CN1968949A - Proline derivatives and their use as dipeptidyl peptidase IV inhibitors - Google Patents
Proline derivatives and their use as dipeptidyl peptidase IV inhibitors Download PDFInfo
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- CN1968949A CN1968949A CN200580015258.8A CN200580015258A CN1968949A CN 1968949 A CN1968949 A CN 1968949A CN 200580015258 A CN200580015258 A CN 200580015258A CN 1968949 A CN1968949 A CN 1968949A
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Abstract
The invention provides compounds of formula (I), prodrugs and stereoisomers thereof, and the pharmaceutically acceptable salts of the compounds, prodrugs, and stereoisomers, wherein R<1>, R<2>, R<3>, HET, n, Q, X, Y, and Z are as described herein; compositions thereof; and uses thereof in treating diabetic complications including diabetic neuropathy, diabetic nephropathy, diabetic microangiopathy, and the like.
Description
Technical field
The present invention relates to the selective depressant of a kind of dipeptidyl peptidase-IV (DPP-IV), its pharmaceutical compositions is used for the treatment of the disease relevant with the protein of handling by DPP-IV and the purposes of illness with it.
Background technology
DPP-IV (EC 3.4.14.5) is a kind of serine protease, the terminal dipeptides of N-that this proteolytic enzyme selective hydrolysis is obtained by the protein that has proline(Pro) or Beta Alanine on 2.It is believed that DPP-IV relates to diabetes, glucose tolerance, obesity, appetite stimulator, lipidemia, osteoporosis, neuropeptide metabolism and T-cell-stimulating etc.Therefore, give the N-that the DPP-IV inhibitor can prevent peptide substrate terminal degraded in the body, thus this cause the circulation composition of this peptide higher and with the concentration dependent treatment benefit of this rising.
Hinted that the running balance of DPP-IV control glucose is because its substrate comprises incretin peptide (incretin peptides), hyperglycemic-glycogenolytic factor class peptide 1 (GLP-1) and Gastric inhibitory polypeptide (GIP).Make their functional inactivations by the cracking of the-terminal amino acid of these peptides.Show that GLP-1 is a kind of potent antidiabetic therapeutical agent in the diabetes B patient, and reduce among the type 1 diabetes patient demand the relevant Regular Insulin of food.It is believed that and be GLP-1 and/or GIP adjusting satiety, lipidemia and osteogenesis.Advised suffering from the patient of acute coronary artery syndrome, angina and ischemic heart disease with external source GLP-1 treatment.
Give the terminal degraded of N-of DPP-IV inhibitor prevention GLP-1 and GIP in the body, this causes the circulation composition of this peptide higher, and insulin secretion increases and glucose tolerance is improved.Based on these observations, think that the DPP-IV inhibitor is a kind of reagent that is used for the treatment of diabetes B (a kind of disease of impaired glucose tolerance).In addition, adopt the DPP-IV inhibitor to treat to prevent the degraded of neuropeptide tyrosine (NPY), the peptide relevant and the peptide YY relevant with gastrointestinal disorder (for example, easily sharp disease of ulcer, intestines and inflammatory bowel) with various central nervous system disorders.
Although early discovery Regular Insulin and find that subsequently it is in treatment purposes widely in the diabetes; (for example found the sulphur urea afterwards; P-607, tolbutamide, acetohexamide), biguanides (for example; phenformin), metformin, thiazolidinedione are (for example; rosiglitazone) and pioglitazone as the purposes of oral hypoglycemia reagent, but still unsatisfactory to treatment of diabetes.
Usually, type 1 diabetes patient and Yue 10% diabetes B patient (in these patients, the oral hypoglycemia reagent that can get at present is invalid) must use Regular Insulin, and this needs the daily dosage of several times usually, use by injection voluntarily.Determine that suitable insulin dose must the frequent glucose concn of assessing in urine or the blood.Give excess insulin and can cause hypoglycemia, and follow pathoglycemia, stupor or even dead.
The treatment diabetes B generally includes the combination of diet, exercise, oral reagent and (under more serious situation) Regular Insulin to carry out.Yet the clinical hypoglycemic method that gets has negative effect, and this negative effect has limited the use of this method.Clear being apparent that: needing the hypoglycemic reagent that can use continuously, this reagent to have can be successful under the situation of less negative effect or the failure of other kind reagent.
Fail to control hyperglycemia and directly cause multiple complications (cataract, neuropathy, ephrosis, retinopathy, cardiomyopathy), these complication are features of senior diabetes B.In addition, diabetes B is a kind of compossibility disease (this disease is usually with hyperlipidaemia, atherosclerosis and hypertension), and this has significantly increased comprehensive M ﹠ M of above-mentioned disease.
The epidemiology evidence has clearly been determined: hyperlipidaemia is the basis risk factor of cardiovascular diseases (CVD) (because atherosclerosis).At US and European, atherosclerosis is generally acknowledged first the cause of death.CVD (at least in part) in the diabetic subject is especially popular, because there are a plurality of independently risks and assumptions (for example, impaired glucose tolerance, left ventricular hypertrophy and hypertension) in these crowds.Therefore, the hyperlipidaemia of successfully treating general crowd and diabetic subject is in particularly important medically.
Hypertension is a kind ofly can occur in many patients illness on one's body, the paathogenic factor the unknown among these patients.This " essence " hypertension is relevant with for example obesity, diabetes and hypertriglyceridema usually, and known hypertension is sure and in heart failure, renal failure is relevant with apoplexy.Hypertension can also be facilitated the development of atherosclerosis and coronary heart disease.Hypertension with insulin resistant disease and hyperlipidaemia comprises that a group is the symptom (being also referred to as insuline resistance syndrome (IRS) and syndrome X) of feature with the metabolic syndrome.
Obesity is the risks and assumptions of known, common development atherosclerosis, hypertension and diabetes.The whole world is fat to be increased with the incidence of its relevant sequela.At present, do not obtain the pharmacological agents of effective, acceptable minimizing obesity.
Osteoporosis is a kind of systemic disease of development gradually, and this disease is hanged down with bone density and osseous tissue microstructure variation is a feature, and these features increase bone vulnerability and are easy to fracture thereupon.Osteoporosis and bone strength are impaired to be to cause fragile major reason and to be that sickness rate increases and the major reason of mortality ratio increase.
Heart trouble is a whole world major health.In the individuality that has a heart disease, myocardial infarction is dead important source.The acute coronary syndromes refers to that the patient has or is in and develops into Acute Myocardial Infarction (MI) excessive risk.
Although have the method that can be used for treating diabetes, hyperglycemia, hyperlipidaemia, hypertension, obesity and osteoporosis, but still need to continue replaceable and improved therapy.
At the Curr.Medicinal Chem. of Augustyns etc.,
6, 311 (1999); The Drugs of the Future of Ohnuki etc., 1999,
24, 665-670 (1999); The Annual Reportsin Medicinal Chemistry of Villhauer etc.,
36, 191-200 (2001); The Expert Opin.Invest.Drugs of Drucker,
12, 87-100 (2003); With the Curr.Opin.Invest.Drugs of Weideman etc.,
4, the various indications of DPP-IV inhibitor have been discussed among the 412-420 (2003).
At present, prepared the oral administration of compound that suppresses DPP-IV, for example those disclosed compound in International Application No. WO 02/14271.
Think that DPP-IV inhibitor (for example those disclosed in WO 02/14271) works by the degraded that suppresses natural hormone, GLP-1 and GIP.Therefore, importantly, in blood plasma, can obtain suitable DPP-IV inhibitor concentration with the synchronous DPP-IV of secretory product of inhibition with these GLP-1 and GIP hormone.In order to reach this plasma concentration, preferably, the plasma concentration of DPP-IV inhibitor compound maintains in for some time on the level that is higher than the desired concentration of other DPP-IV inhibitor compound (for example, those disclosed in WO 02/14271).
Therefore, need a kind of oral DPP-IV inhibitor compound, this compound has the plasma concentration that identical or better DPP-IV suppressed active and keep higher level in for some time.
Summary of the invention
The compound of (I) structure that the present invention relates to have formula,
Or its prodrug, or the pharmaceutically-acceptable salts of described compound or prodrug, or the solvate of described compound, prodrug or salt, wherein:
R
1Be-(C
1-C
6) alkyl ,-(C
1-C
6) alkoxyl group ,-(C
1-C
6) arylalkyl ,-NR
aR
b, hydroxyl, cyano group, aryl or heteroaryl, wherein, described-(C
1-C
6) alkyl, described aryl or described heteroaryl optional independently by 1-3-COOH ,-C (O) (C
1-C
6) alkoxyl group ,-C (O) (C
1-C
6) alkyl ,-C (O) NR
aR
b, cyano group, halogen, nitro, trifluoromethyl ,-(C
1-C
6) alkyl ,-(C
1-C
6) alkoxyl group ,-(C
3-C
6) cycloalkyl or phenyl replace and wherein: R
aAnd R
bBe independently halogen ,-(C
1-C
6) alkyl, aryl or heteroaryl or R
aAnd R
bThe nitrogen-atoms that is connected with them connects together and forms 4-6 unit heterocycle, wherein, and optional other one or two nitrogen, oxygen or the sulphur ring hetero atom of comprising of described ring;
R
2And R
3Be independently hydrogen, halogen ,-(C
1-C
6) alkyl ,-(C
3-C
8) cycloalkyl;
Q be covalent linkage ,-C (O)-or-SO
2-;
HET is the Heterocyclylalkyl loop section, and described loop section is optional by (A) 1-4-(C
1-C
6) alkyl, described-(C
1-C
6) alkyl optional by 1-6 halogen atom ,-(C
1-C
6) alkoxyl group, cyano group, halogen, hydroxyl or-NR
aR
bReplace, or (B)-(C
1-C
6) aralkyl, described-(C
1-C
6) aralkyl optional by 1-6 halogen atom ,-(C
1-C
6) alkoxyl group, cyano group, halogen, hydroxyl or-NR
aR
bReplace, replace;
N is 0 or 1;
X is-CH
2-,-CHF-or-CF
2-; Y is-CH
2-,-CHF-or-CF
2-, condition is: when n was 1, X and Y were not-CH simultaneously
2-; With when n is 0, X is-CH
2-; With
Z is hydrogen or cyano group.
The invention still further relates to pharmaceutical compositions, described composition comprises the The compounds of this invention for the treatment of significant quantity, or its prodrug, or the pharmaceutically-acceptable salts of this compound or prodrug, or the solvate of this compound, prodrug or salt; With pharmaceutically acceptable carrier, vehicle, thinner or excipient.
The invention still further relates to the method for treatment diabetes, described method comprises: the The compounds of this invention that needs the Mammals treatment significant quantity of this treatment, or its prodrug, or the pharmaceutically-acceptable salts of this compound or prodrug, or the solvate of this compound, prodrug or salt.Preferably, the diabetes type of being treated is 2 property diabetes.
The invention still further relates to the method for the illness that mediates by dipeptidyl peptidase-IV in the treatment Mammals, described method comprises: the The compounds of this invention that needs the described Mammals treatment significant quantity of this treatment, or its prodrug, or the pharmaceutically-acceptable salts of this compound or prodrug, or the solvate of this compound, prodrug or salt.
Compound of the present invention and pharmaceutical compositions can be used for treating diabetes, are preferred for treating diabetes B.
Compound of the present invention also can be used for treating the illness relevant with DPP IV with pharmaceutical compositions, described illness comprises, but be not limited to diabetes B, type 1 diabetes, glucose and measure impaired, hyperglycemia, metabolic syndrome (syndrome X and/or insuline resistance syndrome), glycosuria, metabolic acidosis, sacroiliitis, cataract, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, obesity, illness by the obesity aggravation, hypertension, hyperlipidaemia, atherosclerosis, osteoporosis, osteopenia, fragile, bone-loss, fracture, acute coronary artery syndrome, by growth hormone deficiency cause short and small, by polycystic ovary syndrome cause sterile, anxiety disorder, dysthymia disorders, insomnia, confirmed fatigue, epilepsy, the diet sexual maladjustment, chronic pain, alcohol is habit-forming, the disease relevant with bowel movement, ulcer, irritable bowel syndrome, inflammatory bowel; Short bowel syndrome; And be used for preventing the disease progression of diabetes B.
Embodiment
Be used to describe term of the present invention and have following meaning.
Term " pharmaceutically acceptable " refer to other composition chemistry of specified carrier, vehicle, thinner, excipient and/or salt and compositing formula and/or physical compatibility and with its recipient's physical compatibility.
The carbon content of the part of various hydrocarbonaceous can be pointed out by the prefix of minimum number of expression carbon atom and maximum number in this part herein, for example, and prefix (C
a-C
b) alkyl and C
A-bAlkyl refers to comprise the moieties of integer " a " to " b " individual carbon atom.Thus, for example, (C
1-C
6) alkyl and C
1-6Alkyl refers to comprise the alkyl of 1-6 carbon atom.
Term " alkyl " refers to the straight or branched carbon atom, and wherein, this alkyl is chosen wantonly and comprised one or more pair key or triple bond or two key and triple-linked combination.The example of alkyl comprises methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, vinyl, allyl group, 2-methylpropenyl, crotyl, 1,3-butadiene base, ethynyl, propargyl etc.
Term " alkoxyl group " digital is incorporated into the straight or branched, monovalence of the carbon atom on the Sauerstoffatom, saturated aliphatic chain, and this Sauerstoffatom is connected on the core texture.The example of alkoxyl group comprises methoxyl group, oxyethyl group, propoxy-, butoxy, isobutoxy, tert.-butoxy etc.
Term " cycloalkyl " refers to saturated monocycle or bicyclic cycloalkyl.Cycloalkyl can be chosen wantonly and merge to aromatic hydrocarbon (for example benzene) upward to form the condensed ring alkyl, for example, and indenyl etc.The example of cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl etc.
Term " halogen " or " halogen " expression chlorine, bromine, fluorine and iodine atom and substituting group.
Term " aryl " refer to monocycle or polycyclic aromatic alkyl, for example, anthryl, fluorenyl, naphthyl, phenanthryl, phenyl etc.
Term " aralkyl " refers to above-mentioned defined alkyl, and wherein, at least one in its hydrogen atom replaced by above-mentioned defined aryl.The example of aralkyl comprises benzyl etc.
The term used as above-mentioned HET " Heterocyclylalkyl " refers to saturated 4-8 unit heterocyclic system, and this heterocyclic system is optional to condense with 5-6 unit's aromatics or heteroaromatic rings system.The example of Heterocyclylalkyl comprises high piperazinyl (homopiperazinyl), piperazinyl, piperidyl, pyrrolidyl, azelidinyl, 2-aza-bicyclo [2.2.1] heptyl, 3-aza-bicyclo [3.1.0] hexyl, 2,5-diaza-dicyclo [2.2.1] heptyl, 5,6,7,8-tetrahydrochysene-2H-imidazo [1,2-a] pyrazinyl, 5,6,7,8-tetrahydrochysene [1,2,4] triazolo [4,3-a] pyrazinyl, 4,5,6, the 7-tetrahydro-pyrazole is [1,5-a] pyrazinyl also, 5,6,7, the 8-tetrahydropyridine is [3,4-d] pyrimidyl also, 5,6,7, the 8-tetrahydropyridine is [4,3-d] pyrimidyl also, octahydro pyrrolo-[3,4-b] pyrryl, octahydro pyrrolo-[3,4-c] pyrryl, 6-azabicyclo [3.2.1] octyl group, 3,8-diazabicyclo [3.2.1] octyl group, 2,3-dihydro volution [indenes-1,4 '-piperidyl], volution [indenes-1,4 '-piperidyl], 1-oxa--8-azaspiro [4.5] decyl, 8-azabicyclo [3.2.1] octyl group, 2,3,4,5-tetrahydro benzo [f] [1,4] oxa-azelidinyl, six hydrogen-2H-pyrrolo-[3,4-d] isothiazolyl-1, the 1-dioxide, 2,7-diazaspiracyclic [4.4] nonyl, 6,7,8,9-tetrahydrochysene-5H-[1,2,4] triazolo [4,3-g] [1,4] diazacyclo butyl, 5,6-dihydro-8H-imidazo [1,2-a] pyrazinyl, 5,6-dihydro-8H-[1,2,4] triazolo [4,3-a] pyrazinyl, 7,8-dihydro-5H-pyrido [4,3-a] pyrimidyl, 7,8-dihydro-5H-pyrido [4,3-d] pyrimidyl, pyrazolo [1,5-a] pyrimidyl etc.
Term " heteroaryl " refers to monocycle or polycyclic aromatic heterocyclic system.The example of heteroaryl comprises the benzisothiazole base, benzoisoxazole base benzoxazolyl, benzothiazolyl, benzofuryl, benzothienyl, benzimidazolyl-, the cinnolines base, furyl, the furo pyridyl, the imidazopyrimidine base, imidazolyl, indazolyl, indyl, isoquinolyl, isothiazolyl Yi oxadiazole base isoxazolyl oxazole and pyridyl oxadiazole base oxazolyl, phthalazinyl (phthalazinyl), pteridyl (pteridinyl), pyrazinyl, pyridazinyl, pyrrolo-pyrimidine radicals, pyrrolopyridinyl, the pyrazolopyrimidine base, pyrazolyl, pyridyl, pyrimidyl, pyrryl, quinazolyl, quinolyl, quinoxalinyl, tetrazyl, thiazolyl, thiadiazolyl group, thiazole and pyridyl, the thienopyridine base, thienyl, triazinyl, triazolyl, 1,1-dioxo-1H-1,2-benzisothiazole base oxazole and pyridyl etc.
Term " oxo " means the carbonyl that is combined to form by carbon atom and Sauerstoffatom.
The hydrogen atom that term " substituted " means on the molecule is substituted by different atoms or molecule.The atom or the molecule that substitute this hydrogen atom are called as " substituting group ".
Symbol "-" expression covalent linkage.
Phrase " inert solvent " refers to solvent or solvent mixture, and this solvent or solvent mixture do not react in the mode that is unfavorable for their required character with raw material, reagent, vehicle or product.
Term used herein " treatment " comprises prevention (for example preventing disease), alleviation and therepic use or result.
