CN1891689A - Aliphatic nitrogen - containing 5 - membered ring compound - Google Patents
Aliphatic nitrogen - containing 5 - membered ring compound Download PDFInfo
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- CN1891689A CN1891689A CN 200610077863 CN200610077863A CN1891689A CN 1891689 A CN1891689 A CN 1891689A CN 200610077863 CN200610077863 CN 200610077863 CN 200610077863 A CN200610077863 A CN 200610077863A CN 1891689 A CN1891689 A CN 1891689A
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Abstract
Aliphatic nitrogenous five-membered ring compounds of the general formula [I], or pharmacologically acceptable salts thereof: [I] wherein A is CH2- or S-; B is CH or N; R<1> is H, lower alkyl, or the like; X is a single bond, -CO-, -Alk-CO-, -COCH2-, -Alk-O-, -O-CH2-, -SO2-, -S-, -COO-, -CON(R<3>)-, -Alk-CON(R<3>)-, -CON(R<3>)CH2-, -NHCH2-, or the like; R<3> is H or lower alkyl; Alk is lower alkylene; and R<2> is an optionally substituted cyclic group, substituted amino, or the like, with the proviso that when X is CO-, B is N.
Description
The application is to be dividing an application of October 5 calendar year 2001, application number are 01816674.1, denomination of invention is nitrogenous 5-membered ring compounds application the applying date.
Technical field
The present invention relates to a kind of good DPP IV (DPPIV) restraining effect that has, can be as the novel aliphatic nitrogenous 5-membered ring compounds of medicine use.
Background technology
DPP IV (DPPIV) is N-terminal by the poly-peptide chain dipeptides that makes Xaa-Pro or Xaa-Ala (Xaa can be any amino acid) will add a kind of in the serine protease of water decomposition different in naturely.
About the role of DPPIV (being also referred to as CD26) in organism and with the relation of disease, existing various research reports (Holst etc., Diabetes, the 47th volume, 1663 to 1670 pages, 1998 years; Augustyns etc., Current Medicinal Chemistry, the 6th volume, the 311st to 327 page, 1999 years; Meester etc., Immunol.Today, 20 volumes, the 367th to 375 page, 1999; Fleicher etc., Immunol.Today, 15 volumes, 180 to 184 pages, 1994).
GLP-1 (glucagon-like peptide 1) is mainly the peptide hormone with glucose dependency insulin secretion increase effect, and it is mainly secreted by the small intestine bottom after food, and in the pancreas effect.In addition, also there is the GLP-1 of announcement to have the inhibiting report of ingesting.DPPIV adds this GLP-1 water decomposition and makes its deactivation, makes the peptide of its generation as the antagonist effect of GLP-1 simultaneously.
The material that suppresses the enzymic activity of DPPIV, the effect by its restraining effect improves internality GLP-1 improves the insulin secretion of oral glucose load is replied, and improves impaired glucose tolerance (impaired glucose tolerance).
Therefore, the DPPIV Depressant is considered to go up useful in the prevention and the treatment of diabetes (especially diabetes B) etc.In addition, also expect its bring out owing to impaired glucose tolerance or the treatment of the other diseases of ization [blood sugar too high (for example the blood sugar after the food is too high), hyperinsulinemia and diabetic complication, (for example kidney is hindered and nerve is hindered), abnormalities of sugar/lipid metabolism and obesity etc.] and prevention on have effect.
In addition, expect that also it is by strengthening the restraining effect of ingesting of GLP-1, to expecting that amendatory disease (overfeeding and obesity etc.) has prevention and result of treatment.
In addition, the DPPIV (CD26) that is present in the T cell surface, in immune system cell, follow outstanding T cell activityization and by abduction delivering, it is played the part of on T cell activityization and propagation the key player, known if block this DPPIV (CD26) by antibody or inhibitory substance, but with the activation of suppressor T cell.In addition, reach unusually in the dysimmunity disease at collagenic supersession, this enzyme also makes us feeling interest with the cognation of morbid state.For example, DPPIV (CD26) positive rate of peripheral blood T cell rises among the rheumatism patient, and can detect high DPPIV activity in the nephritis patient urine.In addition, serve as the key player aspect DPPIV (CD26) is considered in HIV enters lymphocyte.
Therefore, the material that suppresses DPPIV (CD26) is also had prevention or result of treatment by expectation for autoimmune disease (for example sacroiliitis and chronic joint rheumatism), osteoporosis, acquired immune deficiency syndrome (AIDS), the rejection etc. of transplanting internal organs and tissue.
On the other hand, about having the inhibiting compound of DPPIV, in open communique WO98/19998 of international monopoly and WO00/34241, record has the inhibiting 2-Cyanopyrolidine derivatives of DPPIV.
The invention provides and have the inhibiting novel aliphatic nitrogenous 5-membered ring compounds of good DPPIV.
For addressing the above problem, further investigations such as present inventor found that to have the inhibiting novel aliphatic nitrogenous 5-membered ring compounds of DPPIV, and have finished the present invention.
Summary of the invention
Also promptly, the present invention relates to the salt of permitting on the aliphatic nitrogenous 5-membered ring compounds shown in a kind of general formula [I] or its pharmacology:
In the formula:
A represents-CH
2-or-S-;
B represents CH or N;
R
1Expression hydrogen atom, low-carbon alkyl, hydroxyl hydroxyl low-carbon alkyl or low-carbon alkoxy low-carbon alkyl;
X represent singly-bound ,-CO-,-Alk-CO-, COCH
2-,-Alk-O-,-O-CH
2-,-SO
2-,-S-,-COO-,-CON (R
3)-,-Alk-CON (R
3)-,-CON (R
3) CH
2-,-Alk-CON (R
3) CH
2-,-COCH
2N (R
3)-,-SO
2N (R
3)-or-NHCH
2-, in each definition of above-mentioned X,
The key table of right-hand member record shows and B bonded key,
R
3Expression hydrogen atom or low-carbon alkyl, and
Alk represents the low-carbon (LC) alkylidene group;
R
2Expression is selected from (1), the base of (2) and (3):
(1) can substituted cyclic group, this cyclic group partly is
(i) monocycle or dicyclo alkyl, or
(ii) monocycle or bicyclic heterocyclic radical;
(2) amino that replaces by 1 to 2 the identical or different substituting group that is selected from replacement or unsubstituted low-carbon alkyl;
(3) low-carbon alkyl or the phenyl low-carbon (LC) thiazolinyl of the low-carbon alkyl of low-carbon alkyl, carboxyl low-carbon alkyl, low-carbon alkoxy, low-carbon (LC) thiazolinyl, low-carbon alkoxy replacement, phenoxy group, phenoxy group replacement;
But when X is singly-bound, R
2The base of above-mentioned for being selected from (1) and (2), in addition, X is-CO-in, B is N.
Embodiment
Have the optical isomer that is caused by asymmetric carbon in the target compound of the present invention [I], the present invention also comprises any of these optical isomers, with and mixture.In addition, to the relative position of cyclic group directrix plane and the isomer (cis-isomeride or trans-isomer(ide)) that exists, the present invention also comprises any of these isomer based on substituting group, with and composition thereof.
In the present invention, low-carbon alkyl, lower alkanes sulfenyl, lower alkanes alkylsulfonyl, low-carbon alkoxy and lower alkanes amido, for as the straight chain shape of carbon number 1 to 6 or a chain base, especially with carbon number 1 to 4 for more preferably.In addition, lower alkanes acyl group and lower alkanes amide group are the straight chain shape or the chain base of carbon number 2 to 7, especially with carbon number 2 to 5 for more preferably.Low-carbon naphthenic and low-carbon (LC) cycloalkenyl group are the base of carbon number 3 to 8, especially with carbon number 3 to 6 for more preferably.The low-carbon (LC) alkylidene group is the straight chain shape or the chain base of carbon number 1 to 6, especially with carbon number 1 to 4 for more preferably.Low-carbon (LC) thiazolinyl and low-carbon (LC) alkenylene are the base of carbon number 2 to 7, especially with carbon number 2 to 5 for more preferably.In addition, halogen atom for example is fluorine, chlorine, bromine or iodine.
In compound of the present invention [I], R
1The concrete example of represented " hydrogen atom, low-carbon alkyl, hydroxyl low-carbon alkyl or low-carbon (LC) alcoxyl low-carbon alkyl ", for example hydrogen atom, methyl, methylol and methoxyl methyl etc.Wherein with hydrogen atom or low-carbon alkyl (methyl etc.) for more preferably.
In compound of the present invention [I], R
2The cyclic group of represented " can substituted cyclic group " is partly for for example:
(i) monocycle or dicyclo alkyl, and
(ii) monocycle or bicyclic heterocyclic radical.
This monocycle or dicyclo alkyl can be part or all saturated and carbon number and are 3 to 15 alkyl.
About the monocycle alkyl, be 3 to 7 for more preferably with carbon number, particularly as phenyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, and they part or all is saturated cyclic group.
About the dicyclo alkyl, be 9 to 11 for more preferably with carbon number, particularly as indanyl, indenyl, naphthyl and tetralyl, and they part or all is saturated cyclic group etc.
About monocycle or bicyclic heterocyclic radical, for example for containing 1 to 4 heteroatoms from nitrogen-atoms, Sauerstoffatom and sulphur atom, selecting, and its part or all can be saturated monocycle or bicyclic heterocyclic radical.
The monocyclic heterocycles base, for example for containing from nitrogen-atoms, 1 to 2 heteroatomic heterocyclic radical selecting in Sauerstoffatom and the sulphur atom, for example by saturated or undersaturated 5 to 7 Yuans heterocyclic radicals that ring is formed, particularly, as pyrrolidyl, imidazolidyl, pyrazolidyl, the tetrahydrofuran base, the thiacyclopentane base, pyrrolinyl, imidazolinyl, pyrazolinyl, pyrryl, imidazolyl, pyrazolyl, triazolyl, tetrazyl, furyl, azoles base, different azoles base, the di azoly, thienyl, thiazolyl, isothiazolyl, thiadiazolyl group, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyranyl, tetrahydro pyridyl, the dihydrogen dazin base, perhydro azepine and perhydro sulphur azepine , and they part or all be saturated cyclic group etc.
Bicyclic heterocyclic radical, for example for containing from nitrogen-atoms, 1 to 3 heteroatoms selecting in Sauerstoffatom and the sulphur atom and condense the heterocycle that forms by 2 saturated or undersaturated 5 to 7 Yuans rings, particularly, as indolinyl, iso-dihydro-indole-group, indyl, indazolyl, pseudoindoyl, benzimidazolyl-, benzothiazolyl, the benzoxazol base, benzo dioxolane base, benzothienyl, benzofuryl, the thienopyridine base, thiazole and pyridyl, pyrrolopyridinyl, pyrrolin and pyridyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolyl, phthalazinyl, the cinnolines base, chromanyl, different chromanyl and naphthyridinyl, and they part or all is saturated cyclic group etc.
