ester of hexitol acid anhydrides, for example polyethylene sorbitan monooleate.Described aqueous suspension can also contain one or more sanitass such as para hydroxybenzene acetoacetic ester or p-hydroxybenzoic acid n-propyl, one or more tinting materials, one or more seasoningss and one or more sweeting agents such as sucrose or asccharin.
Containing oil suspension can be by following preparation: activeconstituents is suspended in vegetables oil such as peanut oil, sweet oil, sesame oil or the Oleum Cocois, or activeconstituents is suspended in mineral oil such as the whiteruss.Contain oil suspension and can contain thickening material such as beeswax, paraffinum durum or hexadecanol.Can add aforesaid sweeting agent and seasonings, so that a kind of good to eat oral preparations to be provided.These compositions can be undertaken anticorrosion by adding antioxidant such as xitix.
Be suitable for being prepared as follows: with activeconstituents and dispersion agent or wetting agent, suspension agent and one or more sanitas fusion by adding dispersible powder and the granula that entry prepares aqeous suspension.Suitable dispersion agent or wetting agent and suspension agent be above-mentioned illustrational those.The vehicle that can also have other, for example sweeting agent, seasonings and tinting material.
Pharmaceutical composition of the present invention can also be the form of oil-water emulsifiers.Described oil phase can be vegetables oil such as sweet oil or peanut oil or mineral oil such as whiteruss or these oily mixtures.Suitable emulsifying agent can be naturally occurring natural gum, for example gum arabic or tragacanth gum, naturally occurring phosphatide, for example soybean, Yelkin TTS and derive from lipid acid and the ester of hexitol acid anhydrides or partial ester, for example sorbitan monooleate, and the condensation product of described partial ester and oxyethane such as polyoxyethylene sorbitan monooleate.
Described emulsion can also contain sweeting agent and seasonings.
Syrup and elixir can be prepared with sweeting agent such as glycerine, propylene glycol, Sorbitol Powder or sucrose.These preparations can also contain wetting agent, sanitas and seasonings and tinting material.
Described pharmaceutical composition can exist with sterile injectable aq suspension or the form that contains oil suspension.Use suitable dispersion agent or wetting agent and suspension agent according to known technology, can prepare this suspension.Sterile injectable preparation can also be a kind of at a kind of nontoxic parenteral acceptable diluent or sterile injectable solution or the suspension in the solvent, for example solution in 1,3 butylene glycol.In the middle of acceptable vehicle and solvent, operable is water, Ringer's solution and isotonic sodium chlorrde solution.In addition, aseptic expressed oil is usually as solvent or suspension medium.For this reason, the expressed oil of any gentleness be can use, synthetic monoglyceride and triglyceride comprised.In addition, can in injectable formulation, use for example oleic acid of lipid acid.
Compound of the present invention can also be used for rectal administration with the form of suppository.These compositions can be prepared by medicine is mixed with suitable nonirritant excipient, and these compositions are solid at normal temperatures, but it is liquid under the anus temperature, therefore melts in rectum to discharge medicine.These materials are theobroma oil and polyoxyethylene glycol.
For topical, can use emulsion, ointment, gelifying agent, solution or the suspension etc. that contain The compounds of this invention.(concerning this application, topical should comprise mouth wash shua and mouthwass).Pharmaceutical composition of the present invention and method contain can comprise other therapeutical active compound described herein, and it is generally used in the treatment of above-mentioned pathology symptom.
Need to suppress in the illness of dipeptidyl peptidase-IV enzymic activity in treatment or prevention, the proper dosage level is about the every kg weight in patients of 0.01-500mg every day usually, and it can be with single dose or multiple dose administration.Preferably, described dosage level is about the about 250mg/kg of 0.1-every day; Be more preferably the about 100mg/kg of 0.5-every day.The proper dosage level can be about 0.01-250mg/kg every day, about 0.05-100mg/kg every day, or about 0.1-50mg/kg every day.In this scope, described dosage can be 0.05-0.5,0.5-5 or 5-50mg/kg every day.For oral administration, described composition preferably provides with the form of tablet, this tablet contains the activeconstituents of 1.0-1000 milligram, particularly 1.0,5.0,10.0,15.0,20.0,25.0,50.0,75.0,100.0,150.0,200.0,250.0,300.0,400.0,500.0,600.0,750.0,800.0,900.0 and 1000.0 milligrams activeconstituents; Symptom according to the treatment patient is regulated dosage.Described compound can be with every day 1-4 time, preferred once a day or twice dosage regimen administration.
When treatable other disease of treatment or prevent diabetes and/or hyperglycemia or hypertriglyceridemia or compound of the present invention, when the per daily dose administration of compound of the present invention with about 0.1 milligram-Yue 100 milligrams of every kilogram of the weight of animals, 2-6 time the divided dose administration of preferred single per daily dose or every day, or with the slowly-releasing form administration.For the bigger Mammals of great majority, total per daily dose is about 1.0 milligrams-Yue 1000 milligrams, preferred about 1 milligram-Yue 50 milligrams.In the adult situation of 70kg body weight, total per daily dose is about 7 milligrams-Yue 350 milligrams usually.Can regulate this dosage so that best therapeutic response to be provided.
Yet, be appreciated that, the concrete dosage level and the administration number of times of any particular patient can change, and depend on that various factors comprises the metabolic stability of activity, this compound of the particular compound of using and acting duration, host's the severity of age, body weight, general health situation, sex, diet, administering mode and number of times, drainage rate, drug combination and concrete illness and the treatment of host's experience.
Following scheme and embodiment illustrate several preparation methods of The compounds of this invention.Parent material can be prepared according to methods known in the art or method as herein described.
Compound of the present invention can be shown in scheme 1, by beta amino acids intermediate those and substituted heterocyclic radical intermediate those of formula V, VI and VII for example of formula IV for example, uses standard peptide coupling condition, then deprotection preparation.
These intermediates can have been bought.
Scheme 1
Intermediate compound IV and V such as scheme 1 are shown under the standard peptide coupling condition, for example, use 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC), I-hydroxybenzotriazole (HOBT) and alkali, common diisopropylethylamine, at solvent N for example, in dinethylformamide (DMF) or the methylene dichloride coupling 3-48 hour at ambient temperature, obtain intermediate 1.Then, remove protecting group, for example in the situation of Boc, remove protecting group, obtain required amine I with trifluoroacetic acid or methanolic hydrochloric acid (methanolic hydrogen chloride).If necessary, by recrystallization, development, preparative thin layer chromatography, as W.C.Still etc., J.Org.Chem., 43,2923 (1978) described flash chromatography on silica gel method or HPLC, described product is removed unwanted by product.Can be by the compound that HPLC purifies with the isolated in form of corresponding salt.The purification of intermediate is carried out equally in an identical manner.
In some cases, before removing protecting group, the intermediate 1 that is obtained by coupled reaction described in the scheme 1 can further be modified, for example, and by the substituting group on conversion X or Y or the Z.These conversion can include, but are not limited to, the known reduction of those skilled in the art, oxidation, alkylation, acidylate and hydrolysis reaction.
In some cases, the order of carrying out above-mentioned reaction scheme can change to promote reaction or to avoid unwanted reaction product.Provide the following examples, so that understand the present invention more fully.These embodiment only are illustrative, should not be construed by any way the present invention is construed as limiting.