Phrase " treatment significant quantity " means a certain amount of compound of the present invention, this compound (i) treatment or prevention specified disease, illness or imbalance (ii) weaken, improve or eliminate one or more and plant the symptom of specified disease, illness or imbalances or (iii) prevent or postpone the outbreak that one or more plant specified disease described herein, illness or diagonosis of disorder.
Term " Mammals " is a kind of individual animals, and this animal is the monobasic in the mammals.Mammals comprises, for example, and the mankind, monkey, chimpanzee, gorilla, ox, pig, horse, sheep, dog, cat, mouse and rat.In the present invention, preferred Mammals is human.
Preferably, compound of the present invention has formula (I) structure, wherein:
R
1Be aryl or heteroaryl, this group optional independently by 1-3 cyano group, halogen, nitro, trifluoromethyl ,-(C
1-C
6) alkyl ,-(C
1-C
6) alkoxyl group ,-(C
3-C
6) cycloalkyl or phenyl replacement;
R
2Be-H or-(C
1-C
6) alkyl;
R
3Be-H or-(C
1-C
6) alkyl; With
HET is azelidinyl, piperazinyl, piperidyl, pyrrolidyl, 5,6-dihydro-8H-imidazo [1,2-a] pyrazine-7-base, 5,6-dihydro-8H-[1,2,4] triazolo [4,3-a] pyrazine-7-base or 7,8-dihydro-5H-pyrido [4,3-a] pyrimidine-6-base.
More preferably, compound of the present invention has the structure of formula (IA)
Wherein, R
1Be benzisothiazole base, benzoisoxazole base, isothiazolyl, isoxazolyl, oxazole and pyridyl, pyrazinyl, pyridyl, pyrimidyl, quinolyl, quinoxalinyl, thiadiazolyl group, triazinyl or 1,1-dioxo-1H-1,2-benzisothiazole base.
In the present invention, for formula (IA) compound, preferably, R
1Be pyridyl or pyrimidyl, more preferably, R
1Be pyridyl or pyrimidyl, n is 1, and X is-CF
2-, Y is-CH
2-.
In the present invention, compound (3,3-two fluoropyrrolidines-1-yl)-((2S, 4S)-4-(4-(pyrimidine-2-base) piperazine-1-yl) tetramethyleneimine-2-yl) ketone, or its prodrug, or the pharmaceutically acceptable salt of described compound or described prodrug most preferably.
In interchangeable embodiment, compound is selected from the family that is made up of following compound:
((2S, 4S)-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4] triazolo [4,3-a] pyrazines-7 (8H)-yl) tetramethyleneimine-2-yl)-(3,3-two fluoropyrrolidines-1-yl)-ketone;
(3,3-two fluoropyrrolidines-1-yl)-((2S, 4S)-4-(4-(oxazole is [5,4-b] pyridine-2-yl also) piperazine-1-yl) tetramethyleneimine-2-yl)-ketone;
(3,3-two fluoropyrrolidines-1-yl)-((2S, 4S)-4-(4-(4-methylpyrimidine-2-yl) piperazine-1-yl) tetramethyleneimine-2-yl)-ketone;
((2S, 4S)-4-(2-(trifluoromethyl)-7,8-dihydro pyrido [4,3-d] pyrimidines-6 (5H)-yl) tetramethyleneimine-2-yl)-(3,3-two fluoropyrrolidines-1-yl)-ketone;
((S)-3-fluoro-tetramethyleneimine tetramethyleneimine-1-yl)-(2S, 4S)-4-[4-(3-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-tetramethyleneimine-2-yl }-ketone;
((S)-3-fluoro-tetramethyleneimine-1-yl)-[(2S, 4S)-4-(2-trifluoromethyl-7,8-dihydro-5H-pyrido [4,3-d] pyrimidine-6-yl)-tetramethyleneimine-2-yl]-ketone;
(3,3-two fluoro-tetramethyleneimine-1-yl)-[(2S, 4S)-4-(the 4-oxazole is [4,5-c] pyridine-2-base-piperazine-1-yl also)-tetramethyleneimine-2-yl]-ketone;
[(2S, 4S)-4-(2-cyclopropyl-7,8-dihydro-5H-pyrido [4,3-d] pyrimidine-6-yl)-tetramethyleneimine-2-yl]-(3-fluoro-azetidin-1-yl)-ketone;
(3,3-two fluoro-tetramethyleneimine-1-yl)-[(2S, 4S)-4-(2-oxyethyl group-7,8-dihydro-5H-pyrido [4,3-d] pyrimidine-6-yl)-tetramethyleneimine-2-yl]-ketone;
2-{4-[(3S, 5S)-5-(3-fluoro-azetidine-1-carbonyl)-tetramethyleneimine-3-yl]-piperazine-1-yl }-the nicotinic acid nitrile;
((S)-3-fluoro-tetramethyleneimine-1-yl)-[(2S, 4S)-4-(the 4-oxazole is [5,4-b] pyridine-2-base-piperazine-1-yl also)-tetramethyleneimine-2-yl]-ketone;
(3-fluoro-azetidin-1-yl)-[(2S, 4S)-4-(2-trifluoromethyl-7,8-dihydro-5H-pyrido [4,3-d] pyrimidine-6-yl)-tetramethyleneimine-2-yl]-ketone;
2-{4-[(3S, 5S)-5-((S)-3-fluoro-tetramethyleneimine-1-carbonyl)-tetramethyleneimine-3-yl]-piperazine-1-yl }-the nicotinic acid nitrile;
(3-fluoro-azetidin-1-yl)-(2S, 4S)-4-[4-(2-trifluoromethyl-quinolyl-4)-piperazine-1-yl]-tetramethyleneimine-2-yl }-ketone;
((3R
*, 4S
*)-3,4-two fluoro-tetramethyleneimine-1-yl)-[(2S, 4S)-4-(2-trifluoromethyl-7,8-dihydro-5H-pyrido [4,3-d] pyrimidine-6-yl)-tetramethyleneimine-2-yl]-ketone; With
((3R
*, 4S
*)-3,4-two fluoro-tetramethyleneimine-1-yl)-[(2S, 4S)-4-(the 4-oxazole is [5,4-b] pyridine-2-base-piperazine-1-yl also)-tetramethyleneimine-2-yl]-ketone;
Or the pharmaceutically-acceptable salts of its prodrug or described compound or described prodrug.
Compound of the present invention comprises the compound that all comprise at least two three-dimensional centers, specifically with (2S, 4S) tetramethyleneimine-three-dimensional center of 2-base shown in the following formula (I).
Compound of the present invention can split into pure enantiomer by method known in those skilled in the art, for example, and by forming the diastereo-isomerism salt that can for example pass through Crystallization Separation; Can be by forming for example by crystallization, solution-air phase or isolating diastereo-isomerism derivative of liquid chromatography or title complex; By a kind of enantiomer and enantiomer specific reagent are carried out selective reaction (for example, enzyme esterification); Or by in chiral environment (for example, have tied up chiral ligand chirality upholder (for example tripoli) go up or in the presence of chiral solvent) carry out solution-air mutually or liquid chromatography separate.Those skilled in the art will appreciate that when desirable steric isomer is changed into another kind of chemical entity by a kind of in the above-mentioned separating step, need another step to discharge desirable enantiomer.Replacedly, concrete steric isomer can synthesize by following method: utilize the optical activity raw material, utilize optical activity reagent, substrate, catalyzer or solvent to carry out asymmetric synthesis, or a kind of steric isomer is changed into another kind of steric isomer by asymmetric conversion.
When described compound comprises one or more other three-dimensional center, those skilled in the art will appreciate that all diastereomers of described herein and the compound discussed and non-enantiomer mixture within the scope of the invention.These diastereomers can separate by method known in those skilled in the art, for example, and by crystallization, solution-air phase chromatogram or liquid chromatography.Replacedly, the intermediate in this building-up process can exist with the form of racemic mixture and can split by method known in those skilled in the art, for example, and by forming the diastereo-isomerism salt that can for example pass through Crystallization Separation; Can be by forming for example by crystallization, solution-air phase or isolating diastereo-isomerism derivative of liquid chromatography or title complex; By a kind of enantiomer and enantiomer particular agent are carried out selective reaction (for example, enzyme esterification); Or by in chiral environment (for example, have tied up chiral ligand chirality upholder (for example tripoli) go up or in the presence of chiral solvent) carry out solution-air mutually or liquid chromatography separate.Will appreciate that, when desirable steric isomer is changed into another kind of chemical entity by a kind of in the above-mentioned separating step, need another step to discharge desirable enantiomer.Replacedly, concrete steric isomer can synthesize by following method: utilize optical activity reagent, substrate, catalyzer or solvent to carry out asymmetric synthesis, or by asymmetric conversion a kind of steric isomer is changed into another kind of steric isomer.
Some compound of formula (I) can exist with different stable conformation forms, and the compound of this conformation form can separate.Owing to reverse asymmetric (torsional asymmetry) different conformation thing is separated around asymmetric single bonded rotation limited (for example, because sterically hindered or ring strain) is formed.The present invention includes every kind of conformer and its mixture of formula (I) compound.The technician will appreciate that some compound of formula (I) can exist with tautomeric forms,, has balance between two kinds of isomer that is, is quick balance between this isomer.Tautomeric common instance is a keto-enol tautomerism, promptly
The example of this compounds of the present invention comprises: pyridone (pyridone) and hydroxy pyrimidine (pyrimidone).Particularly, those skilled in the art will recognize that, pyridone of the present invention can with two kinds independently tautomeric forms exist, for example,
A kind of tautomer depends on various factors with respect to the degree that exists of another kind of tautomer, and these factors comprise replacement mode and type of solvent.Those skilled in the art will recognize that other example of the present invention.Whole tautomers of formula (I) are included in the invention scope required for protection.
Compound of the present invention can exist with non-solvent form and the solvation form with pharmacy acceptable solvent (for example, water, ethanol etc.), and this means the mixture that the present invention comprises non-solvent compound, solvate and solvate.
Some compound of formula (I) and their salt and solvate can exist with more than one crystalline forms.Form a part of the present invention by the represented multi-crystalline compounds of formula (I), and can be by the crystallization under different condition of formula (I) compound is prepared.For example, with different solvents or different solvents mixture recrystallization; Crystallization under differing temps; During crystallization, cooling mode difference (being cooled fast to very much very slow cool down).Polymorphic form can also be followed quick cooling and obtain by with heating of formula (I) compound or fusion.The existence of this polymorphic form can be surveyed NMR spectrum, IR spectrum, differential scanning calorimeter, powder x-ray diffraction or other technology by solid phase and measure.
The present invention also comprises compound isotopically labelled, this compound is identical with described those compounds of formula (I), but, the atom that one or more atom is had following atomic mass or total mass number substitutes, and this atomic mass or total mass number are different from atomic mass or the total mass number of finding at occurring in nature usually.Can introduce the isotropic substance that isotopic example in the The compounds of this invention comprises hydrogen, carbon, nitrogen, oxygen, sulphur and fluorine, for example be respectively,
2H,
3H,
13C,
14C,
15N,
18O,
17O,
35S,
36Cl,
125I,
129I and
18F.Other the isotopic compound of the present invention that comprises above-mentioned isotropic substance and/or other atom, its prodrug, the pharmaceutically acceptable salt of this compound and prodrug is within the scope of the invention.(for example, radio isotope (for example for some compound isotopically labelled of the present invention
3H and
14C) can add wherein those compounds) can be used in the measure of spread of medicine and/or substratum tissue.Because tritium (that is,
3H) and carbon-14 (that is,
14C) isotropic substance is easy to preparation and surveys, thus preferred especially they.In addition, (for example, deuterium (promptly to adopt heavier isotropic substance
2H)) replace and can obtain some treatment advantage (because metabolic stability) preferably, for example, increase in the body transformation period or reduce required dosage, therefore, in some cases can be preferred.Isotope-labeled formula of the present invention (I) compound and its prodrug can prepare by being implemented in disclosed step among following synoptic diagram and/or the embodiment (substituting nonisotopically labelled reagent with facile isotope labeling reagent) usually.
The pharmaceutically-acceptable salts relevant with compound of the present invention used herein comprises the pharmaceutically acceptable inorganic salt and the organic salt of described compound.These salt can be during the final separation of compound and purifying in-situ preparing, or by respectively with compound or prodrug and appropriate organic or inorganic acid reaction, and formed salt separated prepare.Representational salt comprises, but be not limited to hydrobromate, hydrochloride, hydriodate, vitriol, hydrosulfate, nitrate, acetate, trifluoroacetate, oxalate, benzene sulfonate, palmitate, embonate (pamoate), propionic salt, stearate, lauroleate, malate, borate, benzoate, lactic acid salt, phosphoric acid salt, hexafluorophosphate, benzene sulfonate, tosylate, formate, Citrate trianion, maleate, fumarate, succinate, tartrate, naphthoate, mesylate, gluceptate, Lactobionate and lauryl sulfonate etc.They can also comprise the positively charged ion based on basic metal and alkaline-earth metal, for example, sodium, lithium, potassium, calcium, magnesium etc., and nontoxic ammonium, quaternary ammonium and amine positively charged ion (comprise, but be not limited to ammonium, tetramethyl-ammonium, tetraethyl ammonium, methylamine, dimethyl amine, Trimethylamine, triethylamine, ethylamine etc.).For other example, referring to the J.Pharm.Sci. of for example Berge etc.,
66, 1-19 (1977).
Can and use itself or use compound separation of the present invention with their pharmaceutically-acceptable salts or solvate forms.According to the present invention, the compound with a plurality of basic nitrogen atoms can form salt with the acid that changes equivalents.The technician will appreciate that all these salt within the scope of the invention.
The prodrug of formula (I) compound is a kind of compound that reacts formation in a conventional manner with functional group's (for example, amino, hydroxyl or carboxyl) of this compound.Term " prodrug " means a kind of compound that transforms in vivo with production (I) compound or this compound pharmaceutically acceptable salt or solvate.This conversion can take place by various mechanism (for example, by hydrolysis in blood)." Pro-drugs as Novel DeliverySystems " and the Bioreversible Carriers of Drug Design of A.C.S.Symposium Series 14 volumes of T.Higuchi and W.Stella, Edward B.Roche edits, American Pharmaceutical Association and Pergamon Press provides the discussion of prodrug purposes in 1987.
For example, if compound of the present invention has amine functional group, then prodrug can form by the hydrogen atom in the amido is substituted with following radicals, for example R-carbonyl, RO-carbonyl, NRR '-carbonyl, and wherein, R and R ' they are (C independently of one another
1-C
10) alkyl, (C
3-C
7) cycloalkyl, benzyl, or the R-carbonyl be natural alpha-amino group acyl group or natural alpha-amino group acyl group-natural the alpha-amino group acyl group ,-(wherein, Y ' is H, (C to C (OH) C (O) OY '
1-C
6) alkyl or benzyl) ,-C (OY
0) Y
1(wherein, Y
0Be (C
1-C
4) alkyl, Y
1Be (C
1-C
6) alkyl, carboxyl (C
1-C
6) alkyl, amino (C
1-C
4) alkyl or list-N-or two-N, N-(C
1-C
6) the alkylamino alkyl) ,-C (Y
2) Y
3(wherein, Y
2Be H or methyl, Y
3Be list-N-or-N, N-(C
1-C
6) alkyl amine group, morpholino base, piperidines-1-base or tetramethyleneimine-1-yl).
Similarly, if compound of the present invention comprises alcohol functional group, then prodrug can form by the hydrogen atom in the alcohol radical is substituted with following radicals, for example, and (C
1-C
6) chain alkyloyloxyethyl methyl, 1-((C
1-C
6) alkanoyloxy) ethyl, 1-methyl isophthalic acid-((C
1-C
6) alkanoyloxy) ethyl, (C
1-C
6) alkoxy carbonyl oxygen methyl, N-(C
1-C
6) alkoxycarbonyl amino methyl, succinyl (succinoyl), (C
1-C
6) alkanoyl, alpha-amino group (C
1-C
4) alkanoyl, aryl-acyl and alpha-amino group acyl group or alpha-amino group acyl-alpha--aminoacyl, wherein, each alpha-amino group acyl group is independently selected from naturally occurring L-amino acid, P (O) (OH)
2,-P (O) (O (C
1-C
6) alkyl)
2Or glycosyl (from the carbohydrate of hemiacetal form, remove hydroxyl and obtain free radical).
If compound of the present invention comprises carboxylic acid functional, then prodrug can comprise by the hydrogen atom in the acidic group is substituted the ester that forms with following radicals, for example, and (C
1-C
8) alkyl, (C
2-C
12) the alkanoyloxy methyl, 1-(alkanoyloxy) ethyl with 4-9 carbon atom, 1-methyl isophthalic acid-(alkanoyloxy)-ethyl with 5-10 carbon atom, alkoxy carbonyl oxygen methyl with 3-6 carbon atom, 1-(alkoxy carbonyl oxygen) ethyl with 4-7 carbon atom, 1-methyl isophthalic acid-(alkoxy carbonyl oxygen) ethyl with 5-8 carbon atom, N-(alkoxy carbonyl) amino methyl with 3-9 carbon atom, 1-(N-(alkoxy carbonyl) amino) ethyl with 4-10 carbon atom, 3-chromene ketone group, 4-crotonolactone base, γ-Ding Suan lactone-4-base,-N, N-(C
1-C
2) alkylamino (C
2-C
3) alkyl (for example, beta-dimethyl-amino-ethyl), formamyl-(C
1-C
2) alkyl, N, N-two (C
1-C
2) alkyl-carbamoyl-(C
1-C
2) alkyl and piperidino-(1-position only), pyrrolidino or morpholino (C
2-C
3) alkyl.
Generally speaking, formula of the present invention (I) compound can prepare by the whole bag of tricks, and these methods comprise method known in the chemical field, specifically the described method that comprises according to this place.Some method that is used to prepare formula of the present invention (I) compound illustrates by following reaction synoptic diagram.Experimental section has been described other method.Disclosed method purpose in order to demonstrate the invention is not to be construed as limiting the invention by any way in synoptic diagram and embodiment.
So place explanation, preparation are used for some starting compounds of reaction process described in synoptic diagram and the embodiment.All other starting compounds can by general commercial source (for example, Sigma-Aldrich Corporation, St.Louis MO) obtains.