In these cyclic groups (monocycle or dicyclo alkyl, perhaps monocycle or bicyclic heterocyclic radical), with following (i) to (iii) for more preferably:
" (i) the monocycle alkyl of carbon number 3 to 7,
(ii) contain 1 to 2 heteroatomic monocyclic heterocycles base from nitrogen-atoms, Sauerstoffatom and sulphur atom, selecting (with 5 to 6 Yuans aliphatics heterocyclic radicals of monocycle for more preferably), and
(iii) contain 1 to 3 heteroatoms from nitrogen-atoms, Sauerstoffatom and sulphur atom, selecting, and condense the bicyclic heterocyclic radical that forms by 25 to 7 Yuans rings " for preferred.
The concrete example that these are basic, as:
" phenyl; cyclohexyl; cyclopentyl; cyclobutyl; cyclopropyl; pyrrolidyl, imidazolidyl, pyrazolidyl, the tetrahydrofuran base, the thiacyclopentane base, pyrrolinyl, imidazolinyl, pyrazolinyl, pyrryl, imidazolyl, pyrazolyl, triazolyl, tetrazyl, furyl, azoles base, different azoles base, the di azoly, thienyl, thiazolyl, isothiazolyl, thiadiazolyl group, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyranyl, tetrahydro pyridyl, the dihydrogen dazin base, perhydro azepine , perhydro sulphur azepine , indolinyl, iso-dihydro-indole-group, indyl, indazolyl, pseudoindoyl, benzimidazolyl-, benzothiazolyl, the benzoxazol base, benzo two azoles bases, benzothienyl, benzofuryl, the thienopyridine base, thiazole and pyridyl, pyrrolopyridinyl, pyrrolin and pyridyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolyl, phthalazinyl, the cinnolines base, chromanyl, different chromanyl and naphthyridinyl, and they part or all is saturated cyclic group etc. ".
Wherein with following (i) and (ii) for more preferably:
" (i) contain 1 to 2 heteroatomic monocyclic heterocycles base from nitrogen-atoms, Sauerstoffatom and sulphur atom, selecting (with 5 to 6 Yuans aliphatics heterocyclic radicals of monocycle for more preferably); And
(ii) contain 1 to 3 heteroatoms from nitrogen-atoms, Sauerstoffatom and sulphur atom, selecting, and condense the bicyclic heterocycle that forms " by 25 to 7 Yuans rings.
Wherein, more preferably concrete example is:
" phenyl; cyclohexyl; cyclopentyl; pyrrolidyl; imidazolidyl; pyrazolidyl, pyrryl, imidazolyl, pyrazolyl, furyl, azoles base, different azoles base, thienyl, thiazolyl, isothiazolyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, iso-dihydro-indole-group, indolinyl, thiazole and pyridyl, pyrrolopyridinyl, pyrrolin and pyridyl, the benzoxazol base, quinolyl, isoquinolyl, quinazolyl, pseudoindoyl and indyl, and they part or all is saturated cyclic group etc. ".
Preferred concrete example is:
" piperidyl (piperidino etc.), piperazinyl (1-piperazinyl), morpholinyl (4-morpholinyl), indolinyl (1-indolinyl), iso-dihydro-indole-group (2-iso-dihydro-indole-group) and thiazole and pyridyl (thiazole is [5,4-b] pyridine-2-base etc. also) "
In addition, wherein special preferred concrete example is:
" piperidino etc., 1-piperazinyl, 4-morpholinyl, 1-indolinyl, 2-iso-dihydro-indole-group and thiazole be [5,4-b] pyridine-2-base etc. also ".
R
2Represented " can substituted cyclic group (monocycle or dicyclo alkyl, or monocycle or bicyclic heterocyclic radical) " can be not substituent, also can be 1 to 3 substituting group person with identical or inequality.
Substituting group in this cyclic group is not particularly limited, but particularly can be the substituting group of selecting from for example following " A organizes substituting group ", serve as preferably special with " A ' group substituting group " wherein.
In target compound of the present invention [I], R
2Represented " by from replace or unsubstituted low-carbon alkyl the amino that replaces of 1 to 2 substituting group being selected " though in substituting group be not particularly limited, but more specifically, can be the low-carbon alkyl of the substituting group replacement of from " cyano group, low-carbon alkoxy (methoxyl group etc.), monocyclic aryl (phenyl etc.), 6 Yuans aromatic heterocycles of nitrogenous monocycle (pyridyl etc.) etc. ", being selected.
------------A organizes substituting group-------------
A group substituting group for example is following person:
Aryl lower alkanes carbonylamino, lower alkanes sulfenyl and sulfamic etc. that halogen atom (Cl, F, Br etc.), cyano group, nitro, amino, ketone group, low-carbon alkyl, low-carbon alkoxy, lower alkanes acyl group, low-carbon (LC) carbalkoxy, low-carbon (LC) alkoxycarbonyl amido, low carbon naphthene acyl group, halo low-carbon alkyl, halo low-carbon alkyl carbonyl, the 6 Yuans aromatic heterocycles of carbonyl, nitrogenous monocycle, monocyclic aryl, the coverlet cyclophane base that are replaced by 5 to 6 Yuans aliphatics heterocyclic radicals of nitrogenous monocycle replace.
(" 5 to the 6 Yuans aliphatics heterocyclic radicals of nitrogenous monocycle " in " carbonyl that is replaced by 5 to 6 Yuans aliphatics heterocyclic radicals of nitrogenous monocycle " particularly, for example are " pyrrolidyl, piperidyl and piperazinyl etc. ";
In addition, " 6 Yuans aromatic heterocycles of nitrogenous monocycle " particularly, for example are pyridyl, pyrimidyl, pyrazinyl, tower coffee base and pyranyl etc. ";
" monocyclic aryl " reaches " monocyclic aryl " part in " coverlet cyclophane base replace aryl lower alkanes carbonylamino ", particularly, and for phenyl etc.).
--------A ' group substituting group (special preferred A group substituting group)---------
More preferably A group substituting group for example is following person:
Ketone group, lower alkanes acyl group, low carbon naphthene acyl group, low-carbon (LC) carbalkoxy and the carbonyl (pyrrolidyl and piperidyl etc.) that is replaced by 5 to 6 Yuans aliphatics heterocyclic radicals of nitrogenous monocycle
With regard to B in the target compound of the present invention [I] is in the compound of CH, when X is singly-bound, and R
2More preferably for for example with following formula
Monocycle or dicyclo that (1) of expression can be substituted close Azacyclyl, or the amino of (2) 1 to 2 substituting group replacement through being selected from replacement or unsubstituted low-carbon alkyl.
In the target compound of the present invention [I] B be in the compound of CH with in 2 kinds of cis-trans isomer of the cyclohexyl ring in [I] structure as reference plane, can obtain higher DPPIV with regard to fumaroid and suppress with regard to the active viewpoint for more preferably.That is, B is the compound of CH in the target compound of the present invention [I], to have following part-structure:
Compound or its pharmacology on the salt of permitting for more preferably.
One compound group of The compounds of this invention for example is in the compound [I], X be singly-bound ,-Alk-CO-,-COCH
2-,-Alk-O-,-O-CH
2-,-SO
2-,-S-,-COO-,-CON (R
3)-,-Alk-CON (R
3)-,-CON (R
3) CH
2-,-Alk-CON (R
3) CH
2-,-COCH
2N (R
3)-,-SO
2N (R
3)-or-NHCH
2-; And R
2The base of the compound group of following for being selected from (1) or (2) (compound group 1, Compound I-e):
(1) can substituted cyclic group, this cyclic group partly is
(i) monocycle or dicyclo alkyl, or
(ii) monocycle or bicyclic heterocyclic radical, perhaps
(2) can be by the amino of 1 to 2 the identical or different substituting group replacement that is selected from replacement or unsubstituted low-carbon alkyl.
In addition, another compound group be in compound [I] or above-claimed cpd group 1, R
2Following for being selected from (1), the base of the compound group of (2) or (3) (compound group 2):
(1) can have 1 to 3 identical or different substituent cyclic group of selecting from A group substituting group, this cyclic group partly is (i) monocycle or dicyclo alkyl, or (iii) monocycle or bicyclic heterocyclic radical;
(2) amino that replaces by identical or different 1 to 2 substituting group, wherein this substituting group is to be selected from " low-carbon alkyl that can be replaced by the base that is selected from cyano group, low-carbon alkoxy, phenyl and 6 Yuans aromatic heterocycles of nitrogenous monocycle "; And,
(3) low-carbon alkyl, carboxyl low-carbon alkyl, low-carbon alkoxy, low-carbon (LC) thiazolinyl, the low-carbon alkyl that is replaced by low-carbon alkoxy, phenoxy group, the low-carbon alkyl or the phenyl low-carbon (LC) thiazolinyl that are replaced by phenoxy group.
In addition, another compound group, in compound [I] or above-claimed cpd group 1 or 2, R
2For can substituted cyclic group and this cyclic group partly following (i), (ii) or the compound group of base (iii) (compound group 3) for being selected from:
(i) the monocycle alkyl of carbon number 3 to 7,
(ii) contain 1 to 2 heteroatomic monocyclic heterocycles base from nitrogen-atoms, Sauerstoffatom and sulphur atom, selecting, and
(iii) contain 1 to 3 heteroatoms from nitrogen-atoms, Sauerstoffatom and sulphur atom, selecting, and condense the bicyclic heterocyclic radical that forms by 25 to 7 Yuans rings.
In addition, preferred another compound group is in compound [I] or above-claimed cpd group 1,2 or 3, R
2For having 1 to 3 identical or different substituent cyclic group of selecting from A ' group substituting group, and this cyclic group partly is the compound group (compound group 4) of the base selected from piperidyl, piperazinyl, morpholinyl, indolinyl, iso-dihydro-indole-group and pyridine azoles and pyridyl
In addition, another more preferably the compound group be that B is CH in compound [I] or above-claimed cpd group 1,2,3 or 4, X is singly-bound and R
2Be following formula:
(1) monocycle or bicyclic nitrogen-containing heterocyclic base that can be substituted of expression, or (2) by from by replace or unsubstituted low-carbon alkyl the compound group (compound group 5) of the amino that replaces of 1 to 2 substituting group selecting.
In addition, in compound [I] or the above-claimed cpd group 1,2,3,4 or 5, preferred compound group for example is:
B is CH, and X is that singly-bound and A are-CH
2-the compound group;
B is CH, and X is a singly-bound, and A is-CH
2-and R
1Compound group for hydrogen atom or low-carbon alkyl;
B is CH, and to be singly-bound and A be the compound group of-S-to X; And
B is CH, and X is a singly-bound, and A is-S-and R
1Be compound group of hydrogen atom or low-carbon alkyl etc.
In addition, in each above-mentioned compound group, more preferably the compound group is for example for B is CH, and has the compound group of following part structure:
In addition, more preferably particular compound for example is following compound:
(S)-and 2-cyano group-1-[t-4-(4-ethanoyl-1-piperazinyl)-1-methyl-r-1-cyclohexylamino] acetyl-pyrrole alkane;
(S)-and 2-cyano group-1-[is trans-4-(1,3-diketo-2-iso-dihydro-indole-group) cyclohexylamino] and acetyl-pyrrole alkane;
(S)-and 2-cyano group-1-[is trans-4-morpholine and cyclohexylamino] and acetyl-pyrrole alkane;
(S)-and 2-cyano group-1-[is trans-4-(thiazole is [5,4-b] pyridine-2-yl also) cyclohexylamino] acetyl-pyrrole alkane etc.
The salt of permitting on target compound of the present invention [I] or its pharmacology has good restraining effect to the enzymic activity of DPPIV.Especially the enzymic activity to human DPPIV has good restraining effect.In addition, show that the DPPIV (also being the dipeptidyl peptidase of IV type) in the various serine proteases (for example Tryptase, zymoplasm, prolyl endopeptidase, trypsinase and dipeptidyl peptidase II etc.) is had highly selective.
In addition, the salt of permitting on target compound of the present invention [I] or its pharmacology can improve the insulin secretion of oral glucose load is replied by its DPPIV restraining effect.
Therefore, the salt of permitting on target compound of the present invention [I] or its pharmacology can be used as the prevention and the medicine for treatment thing of DPPIV relative disease (disease that causes by DPPIV promptly expects to improve by the enzymic activity that suppresses DPPIV the disease of morbid state).
This disease for example is diabetes (for example type 1 diabetes and diabetes Bs etc.), hyperglycemia (for example the blood sugar after the food is high excessively), hyperinsulinemia, diabetic complication (for example kidney is hindered and nerve is hindered etc.), fat, overfeeding, abnormalities of sugar/lipid metabolism (hyperlipidaemia such as for example high triglyceride mass formed by blood stasis etc.), autoimmune disorders (for example sacroiliitis and chronic rheumatic arthritis), osteoporosis, acquired immune deficiency syndrome (AIDS), and the rejection of transplant organ and tissue etc.
The salt of permitting on target compound of the present invention [I] or its pharmacology especially can be as prevention or the medicine to diabetes (especially diabetes B).
Toxicity of compound of the present invention in addition is low, when using as pharmaceutical compound, has high security.In addition, also show the dynamic aspect of medicine good characteristic [biological utilisation and in vitro metabolic stability (stability in the human liver homogenate), P450 restraining effect and with combination of proteins etc.].
The DPPIV restraining effect of The compounds of this invention reaches by the drug effect of its generation (anti-blood sugar effect reaches the insulin secretion of oral glucose load is responded effect etc.), can be by known method or the method (WO98/19998:WO00/34241 equal with it; Holst etc., Diabetes, the 47th volume, 1663 to 1670 pages, 1998; People Current Medicinal Chemistry such as Augustyns, the 6th volume, the 311st to 327 page, 1999 years; Meester etc., Immunol.Today, 20 volumes, the 367th to 375 page, 1999; Fleicher etc., Immunol.Today, 15 volumes, 180 to 184 pages, 1994) confirm.
Target compound of the present invention [I], can its free form or its pharmacology on the salt form of permitting be used in medicinal use.The salt of permitting on the pharmacology of compound [I] for example is inorganic acid salts such as hydrochloride, vitriol, phosphoric acid salt or hydrobromate; Organic acid salts such as acetate, fumarate, oxalate, Citrate trianion, mesylate, benzene sulfonate, tosylate or maleic acid salt.In addition, when having substituting groups such as carbonyl, can be the salt (alkaline earth salt such as for example an alkali metal salt such as sodium salt and sylvite, or calcium salt) that is become with alkali.
Target compound of the present invention [I] or its esters comprise its molecule inner salt and affixture, any of their solvate or hydrate etc.
The salt of permitting on target compound of the present invention [I] or its pharmacology, but oral administration also can non-oral administration, can tablet, habitual pharmaceutical preparations such as granule, capsule, powder, injection and inhalation use.For example, auxiliary material such as tamanori, disintegrating agent, extender, filling agent and the lubricant that compound of the present invention can be able to be permitted on general medicine or thinner use, and give preparationization by usual method.
The dosage of the salt of permitting on target compound of the present invention [I] or its pharmacology, different along with medication, patient age, body weight and state, but usually average one day about 0.01 to 300 milligram/kilogram, especially with about 0.1 to 30 milligram/kilogram for more preferably.
Target compound of the present invention [I] can prepare by following (A method) to (D method), yet is not limited to these methods.
(A method)
Target compound of the present invention [I] is to prepare by the compound or its salt shown in compound shown in the general formula [II] and the general formula [III] is reacted, and optionally also resultant can be made the salt of permitting on the pharmacology,
In the formula, Z
1Expression reactive residue and A have meaning same as described above,
In the formula, R
1, R
2, B and X have meaning same as described above.
The salt of compound [III] can use for example inorganic acid salt such as hydrochloride and vitriol, or the salt that forms of an alkali metal salt and alkaline earth salt etc. and mineral alkali.
About Z
1Reactive residue, suitably use habitual reactive residues such as halogen atom, lower alkanes sulfonyloxy and arylsulfonyloxy, but especially preferred halogen atom.
The reaction of compound [II] and compound [III] or its esters can be carried out in appropriate solvent or in solvent-free in the reductor existence or not.
As solvent, as long as the solvent that reaction is had no adverse effects all can, for example suitable acetonitrile, methyl alcohol, ethanol, Virahol, propyl alcohol, acetone, dimethyl formamide, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), ether, two alkane, ethyl acetate, toluene, methylene dichloride, ethylene dichloride, chloroform or their mixed solvent of using.
This reaction is to carry out at 0 to 120 ℃, especially with room temperature to 80 ℃ for more preferably.
As reductor, suitable mineral alkali (the hydrogenated alkali metal such as sodium hydride for example that uses, alkaline carbonate such as yellow soda ash and salt of wormwood, alkali metal alkoxide such as sodium methylate, basic metal such as sodium, or organic bases (for example triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, xylidine and dimethylamino pyridine etc.) alkali metal hydroxide such as sodium hydroxide and potassium hydroxide etc.).
(B method)
In addition, R in the compound [I]
2For can substituted monocycle or bicyclic nitrogen-containing heterocyclic base; X is-COO-and with the compound shown in the general formula [I-a]; behind the compound or its salt shown in the general formula [IV] and phosgene class or its equal precursor reactant; with the compound reaction shown in the general formula [V]; obtain the compound or its salt shown in the general formula [VI]; then the amino protecting group (R) of resultant is removed and can be prepared
In the formula, R
21Expression can substituted monocycle or dicyclo close Azacyclyl, and R
1, A and B have meaning same as described above,
In the formula, R represents amino protecting group, and R
1, A and B have meaning same as described above,
R
21-H [V]
In the formula, R
21Have meaning same as described above,
In the formula, R, R
1, R
21, A and B have meaning same as described above.
After compound [IV] and phosgene class or the reaction of its coordinator,, can exist down, in appropriate solvent or solvent-freely implement down in phosgene class or its coordinator and reductor again with the reaction of compound shown in the formula V.
About " phosgene class or its coordinator ", can suit to use three surpalites, two surpalites, carbonyl dimidazoles and chloroformic acid (4-nitrophenyl) ester etc.
As reductor, can suit to use mineral alkali (hydrogenated alkali metal such as sodium hydride for example, alkaline carbonate such as yellow soda ash and salt of wormwood, alkali metal amide things such as sodium acid amides and lithium acid amides, alkali metal alkoxide such as sodium methylate, basic metal such as sodium, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide etc.), or organic bases (for example triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, xylidine and dimethylamino pyridine etc.).
As solvent, if the solvent that reaction is had no adverse effects all can, for example suitable methylene dichloride, ethylene dichloride, chloroform, ether, tetrahydrofuran (THF), ethyl acetate, toluene or their mixed solvent of using.This reaction is to carry out at-78 ℃ to 110 ℃, especially should carry out to room temperature at 0 ℃.
Then removing of the amino protecting group (R) of the compound that carries out [VI] can be carried out according to general law, for example can implement by acid treatment, alkaline purification or catalytic reduction in appropriate solvent or under solvent-free.
As acid, mineral acids such as suitable use hydrochloric acid and sulfuric acid, and organic acids such as acetate, trifluoroacetic acid, methylsulfonic acid and tosic acid.
As alkali, suitable mineral alkali (the hydrogenated alkali metal such as sodium hydride for example that uses, alkaline carbonate such as yellow soda ash and salt of wormwood, alkali metal amide things such as sodium acid amides and lithium acid amides, alkali metal alkoxide such as sodium methylate, basic metal such as sodium, and alkali metal hydroxides such as sodium hydroxide and potassium hydroxide etc.), or organic bases (for example triethylamine, diisopropylethylamine, morpholine, N-methylmorpholine, pyridine, piperidines, xylidine and dimethylamino pyridine etc.) etc.
Catalytic reduction reaction can be in hydrogen atmosphere, undertaken by suitably using palladium/carbon, palladium hydroxide/carbon, platinum oxide or Raney Ni etc.
As solvent, as long as the solvent that reaction is had no adverse effects all can, for example suitable methyl alcohol, ethanol, Virahol, propyl alcohol, two alkane, methylene dichloride, chloroform, ethylene dichloride, ether, tetrahydrofuran (THF), ethyl acetate, toluene or their mixed solvent of using.This reaction is to carry out at-78 to 80 ℃, especially with 0 ℃ to room temperature for more preferably.
(C method)
Among the compound [I], B is N, X is-CO-,-Alk-CO-or-SO
2-and with the compound shown in the general formula [I-b], be by the reaction of the compound or its salt shown in compound shown in the general formula [VII] and the general formula [VIII], remove the ligand shown in the general formula [IX] and the resin residue partly can prepare from resultant of reaction then,
In the formula X represent-CO-,-Alk-CO-or-SO
2-, and R
1, R
2Reach A and have meaning same as described above,
N is 0,1,2 or 3 in the formula, and P represents the resin residue, and R
1Reach A and have meaning same as described above,
R
2-V
1 [VIII]
V in the formula
1Expression-COOH ,-Alk-COOH or chlorosulfonyl, and R
2Have meaning same as described above,
P and n have meaning same as described above in the formula.
Perhaps, X in compound [I-b]
1For-CO-and R
2Compound for carboxyl low-carbon (LC) alkylidene group, be by substitute the compound or its salt of general formula [VIII] with the compound shown in the general formula (X), [VII] reacts with compound, removes ligand shown in the general formula [IX] and resin residue then and partly prepare from resultant of reaction
Alk1 represents alkylidene group in the formula.
(D method)
In addition, among the compound [I], B is that CH, X are-CON (R
3)-,-Alk-CON (R
3)-or-SO
2N (R
3)-and with the compound shown in the general formula [I-c], be by the compound of general formula [XI] expression and the compound or its salt reaction of general formula [XII] expression, from resultant of reaction, remove ligand shown in the general formula [IX] and resin residue then and partly prepare,
X in the formula
2Expression-CON (R
3)-,-Alk-CON (R
3)-or-SO
2N (R
3)-, and R
1, R
2, R
3Reach A and have meaning same as described above,
In the formula, R
1, R
3, A, P and n have meaning same as described above,
R
2-V
2 [XII]
In the formula, V
2Expression-COOH ,-Alk-COOH or chlorosulfonyl, and R
2Has meaning same as described above.