In the following description, use following abbreviation: BOC (uncle-butoxy carbonyl), Cbz (benzyloxycarbonyl), DMF (N, dinethylformamide), NMP (N-N-methyl-2-2-pyrrolidone N-), DMAC (N, the N-N,N-DIMETHYLACETAMIDE), DME (glycol dimethyl ether), DMSO (dimethyl sulfoxide (DMSO)), EtOAC (ethyl acetate), EtOH (ethanol), MeOH (methyl alcohol), TFA (trifluoroacetic acid), TFAA (trifluoroacetic anhydride), TEA (triethylamine), THF (tetrahydrofuran (THF)), DIPEA (diisopropyl ethyl amine), EDC (1-(3-dimethylaminopropyl)-3-carbodiimide), DCC (dicyclohexylcarbodiimide), CDI (1,1 '-carbonyl dimidazoles) HATU (O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-urea hexafluorophosphate), HOAT (1-hydroxyl-7-azepine benzotriazole), HOBT (N-hydroxybenzotriazole) and EEDQ (2-oxyethyl group-1-ethoxy carbonyl-1,2-dihydroquinoline).
Following synoptic diagram 1 has been described the general method that is used for preparation formula (I) compound.
Synoptic diagram 1
In synoptic diagram 1, formula (II) compound (wherein, P represents nitrogen-protecting group group) of pressing synoptic diagram 2 preparations is according to the currently known methods deprotection.If P represents BOC; deprotection is realized by following process so: at first will be dissolved in (II) in for example EtOAc, ether dioxane or the water; with acid (for example; hydrogenchloride) handle appropriate time (for example about 5 minutes-Yue 1 hour); this process is chosen wantonly in proper temperature (for example, about 0 ℃) cooling down.This solution is heated to room temperature (RT), then stirs other for some time (stirring usually other 30 minutes-16 hours).Preferably, reaction mixture was stirred 15 minutes, make it reach room temperature, and then stirred other 30 minutes.Replacedly, (II) is dissolved among the TFA, and in due course after (for example, about 30 minutes-Yue 24 hours), excessive TFA vacuum removed, and the solvent of residual product with for example ether ground.If P represents Cbz; then deprotection can be undertaken by following process: at catalyzer (for example; 10% palladium or palladium hydroxide) existence under; at suitable solvent (for example; EtOH or EtOAC) in; under the pressure of the about 60psi of about 30psi-, under about 20 ℃-Yue 80 ℃ temperature, the enough time of hydrogenolysis.Preferably, hydrogenolytic cleavage is at room temperature realized under the pressure of about 45psi.
Formula (II) compound can by the carboxylic acid derivative (III) that will suitably replace and the sulfonamide derivatives (IV) that suitably replaces such as following synoptic diagram 2 description carry out coupling and prepare.
Synoptic diagram 2
Linked reaction is finished usually as follows: mix in inert reaction solvent (preferred non-polar solvent, for example, acetonitrile, methylene dichloride, DMF, THF or chloroform) with (III) with (IV).Choose wantonly then under the existence of alkali (for example, TEA or pyridine) and optional adjuvants (HOBT or HOAT), coupling agent (for example, EDC, HATU, DCC, EEDQ, CDI, pivalyl chloride or diethyl cyanophosphonate) is added.Linked reaction is carried out the suitable time (for example, about 1 hour-Yue 24 hours, 16 hours according to appointment) usually and is realized under 0 ℃-Yue 50 ℃ temperature.To the discussion of other condition of can be used for the coupling carboxylic acid, referring to Houben-Weyl, Vol.XV, Part II, E.Wunsch, Ed., G.Theime Verlag, (1974), Stuttgart; M.Bodansky, " Principlesof Peptide Synthesis ", Springer-Verlag Berlin (1984) and " The Peptides:Analysis; Synthesis and Biology " (ed.E.Gross and J.Meienhofer), Vols.1-5 (AcademicPress NY 1979-1983).Formula (III) and (IV) compound can pass through currently known methods, or replacedly, prepare according to illustrative preparation process described below.For the illustrative preparation method of formula (IV) amine, see PCT International Application No. WO 2003/101958 and U.S. patent 6,710,040, the disclosed content of these documents is inserted herein by reference.
Replacedly, formula (II) compound can be as preparation as described in the following synoptic diagram 3.
Synoptic diagram 3
In synoptic diagram 3, formula (II) compound prepares by following process: will carry out reduction amination with the Heterocyclylalkyl amine (VI) that suitably replaces according to the ketone (V) through protection of following synoptic diagram 4 preparations.This aminating reaction is well known to a person skilled in the art.Referring to, for example, the J.Org.Chem. of A.F.Abdel-Magid etc.,
61, 3849 (1996); The J.Am.Chem.Soc. of R.F.Borch etc.,
93, 2897 (1971) and the Synlett of S.Bhattacharyya etc., 1079 (1995).Formula (VI) amine is known in association area, and can commerce obtains or prepare by currently known methods.Referring to, for example, the Chem.Rev. of D.A.Horton etc.,
103, 893-930 (2003); The Heterocycles of H.Fukui etc.,
56, 257-264 (2002); The J.Org.Chem. of M.Y.Chu-Moyer etc.,
60, the J.Med.Chem. of 5721-5725 (1995) and J.P.Yevich etc.,
29, 359-369 (1986).
Usually, (V) and (VI) (for example going back original reagent, sodium borohydride, sodium cyanoborohydride, nitrilotriacetic base sodium borohydride, nitrilotriacetic base hydroboration tetramethyl-ammonium or hydrogen) existence under, in the presence of catalyzer (10%Pd/C, platinum oxide etc.), choose wantonly under the existence of acid (for example, acetate (AcOH), spirit of salt etc.) and carry out condensation.Linked reaction is finished in inert reaction solvent (for example, 1,2-ethylene dichloride, THF, DMF, EtOH or MeOH) usually.This is reflected under the suitable temp (for example, 0-50 ℃) and carries out the suitable time (for example, between 1-24 hour, as, about 16 hours).
The formula V compound can prepare according to following synoptic diagram 4 described methods, and is suitable, the carboxylic acid that this method can get from commerce (VII), keto-earboxylic acid (IX) or ketone ester (X).
Synoptic diagram 4
At synoptic diagram 4, in the step 1, carry out coupling through the acid (VII) of protection according to above synoptic diagram 2 described methods and amine (IV) and obtain alcohol (VIII).
At synoptic diagram 4, in the step 2, it is oxidized to ketone (Va) by alcohol (VIII) is handled in inert reaction solvent with oxygenant.The example of suitable oxidizing agent is included in the pyridine/sulphur trioxide among the DMSO; Water-based clorox under Sodium Bromide and the existence of TEMPO (2,2,6,6-tetramethyl--1-piperidines oxygen) free radical catalyst; Chromium base reagent, for example, chromium trioxide, pyridine two chromic salt or Pyridinium chlorochromate on silica gel; With the oxalyl chloride in DMSO in the presence of tertiary amine.The example of inert reaction solvent comprises methylene dichloride, EtOAc, toluene or pyridine.Oxidizing reaction is about 24 hours of about 1-(for example, about 16 hours) under-78 ℃ approximately-Yue 50 ℃ temperature usually.This kinds of oxidation reaction is well known to a person skilled in the art, referring to, for example, the J.Org.Chem. of M.Tamaki etc.,
66, 3593 (2001) and the J.Org.Chem. of X-I.Qiu etc.,
67, 7162 (2002).
At synoptic diagram 4, in the step 3, the keto-earboxylic acid (IX) through protecting at first obtains (Va) with amine (IV) coupling according to the method described in the above synoptic diagram 2, then this compound (Va) alkylation is obtained ketone (V).Usually, alkylating is realized as follows: at first ketone (Va) and for example secondary amine of tetramethyleneimine, piperidines or morpholine are reacted the formation enamine, then adopt acylating reagent to choose wantonly under the existence of alkali (for example, salt of wormwood) and handle.Usually, this is reflected in the solvent of for example benzene, toluene, acetonitrile or dioxane and realizes.This conversion process is well known to a person skilled in the art.Referring to, the J.Am.Chem.Soc. of G.Stork etc. for example,
85, 207 (1963); The J.Med.Chem. of M.W.Holladay etc.,
34, 455 (1991) and the Tetrahedron of P.Barraclough etc.,
51, 4195 (1995).
At synoptic diagram 4, in the step 5, through the ketone ester (X) (wherein, R represents moieties or aralkyl moiety) of protection formerly under the condition described in the step 4 alkylation obtain ketone ester (XI).
At synoptic diagram 4, in the step 6, ketone ester (XI) is carried out saponification obtains corresponding carboxylic acid, this carboxylic acid in step 7 according to the previous description of above synoptic diagram 2 and amine (IV) coupling that suitably replaces.Usually, saponification step realizes by following process: with (XI) at alkali (for example, lithium hydroxide or sodium hydroxide) but existence under be dissolved in the miscible solvent of water (for example, MeOH or EtOH and water).Saponification reaction is carried out the suitable time (for example about 1-24 hour, 16 hours according to appointment) and is realized under suitable temperature (for example, about 0 ℃-Yue 100 ℃, preferred room temperature).
Preferably, pharmaceutical compositions of the present invention comprises formula (IA) compound for the treatment of significant quantity, or its prodrug, or the pharmaceutically-acceptable salts of this compound or prodrug, or the solvate of this compound, prodrug or salt and pharmaceutically acceptable carrier, vehicle, thinner or excipient.
More preferably, pharmaceutical compositions of the present invention comprises the compound (3 for the treatment of significant quantity, 3-two fluoropyrrolidines-1-yl)-((2S, 4S)-and 4-(4-(pyrimidine-2-base) piperazine-1-yl) tetramethyleneimine-2-yl) ketone, or its prodrug, or the pharmaceutically-acceptable salts of described compound or prodrug, the solvate of described compound, prodrug or salt and pharmaceutically acceptable carrier, vehicle, thinner or excipient.
Then, can the patient be given by making up the pharmaceutical compositions that compound of the present invention and pharmaceutically acceptable carrier, vehicle or thinner form various formulations (for example, tablet, powder, lozenge, syrup, Injectable solution etc.).If desired, these pharmaceutical compositions can comprise other composition, for example, and seasonings, tackiness agent, excipient etc.
Therefore, for oral purpose, (for example comprise various excipient, Trisodium Citrate, lime carbonate and/or calcium phosphate) tablet can (for example separate agent with various stretching tight, starch, alginic acid and/or some composition silicate), and tackiness agent (for example, Polyvinylpyrolidone (PVP), sucrose, gel and/or Sudan Gum-arabic) uses together.In addition, lubricant (for example, Magnesium Stearate, sodium lauryl sulphate and talcum) can be used for tablet usually.The solids composition of similar type can also be as filler in soft filling and hard gel capsule of filling.For this situation, preferable material comprises lactose and high-molecular weight polyoxyethylene glycol.When wishing that waterborne suspension or elixir are used for when oral, active pharmaceutical agent wherein can with various sweeting agents or seasonings, pigment or dyestuff and emulsifying agent or suspension agent (if desired), and make up with the thinner of for example water, ethanol, propylene glycol, glycerol and/or its combination.
For parenterai administration, can adopt The compounds of this invention or composition in sesame oil or peanut oil, aqueous propylene glycol or at the solution in the sterilization aqueous solution.This aqueous solution should suitably cushion (if necessary) and at first liquid diluent be used the salt or the glucose equipressure of capacity.These specific aqueous solutions are particularly useful for intravenously, muscle, subcutaneous and intraperitoneal administration.In context, used sterilization aqueous medium easily obtains by standard technique well known by persons skilled in the art.
For intranasal administration or inhalation, compound of the present invention or composition are carried (this automiser spray is by patient's extruding or suction) or (are used suitable propelling agent as the aerosol that is present in pressurized vessel or the atomizer by automiser spray with the form of solution or suspension usually, for example, Refrigerant 12, trichlorofluoromethane, dichloro tetrafluoro ethane, carbonic acid gas or other suitable gas).Under the situation of pressure aerosol, dosage device can be determined by a valve that is used for the conveying and metering consumption is provided.Pressurized vessel or atomizer can comprise the solution or the suspension of The compounds of this invention.Can prepare capsule and medicine bullet (for example, from gel, making) and be used in sucker or the insufflator, the powdered mixture of this capsule or medicine bullet inclusion compound and The compounds of this invention and suitable powder matrix (for example, lactose or starch).
The method for preparing the various pharmaceutical compositions with certain consumption activeconstituents is known or discloses those skilled in the art according to this is tangible.For the example of the method for preparing pharmaceutical compositions, referring to Remington ' s Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 19th Edition (1995).
On the other hand, the present invention refers to pharmaceutical compositions, and said composition comprises first kind of formula (I) compound for the treatment of significant quantity, the pharmaceutically-acceptable salts of its prodrug or this compound or prodrug; Second kind of compound, this compound are to be selected from following anti-diabetic reagent, Regular Insulin and insulin analog, short skin, biguanide antidiabetic medicament, the α of giving birth to of Regular Insulin
2-antagonist and tetrahydroglyoxaline, glitazone, aldose reductase inhibitor, the glycogen phosphorglase inhibitor, sorbitol dehydrogenase inhibitors, fatty acid oxidation inhibitors, α-anhydroglucose enzyme inhibitors, β-activator, phosphodiesterase inhibitor, lipopenicillinase reagent, fat-reducing reagent, vanadate and vanadium complex and peroxide vanadium complex, the amylin antagonist, glucagon antagonist, the growth hormone secretogogue, the gluconeogenesis inhibitor, the tethelin inhibitor analogue, lipotropism is separated reagent, the pharmaceutically-acceptable salts of the prodrug of anti-diabetic reagent or anti-diabetic reagent and prodrug.
On the other hand, the present invention refers to tool kit, and this tool kit comprises: first formulation, this formulation comprise formula (I) compound, or the solvate of the pharmaceutically-acceptable salts of its prodrug, this compound or prodrug or this compound, prodrug or salt; Second formulation, this formulation comprise the anti-diabetic reagent that is selected from following substances: Regular Insulin and insulin analog, short skin, biguanide antidiabetic medicament, the α of giving birth to of Regular Insulin
2-antagonist and tetrahydroglyoxaline, glitazone, aldose reductase inhibitor, the glycogen phosphorglase inhibitor, sorbitol dehydrogenase inhibitors, fatty acid oxidation inhibitors, α-anhydroglucose enzyme inhibitors, β-activator, phosphodiesterase inhibitor, lipopenicillinase reagent, fat-reducing reagent, vanadate and vanadium complex and peroxide vanadium complex, the amylin antagonist, glucagon antagonist, the growth hormone secretogogue, the gluconeogenesis inhibitor, the tethelin inhibitor analogue, lipotropism is separated reagent, the pharmaceutically-acceptable salts of the prodrug of anti-diabetic reagent or anti-diabetic reagent and prodrug and the container that comprises described first formulation (a) and described second formulation (b).
In the preferred embodiment of tool kit, first formulation and second formulation comprise pharmaceutical acceptable carrier or thinner independently.
In another aspect, the present invention relates to suppress the methods of treatment of DPP IV, this method comprises formula (I) compound of the described Mammals treatment significant quantity that needs this treatment, or the pharmaceutically-acceptable salts of its prodrug or this compound or prodrug, or the solvate of this compound, prodrug or salt, mentioned reagent can give separately or give with above-mentioned anti-diabetic agent combination.
On the other hand, the present invention relates to treat method by the illness of dipeptidyl peptidase-IV restraining effect mediation, described method comprises: formula (I) compound that needs the described Mammals treatment significant quantity of this treatment, or the pharmaceutically-acceptable salts of its prodrug or described compound or prodrug, or the solvate of described compound, prodrug or salt, mentioned reagent can give separately or give with above-mentioned anti-diabetic agent combination.
In one embodiment, described illness of being treated is a diabetes B, type 1 diabetes, impaired glucose tolerance, hyperglycemia, metabolic syndrome (syndrome X and/or insuline resistance syndrome), glycosuria, metabolic acidosis, sacroiliitis, cataract, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, obesity, illness by the obesity aggravation, hypertension, hyperlipidaemia, atherosclerosis, osteoporosis, osteopenia, fragile, bone-loss, fracture, acute coronary artery syndrome, by growth hormone deficiency cause short and small, by polycystic ovary syndrome cause sterile, anxiety disorder, dysthymia disorders, insomnia, confirmed fatigue, epilepsy, the diet sexual maladjustment, chronic pain, alcohol is habit-forming, the disease relevant with bowel movement, ulcer, irritable bowel syndrome, inflammatory bowel; Short bowel syndrome; With the disease progression in the prevention diabetes B.
In preferred embodiment, described illness of being treated is a diabetes B.
On the other hand, the present invention relates to the insulin secretagogue compositions and methods that a kind of discriminating is used for diabetes, this method comprises, formula (I) reagent is given to be had by fasting the KK/H1J mouse of diabetic symptom; The assessment mouse is to the reaction of afterwards oral glucose, wherein, if described mouse proof doing well,improving differentiates that then described reagent can be used for treating diabetes B, type 1 diabetes, impaired glucose tolerance, hyperglycemia, metabolic syndrome (syndrome X and/or insuline resistance syndrome), glycosuria, metabolic acidosis, sacroiliitis, cataract, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, obesity, illness by the obesity aggravation, hypertension, hyperlipidaemia, atherosclerosis, osteoporosis, osteopenia, fragile, bone-loss, fracture, acute coronary artery syndrome, by growth hormone deficiency cause short and small, by polycystic ovary syndrome cause sterile, anxiety disorder, dysthymia disorders, insomnia, confirmed fatigue, epilepsy, the diet sexual maladjustment, chronic pain, alcohol is habit-forming, the disease relevant with bowel movement, ulcer, irritable bowel syndrome, inflammatory bowel; Short bowel syndrome; With the disease progression in the prevention diabetes B.
The invention still further relates to and be used for the treatment of or prevent above-mentioned treatment of conditions method in the Mammals (comprising the mankind), wherein, give formula of the present invention (I) compound as the part of appropriate dosage forms scheme with the effect that obtains medical treatment.Employed formula of the present invention (I) compound, the type of used pharmaceutical compositions, the feature of the object of being treated and the severity of illness are depended in the interval of each dosage of suitable formulation scheme, the dosage that gives every kind of formulation and compound.
Generally speaking, the effective dose of The compounds of this invention is 0.01mg/kg/ days-30mg/kg/ days, be preferably 0.01mg/kg/ days-5mg/kg/ days active compound (using) with single dose or fractionated dose yet, according to the illness of the object of being treated, must carry out the various variations of dosage.Under any circumstance, the definite of the required suitable dosage of individual subject carried out respectively by the related personnel.The technician will appreciate that " kg " refers to the body weight in the patient of kilogram.
Compound of the present invention or composition can with single (for example, once a day) or multiple doses be taken or inculcate by constant.Compound of the present invention can also be taken with single dose or multiple doses form separately or with pharmaceutically acceptable carrier, vehicle or thinner combination.Suitable pharmaceutical carriers, vehicle and thinner comprise inert solid diluent or filler, sterile water solution and various organic solvent.
Compound of the present invention or composition can need the object of treatment by various traditional modes of taking (comprising that oral and non-enteron aisle is taken (for example, intravenously, subcutaneous and intraperitoneal)).In addition, pharmaceutical compositions of the present invention can take (as suppository) in the nose or utilize fast prescription (that is, make medicine dissolution in mouth and do not need water) take.
Embodiment
Unless otherwise stated, all reagent obtain from commercial channels.
At J.Org.Chem.1978, the method for describing in 43,2923 is carried out flash chromatography according to W.C.Still etc.
Preparation experiment
Compound of the present invention and intermediate are named according to organic compound nomenclature and CAS index rule that IUPAC (International Union for Pureand Applied Chemistry) recommends usually.
The preparation method 1
The tertiary butyl-(2S)-2-[(3,3-two fluoropyrrolidines-1-yl) carbonyl]-4-oxo-pyrrolidine-1-carboxylicesters
Step 1: the tertiary butyl-(2S, 4R)-2-[(3,3-two fluoropyrrolidines-1-yl) carbonyl]-4-hydroxyl pyrrolidine-1-carboxylicesters
(0.77mL 5.5mmol) is added to 3,3-difluoro pyrrolidine hydrochloride (0.79g, 5.5mmol with TEA; Synlett, 55 (1995)) in the 10mL methylene dichloride suspension.After 5 minutes, add (4R)-1-(uncle-butoxy carbonyl)-4-hydroxyl-L-proline(Pro) (1.16g, 5mmol), HOBt (0.74g, 5.5mmol) and EDC (1.05g, 5.5mmol).After with the reaction mixture stirred overnight, mixture is used sodium bicarbonate and salt water washing successively, with dried over mgso, filtration and concentrated.Resistates is passed through chromatogram (Biotage
Flash 40S (A Dynax Corp.; Charlottesville, VA), 9: 1 methylene dichloride: methyl alcohol) purifying obtains 1.07g lightpink foam.By water layer being repeated obtain additional product (0.26g) with dichloromethane extraction, ultimate production is 1.33g (83%).MS m/z 321(MH
+)。
Step 2
(0.57mL, 3mL dichloromethane solution 8mmol) are added drop-wise to oxalyl chloride under-65 ℃ (0.38mL is in 10ml dichloromethane solution 4.4mmol) with DMSO.After 5 minutes, add step 1 product (1.28g, 20ml dichloromethane solution 4mmol).After 15 minutes, and adding TEA (2.79mL, 20mmol).Reaction mixture is warming to room temperature.Behind 2hr, mixture is poured in the ice.Organic layer is separated, uses successively 10%NaHCO
3Solution and salt water washing, dry (MgSO
4) and concentrate.With resistates chromatogram (Biotage
Flash 40S, 95: 5 methylene dichloride: MeOH) purifying obtains the 765mg title compound.MS m/z 319(MH
+)。
Replacedly, the tertiary butyl-(2S)-2-[(3,3-two fluoropyrrolidines-1-yl) carbonyl]-4-oxo-pyrrolidine-1-carboxylicesters can prepare according to following process.
With 1-(tert-butoxycarbonyl)-4-oxo-L-proline(Pro) (6.88g, 30mmol), HOBt (4.46g, 33mmol), EDC (6.326g, 33mmol) with 3,3-difluoro pyrrolidine hydrochloride (4.52g, 31.5mmol) be dissolved in the 100mL methylene dichloride and add TEA (84mL, 60mmol) before, reaction mixture is cooled to 0 ℃.Then, reaction mixture is warming to room temperature.After stirred overnight, add saturated sodium bicarbonate (100mL) and use the dichloromethane extraction water layer.With the water washing of organic layer usefulness salt, usefulness dried over mgso, the filtration and concentrated that merges.With resistates chromatogram (Biotage
Flash 40M, with 1: 10 methylene dichloride: the hexane wash-out) purifying obtained 7.85g (productive rate 82%) title compound.MS(EI)m/z 319.3(MH
+)。
The preparation method 2
The tertiary butyl (2S)-2-{[(3R
*, 4S
*)-3,4-two fluoropyrrolidines-1-yl] carbonyl }-4-oxo-pyrrolidine-1-carboxylicesters
Step 1: the tertiary butyl (2S, 4R)-2-{[(3R
*, 4S
*)-3,4-two fluoropyrrolidines-1-yl] carbonyl }-4-hydroxyl pyrrolidine-1-carboxylicesters
With (4R)-1-(uncle-butoxy carbonyl)-4-hydroxyl-L-proline(Pro) (2.31g, 10mmol) adopt (3R, 4S)-rel-3,4-difluoro pyrrolidine hydrochloride (1.44g, 10mmol, the preparation method 4) carry out coupling with the similar fashion described in preparation method's 1 step 1 and obtain 2.15g (67%) canescence spumescence title product.MS m/z 321(MH
+)。
Step 2
(1.97g 6.15mmol) obtains 0.74g (38%) light yellow solid shape title compound with the described similar fashion oxidation of preparation method's 1 step 2 with the product of step 1.MS m/z 319(MH
+)。
The preparation method 3
(4S)-1-(uncle-butoxy carbonyl)-4-(4-pyrimidine-2-base piperazine-1-yl)-L-proline(Pro)
With 1-(uncle-butoxy carbonyl)-4-oxo-L-proline(Pro) (1.0g, 4.4mmol), 2-piperazine-1-yl pyrimidines (0.73g, 4.4mmol) and acetate (275 μ L, 4.6mmol) be dissolved in 20mL anhydrous 1, in the 2-ethylene dichloride, and adding nitrilotriacetic base sodium borohydride (1.85g, 8.7mmol).Under RT, stir after 24 hours, the saturated NaHCO of reaction mixture
3Quencher.By adding solid NaHCO
3With dense HCl, pH regulator to pH7, with the mixture dichloromethane extraction, is used MgSO
4Dry, filter and concentrate and obtain 1.0g (61%) for the enough pure rough material of further use.MSm/z 378(MH
+)。
The preparation method 4
(3R, 4S)-rel-3,4-two fluoro-pyrrolidine hydrochlorides
Step 1:2,5-dihydro-pyrroles-1-benzyl carboxylate
(10g, (14g is in toluene 0.17mol) (100mL) slurries 0.145mol) to be added to sodium bicarbonate with the 3-pyrroline.With mixture be cooled to 0 ℃ and dropwise add chloroformic acid benzyl ester (23mL, 0.16mol).After stirred overnight, solution is diluted with methylene dichloride, with cold water and salt water washing, with dried over mgso and the concentrated light yellow oil (vacuum distilling) that obtains.Bp 119-126℃(0.32mm)。
Step 2:6-oxa--3-aza-bicyclo [3.1.0] hexane-3-benzyl carboxylate
(3.0g 15mmol) is dissolved in and comprises EDTA disodium salt dihydrate (11mg is in the mixture of acetonitrile 0.03mmol) (100mL) and water (70mL) with the title compound of step 1.This solution is cooled to 0 ℃, and in 10 minutes, adds 1,1, and 1-trifluoro ethyl ketone (14.5mL, 160mmol).(45g 74mmol) adds in batches in 40 minutes simultaneously that to keep pH be 7 by adding sodium bicarbonate with peroxide one vitriolate of tartar.Mixture is stirred down 1.5hr at 0 ℃, pour in the water then and use dichloromethane extraction.With the extract that merges with dried over mgso and concentrate and obtain water white oil (3.45g, 100%).
Step 3:(3RS, 4RS)-3-fluoro-4-hydroxyl-tetramethyleneimine-1-benzyl carboxylate
With TEA three hydrofluorides (1.95mL, 12mmol) and the title compound of step 2 (cooling also distributes between water and methylene dichloride for 2.62g, mixture heating up to 155 12mmol) ℃ 3 hours.Water is extracted once more with methylene dichloride, and with the organic extract salt water washing that merges, with dried over mgso and concentrated.Resistates is obtained pale asphyxia oily title compound (1.14g, 40%) with flash chromatography (1% methyl alcohol in the methylene dichloride) purifying.
Step 4:(3R, 4S)-rel-3,4-two fluoro-tetramethyleneimine-1-benzyl carboxylate
With methylene dichloride (15mL) solution of the title compound of step 3 be cooled to-50 ℃ and add [two (2-methoxy ethyl) amino] sulphur trifluoride (1.3mL, 6.9mmol).Solution is warming to room temperature 18hr, between water and EtOAc, distributes then.Water is extracted once more with EtOAc and, also concentrate with dried over mgso with the organic extract salt water washing that merges.Resistates is obtained brown oily product (1.14g, 40%) with flash chromatography (methylene dichloride) purifying.
Step 5
Title compound (675mg, ethanol 2.8mmol) (10mL) (containing 10%Pd/C (200mg)) solution hydrogenation 18hr in the Parr of 40psi device with step 4.Solution is concentrated into drying by diatomite filtration and with filtrate, residue yellow solid (400mg, 100%).
The preparation method 5
(S)-2-(3-fluoro-azetidine-1-carbonyl)-4-oxo-tetramethyleneimine-1-carboxylic acid tert-butyl ester
Step 1: diphenyl-methyl-3-fluoro-azetidine hydrochloride
With 1-diphenyl-methyl-azetidin-3-alcohol (5.0g 20.9mmol) is dissolved in the 50mL benzene, and solution is cooled to 15 ℃, and dropwise add (diethylamino) sulphur trifluoride (10.1g, 62.7mmol).At room temperature after the stirred overnight, add saturated sodium bicarbonate.Mixture is extracted with EtOAc, with dried over mgso, filtration and concentrated.With resistates chromatogram (Biotage
40S, the 10%EtOAc/ hexane) purifying.Product is dissolved among the EtOAc, handles with HCl (15mL is 2N in ether), of short duration heating also concentrates.Grinding, filter also with ether solid, drying obtains the 2.58g title compound.MS m/z 242.3(MH
+)。
Step 2:3-fluoro-azetidine hydrochloride
With step 1 product (2.58g, (comprising 10%Pd/C (the 0.38g)) methanol solution of 30mL 9.3mmol) hydrogenation 60hr in the 30-50psiParr device.Solution is concentrated into drying by diatomite filtration and with filtrate.Solid is obtained 0.62g (60%) title compound by the MeOH/EtOAc recrystallization.
Step 3
With uncle N--Boc-4-oxo-L-proline(Pro) (917mg, 4mmol), the title compound of step 2 (446mg, 4mmol) and HATU (1.673g 4.4mmol) mixes in anhydrous methylene chloride under nitrogen atmosphere.Add DIEA (1.4mL, 8mmol) before, this solution is cooled to 0 ℃ in ice bath.Reaction mixture is warming to room temperature and stirred overnight.Add saturated sodium bicarbonate, will respectively be separated and the water dichloromethane extraction.With the organic moiety salt water washing that merges, use dried over mgso.With raw product (2.11g) chromatogram (Biotage
Flash 40S, 95: 5EtOAc: MeOH) purifying obtains lightpink spumescence title product (1.06g, 92%).MSm/z 287.3(MH
+)。
The preparation method 6
(S)-2-(each alkane of (S)-3-fluoro-pyrrole-1-carbonyl)-4-oxo-tetramethyleneimine-1-carboxylic acid tert-butyl ester
With uncle N--Boc-4-oxo-L-proline(Pro) (2.29g, 10mmol), (S)-3-fluoropyrrolidine hydrochloride (1.38g, 11mmol) and TEA (2.09mL 15mmol) mixes in anhydrous methylene chloride (30mL) under nitrogen atmosphere.Add HOBT (2.03g, 15mmol), add EDC (2.10,11mmol) before, this solution is cooled to 0 ℃ in ice bath.Reaction mixture is heated to room temperature and stirred overnight.With mixture with saturated sodium bicarbonate and salt water washing and use dried over mgso.Raw product (3.15g) is obtained light yellow needle-like title compound (2.18g, 73%) by hexane: EtOAc (2: 1) recrystallization.MS m/z 301.3(MH
+)。
The preparation method 7
(2S, 4S)-2-(3,3-two fluoro-tetramethyleneimine-1-carbonyl)-4-piperazine-1-base-tetramethyleneimine-1-carboxylic acid tert-butyl ester
Step 1:4-[(3S, 5S)-uncle 1--butoxy carbonyl-5-(3,3-two fluoro-tetramethyleneimine-1-carbonyl)-tetramethyleneimine-3-yl]-piperazine-1-benzyl carboxylate
With AcOH (0.3mL, 1.05 equivalents) be added to preparation method 1 title compound (1.59g, 5mmol) and 1-(benzyloxycarbonyl) piperazine (1.21g, 5.5mmol) 1, in 2-methylene dichloride (20mL) solution, then add nitrilotriacetic base sodium borohydride (2.119g, 10mmol).Reaction mixture is stirred 4hr under RT.Add saturated sodium bicarbonate and with the product dichloromethane extraction.With organic phase with the salt water washing and use dried over mgso.After evaporation, raw product (the yellow foam of 2.28g) is obtained white foam shape title compound (1.28g, 49%) with flash chromatography (utilizing the EtOAc wash-out) purifying.MS m/z 523.3(MH
+)。
Step 2
(1g 1.91mmol) is dissolved among the EtOH (50mL), and carefully adds 10%Pd/C (1g, 1 equivalent w/w), then adds 1 (1.81mL, 10 equivalents) with the product of step 1.With mixture in having the flask of tight lid, stirred overnight gently under RT.With reaction mixture by diatomite filtration and concentrate and to obtain yellow semi-solid product (758mg, 100%).MSm/z 389.4(MH
+)。
The preparation method 8
(S)-2-(3,3-two fluoro-azetidine-1-carbonyl)-4-oxo-tetramethyleneimine-1-carboxylic acid tert-butyl ester
With uncle N--BOC-4-oxo-L-proline(Pro) (458mg, 2mmol), 3, (258mg, 2mmol) (0.35mL 2mmol) sneaks in the anhydrous methylene chloride (10mL) and is cooled to 0 ℃ 3-difluoro azetidine hydrochloride for (according to the preparation of the method described in the WO 2000/47582) and DIPEA.Yet disposable adding HOBT (405mg, 3mmol), then add the EDC hydrochloride (422mg, 2.2mmol).The gained mixture is warming to room temperature and stirred overnight.Add saturated sodium bicarbonate, with the organic layer separation and with the water dichloromethane extraction.With the organic extract salt solution washed twice that merges, with dried over mgso, filtration and concentrated.(570mg) uses hexane with raw product: the shallow tangerine toner powder title product that methylene dichloride (10: 1) grinds, filters and drying obtains 510mg (productive rate 84%) in vacuum drying oven.MS(m/z)：305.1(MH
+)。
The preparation method 9
(2S, 4S)-4-fluoro-tetramethyleneimine-2-nitrile hydrochloride
Step 1:(2S, 4S)-4-fluoro-tetramethyleneimine-1,2-dicarboxylic acid uncle 2--butyl ester 1-(2,5-dioxo-tetramethyleneimine-1-yl) ester
With N-hydroxy-succinamide (380mg, 3.3mmol) 0 ℃ next time property be added to uncle N--BOC-cis-4-fluoro-L-proline(Pro) (700mg in dry DMF 3mmol) (8mL) solution, then press aliquot and adds 1, the 3-DIC (391mg, 3.1mmol).Reaction mixture is warming to room temperature and stirred overnight.Mixture with the dilution of 100mL water, is collected precipitation, and drying is whole night with cold water washing and in vacuum drying oven.Directly use product (1.093g) and need not be further purified.MS m/z 331.3(MH
+)。
Step 2:(2S, 4S)-2-formamyl-4-fluoro-tetramethyleneimine-1-carboxylic acid tert-butyl ester
(1.03g 3.12mmol) is dissolved under RT in the dioxane (12mL), and solution is dropwise handled with dense ammonium hydroxide aqueous solution (10mmol) with the title compound of step 1.The gained strong solution is stirred 3hr under RT, being acidified to pH with 6N HCl then is 4-5, and extracts with methylene dichloride (2 *).With extract saturated sodium bicarbonate and the salt water washing that merges, with dried over mgso, filtration and the concentrated limpid oil of 562mg (productive rate 78%) that obtains.MSm/z 233.3(MH
+)。
Step 3:(2S, 4S)-2-cyano group-4-fluoro-tetramethyleneimine-1-carboxylic acid tert-butyl ester
The 2mL dichloromethane solution of TFAA is added in the title compound of 0 ℃ step 2 under nitrogen atmosphere (550mg is 2.37mmol) and in anhydrous methylene chloride (15mL) solution of dry pyridine (0.4mL, 2 equivalents).This solution is stirred 2hr, 1hr under RT then down at 0 ℃.Reaction mixture with saturated sodium bicarbonate aqueous solution and salt water washing, is used dried over mgso, filtration and concentrated.Resistates is obtained 458mg (productive rate 90%) oil with flash chromatography purifying on silica gel, and this oil leaves standstill and solidifies.MS m/z 215.3(MH
+)。
Step 4
The title compound (400mg) of step 3 is dissolved in the dry acetonitrile (8mL) and the 4N HCl dioxane solution of 0.5mL is added under nitrogen atmosphere.With gained solution under RT stirred overnight and formed white depositions filtered and in vacuum drying oven drying obtain 128mg (productive rate 46%) title compound.MS m/z 115.1(MH
+)。From filtrate, can obtain extra product.