Perhaps, X in the compound [I-c]
2For-CON (R
3)-and R
2Be the compound of carboxyl low-carbon alkyl, can be by with compound [X] alternative compounds [XII] or its salt and compound [XI] reaction, remove the ligand shown in the general formula [IX] and the resin residue partly prepares from resultant of reaction then.
In addition, among the compound [I], B is CH, and X is-CON (R
3) CH
2-or-Alk-CON (R
3) CH
2-, and with the compound shown in the general formula [I-d], by the reaction of the compound or its salt shown in compound shown in the general formula [XIII] and the above-mentioned general formula [XII], from resultant of reaction, remove ligand shown in the general formula [IX] and resin residue then and partly prepare,
In the formula, X
3For-CON (R
3) CH
2-or-Alk-CON (R
3) CH
2-, and R
1, R
2, R
3Reach A and have meaning same as described above,
In the formula, R
1, R
3, A, P and n have meaning same as described above.
Perhaps, in the compound [I-d], X
2For-CON (R
3) CH
2-and R
2Be the compound of carboxyl low-carbon alkyl, can be by with compound [X] substitution compound [XII] or its salt, carry out the reaction with compound [XIII], from resultant of reaction, remove ligand shown in the general formula [IX] and resin residue part then and prepare.
(reaction in C method and the D method)
Reaction in the C method [reaction of compound [VII] and compound [VIII] or its salt (or compound [X])]; And the reaction in the D method [compound [XI] or [XIII] and compound [XII] or its salt (or with compound [XI] reaction), optionally can be in the presence of condensing agent and/or reductor, in appropriate solvent or under solvent-free, carry out, remove ligand and resin residue part with general method then, optionally can make with extra care by extraction, distribution, redeposition, crystallization, recrystallization, various chromatogram layer analysis and high speed chromatography etc.
As ligand, for example can enumerate the base of from shown in the general formula [IX], removing resin residue (P) part.
The resin residue of representing as P, can enumerate the used resin of common solid-phase synthesis, for example Merrifield resin (4-chloromethyl polystyrene resin etc.), Wang resin (4-benzyloxy benzylalcohol resin etc.) and methylol polystyrene resin resin residues such as (4-methylol polystyrene resins etc.).About the kind of resin, as long as to the reaction person of having no adverse effects, the kind of visual object compound is suitable to be selected, and generally speaking, particle more preferably is 70 to 200 μ m directly, and loading capacity more preferably is 0.1 to 2mmol/g.
As condensing agent, can suit to use O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea hexafluorophosphate, DCC (dicyclohexyl carbodiimide), EDC (1-ethyl-3-(3-dimethylamine propyl) carbodiimide), chloro-formic ester class (for example Vinyl chloroformate and isobutyl chlorocarbonate) and carbonyl dimidazoles etc.In addition, for promoting reaction, can be with alkali (yellow soda ash, sodium bicarbonate, triethylamine, pyridine, 4-dimethylamino pyridine, diisopropylethylamine, 1,8-diazabicyclo [5,4,0] 11 carbon-7-alkene etc.) or additives such as I-hydroxybenzotriazole, 1-N-Hydroxysuccinimide make an addition in the above-mentioned condensing agent.
As reductor, can suit to use alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal hydrocarbonates such as sodium bicarbonate and saleratus, alkaline carbonates such as yellow soda ash and salt of wormwood, or organic bases (for example triethylamine and pyridine etc.).
Then removing of ligand of carrying out and resin residue part, more fortunately in the appropriate solvent or solvent-free down, by implementing with trifluoroacetic acid, trifluoromethanesulfonic acid, hydrofluoric acid, Hydrogen bromide and spirit of salt etc. or its mixture process.
As the solvent in the reaction, if the solvent that reaction is had no adverse effects all can, for example methylene dichloride, N-methylmorpholine, dimethyl formamide, tetrahydrofuran (THF), N,N-DIMETHYLACETAMIDE or their mixed solvent.
Reaction in the C method is adapted at 0 to 120 ℃, especially carries out under 20 to 50 ℃.In addition, the reaction in the D method is adapted at 0 to 50 ℃, and especially in 0 to 30 ℃ is carried out.
At the solvent in the dereaction of removing of the ligand of carrying out and the resin residue part that continues, if the solvent that reaction is had no adverse effects all can, for example methylene dichloride, acetate, trifluoroacetic acid or their mixed solvent.This reaction is adapted at 0 to 50 ℃, especially carries out at 0 to 30 ℃.
(starting compound of A method)
Starting compound of the present invention [II] for example, can be according to international monopoly publication WO98/19998), the method for record in WO00/34241 and the following reference example (reference example 1 or 2) etc. and preparing.
For example, compound [II], be by with the compound shown in compound shown in the general formula [20] and the general formula [21], reaction in the presence of reductor (for example triethylamine etc.), obtain the compound shown in the general formula [22], then with resultant according to general method, handle to make by dewatering agent (for example Phosphorus Oxychloride and trifluoroacetic anhydride etc.)
In the formula, A has meaning same as described above,
Z
2-CH
2CO-Z
3 [21]
In the formula, Z
2And Z
3Expression can be the reactive residue of identical or inequality,
In the formula, Z
2And A has meaning same as described above.
As Z
3And Z
3Reactive residue, can suit to use and above-mentioned Z
1Same habitual reactive residue.
About starting compound [III], particularly, for example can be according to preparing with the same mode of the method for aftermentioned reference example (reference example 7 to 10) record.
For example, X is-O-CH
2-or-NHCH
2-compound [III]; can pass through the compound shown in the compound shown in the general formula [23], its amido protecting body or their salt and the general formula (24); exist or do not react down at reductor (for example mineral alkalis such as organic bases such as triethylamine and diisopropylethylamine, sodium hydride and salt of wormwood etc.); optionally the protecting group of amino can be prepared by the general method deprotection then
In the formula, V
3Expression hydroxyl or amido, and R
1Reach B and have meaning same as described above,
R
2-Z
4 [24]
In the formula, Z
4The expression reactive residue, and other mark has meaning same as described above.
As the protecting group of amino, can suit to use and any of the same habitual protecting group of above-mentioned R.
As Z
4Reactive residue, can suit to use and above-mentioned Z
1Same habitual reactive residue.
In addition; X is-Alk-O-or-compound [III] of S-; be by with the compound shown in the compound shown in the general formula [25], its amido protecting body or their salt and general formula [26a] or the general formula [26b]; at reductor (organic bases such as triethylamine and diisopropylethylamine for example; mineral alkali such as sodium hydride and salt of wormwood etc.) there is or do not exist reaction down; optionally the protecting group of amino can be able to be prepared by the general method deprotection then
In the formula, V
4Expression hydroxyl or thiol group, and R
1Reach B and have meaning same as described above,
R
2-Z
51[26a] or
R
2-Alk-Z
52 [26b]
In the formula, Z
51And Z
52Expression reactive residue, and R
2And Alk has meaning same as described above.
As the protecting group of amino, can suit to use and any of the same habitual protecting group of above-mentioned R.
As Z
51And Z
52Reactive residue, be suitable for using and above-mentioned Z
1Same habitual reactive residue.
In addition, X is two COCH
2H (R
3)-or-SO
2N (R
3)-compound [III]; be by with the compound shown in the compound shown in the general formula [27], its amido protecting body or their salt and general formula [28a] or the general formula [28b]; at reductor (organic bases such as triethylamine and diisopropylethylamine for example; mineral alkali such as sodium hydride and salt of wormwood etc.) there is or do not exist reaction down; and optionally the protecting group of amino can be prepared by the general method deprotection
In the formula, V
5Expression ,-N (R
3)-H, and R
1, R
3Reach B and have meaning same as described above,
R
2-COCH
2-Z
61[28a] or
R
2-SO
2-Z
62 [28b]
In the formula, Z
61And Z
62Expression reactive residue, and R
2Has meaning same as described above.
As the protecting group of amino, can suit to use and any of the same habitual protecting group of above-mentioned R.
As Z
61And Z
62Reactive residue, can suit to use and above-mentioned Z
1Same habitual reactive residue.
In addition, X is-CON (R
3)-,-Alk-CON (R
3)-or-SO
2N (R
3)-compound [III]; be by with the compound or its salt shown in the compound shown in the above-mentioned general formula [27], its amido protecting body or their salt and the general formula [29]; reaction in the presence of condensing agent (1-ethyl-3-(3-dimethylamine propyl) carbodiimide etc.); and optionally the protecting group of amino can be prepared by the general method deprotection
R
2-V
6 [29]
V
6Expression-COOH ,-Alk-COOH or-SO
2H, and R
2Have meaning same as described above,
As the protecting group of amino, can suit to use and any of the same habitual protecting group of above-mentioned R.
In addition, X is-CON (R
3) CH
2-or-Alk-CON (R
3) CH
2-compound [III]; be by with the compound or its salt shown in the compound shown in the above-mentioned general formula [30], its amido protecting body or their salt and the general formula [31]; reaction in the presence of condensing agent (1-ethyl-3-(3-dimethylamine propyl) carbodiimide etc.); and optionally the protecting group of amino can be prepared by the general method deprotection
In the formula, V
7Expression-N (R
3) H, and R
1, R
3Reach B and have meaning same as described above,
R
2-V
8 [31]
V
8Expression-COOH or-Alk-COOH, and R
2Has meaning same as described above.
As the protecting group of amino, can suit to use and any of the same habitual protecting group of above-mentioned R.
In addition, B is CH, X is-CO-or-Alk-CO-, and R
2Be following formula:
(1) of expression can be by the monocycle or the bicyclic nitrogen-containing heterocyclic base that replace; Or (2) are by the compound [III] of the amino of 1 to 2 the substituting group replacement that is selected from replacement or unsubstituted low-carbon alkyl; By with the compound or its salt shown in compound shown in the general formula [32], its amido protecting body or their salt and the general formula [33a]; Reaction in the presence of condensing agent (1-ethyl-3-(3-dimethylamine propyl) carbodiimides etc.); And optionally the protecting group of amino can be prepared by the conventional method deprotection
In the formula, V
9Expression-COOH, and R
1Has meaning same as described above
R
22-Alk-H [33a]
In the formula, R
22For with following formula
(1) monocycle or bicyclic nitrogen-containing heterocyclic base that can be substituted of expression, or (2) by be selected from replace or unsubstituted low-carbon alkyl in the amino that replaces of 1 to 2 substituting group selecting, and Alk has meaning same as described above.
As the protecting group of amino, any of the habitual protecting group that suitable use and above-mentioned R are same.