The preparation method 10
(2S)-4,4-two fluoro-tetramethyleneimine-2-nitrile hydrochloride
Step 1:N-uncle-BOC-4,4-two fluoropyrrolidines-2-nitrile
The 1mL dichloromethane solution of TFAA (252mg, 1.2 equivalents) is added in uncle N--BOC-4 of 0 ℃, and (250mg is 1mmol) and in the anhydrous methylene chloride solution of dry pyridine (97 μ L, 1.2 equivalents) for 4-two fluoropyrrolidines-L-proline(Pro) acid amides.This solution is heated to room temperature and stirs 36hr.With reaction mixture saturated ammonium chloride quencher, organic phase is used 1N HCl, saturated sodium bicarbonate and salt water washing successively, with dried over mgso, filtration and the concentrated 252mg white semisolid that obtains.MSm/z 233.1(MH
+)。
Step 2
The title compound (245mg) of step 1 is dissolved in the exsiccant acetonitrile (10mL), and adds the 4N HCl of 0.5mL.Gained solution is stirred 5hr and solvent is removed under RT.Resistates is ground with EtOAc, and with solid filtering, drying obtains 105 (productive rate 59%) white solid title compound under high vacuum then.MS m/z 133.2(MH
+)。
Formula (I) compound, the pharmaceutically-acceptable salts of its steric isomer and this compound and steric isomer can prepare according to following examples.Free alkali compound of the present invention can by they salt by for example herein among the embodiment 113 disclosed traditional way obtain.
Embodiment 1
((2S, 4S)-4-(4-(3-(trifluoromethyl) phenyl) piperazine-1-yl) tetramethyleneimine-2-yl)-(3,3-two fluoropyrrolidines-1-yl)-ketone dihydrochloride
Step 1:(2S, 4S)-2-[(3,3-two fluoropyrrolidines-1-yl) carbonyl]-4-{4-[3-(trifluoromethyl) phenyl] piperazine-1-yl } tetramethyleneimine-1-carboxylic acid tert-butyl ester
With preparation method 1 title compound (96mg, 0.3mmol), 1-[3-(trifluoromethyl) phenyl] piperazine (70mg, 0.3mmol) and AcOH (18 μ L, it is anhydrous 1 0.3mmol) to be dissolved in 8mL, in the 2-ethylene dichloride.Adding nitrilotriacetic base sodium borohydride (127mg, 0.6mmol).Under RT, behind the stirred reaction mixture 3hr,,, use the salt water washing, with dried over mgso, filtration and concentrated with the EtOAc extraction with reaction mixture saturated sodium bicarbonate quencher.With rough material chromatogram (Biotage
Flash 40S, 95: 5 methylene dichloride: MeOH) purifying obtains 126mg (79%) white foam shape title compound.MS m/z 533(MH
+)。
Step 2
(120mg 0.225mmol) handles with the dioxane (5mL) of 4N HCl with the product of step 1.Behind the 2hr, mixture is concentrated into drying under RT, grinds with ether, filtering also, vacuum-drying obtains 92mg white solid title compound.MS m/z 433(MH
+)。
Use suitable raw material, to have prepared the hydrochloride (in following table 1 open) of embodiment 2-112 compound with embodiment 1 described similar fashion.
Table 1
| Embodiment | Title | MS (M+1) |
| 2 | ((2S, 4S)-4-(4-(5-(trifluoromethyl) pyridine-2-yl) piperazine-1-yl) tetramethyleneimine-2-yl)-(3,3-two fluoropyrrolidines-1-yl)-ketone | 434 |
| 3 | ((2S, 4S)-4-(4-(5-(trifluoromethyl) pyridine-2-yl)-1,4-Diazesuberane-1-yl) tetramethyleneimine-2-yl)-(3,3-two fluoropyrrolidines-1-yl)-ketone | 448 |
| 4 | ((2S, 4S)-4-(4-(3-(trifluoromethyl) phenyl) piperazine-1-yl) tetramethyleneimine-2-yl)-((3R *，4S *)-3,4-two fluoropyrrolidines-1-yl)-ketone | 433 |
| 5 | ((2S, 4S)-4-(4-(2-(trifluoromethyl) quinolyl-4) piperazine-1-yl) tetramethyleneimine-2-yl)-(3,3-two fluoropyrrolidines-1-yl)-ketone | 484 |
| 6 | (3,3-two fluoropyrrolidines-1-yl)-((2S, 4S)-4-(4-(5-nitropyridine-2-yl) piperazine-1-yl) tetramethyleneimine-2-yl)-ketone | 411 |
| 7 | ((2S, 4S)-4-(4-(3-cyanopyridine-2-yl) piperazine-1-yl) tetramethyleneimine-2-yl)-(3,3-two fluoropyrrolidines-1-yl)-ketone | 391 |
| 8 | ((2S, 4S)-4-(4-(5-(trifluoromethyl) pyridine-2-yl) piperazine-1-yl) tetramethyleneimine-2-yl)-((3R *，4S *)-3,4-two fluoropyrrolidines-1-yl)-ketone | 434 |
| 9 | ((2S, 4S)-4-(4-(3-cyanopyridine-2-yl) piperazine-1-yl) tetramethyleneimine-2-yl)-((3R *，4S *)-3,4-two fluoropyrrolidines-1-yl)-ketone | 391 |
| 10 | ((2S, 4S)-4-(4-(3-cyanopyrazine-2-yl) piperazine-1-yl) tetramethyleneimine-2-yl)-((3R *，4S *)-3,4-two fluoropyrrolidines-1-yl)-ketone | 392 |
| 11 | ((2S, 4S)-4-(4-(4-(trifluoromethyl) phenyl) piperazine-1-yl) tetramethyleneimine-2-yl)-((3R *，4S *)-3,4-two fluoropyrrolidines-1-yl)-ketone | 433 |
| 12 | ((2S, 4S)-4-(2-(trifluoromethyl)-5,6-glyoxalidine be [1,2-a] pyrazine-7 (8H)-yl) tetramethyleneimine-2-yl also)-((3R *，4S *)-3,4-two fluoropyrrolidines-1-yl)-ketone | 394 |
| 13 | ((2S, 4S)-4-(4-(3-cyanopyrazine-2-yl) piperazine-1-yl) tetramethyleneimine-2-yl)-(3,3-two fluoropyrrolidines-1-yl)-ketone | 392 |
| 14 | ((2S, 4S)-4-(2-(trifluoromethyl)-5,6-glyoxalidine also [1,2-a] pyrazine-7 (8H)-yl) tetramethyleneimine-2-yl)-(3,3-two fluoropyrrolidines-1-yl)-ketone | 394 |
| 15 | ((3R *，4S *)-3,4-two fluoropyrrolidines-1-yl)-((2S, 4S)-4-(4-(pyrimidine-2-base) piperazine-1-yl) tetramethyleneimine-2-yl)-ketone | 367 |
| 16 | ((2S, 4S)-4-(4-(2-(trifluoromethyl) phenyl) piperazine-1-yl) tetramethyleneimine-2-yl)-(3,3-two fluoropyrrolidines-1-yl)-ketone | 433 |
| 17 | ((2S, 4S)-4-((1S, 5R, 6R)-and 6-amino-3-aza-bicyclo [3.1.0] hexane-3-yl) tetramethyleneimine-2-yl)-(3,3-two fluoropyrrolidines-1-yl)-ketone | 301 |
| 18 | ((2S, 4S)-4-(4-cyano group-4-Phenylpiperidine-1-yl) tetramethyleneimine-2-yl)-(3,3-two fluoropyrrolidines-1-yl) ketone | 389 |
| 19 | ((2S, 4S)-(4-(1 for 4-, 1-dioxo-1H-1,2-benzo [d] isothiazole-3-yl)-and piperazine-1-yl) tetramethyleneimine-2-yl)-(3,3-two fluoro-tetramethyleneimine-1-yl)-ketone | 454 |
| 20 | ((2S, 4S)-4-(4-(5-(trifluoromethyl)-1,3,4-thiadiazoles-2-yl) tetramethyleneimine-2-yl piperazine-1-yl))-(3,3-two fluoropyrrolidines-1-yl)-ketone | 441 |
| 21 | (3,3-two fluoropyrrolidines-1-yl)-((2S, 4S)-4-(4-(isothiazole-3-yl) piperazine-1-yl) tetramethyleneimine-2-yl) ketone | 372 |
| 22 | (3,3-two fluoropyrrolidines-1-yl)-((2S, 4S)-4-(4-(8-methyl-[1,2,4] tetramethyleneimine-2-yl piperazine-1-yl triazolo [4,3-a] pyrazine-3-yl)))-ketone | 421 |
| 23 | ((2S, 4S)-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4] triazolo [4,3-a] pyrazine-7 (8H)-yl) tetramethyleneimine-2-yl)-(3,3-two fluoropyrrolidines-1-yl)-ketone | 395 |
| 24 | (3,3-two fluoropyrrolidines-1-yl)-((2S, 4S)-4-(4-(2,6-dimethyl pyrimidine-4-yl) piperazine-1-yl) tetramethyleneimine-2-yl)-ketone | 395 |
| 25 | ((2S, 4S)-4-(4-(benzo [d] isothiazole-3-yl) piperazine-1-yl) tetramethyleneimine-2-yl)-(3,3-two fluoropyrrolidines-1-yl)-ketone | 422 |
| 26 | ((2S, 4S)-4-(4-(4-(trifluoromethyl)-6-picoline-2-yl) piperazine-1-yl) tetramethyleneimine-2-yl)-(3,3-two fluoropyrrolidines-1-yl)-ketone | 448 |
| 27 | (3,3-two fluoropyrrolidines-1-yl)-((2S, 4S)-4-(4-(oxazole is [5,4-b] pyridine-2-yl also) piperazine-1-yl) tetramethyleneimine-2-yl)-ketone | 407 |
| 28 | (3,3-two fluoropyrrolidines-1-yl)-((2S, 4S)-((the 4-methyl is phonetic for 4-for 4- |
| Pyridine-2-yl) tetramethyleneimine-2-yl piperazine-1-yl))-ketone | 381 | |
| 29 | ((2S, 4S)-4-(4-(4-cyanopyridine-2-yl) piperazine-1-yl) tetramethyleneimine-2-yl)-(3,3-two fluoropyrrolidines-1-yl)-ketone | 391 |
| 30 | ((2S, 4S)-4-(4-(7-(trifluoromethyl) quinolyl-4) piperazine-1-yl) tetramethyleneimine-2-yl)-(3,3-two fluoropyrrolidines-1-yl)-ketone | 484 |
| 31 | ((2S, 4S)-4-(4-(5-cyanopyridine-2-yl) piperazine-1-yl) tetramethyleneimine-2-yl)-(3,3-two fluoropyrrolidines-1-yl)-ketone | 391 |
| 32 | (3,3-two fluoropyrrolidines-1-yl)-((2S, 4S)-4-(4-(pyridine-2-yl) piperazine-1-yl) tetramethyleneimine-2-yl) ketone | 366 |
| 33 | ((2S, 4S)-4-(4-(6-(trifluoromethyl) quinolyl-4) piperazine-1-yl) tetramethyleneimine-2-yl)-(3,3-two fluoropyrrolidines-1-yl)-ketone | 484 |
| 34 | (3,3-two fluoropyrrolidines-1-yl)-((2S, 4S)-4-(4-(5-picoline-2-yl) piperazine-1-yl) tetramethyleneimine-2-yl)-ketone | 380 |
| 35 | ((2S, 4S)-4-(4-(4-(trifluoromethyl) pyrimidine-2-base) piperazine-1-yl) tetramethyleneimine-2-yl)-(3,3-two fluoropyrrolidines-1-yl)-ketone | 435 |
| 36 | (3,3-two fluoropyrrolidines-1-yl)-((2S, 4S)-4-(4-(3-methyl-1,2,4-oxadiazole-5-yl) piperidines-1-yl) tetramethyleneimine-2-yl)-ketone | 370 |
| 37 | (3,3-two fluoropyrrolidines-1-yl)-((2S, 4S)-4-(4-(quinoline-2-yl) piperazine-1-yl) tetramethyleneimine-2-yl)-ketone | 416 |
| 38 | (3,3-two fluoropyrrolidines-1-yl)-((2S, 4S)-4-(4-(6-methoxypyridine-2-yl) piperazine-1-yl) tetramethyleneimine-2-yl)-ketone | 396 |
| 39 | (3,3-two fluoropyrrolidines-1-yl)-((2S, 4S)-4-(4-(5-methyl-1,2,4-oxadiazole-3-yl) piperidines-1-yl) tetramethyleneimine-2-yl)-ketone | 370 |
| 40 | (3,3-two fluoropyrrolidines-1-yl)-((2S, 4S)-4-(4-(quinoline-8-yl) piperazine-1-yl) tetramethyleneimine-2-yl)-ketone | 416 |
| 41 | (3,3-two fluoropyrrolidines-1-yl)-((2S, 4S)-4-(4-(1-phenyl-1H-imidazoles-2-yl) piperidines-1-yl) tetramethyleneimine-2-yl)-ketone | 430 |
| 42 | (3,3-two fluoropyrrolidines-1-yl)-((2S, 4S)-4-(4-(quinoxaline-5-yl) piperazine-1-yl) tetramethyleneimine-2-yl)-ketone | 417 |
| 43 | ((2S, 4S)-4-(4-(benzo [d] isoxazole-3-base) piperazine-1-yl) tetramethyleneimine-2-yl)-(3,3-two fluoropyrrolidines-1-yl) ketone | 406 |
| 44 | (3,3-two fluoro-tetramethyleneimine-1-yl)-[(2S, 4S)-4-(8-trifluoromethyl-3,4-dihydro-1H-benzo [4,5] imidazo [1,2-a] pyrazine-2-yl)-tetramethyleneimine-2-yl]-ketone | 444 |
| 45 | (3,3-two fluoropyrrolidines-1-yl)-((2S, 4S)-4-(4-Phenylpiperidine-1-yl) tetramethyleneimine-2-yl)-ketone | 364 |
| 46 | ((2S, 4S)-4-(4-(3-(trifluoromethyl) phenyl) piperidines-1-yl) tetramethyleneimine-2-yl)-(3,3-two fluoropyrrolidines-1-yl)-ketone | 432 |
| 47 | ((2S, 4S)-4-(4-(3-(trifluoromethyl) pyridine-2-yl) piperazine-1-yl) tetramethyleneimine-2-yl)-(3,3-two fluoropyrrolidines-1-yl)-ketone | 434 |
| 48 | ((2S, 4S)-4-(4-(4-(trifluoromethyl) quinoline-2-yl) piperazine-1-yl) tetramethyleneimine-2-yl)-(3,3-two fluoropyrrolidines-1-yl)-ketone | 484 |
| 49 | ((2S, 4S)-4-(2-(trifluoromethyl)-7,8-dihydro pyrido [4,3-d] pyrimidine-6 (5H)-yl) tetramethyleneimine-2-yl)-(3,3-two fluoropyrrolidines-1-yl)-ketone | 406 |
| 50 | (3,3-two fluoropyrrolidines-1-yl)-((2S, 4S)-4-(4-(4-methyl-6-phenyl pyrimidine-2-yl) piperazine-1-yl) tetramethyleneimine-2-yl)-ketone | 457 |
| 51 | ((2S, 4S)-4-(4-(1H-benzo [d] [1,2,3] triazol-1-yl) piperidines-1-yl) tetramethyleneimine-2-yl)-(3,3-two fluoropyrrolidines-1-yl)-ketone | 405 |
| 52 | (3,3-two fluoropyrrolidines-1-yl) ((2S, 4S)-4-(4-(thiazol-2-yl) piperazine-1-yl) tetramethyleneimine-2-yl)-ketone | 372 |
| 53 | (3,3-two fluoropyrrolidines-1-yl)-((2S, 4S)-4-(4-(3-picoline-2-yl) piperazine-1-yl) tetramethyleneimine-2-yl)-ketone | 380 |
| 54 | ((2S, 4S)-4-(4-(benzo [d] oxazole-2-yl) piperazine-1-yl) tetramethyleneimine-2-yl)-(3,3-two fluoropyrrolidines-1-yl)-ketone | 406 |
| 55 | (3,3-two fluoropyrrolidines-1-yl)-((2S, 4S)-4-(4-(6-phenylpyridine-2-yl) piperazine-1-yl) tetramethyleneimine-2-yl)-ketone | 442 |
| 56 | (3,3-two fluoropyrrolidines-1-yl)-((2S, 4S)-((3R, 5S)-3,5-two for 4- |
| Methyl-4-(4,6-dimethyl-1,3,5-triazines-2-yl) piperazine-1-yl) tetramethyleneimine-2-yl)-ketone | 424 | |
| 57 | [(2S, 4S)-4-(2-cyclopropyl-7,8-dihydro-5H-pyrido [4,3-d] pyrimidine-6-yl)-tetramethyleneimine-2-yl]-(3,3-two fluoro-tetramethyleneimine-1-yl)-ketone | 378.4 |
| 58 | (3,3-two fluoro-tetramethyleneimine-1-yl)-[(2S, 4S)-4-(2-methoxyl group-7,8-dihydro-5H-pyrido [4,3-d] pyrimidine-6-yl)-tetramethyleneimine-2-yl]-ketone | 368.3 |
| 59 | (3,3-two fluoro-tetramethyleneimine-1-yl)-[(2S, 4S)-4-(2-phenyl-7,8-dihydro-5H-pyrido [4,3-d] pyrimidine-6-yl)-tetramethyleneimine-2-yl]-ketone | 414.4 |
| 60 | (3,3-two fluoro-tetramethyleneimine-1-yl)-[(2S, 4S)-4-(the 4-oxazole is [4,5-c] pyridine-2-base-piperazine-1-yl also)-tetramethyleneimine-2-yl]-ketone | 407.4 |
| 61 | (3,3-two fluoro-tetramethyleneimine-1-yl)-[(2S, 4S)-4-(the 4-oxazole is [5,4-c] pyridine-2-base-piperazine-1-yl also)-tetramethyleneimine-2-yl]-ketone | 407.4 |
| 62 | (3,3-two fluoro-tetramethyleneimine-1-yl)-[(2S, 4S)-4-(2,3,4, join pyrazine-4-yl 5-tetrahydrochysene-[1,2 '])-tetramethyleneimine-2-yl]-ketone | 367.4 |
| 63 | (2S, 4S)-4-[4-(3,5-two chloro-pyridin-4-yls)-piperazine-1-yl]-tetramethyleneimine-2-yl }-(3,3-two fluoro-tetramethyleneimine-1-yl)-ketone | 434.2 |
| 64 | (3,3-two fluoro-tetramethyleneimine-1-yl)-[(2S, 4S)-4-(4-quinoxaline-2-base-piperazine-1-yl)-tetramethyleneimine-2-yl]-ketone | 417.4 |