In addition, B is N, X is-CO-or-Alk-CO-, and R
2Be following formula:
Monocycle or bicyclic nitrogen-containing heterocyclic base that (1) of expression can be substituted; Or the compound [III] of the amino of (2) 1 to 2 substituting group replacement through being selected from replacement or unsubstituted low-carbon alkyl; By with the compound or its salt class shown in the compound shown in the general formula [330], its amido protecting body or their salt and general formula [331] or [332]; At deoxidier (organic bases such as triethylamine and diisopropylethylamine; The inorganic base such as sodium hydride and potash etc.) there is or do not exist lower reaction; And optionally the protecting group of amino can be prepared by the conventional method deprotection
In the formula, R
1Have meaning same as described above,
R
22-CO-Z
7 [331]
R
22-Alk-COOH [332]
In the formula, R
22For with following formula
Monocycle or dicyclo that (1) of expression can be substituted close Azacyclyl, or the amino of (2) 1 to 2 substituting group replacement through being selected from replacement or unsubstituted low-carbon alkyl, and Z
7The expression reactive residue.
As the protecting group of amino, can suit to use the habitual protecting group same with above-mentioned R.About Z
7Reactive residue, can suit to use and above-mentioned Z
1Same habitual reactive protecting group.
In addition, B is CH, and X is singly-bound and R
2Be following formula:
Monocycle or bicyclic nitrogen-containing heterocyclic base that (1) of expression can be substituted; or the compound [III] of the amino of (2) 1 to 2 substituting group replacement through being selected from replacement or unsubstituted low-carbon alkyl; be by with the compound shown in the compound shown in the general formula [34], its amido protecting body or their salt and the general formula [33b]; reaction in the presence of reductive agent (sodium triacetoxy borohydride etc.); and optionally the protecting group of amino can be prepared by the general method deprotection
In the formula, R
1Have meaning same as described above,
R
22-H [33b]
In the formula, R
22Has meaning same as described above.
As the protecting group of amino, can suit to use and any of the same habitual protecting group of above-mentioned R.
In addition, B is CH, and X is singly-bound and R
2Be following formula:
The compound [III] of the base of expression; be by with the compound shown in the compound shown in the general formula [35], its amido protecting body or their salt and the general formula [36]; at reductor (organic bases such as triethylamine and diisopropylethylamine for example; mineral alkali such as sodium hydride and salt of wormwood etc.) there is or do not exist reaction down; and optionally the protecting group of amino can be prepared by the general method deprotection
In the formula, R
1Have meaning same as described above,
In the formula, cyclic group Ar represents to have substituent arylidene (phenylene etc.).
As the protecting group of amino, can suit to use and any of the same habitual protecting group of above-mentioned R.
In addition, B is CH, and X is singly-bound and R
2Be following formula:
Expression can substituted nitrogen heterocycle compound [III]; it is the compound or its salt of serving as reasons with shown in the compound shown in the general formula [35], its amido protecting body or their salt and the general formula [37]; at reductor (organic bases such as triethylamine and diisopropylethylamine for example; mineral alkali such as sodium hydride and salt of wormwood etc.) there is or do not exist reaction down; and optionally the protecting group of amino can be prepared by the general method deprotection
In the formula, Z
81And Z
82The reactive residue of expression.
As the protecting group of amino, can suit to use and any of the same habitual protecting group of above-mentioned R.
About Z
81And Z
82Reactive residue, can suit to use the habitual reactive residue same with above-mentioned Z1.
In addition; B is that N and X are single bonded compound [III]; be by the represented compound of general formula [38]; compound shown in its amido protecting body or its salt and the general formula [24]; at reductor (organic bases such as triethylamine and diisopropylethylamine for example; mineral alkali such as sodium hydride and salt of wormwood etc.) there is or do not exist reaction down, and optionally the protecting group of amino can be prepared by the general method deprotection
In the formula, R
1Have meaning same as described above,
R
2-Z
4 [24]
In the formula, R
2And Z
4Has meaning same as described above.
As the protecting group of amino, can suit to use and any of the same habitual protecting group of above-mentioned R.
In addition; X is-compound [III] of COO-; be amido protective or its salt and the represented compound of general formula [40] by the compound that general formula [39] is represented; react in reductor (dimethylamine pyridine etc.) existence or not; and the protecting group of amino prepared by the general method deprotection
In the formula, R
1And B has meaning same as described above
R
2-COCl [40]
In the formula, R
2Has meaning same as described above.
As the protecting group of amino, can suit to use and any of the same habitual protecting group of above-mentioned R.
Starting compound [20] to [40] can prepare by currently known methods or with the same mode of the method for aftermentioned reference example record.At B is in the starting compound [III] of CH, owing to exist with the cis and the trans-isomer(ide) compound of cyclohexane ring as reference plane, so by according to the discrete target compound, use the suitable isomer of raw material compounds, can obtain the target isomer of starting compound [III].
Perhaps, can behind the starting compound [III] of the mixture that obtains cis and trans-isomer(ide), isolate target isomer by chromatography.
(starting compound of B method)
In the formula, R, R
1, Z
1, A and B have meaning same as described above.
Compound or its salt shown in the general formula [IV], be by the compound or its salt shown in compound shown in the above-mentioned general formula [II] and the general formula [41] is reacted, and obtain the compound or its salt shown in the general formula [42], then with the compound reaction shown in itself and general formula [43] or the general formula [44] and get.
The reaction of compound [II] and compound [41] or its salt is in the reductor existence or not, implements in appropriate solvent or under solvent-free.As solvent, need only the solvent that reaction is had no adverse effects, for example suitable acetonitrile, methyl alcohol, ethanol, Virahol, propyl alcohol, acetone, dimethyl formamide, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), ether, two alkane, ethyl acetate, toluene, methylene dichloride, ethylene dichloride, chloroform or their mixed solvent of using.This reaction is to carry out at 0 to 120 ℃, especially suits ℃ to carry out in room temperature to 80.
As reductor, can suit to use mineral alkali (hydrogenated alkali metal such as sodium hydride for example, alkaline carbonate such as yellow soda ash and salt of wormwood, alkali metal alkoxide such as sodium methylate, basic metal such as sodium, or organic bases (for example triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, xylidine and dimethylamino pyridine etc.) alkali metal hydroxide such as sodium hydroxide and potassium hydroxide etc.).
The reaction of compound [42] or its salt and compound [43] or [44] is to exist down in reductor, implements in appropriate solvent or under solvent-free.
As solvent, as long as the solvent that reaction is had no adverse effects all can, for example can suit to use acetonitrile, methyl alcohol, ethanol, Virahol, propyl alcohol, acetone, tetrahydrofuran (THF), ether, two alkane, ethyl acetate, toluene, methylene dichloride, ethylene dichloride, chloroform, water or their mixed solvent.This reaction is to carry out at 0 to 120 ℃, especially suits ℃ to carry out in room temperature to 80.
As reductor, can suit to use alkaline carbonates such as mineral alkali (for example hydrogenated alkali metal such as sodium hydride) yellow soda ash and salt of wormwood, alkali metal alkoxide such as sodium methylate, basic metal such as sodium, or organic bases (for example triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, xylidine and dimethylamino pyridine etc.) alkali metal hydroxide such as sodium hydroxide and potassium hydroxide etc.).
(starting compound in C method and the D method,
Compound [VII], compound [XI] or compound [XIII]; be to pass through respectively with compound shown in general formula [50], general formula [51] or the general formula [52] and the compound shown in the general formula [53]; in the presence of reductive agent (for example sodium triacetoxy borohydride); react with general method; then with resultant and compound [II] after reaction in the presence of the reductor (diisopropylethylamine etc.); remove the protecting group deaminize and get with general method
In the formula, V
10, V
11And V
12The protecting group that expression is amino, and R
1And R
3Have meaning same as described above,
In the formula, P and n have meaning same as described above.
As the protecting group of amino, can suit to use the habitual protecting group same with above-mentioned R.
As The compounds of this invention [I] or its starting compound that above-mentioned mode prepares, can be according to original unbound state or with refining after its esters isolated in form.Its esters can be handled by the salify of using always and prepare.
Common chemical operation such as separation and purification can adopt extraction, concentrates, crystallization, filtration, recrystallization and various chromatography are suitably carried out.
In addition, The compounds of this invention or its starting compound can the racemization isomer, optical isomers such as optically active body, diastereomer separately or form of mixtures exist.Be the isomer of pure matter on stereochemistry, can use on stereochemistry, perhaps optical isomer is separated and reach with general racemization method of analysis to pure starting compound prepares.In addition, the mixture of diastereomer can pass through general method, and for example fractional crystallizaton or chromatography etc. are separated.
Embodiment
The present invention is described by the following examples in further detail, yet these embodiment do not limit the present invention.
Embodiment 1-1
With the acetonitrile-methanol solution of 247 milligrams of 100 milligrams of (S)-1-acetyl bromide-2-Cyanopyrolidines (aftermentioned reference example 1) and 4-amino-1-(2-pyrimidyl) piperidines (reference example 7-1), under room temperature, stirred 15 hours.Add to water in the reaction mixture and use chloroform extraction.With extraction liquid with anhydrous sodium sulfate drying after, underpressure distillation removes desolvates.Resistates is refining by glycol column chromatography (solvent: 0 to 10% methyl alcohol-chloroform), it is dissolved in 0.5 milliliter of the 0.5 milliliter-chloroform of ethyl acetate, add 1.0 milliliters of 2N hydrochloric acid-ether, then add 2 milliliters of ether, the leaching throw out of separating out then, clean with ether, obtain (S)-2-cyano group-1-[1-(2-pyrimidyl) piperidin-4-yl amino] acetyl-pyrrole alkane 2 hydrochlorides (the embodiment 1-1 of table 1).
Embodiment 1-2 to 1-90 and 1-92 to 1-109
Use (S)-1-acetyl bromide-2-Cyanopyrolidine and corresponding starting compound; and, obtain the compound (but the compound of embodiment 1-93 is to obtain with the by product of embodiment 1-33) of aftermentioned table 1 (embodiment 1-2 to 1-90 and 1-92 to 1-109) to handle with the same mode of the foregoing description 1-1.
Corresponding starting compound is by method or the known method same with the aftermentioned reference example, or the method for their combinations is obtained.
Embodiment 1-91
At anti-form-1,300 milligrams of 4-cyclohexanediamine and N in the solution that the acetonitrile of N-diisopropylethylamine 457 microlitres is 5 milliliters, add 570 milligrams of (S)-1-acetyl bromides-2-Cyanopyrolidine, then in stirring at room 3 hours.Reaction solution is diluted with saturated aqueous common salt, and use chloroform extraction.Extraction liquid removed with anhydrous sodium sulfate drying and underpressure distillation desolvate.With resistates by silica gel column chromatography (solvent: the refining oily matter that obtains chloroform-methanol (100: 0 to 95: 5)).It is dissolved in 0.5 milliliter of chloroform, add 0.5 milliliter of 1N hydrochloric acid-ether then, then add 4 milliliters of ether, the precipitation of separating out is cleaned with ether, obtain (S)-2-cyano group-1-{ trans-4-[(S)-(2-cyano group-1-pyrrolidyl) carbonyl methylamino] cyclohexylamino 307 milligrams of acetylpyridine 2 hydrochlorides (the embodiment 1-91 of table 1).