| 65 | 4-[(3S, 5S)-5-(3,3-two fluoro-tetramethyleneimine-1-carbonyl)-tetramethyleneimine-3-yl]-piperazine-1-sulfonic acid diformamide | 396.3 |
| 66 | [(2S, 4S)-4-(2-amino-7,8-dihydro-5H-pyrido [4,3-d] pyrimidine-6-yl)-tetramethyleneimine-2-yl]-(3,3-two fluoro-tetramethyleneimine-1-yl)-ketone | 353.3 |
| 67 | (3,3-two fluoro-tetramethyleneimine-1-yl)-[(2S, 4S)-4-(2-methyl-4-pyrimidine-2-base-piperazine-1-yl)-tetramethyleneimine-2-yl]-ketone | 381.4 |
| 68 | (3,3-two fluoro-tetramethyleneimine-1-yl)-(2S, 4S)-4-[4-(5-ethyl-phonetic |
| Pyridine-2-yl)-piperazine-1-yl]-tetramethyleneimine-2-yl }-ketone | 395.4 | |
| 69 | (2S, 4S)-4-[4-(5-bromo-pyrimidine-2-base)-piperazine-1-yl]-tetramethyleneimine-2-yl }-(3,3-two fluoro-tetramethyleneimine-1-yl)-ketone | 445.4 |
| 70 | 4-[(3S, 5S)-5-(3,3-two fluoro-tetramethyleneimine-1-carbonyl)-tetramethyleneimine-3-yl]-piperazine-1-benzyl carboxylate | 423.4 |
| 71 | ((2S, 4S)-4-(2-(4-chloro-phenyl-)-7,8-dihydro pyrido [4,3-d] pyrimidine-6 (5H)-yl) tetramethyleneimine-2-yl) (3,3-two fluoropyrrolidines-1-yl) ketone | 448.4 |
| 72 | (3,3-two fluoropyrrolidines-1-yl) ((2S, 4S)-4-(7,8-dihydro-2-propyl group pyrido [4,3-d] pyrimidines-6 (5H)-yl) tetramethyleneimine-2-yl) ketone | 382.4 |
| 73 | (2S, 4S)-4-[4-(5-chloro-benzoxazole-2-yl)-piperazine-1-yl]-tetramethyleneimine-2-yl }-(3,3-two fluoro-tetramethyleneimine-1-yl)-ketone | 440.4 |
| 74 | (3,3-two fluoro-tetramethyleneimine-1-yl)-[(2S, 4S)-4-((2-pyridine-2-yl)-7,8-dihydro-5H-pyrido [4,3-d] pyrimidine-6-yl)-tetramethyleneimine-2-yl]-ketone | 415.4 |
| 75 | (3,3-two fluoro-tetramethyleneimine-1-yl)-[(2S, 4S)-4-(2-pyridin-4-yl-7,8-dihydro-5H-pyrido [4,3-d] pyrimidine-6-yl)-tetramethyleneimine-2-yl]-ketone | 415.4 |
| 76 | (3,3-two fluoro-tetramethyleneimine-1-yl)-(2S, 4S)-4-[4-(5-methyl-benzoxazole-2-yl)-piperazine-1-yl]-tetramethyleneimine-2-yl }-ketone | 420.4 |
| 77 | (2S, 4S)-4-[4-(6-chloro-benzoxazole-2-yl)-piperazine-1-yl]-tetramethyleneimine-2-yl }-(3,3-two fluoro-tetramethyleneimine-1-yl)-ketone | 440.4 |
| 78 | (3,3-two fluoro-tetramethyleneimine-1-yl)-[(2S, 4S)-4-(7,8-dihydro-5H-pyrido [4,3-d] pyrimidine-6-yl)-tetramethyleneimine-2-yl]-ketone | 338.4 |
| 79 | ((S)-3-fluoro-tetramethyleneimine-1-yl)-[(2S, 4S)-4-(the 4-oxazole is [5,4-c] pyridine-2-base-piperazine-1-yl also)-tetramethyleneimine-2-yl]-ketone | 389.4 |
| 80 | 4-[(3S, 5S)-5-((S)-3-fluoro-tetramethyleneimine-1-carbonyl)-tetramethyleneimine-3-yl]-3,4,5,6-tetrahydrochysene-2H-[1,2 '] connection pyrazine-3 '-nitrile | 374.4 |
| 81 | ((S)-3-fluoro-tetramethyleneimine-1-yl)-(2S, 4S)-4-[4-(5-fluoroform | 416.4 |
| Base-pyridine-2-yl)-piperazine-1-yl]-tetramethyleneimine-2-yl }-ketone | ||
| 82 | ((S)-3-fluoro-tetramethyleneimine-1-yl)-[(2S, 4S)-4-(the 4-oxazole is [5,4-b] pyridine-2-base-piperazine-1-yl also)-tetramethyleneimine-2-yl]-ketone | 389.4 |
| 83 | 2-{4-[(3S, 5S)-5-((S)-3-fluoro-tetramethyleneimine-1-carbonyl)-tetramethyleneimine-3-yl]-piperazine-1-yl }-the nicotinic acid nitrile | 373.4 |
| 84 | ((S)-3-fluoro-tetramethyleneimine-1-yl)-(2S, 4S)-4-[4-(3-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-tetramethyleneimine-2-yl }-ketone | 416.5 |
| 85 | ((2S, 4S)-4-(2-(trifluoromethyl)-7,8-dihydro pyrido [4,3-d] pyrimidines-6 (5H)-yl) tetramethyleneimine-2-yl) ((S)-3-fluoropyrrolidine-1-yl) ketone | 388.4 |
| 86 | ((S)-3-fluoro-tetramethyleneimine-1-yl)-(2S, 4S) 4-[4-(4-methyl-pyrimidine-2-base)-piperazine-1-yl]-tetramethyleneimine-2-yl }-ketone | 363.5 |
| 87 | ((S)-3-fluoropyrrolidine-1-yl) ((2S, 4S)-4-(4-(pyrazine-2-yl) piperazine-1-yl) tetramethyleneimine-2-yl) ketone | 349.4 |
| 88 | [(2S, 4S)-4-(2-cyclopropyl-7,8-dihydro-5H-pyrido [4,3-d] pyrimidine-6-yl)-tetramethyleneimine-2-yl]-((S)-3-fluoro-tetramethyleneimine-1-yl)-ketone | 360.4 |
| 89 | ((S)-3-fluoro-tetramethyleneimine-1-yl)-(2S, 4S)-4-[4-(2-trifluoromethyl-quinolyl-4)-piperazine-1-yl]-tetramethyleneimine-2-yl }-ketone | 466.5 |
| 90 | (3-fluorine azetidin-1-yl) ((2S, 4S)-4-(4-(pyrazine-2-yl) piperazine-1-yl) tetramethyleneimine-2-yl) ketone | 335.4 |
| 91 | 4-[(3S, 5S)-5-(3-fluoro-azetidine-1-carbonyl)-tetramethyleneimine-3-yl]-3,4,5,6-tetrahydrochysene-2H-[1,2 '] connection pyrazine-3 '-nitrile | 360.4 |
| 92 | (3-fluoro-azetidin-1-yl)-[(2S, 4S)-4-(the 4-oxazole is [5,4-b] pyridine-2-base-piperazine-1-yl also)-tetramethyleneimine-2-yl]-ketone | 375.4 |
| 93 | (3-fluoro-azetidin-1-yl)-(2S, 4S)-4-[4-(3-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-tetramethyleneimine-2-yl }-ketone | 402.4 |
| 94 | (3-fluoro-azetidin-1-yl)-[(2S, 4S)-4-(the 4-oxazole is [5,4-c] pyridine-2-base-piperazine-1-yl also)-tetramethyleneimine-2-yl]-ketone | 375.4 |
| 95 | [(2S, 4S)-4-(2-cyclopropyl-7,8-dihydro-5H-pyrido [4,3-d] pyrimidine-6-yl)-tetramethyleneimine-2-yl]-(3-fluoro-azetidin-1-yl)-ketone | 346.4 |
| 96 | 2-{4-[(3S, 5S)-5-(3-fluoro-azetidine-1-carbonyl)-tetramethyleneimine-3-yl]-piperazine-1-yl }-the nicotinic acid nitrile | 359.4 |
| 97 | (3-fluorine azetidin-1-yl) ((2S, 4S)-4-(4-(5-(trifluoromethyl) pyridine-2-yl) piperazine-1-yl) tetramethyleneimine-2-yl) ketone | 402.4 |
| 98 | (3-fluoro-azetidin-1-yl)-[(2S, 4S)-4-(2-trifluoromethyl-7,8-dihydro-5H-pyrido [4,3-d] pyrimidine-6-yl)-tetramethyleneimine-2-yl]-ketone | 374.4 |
| 99 | (3-fluoro-azetidin-1-yl)-(2S, 4S)-4-[4-(4-methyl-pyrimidine-2-base)-piperazine-1-yl]-tetramethyleneimine-2-yl }-ketone | 349.4 |
| 100 | (3-fluoro-azetidin-1-yl)-(2S, 4S)-4-[4-(2-trifluoromethyl-quinolyl-4)-piperazine-1-yl]-tetramethyleneimine-2-yl }-ketone | 452.5 |
| 101 | [(2S, 4S)-4-(4-benzoxazole-2-base piperazine-1-yl)-tetramethyleneimine-2-yl]-((3R *，4S *)-3,4-two fluoro-tetramethyleneimine-1-yl)-ketone | 406.4 |
| 102 | ((3R *，4S *)-3,4-two fluoro-tetramethyleneimine-1-yl)-[(2S, 4S)-4-(2-trifluoromethyl-7,8-dihydro-5H-pyrido [4,3-d] pyrimidine-6-yl)-tetramethyleneimine-2-yl]-ketone | 406.4 |
| 103 | ((3R *，4S *)-3,4-two fluoro-tetramethyleneimine-1-yl)-[(2S, 4S)-4-(the 4-oxazole is [5,4-c] pyridine-2-base-piperazine-1-yl also)-tetramethyleneimine-2-yl]-ketone | 407.4 |
| 104 | ((3R *，4S *)-3,4-two fluoro-tetramethyleneimine-1-yl)-[(2S, 4S)-4-(the 4-oxazole is [5,4-b] pyridine-2-base-piperazine-1-yl also)-tetramethyleneimine-2-yl]-ketone | 407.4 |
| 105 | ((3R *，4S *)-3,4-two fluoro-tetramethyleneimine-1-yl)-(2S, 4S)-4-[4-(4-methyl-pyrimidine-2-base)-piperazine-1-yl]-tetramethyleneimine-2-yl }-ketone | 381.4 |
| 106 | (3,3-two fluoro-azetidin-1-yl)-(2S, 4S)-4-[4-(3-trifluoro | 420.2 |
| Methyl-pyridine-2-yl)-piperazine-1-yl]-tetramethyleneimine-2-yl }-ketone | ||
| 107 | 2-{4-[(3S, 5S)-5-(3,3-two fluoro-azetidine-1-carbonyl)-tetramethyleneimine-3-yl]-piperazine-1-yl }-the nicotinic acid nitrile | 377.2 |
| 108 | (3,3-two fluoro-azetidin-1-yl)-[(2S, 4S)-4-(2-trifluoromethyl-7,8-dihydro 5H-pyrido [4,3-d] pyrimidine-6-yl)-tetramethyleneimine-2-yl]-ketone | 392.2 |
| 109 | (3,3-two fluoro-azetidin-1-yl)-(2S, 4S)-4-[4-(2-trifluoromethyl-quinolyl-4)-piperazine-1-yl]-tetramethyleneimine-2-yl }-ketone | 470.2 |
| 110 | (3,3-two fluoro-azetidin-1-yl)-[(2S, 4S)-4-(the 4-oxazole is [5,4-c] pyridine-2-base-piperazine-1-yl also)-tetramethyleneimine-2-yl]-ketone | 393.2 |
| 111 | (2S, 4S)-4-[5-(4-chloro-phenyl)-2-aza-bicyclo [2.2.1] heptan-2-yl]-tetramethyleneimine-2-yl }-(3,3-two fluoro-tetramethyleneimine-1-yl)-ketone | 410.2 |
| 112 | (3,3-two fluoro-tetramethyleneimine-1-yl)-[(2S, 4S)-4-(2-trifluoromethyl-5,8-dihydro-6H-pyrido [3,4-d] pyrimidin-7-yl)-tetramethyleneimine-2-yl]-ketone | 406.1 |
Embodiment 113
(3,3-two fluoropyrrolidines-1-yl)-((2S, 4S)-4-(4-(pyrimidine-2-base) piperazine-1-yl) tetramethyleneimine-2-yl)-ketone
Step 1:(S)-2-(3,3-two fluoro-tetramethyleneimine-1-carbonyl)-4-oxo-tetramethyleneimine-1-carboxylic acid tert-butyl ester
With (S)-4-oxo-tetramethyleneimine-1, the 2-dicarboxylic acid 1-tert-butyl ester (6.6kg, 1.0 equivalents) adds in the reactor, then adds methylene dichloride (15 volume).Reaction mixture is cooled to 0 ℃.Triethylamine (4.82 liters, 1.2 equivalents) was added in 30 minutes.Add latter stage at triethylamine, this mixture becomes clear solution by suspension.With mixture remain on 0 ℃-5 ℃ 10 minutes.Slowly add pivalyl chloride (3.65kg, 1.05 equivalents) and simultaneously temperature of reaction is remained on 0 ℃-5 ℃.This reaction mixture becomes slurries again.Maintenance is after 1 hour down at 0 ℃-5 ℃, and this reaction mixture of taking a sample is used to finish HPLC (utilizing diethylamine to arrive its derivative).With 3,3-two fluoro-pyrrolidine hydrochlorides (4.13kg, 1.0 equivalents) were added in the said mixture in 10 minutes under-10 ℃-0 ℃.Triethylamine (4.0 liters, 1.0 equivalents) was slowly introduced in 70 minutes under-10 ℃-0 ℃.After finishing the triethylamine interpolation, mixture is stirred 1h down at 0-5 ℃.Determine to finish this reaction (～1% raw material) by the HPLC test.With reaction mixture in 0 ℃-5 ℃ following waters (10 volume) quencher.With mixture heating up to 20 ℃-25 ℃.Each layer separated, and organic layer is washed with 0.5M HCl (5 volume).With the 5%NaHCO of organic layer with combination
3(2 volume) and half saturated salt brine solution (1.64M, 3 volumes) wash once more.Organic solution under atmospheric pressure is concentrated into the volume (about 20 liters) that can hang down stirring.Add ethyl acetate (12.6 volumes, 82.8 liters), solution under atmospheric pressure is concentrated into～6 volumes.Mixture was kept 2 hours down and cool to room temperature 3 hours at 60 ℃-65 ℃.Mixture was kept 8 hours down at 20 ℃-25 ℃.Add heptane (8 volume) and with minimum 2 hours of mixture granulating.With solid filtering, with the flushing of 2: 1 heptane/ethyl acetate (1 volume) and under 25 ℃-35 ℃ in pan dryer dry minimum 12 hours.Output: 7.26kg, 79%.HPLC purity: 99.7%.Mother liquor (86 liters) is concentrated into 12 liters under the partial vacuum condition under 65 ℃-70 ℃.Mixture is cooled to 60 ℃-65 ℃.Ethyl acetate (4.0 liters) was slowly added in 15 minutes.Mixture was kept 2 hours 2 hours internal cooling to 20 ℃-25 ℃ and in this temperature at least.Wash with solid filtering and with heptane/ethyl acetate (3: 1v/v, 1.7 liters).Drying obtained 435 gram products in 12 hours in pan dryer under 35 ℃-45 ℃.HPLC purity: 96.4%.
Step 2:(2S, 4S)-2-(3,3-two fluoro-tetramethyleneimine-1-carbonyl)-4-(4-pyrimidine-2-base-piperazine-1-its)-tetramethyleneimine-1-carboxylic acid tert-butyl ester
The product (4.00kg, 1.0 equivalents) of THF (20 volume), 2-piperazine-1-base-pyrimidine (2.17kg, 1.05 equivalents) and step 1 is added in the reactor.Mixture is remained on 20 ℃-25 ℃ to be dissolved in 30 minutes up to all material.Add acetate (0.792kg, 1.05 equivalents).Mixture was stirred 1 hour, and during this period, it is muddy that reaction mixture becomes.With reaction mixture refluxed 30 minutes, concentrate down up to observing 66.9 ℃ equilibrium temperature distillating head at 60 ℃-70 ℃ then, this shows that water removes fully from system.If necessary, add more THF.When finishing, add THF so that the cumulative volume in the reactor is 15 volume limiting quantity reagent.Reaction mixture is cooled to-3 ℃-7 ℃ and sampling and is used for finishing the formation (utilize nitrilotriacetic base sodium borohydride with reduction imines) of imines by HPLC.Nitrilotriacetic base sodium borohydride (5.33kg, 2.0 equivalents) is added in the suspension at-5 ℃-15 ℃ in batches.Reaction mixture is heated to 20 ℃-25 ℃ and kept 12 hours.HPLC result confirms that this reaction is over 99.8%.Add sodium bicarbonate aqueous solution (10%w/w, 10 volumes).These slurries are concentrated to remove 10 volume THF under the partial vacuum condition under 30 ℃-60 ℃.Be cooled to after 20 ℃-25 ℃ ethyl acetate (10 volume) is added in the suspension at suspension.Check water with the organic phase separation and by HPLC.Aqueous phase comprises the product less than 2%.Organic phase water (5 volume), saturated brine solution (5 volume) are washed and are concentrated into small volume (2 volume) under the partial vacuum condition under 45 ℃-50 ℃.Heptane (10 volume) is added in the slurries in following 30 minutes at 45 ℃-50 ℃.Mixture was cooled to 20 ℃-25 ℃ and granulating 2 hours.Solid by filtration is collected, with heptane (2 volume) flushing.Drying obtained 5.35kg (91.3%) product in 12 hours in pan dryer under 35 ℃-45 ℃.