Embodiment 2-1 to 2-9
(1) with 600 milligrams of 4-t-butoxycarbonyl amino-4-methylcyclohexanone (reference example 6-1 (3) compound), 783 milligrams of sodium triacetoxy borohydrides, 252 milligrams of morpholines, the mixture that 159 milligrams of acetate and ethylene dichloride are 6 milliliters stirred 16 hours under room temperature.After the saturated sodium bicarbonate aqueous solution dilution, with chloroform extraction.With extraction liquid with anhydrous sodium sulfate drying after, underpressure distillation removes desolvates.Resistates is passed through silicon gel filtration chromatography method (solvent: chloroform-methanol (20: 1) → chloroform-methanol (10: 1)+1% ammoniacal liquor) make with extra care, obtain mixture (the reference example 8-54 of N-tertbutyloxycarbonyl-1-methyl-c-4-morpholineization-r-1-hexahydroaniline and N-tertbutyloxycarbonyl-1-methyl-t-4-morpholineization-r-1-hexahydroaniline; Compound before the deprotection) 600 milligram.220 milligrams of this compounds in the mixed solution of 2 milliliters of 4N hydrochloric acid/2 milliliters in two alkane and ethanol, in stirring at room 15 hours, behind N-tertbutyloxycarbonyl deprotection, are concentrated reaction solution and obtain residue.
(2) in the compound that above-mentioned (1) obtains, add 320 milligrams of (S)-1-acetyl bromides-2-Cyanopyrolidine, 0.6 milliliter of triethylamine, 1 milliliter of 3.5 milliliters of acetonitriles and methyl alcohol are then in stirring at room 15 hours.After the saturated sodium bicarbonate aqueous solution dilution, use chloroform extraction.With the extraction liquid anhydrous sodium sulfate drying, underpressure distillation removes and desolvates then.Resistates is passed through silica gel column chromatography (solvent: chloroform-hexane (1: 1) → chloroform) make with extra care, obtain 2 kinds of oily matter.
Compound salt acid treatment with low polarity side obtains (S)-2-cyano group-1-[1-methyl-C-t-4-morpholino-r-1-cyclohexylamino] acetylpyridine 2 hydrochlorides (table 2: embodiment 2-2) 82 milligrams.
In addition, with above-mentioned same, obtain the compound of the embodiment 2-3 to 2-9 of table 2.
Embodiment 3
(1) in (3/1) 60 milliliter of the acetonitrile-methyl alcohol mixed liquor of trans-4-Trans-4-Amino Cyclohexanol 4.78 gram, adds (S)-1-acetyl bromide-2-Cyanopyrolidine 3.00 grams down, under room temperature, stirred 14 hours in ice-cold.In reaction solution, add 1.93 milliliters of triethylamines, add 16 milliliters of the acetonitrile solutions of tert-Butyl dicarbonate then in room temperature, directly stirred 3 hours.Underpressure distillation adds to water in the resistates after removing and desolvating, and then with the sodium bicarbonate aqueous solution neutralization and use chloroform extraction, dry back is concentrated.The resistates that obtains is refining by the silicon gel filtration chromatography, obtain (S)-1-(N-tertbutyloxycarbonyl-trans-4-hydroxyl-1-cyclohexylamino) acetyl-2-Cyanopyrolidine 4.72 grams.
(2) in the solution of 2 milliliters of the methylene dichloride of 150 milligrams of compounds that obtain in above-mentioned (1) and pyridine 121 microlitres, add 84 milligrams of three surpalites, directly stirred then 1 hour in room temperature.Then add 1 milliliter of the dichloromethane solution of morpholine 186 microlitres, after 1 hour, dilute with aqueous citric acid solution in stirring at room.Use ethyl acetate extraction, dry and concentrate after, refining by the silicon gel filtration chromatography, obtain (S)-1-[N-tertbutyloxycarbonyl-trans-4-(morpholino carbonyl oxygen base) cyclohexylamino] 174 milligrams in acetyl-2-Cyanopyrolidine.
(3) 157 milligrams of compounds that above-mentioned (2) are obtained are dissolved in 1.5 milliliters of the trifluoroacetic acids and in stirring at room 1 hour.After the solvent underpressure distillation removed, in resistates, add sodium bicarbonate aqueous solution furnishing alkalescence, concentrate with chloroform extraction, dry back then.Then, resistates is made with extra care by chromatography (solvent: 0 to 5% methyl alcohol-chloroform), obtained oily matter.It is dissolved in 1 milliliter of the ethyl acetate, add 0.5 milliliter of 1N hydrochloric acid-ether, then add 2 milliliters of ether, after the precipitation separated out is cleaned with ether, obtain (S)-2-cyano group-1-[trans-4-(morpholine carbonyl oxygen base) cyclohexylamino] 97 milligrams of acetyl-pyrrole heptane hydrochloride salt (embodiment 3 of table 3).
Embodiment 4-1
(1) with the mixture of 500 milligrams of 3 (2) resin compounds that obtain of aftermentioned reference example and 0.5M methylsulfonic acid-two alkane/methylene dichloride (1/9) in stirring at room 18 hours.The leaching resin is used dimethyl formamide, 10% triethylamine-methylene dichloride, and dimethyl formamide-water (1: 1), methyl alcohol, tetrahydrofuran (THF), methyl alcohol and methylene dichloride clean.With the mixture of 4 milliliters of the resin that obtains and benzyl mustard oil 277 microlitres and methylene dichloride in stirring at room 18 hours.The leaching resin is used dimethyl formamide, dimethyl formamide-water (1: 1), and methyl alcohol, tetrahydrofuran (THF), after methyl alcohol and methylene dichloride cleaned, drying under reduced pressure obtained resin.
(2) mixture of 4 milliliters of resin that above-mentioned (1) is obtained and trifluoroacetic acids stirred under room temperature 18 hours.Clean with methylene dichloride behind the elimination resin, then with filtrate and washing lotion merging and concentrated.After in resistates, adding sodium bicarbonate aqueous solution furnishing alkalescence, use chloroform extraction, and after drying, concentrate.The resistates that obtains is made with extra care by using glycol column chromatography (solvent: 0 to 5% methyl alcohol-chloroform), obtained oily matter.It is dissolved in 0.5 milliliter of ethyl acetate, add 0.5 milliliter of 1N hydrochloric acid-ether, then add 2 milliliters of ether, the precipitation of separating out cleaned with ether, obtain (S)-2-cyano group-1-[1-(benzylamine carbonyl) piperidin-4-yl amino] acetyl-pyrrole heptane hydrochloride salt (the embodiment 4-1 of table 4).
Embodiment 4-2 to 4-5
Use corresponding starting compound (isocyanic acid compound),, obtain the compound of the embodiment 4-2 to 4-3 of table 4 in the mode same with embodiment 4-1.Use the intramolecularly cyclic anhydride (succinyl oxide and Pyroglutaric acid) of dicarboxylic acid to replace the isocyanic acid compound, and, obtain the compound of the embodiment 4-4 to 4-5 of table 4 in the mode same with embodiment 4-1 as starting compound.
Embodiment 4-6 to 4-10
Except replacing benzyl mustard oil as starting compound with methyl-chloroformate, and outside there is the reaction of carrying out (1) item down in triethylamine, in the mode same with the foregoing description 4-1, obtain the compound of the embodiment 4-6 of table 4, in addition, use corresponding starting compound (muriate), with above-mentioned same mode, obtain the compound of the embodiment 4-7 to 4-10 of table 4.
Embodiment 4-11
With the mixture of 500 milligrams of 3 (2) resin compounds that obtain of reference example and 0.5M methylsulfonic acid-two alkane/methylene dichloride (1/9) in stirring at room 18 hours.The leaching resin is used dimethyl formamide, 10% triethylamine-methylene dichloride, and dimethyl formamide-water (1: 1), methyl alcohol, tetrahydrofuran (THF), methyl alcohol and methylene dichloride clean.With 177 milligrams of the resin that obtains and quinaldinic acid, 138 milligrams of I-hydroxybenzotriazoles, adjacent benzotriazole-1-base-N, N, N ', 387 milligrams of N '-tetramethyl-urea hexafluorophosphate, the mixture that 224 milliliters of N-methylmorpholines and dimethyl formamide are 4 milliliters was in stirring at room 18 hours.The leaching resin is used dimethyl formamide, dimethyl formamide-water (1: 1), and methyl alcohol, tetrahydrofuran (THF), after methyl alcohol and methylene dichloride cleaned, drying under reduced pressure obtained resin.This resin is used and embodiment 4-1 (2) same handling with trifluoroacetic acid, obtains (S)-2-cyano group-1-[1-(2-quinoline carbonyl) piperidin-4-yl amino] 136 milligrams of acetyl-pyrrole alkane 2 hydrochlorides (the embodiment 4-11 of table 4).
Embodiment 4-12 to 4-19
Use corresponding starting compound (carboxylic acid cpd),, obtain the compound of the embodiment 4-12 to 4-19 of table 4 to handle with the same mode of embodiment 4-11.
Embodiment 5-1 to 5-12
The resin compound that obtains with reference example 4 replaces the resin compound of 3 (2) of reference examples, to handle with the same mode of embodiment 4-1 to 4-10, obtains the compound of the embodiment 5-1 to 5-12 of table 5.
Embodiment 5-13 to 5-36
The resin compound that obtains with reference example 4 replaces the resin compound of 3 (2) of reference examples, to handle with the same mode of embodiment 4-11, obtains the compound of the embodiment 5-13 to 5-30 of table 5.In addition, use 5 (5) resin compounds that obtain of reference example, obtain the compound of the embodiment 5-31 to 5-36 of table 5 with the same manner.
Embodiment 5-37 to 5-39
With the mixture of 500 milligrams of 5 (5) resin compounds that obtain of reference example (1.01 mmole/gram) and 0.5M methylsulfonic acid-two alkane/methylene dichloride (1/9) in room temperature jolting 30 minutes.The leaching resin is used methylene dichloride, 10% triethylamine-methylene dichloride, and methylene dichloride, dimethyl formamide, dimethyl formamide-water (1: 1), tetrahydrofuran (THF), methyl alcohol, tetrahydrofuran (THF), methyl alcohol and N,N-DIMETHYLACETAMIDE clean.With the mixture of the resin that obtains and 293 milligrams of 2-chloro-5-bromo pyrimi piperidines and triethylamine 211 microlitres in 55 ℃ of joltings 16 hours.The leaching resin is used dimethyl formamide, methylene dichloride, and 10% triethylamine-methylene dichloride, methylene dichloride, dimethyl formamide, dimethyl formamide-water (1: 1), tetrahydrofuran (THF), methyl alcohol, tetrahydrofuran (THF), methyl alcohol and methylene dichloride clean.The full dose resin that obtains is handled with trifluoroacetic acid, obtain (S)-1-[trans-4-(5-bromo pyrimi piperidine-2-base aminomethyl) cyclohexylamino] 61 milligrams of ethanoyl-2-Cyanopyrolidine hydrochloride (the embodiment 5-37 of table 5).
In addition, use corresponding starting compound, obtain the compound of the embodiment 5-38 to 5-39 of table 5 with the same manner.
Embodiment 6-1
(1) with 519 milligrams of trans-4-(t-butoxycarbonyl amino methyl) hexahydroaniline ((3) item of aftermentioned reference example 5), 2,4,446 milligrams of 6-TMB, the mixture of 608 milligrams of sodium triacetoxy borohydrides and 11 milliliters of methylene dichloride was in stirring at room 14 hours.Reaction solution with after the saturated sodium bicarbonate aqueous solution dilution, is used chloroform extraction.After extraction liquid cleaned with saturated aqueous common salt, use anhydrous sodium sulfate drying, underpressure distillation is except that desolvating then.Resistates is refining with glycol column chromatography (solvent: 0 to 20% methyl alcohol-chloroform).With gained compound (969 milligrams) (S)-641 milligrams of 1-acetyl bromides-2-Cyanopyrolidine, the mixture that diisopropylethylamine 791 microlitres and N,N-DIMETHYLACETAMIDE are 8 milliliters stirred 1 hour in 50 ℃.Behind the reaction solution dilute with water, use ethyl acetate extraction.After extraction liquid water and saturated aqueous common salt cleaning, use anhydrous sodium sulfate drying, underpressure distillation removes and desolvates then.Resistates is refining with glycol column chromatography (solvent: 50 to 0% hexane-chloroform), obtain (S)-2-cyano group-1-[N-(2,4,6-trimethoxy phenmethyl)-trans-4-(t-butoxycarbonyl amino methyl) cyclohexylamino] 834 milligrams in acetyl-pyrrole alkane.
(2) mixture of 818 milligrams of compounds that above-mentioned (1) is obtained and (1/9) 20 milliliter of 0.5M methylsulfonic acid-two alkane/methylene dichloride was in stirring at room 2 hours.Reaction solution with after the saturated sodium bicarbonate aqueous solution dilution, is used chloroform extraction.After extraction liquid cleaned with saturated aqueous common salt, use anhydrous sodium sulfate drying, and underpressure distillation obtains (S)-2-cyano group-1-[N-(2,4,6-trimethoxy phenmethyl)-trans-4-(amine methyl) cyclohexylamino except that desolvating] 647 milligrams in acetyl-pyrrole alkane.
(3) compound that above-mentioned (2) are obtained is 155 milligrams, and 2,104 milligrams of 5-dichloro pyrimidines, triethylamine 146 microlitres, the mixture that 1 milliliter of tetrahydrofuran (THF) and dimethyl formamide are 1 milliliter stirred 14 hours in 60 ℃.Behind the reaction solution dilute with water, use ethyl acetate extraction.After extraction liquid water and saturated aqueous common salt cleaning, use anhydrous sodium sulfate drying, underpressure distillation removes and desolvates.With resistates glycol column chromatography (solvent: 0 to 20% methyl alcohol (33% hexane-chloroform)) refining, obtain (S)-2-cyano group-1-[N-(2,4,6-trimethoxy phenmethyl)-and trans-4-(5-chloropyrimide-2-base amine methyl) cyclohexylamino] 104 milligrams in acetyl-pyrrole alkane.
(4) mixture of 90 milligrams of compounds that above-mentioned (3) are obtained and 4 milliliters of trifluoroacetic acids was stirring at room 18 hours.After the trifluoroacetic acid underpressure distillation removed, in resistates, add saturated sodium bicarbonate aqueous solution, use chloroform extraction then.With the extraction liquid anhydrous sodium sulfate drying; underpressure distillation removes and desolvates then; with resistates glycol column chromatography (solvent: 40 to 0% hexane-chloroform)) refining; the compound that obtains is dissolved in 0.5 milliliter of chloroform; add 0.5 milliliter of 1N hydrochloric acid-ether; then add 2 milliliters of ether, clean the precipitation separate out with ether then, obtain (S)-1-[trans-4-(5-chloropyrimide-2-base amine methyl) cyclohexylamino] 22 milligrams of ethanoyl-2-Cyanopyrolidine 2 hydrochlorides (the embodiment 6-1 of table 6).
Embodiment 6-2 to 6-4
Use the compound and the corresponding starting compound of the foregoing description 6-1 (2) gained, with (3) to (4) same mode of embodiment 6-1, obtain the compound of the embodiment 6-2 to 6-4 of table 6.
Embodiment 7-1 to 7-10
Replace (S)-1-acetyl bromide-2-Cyanopyrolidine with (R)-3-chloracetyl-4-cyano-tetrahydrothiazole (compound of aftermentioned reference example 2),, obtain the compound of the embodiment 7-1 to 7-10 of table 7 to handle with the same mode of the foregoing description 1.
Embodiment 8-1 to 8-8
Except usefulness (R)-3-chloracetyl-4-cyano-tetrahydrothiazole replacement (S)-1-acetyl bromide-2-Cyanopyrolidine; to handle with the foregoing description 6-1 (1) to (2) same mode; obtain (R)-4-cyano group-3-[N-(2; 4,6-trimethoxy phenmethyl)-trans-4-aminomethyl cyclohexylamino] acetyl thiazole alkane.Use this compound and corresponding starting compound,, obtain the compound of the embodiment 8-1 to 8-8 of table 8 in the mode same with embodiment 6-1 (3) to (4).(but in embodiment 8-7 and 8-8, in corresponding to embodiment 6-1 (3) step, be to use starting compound and carboxylic acid cpd, under I-hydroxybenzotriazole and the existence of 1-ethyl-3-(3-dimethylamine propyl) carbodiimide, react)
Reference example 1
According to the method for document (WO98/19998) record, after being reacted, L-prolineamide (commercially available product) and acetyl bromide bromide carry out dehydration reaction, obtain (S)-1-acetyl bromide-2-Cyanopyrolidine.
Reference example 2
According to the method for document (AShworth etc., Bioorg.Med.Chem.Lett., the 6th volume, 2745 to 2748 pages, 1996) record, synthetic L-sulfo-prolineamide hydrochloride.In methylene dichloride 150 ml solns of 8.67 milliliters of the L-sulphur prolineamide hydrochloride that obtains 5.00 grams and triethylamines, add 2.36 milliliters of chloracetyl muriates down in ice-cold, and under equality of temperature, stirred 1 hour.In reaction solution, add 8.4 milliliters of 4.8 milliliters of pyridines and trifluoroacetic anhydrides, then in stirring at room 1 hour.Reaction solution is cleaned with 10% aqueous hydrochloric acid and water, with anhydrous magnesium sulfate drying, filter and concentrating under reduced pressure after, with resistates crystallization from ether, to obtain be tawny crystalline (R)-3-chloracetyl-4-cyano-tetrahydrothiazole 4.82 grams.
Reference example 3
(1) with resin ((4-formyl radical-3; 5-dimethoxy phenoxy group) methylated polystyrene) [by people's such as Cecile Pegurier method (Bioorg.Med.Chem. the 8th volume; 163 to 171 pages; 2000) and synthetic] 14.5 grams (1.40 mmole/gram); 4-amino-1-tertiary butyloxycarbonyl phenylpiperidines 7.85 grams, the mixture that sodium triacetoxy borohydride 10.71 grams and methylene dichloride are 180 milliliters was in stirring at room 18 hours.The leaching resin is by using methylene dichloride, dimethyl formamide-water (1: 1), 10% triethylamine-methylene dichloride, dimethyl formamide-water (1: 1), methyl alcohol, drying under reduced pressure after tetrahydrofuran (THF) and the washed with methanol obtains resin compound (1) 16.83 gram (1.17 mmole/gram) shown in the last figure.
(2) resin compound 16.73 grams that above-mentioned (1) obtained, (S)-1-acetyl bromide-2-Cyanopyrolidine 8.50 grams, the mixture that 6.82 milliliters of diisopropylethylamine and dimethyl formamide are 80 milliliters stirred 18 hours in 50 ℃.The leaching resin, by using dimethyl formamide, 10% triethylamine-methylene dichloride, dimethyl formamide-water (1: 1), methyl alcohol, drying under reduced pressure after tetrahydrofuran (THF) and the washed with methanol obtains resin compound (2) 19.14 grams (1.02 mmole/gram) shown in the last figure.
Reference example 4
1,4-is trans-ethanol 250 ml solns of 131 milliliters of cyclohexanediamine 30.00 grams and 2N hydrochloric acid in, in ice-cold ethanol 150 ml solns that splashed into two carbonic acid two (tert-butyl ester), 52.13 grams down through 4 hours.Reaction solution was stirred 20 hours, after concentrating,, clean with chloroform with the aqueous citric acid solution dilution, and with aqueous sodium hydroxide solution furnishing alkalescence.By chloroform extraction, dry and concentrated, obtain N-tertbutyloxycarbonyl-anti-form-1,4-cyclohexanediamine 22.33 grams.Use this compound and resin ((4-formyl radical-3,5-dimethoxy phenoxy group) methylated polystyrene), handle, obtain the resin compound shown in the last figure with (1) to (2) same mode of above-mentioned reference example 3.
Reference example 5
(1) with trans-4-amine methylcyclohexanecarboxylic acid 10.0 gram, two alkane-water (1: 1), 200 ml solns of tert-Butyl dicarbonate 14.6 grams and sodium bicarbonate 11.2 grams were in stirring at room 72 hours.In reaction mixture, add 300 milliliters of 50 milliliters of the 10%NaOH aqueous solution and ether, after the separation organic phase, water with 10%HCl aqueous solution furnishing acidity, is used ethyl acetate extraction then.Extraction liquid is cleaned with saturated aqueous common salt, remove with underpressure distillation behind the anhydrous sodium sulfate drying and desolvate.Resistates is cleaned with isopropyl ether, obtain trans-4-(t-butoxycarbonyl amino methyl) hexahydrobenzoic acid 15.3 grams.
(2) compound that above-mentioned (1) obtained 5.15 grams, the toluene 100 ml soln reflux that diphenylphosphine acid amides 6.05 grams and triethylamine are 3.1 milliliters were added 2.3 milliliters of benzylalcohols after 3 hours, and then one night of reflux.With cooled reaction solution concentrating under reduced pressure, (solvent: ethyl acetate-chloroform (1: 20)) refining, crystallization from hexane obtains N-carbobenzoxy-(Cbz)-trans-4-(t-butoxycarbonyl amino methyl) hexahydroaniline 5.32 grams to resistates with silicon gel rapid column chromatography.
(3) compound 5.19 grams that above-mentioned (2) item obtained and ethanol 200 ml solns of 10% palladium/carbon stirred 6 hours under the nitrogen atmosphere of 1 air pressure.Filtration catalizer cleans with ethanol, then filtrate and washing lotion is merged.After underpressure distillation removes and desolvates, by (solvent: chloroform-methanol-strong aqua (50: 10: 1) is refining with the silicon gel filtration chromatography with resistates, and crystallization from isopropyl ether-hexane mixing solutions, obtain trans-4-(t-butoxycarbonyl amino methyl) hexahydroaniline 2.55 grams.