Step 3:(3,3-two fluoro-tetramethyleneimine-1-yl)-[(2S, 4S)-4-(4-pyrimidine-2-base-piperazine-1-yl)-tetramethyleneimine-2-yl]-ketone
Water (19 liters, 2 volumes) is added in the reactor, then adds the product (9.57kg, 1.0 equivalents) of step 2.Spissated HCl (37wt% in water, 19.1 liters, 2 volumes) was slowly added in the slurries in 4 hours under 20 ℃-30 ℃.。After adding 12 liters of HCl, slurries become solution.After interpolation was finished, this reaction was tested by HPLC and is determined to finish.Reaction mixture is cooled to 5 ℃-15 ℃.Slowly being added to the 50%NaOH aqueous solution in the mixture and being stirred to pH is 10-11.During neutralizing, this pH monitors with pH meter.The cumulative volume of the 50%NaOH that is added is 12.45 liters.With mixture heating up to 20 ℃-25 ℃ and with twice of ethyl acetate extraction (being respectively 115 liters, 12 volumes and 57 liters, 6 volumes).To analyze by HPLC at the sample of the water layer after the extraction for the second time, the result shows only 1% product in aqueous solution.Handled 1 hour with the organic layer merging and with sal epsom (5kg).Mixture is filtered.Filter cake is washed with ethyl acetate (10 liters).The pot strainer that be used for dustless operation (speck free operation) of filtrate by 0.2 micron is added back to reaction.(below operate under the dustless condition carry out).Solution is concentrated into 20 liters (2 volumes) under the partial vacuum condition under 50 ℃-60 ℃.With mixture 30 minutes internal cooling to 20 ℃-25 ℃.When cool to room temperature, crystallization has appearred.Mixture was kept 30 minutes.Hexane (20 liters, 2 volumes) was slowly added at 1 hour.With mixture granulating 2 hours.With solid product by filter to collect and with hexane/ethyl acetate (10 liters, 1: 1v/v) wash.Strainer is dried up minimum 2 hours with nitrogen.With product under 44 ℃ in pan dryer dry 12 hours.Output: 5.7kg, 75.9%.m.p.156℃。MS m/z 367(MH
+)。
1H NMR (400MHz, D
2O): δ 8.15 (d, 2H, J=5.0Hz, the CH of pyrimidine), 6.55 (t, 1H, J=4.8Hz, the CH of pyrimidine), 3.87-3.81 (dd, 1H, the H of proline(Pro)
2b), 3.78-3.50 (m, 4H, the N-CH of tetramethyleneimine
2), 3.55-3.40 (m, 4H, the N-CH of piperazine
2), 2.97 (dd, 1H, J=10.2,6.6Hz, the H of proline(Pro)
5a), 2.85-2.75 (m, 1H, the H of proline(Pro)
4b), 2.69 (dd, 1H, J=10.0,9.1Hz, the H of proline(Pro)
5b), 2.55-2.20 (m, 7H, eclipsed piperazine N-CH
2, the CH of tetramethyleneimine
2H with proline(Pro)
3b), 1.47-1.38 (m, 1H, the H of proline(Pro)
3a).
Replacedly, the dihydrochloride of title compound is according to the method preparation of embodiment 1.
Embodiment 114
(2S, 4S)-[4-(4-pyrimidine-2-base-piperazine-1-yl)-tetramethyleneimine-2-yl] }-(3,3,4,4-tetrafluoro-tetramethyleneimine-1-yl)-ketone dihydrochloride
Step 1:(2S, 4S)-4-(4-pyrimidine-2-base piperazine-1-yl)-2-[(3,3,4,4-tetrafluoro tetramethyleneimine-1-yl) carbonyl] tetramethyleneimine-1-carboxylic acid tert-butyl ester
With DIPEA (261mL, 1.5mmol) be added drop-wise to preparation method 3 title compound (114mg, 0.3mmol), (128mg, 0.33mmol) and 3,3,4, (54mg is in 5mL methylene dichloride suspension 0.3mmol) for 4-tetrafluoro pyrrolidine hydrochloride for HATU.After stirred overnight, add saturated sodium bicarbonate, with the mixture dichloromethane extraction, extract is also concentrated with dried over mgso.With resistates chromatogram (Biotage
Flash 40S, EtOAc) purifying obtains title compound.MS m/z503(MH
+)。
Step 2
The EtOAc/MeOH solution of step 1 product is handled in dioxane (about 5mL) with 4M HCl.Behind 18hr, solvent removed and resistates absorbed in own nitrile and concentrate.Absorbing, filter solid also in hexane, drying obtains 50mg (33%, two step) title compound.MS m/z 403(MH
+)。
Adopt suitable raw material, to have prepared the hydrochloride (in following table 2 open) of embodiment 115-122 compound with embodiment 114 described similar fashion.
Table 2
| Embodiment | Title | MS (M+1) |
| 115 | (3-fluorine azetidin-1-yl)-((2S, 4S)-4-(4-(pyrimidine-2-base) piperazine-1-yl) tetramethyleneimine-2-yl)-ketone | 335 |
| 116 | ((3R *，4R *)-3,4-two fluoropyrrolidines-1-yl)-((2S, 4S)-4-(4-(pyrimidine-2-base) piperazine-1-yl) tetramethyleneimine-2-yl)-ketone | 367 |
| 117 | ((S)-3-fluoropyrrolidine-1-yl)-((2S, 4S)-4-(4-(pyrimidine-2-base) piperazine-1-yl) tetramethyleneimine-2-yl)-ketone | 349 |
| 118 | ((R)-3-fluoropyrrolidine-1-yl)-((2S, 4S)-4-(4-(pyrimidine-2-base) piperazine-1-yl) tetramethyleneimine-2-yl)-ketone | 349 |
| 119 | (3,3-difluoro azetidin-1-yl) ((4S)-4-(4-(pyrimidine-2-base) piperazine-1-yl) tetramethyleneimine-2-yl) ketone | 353.3 |
| 120 | (2S, 4S)-4-fluoro-1-[(2S, 4S)-4-(4-pyrimidine-2-base-piperazine-1-yl)-tetramethyleneimine-2-carbonyl]-tetramethyleneimine-2-nitrile | 374.1 |
| 121 | (S)-4,4-two fluoro-1-[(2S, 4S)-4-(2-trifluoromethyl-7,8-dihydro-5H-pyrido [4,3-d] pyrimidine-6-yl)-tetramethyleneimine-2-carbonyl]-tetramethyleneimine-2-nitrile | 431.2 |
| 122 | (2S, 4S)-4-fluoro-1-[(2S, 4S)-4-(2-trifluoromethyl-7,8-dihydro-5H-pyrido [4,3-d] pyrimidine-6-yl)-tetramethyleneimine-2-carbonyl]-tetramethyleneimine-2-nitrile | 413.3 |
| 123 | (azetidin-1-yl) ((2S, 4S)-4-(4-(pyrimidine-2-base) piperazine-1-yl) tetramethyleneimine-2-yl) ketone | 317 |
Embodiment 124
((2S, 3R, 4S)-and 4-(4-(3-(trifluoromethyl) pyridine-2-yl) piperazine-1-yl)-3-methylpyrrolidin-2-yl) (3,3-two fluoropyrrolidines-1-yl) ketone dihydrochloride
Step 1
(5.6g 20mmol) is dissolved in that (2.0mL 24mmol) handles in the benzene (50mL) that comprises 4 molecular sieves (7.9g) and with tetramethyleneimine with preparation method 1 title compound.Solution is filtered and be concentrated into drying, stay tangerine look foam (7.0g, productive rate 100%).
Step 2
With step 1 product (7.0g, acetonitrile 20mmol) (100mL) solution be added to crushing salt of wormwood (5.2g, 38mmol) in, and with methyl iodide (1.5mL 24mmol) handles.With mixture heating up to 90 ℃ 16 hours, be cooled to RT and concentrate.Resistates is absorbed and adds the mixture of AcOH (5mL) and water (45mL) in chloroform (150mL).Under RT after three hours, each layer separated, with water layer with chloroform (3 * 25mL) extractions and with the organic phase that merges (2 * 25mL) with the salt water washing and be concentrated into brown oil with saturated sodium bicarbonate.This oil is dissolved in the ether (75mL), filters and be concentrated into light brown solid (0.97g, productive rate 16%).
Step 3
With sodium cyanoborohydride (21mg, 0.28mmol) be added to the product (74mg of step 2,0.25mmol), 1-(3-trifluoromethyl) pyridine-2-base-piperazine (63mg, 0.28mmol), (23mg is in the mixture of MeOH 0.28mmol) (1mL) for AcOH (16 μ L) and sodium acetate.Mixture at room temperature stirred concentrated then in 65 hours.Resistates absorbed in EtOAc (20mL) and with solution with 1N sodium hydroxide (2 * 3mL) and salt solution (5mL) wash, with dried over mgso and be concentrated into drying.Resistates is passed through preparation HPLC (Shimadzu, Columbia, MD; 30 * 50cm Waters-Xterra
C18 post-Waters Instrument Co., Milford, MA; 15% acetonitrile with 0.1% ammonium hydroxide was with the gradient of 30mL/min 10 minutes) purifying obtains colorless solid (35.7mg, productive rate 26%).
Step 4
Dioxane (0.5mL) solution of HCl (4M) is added to the product of step 3, and (35mg is in acetonitrile 0.064mmol) (1mL) solution.Behind 16hr, mixture is concentrated into drying and uses ether (2mL) to grind resistates.Obtain solid state title compound (32mg, productive rate 96%).MS m/z 448.4(MH
+)。
Adopt suitable raw material, to have prepared the hydrochloride (in following table 3 open) of embodiment 125-127 compound with embodiment 124 described similar fashion.
Table 3
| Embodiment | Title | MS (M+1) |
| 125 | ((2S, 3R, 4S)-4-(4-(2-tert-butyl-5-(trifluoromethyl) pyrazolo [1,5-a] pyrimidin-7-yl) piperazine-1-yl)-3-methylpyrrolidin-2-yl) (3,3-two fluoropyrrolidines-1-yl) ketone | 544.5 |
| 126 | (3,3-two fluoro-tetramethyleneimine-1-yl)-{ (2S, 3R, 4S)-3-methyl-4-[4-(5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-tetramethyleneimine-2-yl }-ketone | 448.4 |
| 127 | (3,3-two fluoro-tetramethyleneimine-1-yl)-[(2S, 3R, 4S)-3-methyl-4-(4-pyrimidine-2-base-piperazine-1-yl)-tetramethyleneimine-2-yl]-ketone | 381.4 |
Embodiment 128
(2,4-two fluoro-phenyl)-4-[(3S, 5S)-5-(3,3-two fluoro-tetramethyleneimine-1-carbonyl)-tetramethyleneimine-3-yl]-piperazine-1-yl }-the ketone dihydrochloride
Step 1:(2S, 4S)-4-[4-(2,4-two fluoro-benzoyls)-piperazine-1-yl]-2-(3,3-two fluoro-tetramethyleneimine-1-carbonyl)-tetramethyleneimine-1-carboxylic acid tert-butyl ester
With preparation method 7 title compound (97mg, 0.25mmol), 2,4 difluorobenzene formic acid (40mg, 0.25mmol) and HATU (95mg 0.3mmol) mixes to be incorporated under nitrogen atmosphere in anhydrous methylene chloride and adds DIEA (32mg, 45 μ L, 0.3mmol) before, in ice bath, be cooled to 0 ℃.Reaction mixture is warming to room temperature and stirs spend the night.To react and adopt the saturated sodium bicarbonate quencher and the water layer dichloromethane extraction.With the extract that merges with the salt water washing and use dried over mgso.Rough product is utilized methylene dichloride with flash chromatography: MeOH (95: 5) purifying obtains the white powder final product.MS m/z 529.4(MH
+)。
Step 2: the acetonitrile solution of step 1 product (120mg) is handled easily with the dioxane (1mL) of 4N HCl.With reaction mixture stirred overnight and evaporation under RT.Resistates is soluble in water, filter and freeze-drying obtains white powder title product (110mg, 96%) whole night.MS m/z 429.2(MH+)。
Adopt suitable raw material, to have prepared the hydrochloride (in following table 4 open) of embodiment 129-133 compound with embodiment 128 described similar fashion.
Table 4
| Embodiment | Title | MS (M+1) |
| 129 | (3,3-two fluoro-tetramethyleneimine-1-yl)-(2S, 4S)-4-[4-(toluene-4-alkylsulfonyl)-piperazine-1-yl]-tetramethyleneimine-2-yl }-ketone | 443.2 |
| 130 | (3-amino-pyrazino-2-yl)-4-[(3S, 5S)-5-(3,3-two fluoro-tetramethyleneimine-1-carbonyl)-tetramethyleneimine-3-yl]-piperazine-1-yl }-ketone | 410.2 |
| 131 | 4-[(3S, 5S)-5-(3,3-two fluoro-tetramethyleneimine-1-carbonyl)-tetramethyleneimine-3-yl]-piperazine-1-yl }-quinolyl-4-ketone | 444.3 |
| 132 | 4-[(3S, 5S)-5-(3,3-two fluoro-tetramethyleneimine-1-carbonyl)-tetramethyleneimine-3-yl]-piperazine-1-carboxylic acid-buserelin | 360.2 |
| 133 | 4-[(3S, 5S)-5-(3,3-two fluoro-tetramethyleneimine-1-carbonyl)-tetramethyleneimine-3-yl]-piperazine-1-carboxylic acid-(4-fluoro-phenyl)-acid amides | 426.2 |
Biological method
The purposes of the pharmaceutically acceptable salt of formula (I) compound, its prodrug and steric isomer and this compound, prodrug and steric isomer in the above cited illness in Mammals of treatment or prevention can prove that these test methods comprise the interior and in vitro tests of following described body with the known conventional tests method of person of ordinary skill in the relevant.These tests also provide a kind of method, by this method, and can comparison expression (I) compound, the activity of active and other compound of the pharmaceutically-acceptable salts of its prodrug and steric isomer and this compound, prodrug and steric isomer.
For the inhibiting in vitro tests of DPP-IV
Can be by following test in external proof DPP-IV restraining effect, this test be from Scharpe etc. at A.Clin.Chem., in 2299 (1988) and Lodja, Z. is at Czechoslovak Medicine, the method in 181 (1988) is revised.150 μ L enzyme culture medium solutions are sucked in the microtiter well of polystyrene 96 porose discs and maintain 4 ℃.It is 50 μ M Gly-Pro-4-methoxyl group-β-naphthalene amino acid hydrochlorides in 7.3 the Tris test damping fluid that this enzyme culture medium solution is included in 50mM pH, this damping fluid comprises 0.1M sodium-chlor, 0.1% (v/v) Triton and 50 μ U/mL DPP-IV (MPBiomedicals, Livermore, CA; DPP-IV 5mU/mL stock).Add 5 μ L formula (I) compounds in every hole, the ultimate density that makes every hole Chinese style (I) compound is 3 μ M-10 μ M.
Do not add enzyme (as blank reagent) to impinging upon in four (4) holes.3mM Diprotin A (Bachem Bioscience, Inc. with 5 μ L; King of Prussia PA) is added in these four holes as positive control, and the ultimate density of the DiprotinA that provides is 100 μ M.5 μ L distilled water are added in these four holes to measure total enzymic activity (that is negative control) (without any the influence of formula (I) compound).
Total Test is cultivated (14-18 hour) whole night down at 37 ℃.This reaction is passed through 10 μ L Fast Blue B solution (0.5mg/mLFast Blue B, in comprising the damping fluid that 0.1M pH is 4.2 sodium acetate and 10% (v/v) Triton X-100) be added in each hole, then at room temperature shake and came quencher in about 5 minutes.This dish can be at Spectramax spectrophotometer (MolecularDevices; Sunnyvale analyzes CA) or on the equality unit (maximum absorption is 525nm).The IC of compound
50The activity of DPP-IV when data can be 10nM-3 μ M by the measurement compound concentration obtains.
For the in vivo test that reduces glucose
The reduction glucose effect of DPP-IV inhibitor (comprising formula (I) compound) can be in 4-6 week big KK/H1J mouse be tested according to oral glucose tolerance and is illustrated.
At least since twentieth century thirties, oral glucose tolerance test (OGTT) has been used among the mankind, this method by Pincus etc. at et al., Am.J.Med.Sci., describe in 782 (1934) and be used in usually in the diagnosis of human diabetes, but this method is not used for being evaluated at the curative effect of patient's treatment reagent.
The KK mouse is used for assessment (i) glitazone (Diabetes of Fujita etc., 804 (1983); The Diabetes of Fujiwara etc., 1549 (1988); With the Biopharm Drug.Dispos. of Izumi etc., 247 (1997)); (ii) metformin (Diabet.Metabol. of Reddi etc., 44 (1993)); The (iii) anhydroglucose enzyme inhibitors (Jap.Pharmacol.Ther. of Hamada etc., 17 (1988) and the Am.J.Clin.Nutr. of Matsuo etc., 314S (1992)) and (iv) outer pancreas effect (the Arzneim.Forsch./Drug Res. of Kameda etc. of sulfonylurea, 39044 (1982) and the Horm.Metabl.Res. of Muller etc., 469 (1990)).
The KK mouse derives from inbred lines (inbred line) (at first by Kondo etc. at Bull.Exp.Anim., set up also in 107 (1957) and describe).These mouse are natural to suffer from hereditary form polygene diabetes, these diabetes development cause with observed to similar kidney, retina and neural complication in human diabetic patient, yet these mouse do not need Regular Insulin or other medicines just can survive.
Other method of the present invention relates to the next effect according to oral glucose tolerance testing evaluation insulin secretagogue reagent of KK mouse that utilizes.Make this mouse fasting (about 14-18hr) whole night, but allow freely to drink water.After fasting, (time " t "=0) extracts 25 μ L blood out and is added on ice the 0.025% heparinization salt (100 μ L) from back eye socket (retro-orbital sinus).Then, make 0.5% methocel solution (every mouse of 0.2mL/) of mouse (per 10 group) oral formula (I) compound.Two groups of control groups only obtain 0.5% methylcellulose gum.In the time of t=15 minute, make mouse take 1mg/kg glucose distilled water solution (every mouse of 0.2mL/) then for the mouse blood drawing as mentioned above.First group of control group taken glucose.Second group of control group taken water.In the time of t=45 minute, as mentioned above, be the mouse blood drawing once more.Blood sample is centrifugal, with plasma collection and at Roche-Hitachi 912 glucose analysers (Roche Diagnostics Corp.; Indianapolis IN) goes up the analysis glucose content.Data can be used with respect to the inhibition percentage (%) of two groups of control group glucose drifts (glucose excursion) and express (promptly, represent that at the glucose level of taking glucose but not taking in the animal of test compounds 0% suppresses, the concentration of the glucose in the animal of only taking water represents that 100% suppresses)
Formula (I) compound shows that usually inhibition is active, is expressed as the IC to DPP-IV
50Value, its＜1,000nM.Generally speaking, the IC of preferred compound
50＜100nM.For example, ((2S, 4S)-4-(4-(3-cyanopyrazine-2-yl) piperazine-1-yl) tetramethyleneimine-2-yl)-((3R
*, 4S
*)-3,4-two fluoropyrrolidines-1-yl)-IC of ketone dihydrochloride
50Be 3.5nM.
The pharmacokinetic experiment of contrast rat
Carrying out the rat pharmacokinetic experiment proves: with usually in International Application No. WO 02/14271 the existing compound of disclosed similar compare, compound of the present invention has improved the plasma concentration of being kept as time passes.Particularly, for taking (a) (3,3-two fluoropyrrolidines-1-yl)-((2S, 4S)-4-(4-(pyrimidine-2-base) piperazine-1-yl) tetramethyleneimine-2-yl)-dihydrochloride of ketone (after this be " CPD 113) (this compound is according to embodiment 113 described preparations) and (b) ((2S; 4S)-4-(4-(pyrimidine-2-base) piperazine-1-yl) tetramethyleneimine-2-yl) the contrast dihydrochloride (after this being " relatively thing ") (this compound is according to the method for embodiment 1 or according to usually in the described preparation of WO02/14270) of (tetramethyleneimine-1-yl) ketone, measure the plasma concentration that changes along with the time.
In this test, implanting has the male Sprague-Dawley rat (200-250 gram) of jugular vein sleeve pipe (JVC) to be obtained by Charles River Laboratories.Make two rats take every kind of compound or make it to take by oral raising by force.Oral dosage is taken with the solution in 0.5% methylcellulose gum with the dose volume of 10mL/kg.The amount of every kind of compound being taken is the 5mg/kg body weight.Put in the test tube that comprises Vitrum AB lithium (Becton Dickinson, Microtainer ) at a plurality of somes collection blood samples (0.25mL) of 0-24 hour and with blood sample.Then, with blood sample under 12000rpm centrifugal 10 minutes.Take out the blood plasma aliquots containig and be used for determining compound plasma concentration (pharmacokinetic analysis).Plasma sample is freezing up to analyzing down at-70 ℃.
Compound concentration by LC/MS/MS (Applied Biosystems API 4000 mass spectrographs) analyzing rat plasma sample.Briefly, the typical curve of compound is according to the blood plasma preparation of the control rats with 1.0-2000ng/mL dynamicrange.The aliquots containig (0.02mL) of standard and sample is placed on the Marsh of 96 orifice plates
TMIn the pipe.Comprise target 0.1mL acetonitrile precipitation protein in the 0.1 μ g/mL by interpolation.With 96-orifice plate rotation, when 3000rpm centrifugal 5 minutes then.The gained supernatant liquid is removed and is placed in the new 96-orifice plate, take out under nitrogen atmosphere dry down then at 50 ℃.Resistates is regenerated in mobile phase (60%5mM ammonium acetate and 40% acetonitrile).Then, aliquots containig being injected LC/MS/MS is used for analyzing.
Following table shows average plasma concentration.
| Compound/time (hr) | CPD 113 average plasma levels ng/ml | Standard deviation | Control compound average plasma levels ng/ml | Standard deviation |
| 0.25 | 1406.0 | 338.0 | 446 | 71.1 |
| 0.5 | 1322.5 | 359.9 | 425 | 108 |
| 0.75 | 979.2 | 137.0 | 319 | 59.8 |
| 1 | 768.2 | 314.0 | 283 | 13.3 |
| 2 | 289.2 | 71.8 | 128 | 40.4 |
| 4 | 97.8 | 69.2 | 27.3 | 11.2 |
| 6 | 49.3 | 19.1 | 12.7 | 1.2 |
| 8 | 32.8 | 25.5 | 6.16 | 2.62 |
Shown in each plasma concentration, compare with control compound, CPD 113 reaches and has kept obviously higher plasma concentration.
Claims (14)
1. the compound of formula (I)
Or its prodrug, or the pharmaceutically-acceptable salts of described compound or prodrug, or the solvate of described compound, prodrug or salt, wherein:
R
1Be-(C
1-C
6) alkyl ,-(C
1-C
6) alkoxyl group ,-(C
1-C
6) arylalkyl ,-NR
aR
b, hydroxyl, cyano group, aryl or heteroaryl, wherein, described-(C
1-C
6) alkyl, described aryl or described heteroaryl optional independently by 1-3-COOH ,-C (O) (C
1-C
6) alkoxyl group ,-C (O) (C
1-C
6) alkyl ,-C (O) NR
aR
b, cyano group, halogen, nitro, trifluoromethyl ,-(C
1-C
6) alkyl ,-(C
1-C
6) alkoxyl group ,-(C
3-C
6) cycloalkyl or phenyl replacement, wherein:
R
aAnd R
bBe independently hydrogen ,-(C
1-C
6) alkyl, aryl or heteroaryl; Or
R
aAnd R
bThe nitrogen-atoms that is connected with them connects together and forms 4-6 unit heterocycle, wherein, and optional other one or two nitrogen, oxygen or the sulphur ring hetero atom of comprising of described ring;
R
2And R
3Be independently hydrogen, halogen ,-(C
1-C
6) alkyl ,-(C
3-C
8) cycloalkyl;
Q be covalent linkage ,-C (O)-or-SO
2-;
HET is the Heterocyclylalkyl loop section, and described loop section is chosen quilt wantonly
(A) 1-4-(C
1-C
6) alkyl, described-(C
1-C
6) alkyl optional by 1-6 halogen atom ,-(C
1-C
6) alkoxyl group, cyano group, halogen, hydroxyl or-NR
aR
bReplace, or quilt
(B)-(C
1-C
6) aralkyl, described-(C
1-C
6) aralkyl optional by 1-6 halogen atom ,-(C
1-C
6) alkoxyl group, cyano group, halogen, hydroxyl or-NR
aR
bReplace,
Replace;
N is 0 or 1;
When n was 0, X was-CH
2-, Y is-CH
2-,-CHF-or-CF
2-,
Or when n was 1, X was-CH
2-,-CHF-or-CF
2-; Y is-CH
2-,-CHF-or-CF
2-, but condition is that X and Y are not-CH simultaneously
2-; With
Z is hydrogen or cyano group.
2. compound as claimed in claim 1, wherein:
R
1Be aryl or heteroaryl, its optional independently by 1-3 cyano group, halogen, nitro, trifluoromethyl ,-(C
1-C
6) alkyl ,-(C
1-C
6) alkoxyl group ,-(C
3-C
6) cycloalkyl or phenyl replacement;
R
2Be-H or-(C
1-C
6) alkyl;
R
3Be-H or-(C
1-C
6) alkyl; With
HET is azelidinyl, piperazinyl, piperidyl, pyrrolidyl, 5,6-dihydro-8H-imidazo [1,2-a] pyrazine-7-base, 5,6-dihydro-8H-[1,2,4] triazolo [4,3-a] pyrazine-7-base or 7,8-dihydro-5H-pyrido [4,3-a] pyrimidine-6-base.
3. compound as claimed in claim 1, wherein:
R
1Be benzisothiazole base, benzoisoxazole base, isothiazolyl, isoxazolyl, oxazole and pyridyl, pyrazinyl, pyridyl, pyrimidyl, quinolyl, quinoxalinyl, thiadiazolyl group, triazinyl or 1,1-dioxo-1H-1,2-benzisothiazole base;
R
2And R
3Be-H;
Q is a covalent linkage; And
HET is a piperazinyl.
4. compound as claimed in claim 3, wherein, R
1Be pyridyl or pyrimidyl.
5. compound as claimed in claim 4, wherein, n is 1, X is-CF
2-, Y is-CH
2-
6. compound as claimed in claim 1, described compound are selected from the group that following compound is formed:
((2S, 4S)-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4] triazolo [4,3-a] pyrazines-7 (8H)-yl) tetramethyleneimine-2-yl)-(3,3-two fluoropyrrolidines-1-yl)-ketone;
(3,3-two fluoropyrrolidines-1-yl)-((2S, 4S)-4-(4-(oxazole is [5,4-b] pyridine-2-yl also) piperazine-1-yl) tetramethyleneimine-2-yl)-ketone;
(3,3-two fluoropyrrolidines-1-yl)-((2S, 4S)-4-(4-(4-methylpyrimidine-2-yl) piperazine-1-yl) tetramethyleneimine-2-yl)-ketone;
((2S, 4S)-4-(2-(trifluoromethyl)-7,8-dihydro pyrido [4,3-d] pyrimidines-6 (5H)-yl) tetramethyleneimine-2-yl)-(3,3-two fluoropyrrolidines-1-yl)-ketone;
((S)-3-fluoro-tetramethyleneimine-1-yl)-(2S, 4S)-4-[4-(3-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-tetramethyleneimine-2-yl }-ketone;
((S)-3-fluoro-tetramethyleneimine-1-yl)-[(2S, 4S)-4-(2-trifluoromethyl-7,8-dihydro-5H-pyrido [4,3-d] pyrimidine-6-yl)-tetramethyleneimine-2-yl]-ketone;
(3,3-two fluoro-tetramethyleneimine-1-yl)-[(2S, 4S)-4-(the 4-oxazole is [4,5-c] pyridine-2-base-piperazine-1-yl also)-tetramethyleneimine-2-yl]-ketone;
[(2S, 4S)-4-(2-cyclopropyl-7,8-dihydro-5H-pyrido [4,3-d] pyrimidine-6-yl)-tetramethyleneimine-2-yl]-(3-fluoro-azetidin-1-yl)-ketone;
(3,3-two fluoro-tetramethyleneimine-1-yl)-[(2S, 4S)-4-(2-oxyethyl group-7,8-dihydro-5H-pyrido [4,3-d] pyrimidine-6-yl)-tetramethyleneimine-2-yl]-ketone;
2-{4-[(3S, 5S)-5-(3-fluoro-azetidine-1-carbonyl)-tetramethyleneimine-3-yl]-piperazine-1-yl }-the nicotinic acid nitrile;
((S)-3-fluoro-tetramethyleneimine-1-yl)-[(2S, 4S)-4-(the 4-oxazole is [5,4-b] pyridine-2-base-piperazine-1-yl also)-tetramethyleneimine-2-yl]-ketone;
(3-fluoro-azetidin-1-yl)-[(2S, 4S)-4-(2-trifluoromethyl-7,8-dihydro-5H-pyrido [4,3-d] pyrimidine-6-yl)-tetramethyleneimine-2-yl]-ketone;
2-{4-[(3S, 5S)-5-((S)-3-fluoro-tetramethyleneimine-1-carbonyl)-tetramethyleneimine-3-yl]-piperazine-1-yl }-the nicotinic acid nitrile;
(3-fluoro-azetidin-1-yl)-(2S, 4S)-4-[4-(2-trifluoromethyl-quinolyl-4)-piperazine-1-yl]-tetramethyleneimine-2-yl }-ketone;
((3R
*, 4S
*)-3,4-two fluoro-tetramethyleneimine-1-yl)-[(2S, 4S) 4-(2-trifluoromethyl-7,8-dihydro-5H-pyrido [4,3-d] pyrimidine-6-yl)-tetramethyleneimine-2-yl]-ketone; With
((3R
*, 4S
*)-3,4-two fluoro-tetramethyleneimine-1-yl)-[(2S, 4S)-4-(the 4-oxazole is [5,4-b] pyridine-2-base-piperazine-1-yl also)-tetramethyleneimine-2-yl]-ketone;
Or its prodrug, or the pharmaceutically-acceptable salts of described compound or described prodrug.
7. (3,3-two fluoropyrrolidines-1-yl)-((2S, 4S)-4-(4-(pyrimidine-2-base) piperazine-1-yl) tetramethyleneimine-2-yl) ketone, or its prodrug, or the pharmaceutically-acceptable salts of described compound or prodrug.
8. be used in the claim 1,2,3,4 in the treatment, 5 or 7 compound, or its prodrug, or the pharmaceutically-acceptable salts of described compound or prodrug, or the solvate of described compound, prodrug or salt.
9. pharmaceutical compositions, described pharmaceutical compositions comprises:
(a) claim 1,2,3,4,5 or 7 compound, or its prodrug, or the pharmaceutically-acceptable salts of described compound or prodrug, or the solvate of described compound, prodrug or salt; With
(b) pharmaceutically acceptable carrier, vehicle, thinner or excipient.
10. the method that suppresses dipeptidyl peptidase-IV in the Mammals, described method comprises: need the claim 1,2,3,4 of the described Mammals treatment significant quantity of this treatment, 5 or 7 compound, or its prodrug, or the pharmaceutically-acceptable salts of described compound or prodrug, or the solvate of described compound, prodrug or salt.
11. the method for the illness that mediates by dipeptidyl peptidase-IV in the treatment Mammals, described method comprises: need the claim 1,2,3,4 of the described Mammals treatment significant quantity of this treatment, 5 or 7 compound, or its prodrug, or the pharmaceutically-acceptable salts of described compound or prodrug, or the solvate of described compound, prodrug or salt.
12. method as claimed in claim 11, wherein, described illness of being treated is a diabetes B, type 1 diabetes, impaired glucose tolerance, hyperglycemia, metabolic syndrome (syndrome X and/or insuline resistance syndrome), glycosuria, metabolic acidosis, sacroiliitis, cataract, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, obesity, illness by the obesity aggravation, hypertension, hyperlipidaemia, atherosclerosis, osteoporosis, osteopenia, fragile, bone-loss, fracture, acute coronary artery syndrome, by growth hormone deficiency cause short and small, by polycystic ovary syndrome cause sterile, anxiety disorder, dysthymia disorders, insomnia, confirmed fatigue, epilepsy, the diet sexual maladjustment, chronic pain, alcohol is habit-forming, the disease relevant with bowel movement, ulcer, irritable bowel syndrome, inflammatory bowel; Short bowel syndrome; With the disease progression in the prevention diabetes B.
13. method as claimed in claim 12, wherein, described illness of being treated is a diabetes B.
14. the method for treatment diabetes, comprise, need the claim 1,2,3,4 of the described Mammals treatment significant quantity of this treatment, 5 or 7 compound, or its prodrug, or the pharmaceutically-acceptable salts of described compound or prodrug, or the solvate of described compound, prodrug or salt.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US57030004P | 2004-05-12 | 2004-05-12 | |
| US60/570,300 | 2004-05-12 | ||
| US66430505P | 2005-03-21 | 2005-03-21 | |
| US60/664,305 | 2005-03-21 | ||
| PCT/IB2005/001194 WO2005116014A1 (en) | 2004-05-12 | 2005-04-29 | Proline derivatives and their use as dipeptidyl peptidase iv inhibitors |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1968949A true CN1968949A (en) | 2007-05-23 |
| CN1968949B CN1968949B (en) | 2011-05-04 |
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ID=38077110
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|---|---|---|---|
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|---|---|
| CN (1) | CN1968949B (en) |
| HN (1) | HN2005000205A (en) |
| TN (1) | TNSN06366A1 (en) |
| UA (1) | UA83133C2 (en) |
| ZA (1) | ZA200608741B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107108610A (en) * | 2014-12-30 | 2017-08-29 | 豪夫迈·罗氏有限公司 | New tetrahydropyridine and pyrimidine and tetrahydropyridine and pyridine compounds for treating and preventing hepatitis b virus infection |
| CN107624113A (en) * | 2015-05-04 | 2018-01-23 | 豪夫迈·罗氏有限公司 | It is used to treat hepatitis b virus infected tetrahydropyridine simultaneously pyrimidine and tetrahydropyridine and pyridine compounds and their as the inhibitor that HBsAg (HBsAg) and HBV DNA is generated |
| CN114213504A (en) * | 2021-12-24 | 2022-03-22 | 西南医科大学 | Compound with anti-diabetic activity and application thereof |
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| JP4101053B2 (en) * | 2000-08-10 | 2008-06-11 | 田辺三菱製薬株式会社 | Proline derivative and its pharmaceutical use |
| GB0115517D0 (en) * | 2001-06-25 | 2001-08-15 | Ferring Bv | Novel antidiabetic agents |
-
2005
- 2005-04-29 CN CN2005800152588A patent/CN1968949B/en active Active
- 2005-04-29 UA UAA200611856A patent/UA83133C2/en unknown
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-
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107108610A (en) * | 2014-12-30 | 2017-08-29 | 豪夫迈·罗氏有限公司 | New tetrahydropyridine and pyrimidine and tetrahydropyridine and pyridine compounds for treating and preventing hepatitis b virus infection |
| CN107108610B (en) * | 2014-12-30 | 2019-06-04 | 豪夫迈·罗氏有限公司 | For treating and preventing the new tetrahydropyridine and pyrimidine and tetrahydropyridine and pyridine compounds that hepatitis b virus infects |
| CN107624113A (en) * | 2015-05-04 | 2018-01-23 | 豪夫迈·罗氏有限公司 | It is used to treat hepatitis b virus infected tetrahydropyridine simultaneously pyrimidine and tetrahydropyridine and pyridine compounds and their as the inhibitor that HBsAg (HBsAg) and HBV DNA is generated |
| CN114213504A (en) * | 2021-12-24 | 2022-03-22 | 西南医科大学 | Compound with anti-diabetic activity and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| TNSN06366A1 (en) | 2008-02-22 |
| ZA200608741B (en) | 2008-07-30 |
| UA83133C2 (en) | 2008-06-10 |
| CN1968949B (en) | 2011-05-04 |
| HN2005000205A (en) | 2009-10-30 |
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