(4) compound that above-mentioned (3) are obtained (2.54 gram); resin (4-formyl radical-3.5-dimethoxy phenoxy group) methylated polystyrene) (1.43 mmole/gram) 4.15 gram, sodium triacetoxy borohydride 3.24 public affairs fill and the mixture of 80 milliliters of methylene dichloride in stirring at room 20 hours.The leaching resin is used methylene dichloride, dimethyl formamide, methylene dichloride, 10% triethylamine-methylene dichloride, methylene dichloride, dimethyl formamide, dimethyl formamide-water (1: 1), dimethyl formamide, methyl alcohol, tetrahydrofuran (THF), methyl alcohol is after tetrahydrofuran (THF) and the washed with methanol, by drying under reduced pressure, obtain resin compound (4) 5.19 grams (1.14 mmole/gram) shown in the last figure.
(5) resin that above-mentioned (4) are obtained (1.14 mmole/gram) 5.12 grams, (S)-1-acetyl bromide-2-Cyanopyrolidine 2.53 grams, the mixture that 2.03 milliliters of diisopropylethylamine and dimethyl formamide are 50 milliliters stirred 18 hours in 50 ℃.The leaching resin is used dimethyl formamide, dimethyl formamide-water (1: 1), dimethyl formamide, methyl alcohol, tetrahydrofuran (THF), methyl alcohol, after tetrahydrofuran (THF) and the washed with methanol,, obtain resin compound (5) 5.78 grams (1.01 mmole/gram) shown in the last figure by drying under reduced pressure.
Reference example 6-1
(1) according to the method for document (JP83-118577) record, makes 1,4-dioxo spiro [4,5] decane-8-carboxylate methyl ester exists down and iodomethane reaction in LDA (diisopropyl amide lithium), obtains the 8-methyl isophthalic acid, 4-dioxo spiro [4,5] decane-8-carboxylate methyl ester (compound of last figure (1)).
(starting compound, be to use people's such as document according to people such as Rosemmund (Chem.Ber.,, 108 volumes, 1871 to 1895 pages in 1975) and Black the method for document (Synthesis,, the 829th page in 1981) record synthetic).
(2) compound 3.80 grams that above-mentioned (1) obtained, sodium hydroxide 3.55 grams, the mixture heating up that 16 milliliters of methyl alcohol and water are 25 milliliters refluxed 2 hours.With reaction solution ice-cold it, with 2N hydrochloric acid and 10% aqueous citric acid solution furnishing pH 5, use ethyl acetate extraction then.After extraction liquid water and saturated aqueous common salt cleaning, use anhydrous sodium sulfate drying, remove by underpressure distillation then and desolvate, obtain the 8-methyl isophthalic acid, 4-dioxo spiro [4,5] decane-8-carboxylic acid (compound of last figure (2)) 3.46 grams.
(3) compound 16.19 grams that above-mentioned (2) obtained, diphenylphosphine acid amides 24.51 grams, the mixture heating up that triethylamine 9.00 grams and toluene are 160 milliliters refluxed 2.5 hours.With ice-cooled and with saturated sodium bicarbonate aqueous solution, water and saturated aqueous common salt use anhydrous sodium sulfate drying after cleaning with reaction solution, and underpressure distillation is except that desolvating then.In N,N-DIMETHYLACETAMIDE 100 ml solns of gained compound, in ice-cooled potassium tert.-butoxide 9.55 grams that add slowly down, then in stirring at room 1 hour.Reaction solution is injected frozen water, the crystallization that leaching is separated out, washing and dry.100 milliliters of the aqueous solution of tosic acid hydrate 30.87 gram are added in tetrahydrofuran (THF) 100 ml solns of gained compound, then in stirring at room 16 hours.After the saturated sodium bicarbonate aqueous solution dilution, use ethyl acetate extraction.After extraction liquid water and saturated aqueous common salt cleaning, use anhydrous sodium sulfate drying, distill down to remove in decompression then and desolvate, obtain 4-t-butoxycarbonyl amino 4-methylcyclohexanone (compound of last figure (3)) 10.41 and restrain.
(4) compound that above-mentioned (3) obtained 10.41 grams, sodium triacetoxy borohydride 11.01 grams, the mixture that 5.10 milliliters of benzylamines and methylene dichloride are 150 milliliters was in stirring at room 16 hours.After the saturated sodium bicarbonate aqueous solution dilution, use ethyl acetate extraction.After extraction liquid water and saturated aqueous common salt cleaning, use anhydrous sodium sulfate drying, distill down to remove in decompression then and desolvate.In 15 milliliters of the methanol solutions of gained compound, add tosic acid hydrate 3.32 grams, then add 160 milliliters of ether, the leaching precipitate, after ether cleaning and drying, obtain N-benzyl-t-4-t-butoxycarbonyl amino-4-methyl-r-1-hexahydroaniline tosilate (compound of last figure (4)) 7.49 grams.
(5) compound 16.63 grams that above-mentioned (4) obtained, the mixture that 10% palladium/carbon 5.0 grams and methyl alcohol are 400 milliliters stirred 24 hours down in nitrogen atmosphere (1 air pressure).Elimination 10% palladium/carbon and filtrate is concentrated.The resistates that obtains is dissolved in the mixture of 50 milliliters of 10% aqueous sodium hydroxide solutions and 300 milliliters of ether, after ether layer water and saturated aqueous common salt cleaning, remove with anhydrous sodium sulfate drying and underpressure distillation and to desolvate, obtain t-4-t-butoxycarbonyl amino-4-methyl-r-1-hexahydroaniline (compound of last figure (5)) 6.87 and restrain.
(6) chloroform extraction is handled and used to the filtrate of the step of above-mentioned (4) with aqueous sodium hydroxide solution.After extraction liquid water and saturated aqueous common salt cleaned, remove with anhydrous sodium sulfate drying and underpressure distillation and to desolvate.By (solvent: hexane-ethyl acetate (30: 1 → 3: 1) is refining, obtains N-benzyl-c-4-t-butoxycarbonyl amino-4-methyl-r-1-hexahydroaniline with NH-silicon gel filtration chromatography with resistates.Then it is used with above-mentioned (5) same mode and handle, obtain c-4-t-butoxycarbonyl amino-4-methyl-r-1-hexahydroaniline (compound of last figure (6)).
Reference example 6-2
Except the methyl iodide in (1) step of reference example 6-1 is replaced with the benzyloxymethyl muriate, with with reference example 6-1 (1) to (5) or (6) same mode, obtain t-4-t-butoxycarbonyl amino-4-methylol-r-1-hexahydroaniline or c-4-t-butoxycarbonyl amino-4-methylol-r-1-hexahydroaniline.
In addition, except the methyl iodide in (1) step of reference example 6-1 is replaced with the methoxyl methyl chloro, with with reference example 6-1 (1) to (5) or (6) same mode, obtain t-4-t-butoxycarbonyl amino-4-methoxyl methyl-r-1-hexahydroaniline or c-4-t-butoxycarbonyl amino-4-methoxyl methyl-r-1-hexahydroaniline.
Reference example 6-3
(1) use N-tertbutyloxycarbonyl-4-ethoxy carbonyl piperidines [according to (people's such as Gilligan document (J.Med.Chem., the 37th volume, the the 364th to 370 page, 1994) method of record is synthetic) and the methoxymethyl muriate, to handle, obtain N-tertbutyloxycarbonyl-4-carbonyl-4-methoxyl methyl piperidines with (1) same mode of reference example 6-1.
Except using this compound, and replace outside the potassium tert.-butoxide,, obtain N-tertbutyloxycarbonyl-4-benzyloxycarbonyl amino-4-methoxy methyl phenylpiperidines to handle with reference example 6-1 (3) same mode with benzylalcohol.
(2) compound 9.4 grams that above-mentioned (1) obtained, the mixture (1 air pressure) under nitrogen atmosphere that 10% palladium/carbon 1.9 grams and methyl alcohol are 190 milliliters stirred 2 hours.Concentrate by elimination 10% palladium/carbon and with filtrate, can obtain 4-amino-N-tertbutyloxycarbonyl-4-methoxy methyl phenylpiperidines 6.02 grams.
Next, this compound is removed protecting group (tertbutyloxycarbonyl) with acid treatment, and obtain 4-amino-4-methoxyl methyl piperidines.
Reference example 6-4
The mixture of 38 milliliters of N-tertbutyloxycarbonyl-4-benzyloxycarbonyl amino-4-methoxyl methyl piperidines (compound that reference example 6-3 (1) item obtains) 3.78 grams and concentrated hydrochloric acids was refluxed 3.After reaction mixture concentrated, resistates cleaned by tetrahydrofuran (THF), obtains 4-amino-4-hydroxymethyl piperidine 2 hydrochlorides 2.8 grams.
Reference example 7-1 to 7-7
(1) be dissolved in the solution of 200 milliliters of tetrahydrofuran (THF)s at 4-amino-1-tertbutyloxycarbonyl piperidinyl-1 6 grams and N-ethoxycarbonyl phthalimide 17.5 grams, in ice-cooled 16.7 milliliters of the triethylamines that add down, and in stirring at room 4 hours.In reaction mixture, add water and use ethyl acetate extraction.Extraction liquid is cleaned with saturated sodium bicarbonate aqueous solution, water, saturated aqueous common salt, and then with behind the anhydrous sodium sulfate drying, underpressure distillation removes and desolvates.Resistates is suspended in ether-hexane,, and obtains 2-(1-tertbutyloxycarbonyl-4-piperidyl) isoindoline-1,3-diketone 25.7 grams by the leaching crystallization.
With 15% hydrochloric acid-170 milliliters of suspension of ethanol of this compound 25.5 grams in stirring at room 5 hours.Filter precipitate, obtain 2-(4-piperidyl) isoindoline-1,3-dione hydrochloride 16.0 grams.
(2) in the solution that the 15 milliliters-N,N-dimethylacetamide of tetrahydrofuran (THF) that compound 1.57 grams that obtain in above-mentioned (1) and 2-chloropyrimide are 644 milligrams is 3 milliliters, add 3.13 milliliters of triethylamines and stirred 12 hours in 50 ℃.After the cooling, in reaction mixture, add saturated sodium bicarbonate aqueous solution, use ethyl acetate extraction then.Extraction liquid water and saturated aqueous common salt are cleaned and with behind the anhydrous sodium sulfate drying, underpressure distillation removes and desolvates.Resistates is suspended in ether-hexane, and leaching crystallization then obtains 2-[1-(2-pyrimidyl)-4-piperidyl] isoindoline-1,3-diketone 1.50 gram (yields: 87%).
Next in 15 milliliters of suspension of ethanol of 800 milligrams of this compounds, add 0.25 milliliter of hydrazine hydrate, and refluxed 2 hours.Cooling back filtering insolubles, underpressure distillation removes and desolvates.With resistates NH-silicon gel rapid column chromatography (solvent: chloroform-methanol (500: 1)) make with extra care, obtain 417 milligrams of 4-amino-1-(2-pyrimidyl) piperidines (the reference example 7-1 of table 9).
In addition, use corresponding starting compound, with above-mentioned same mode, obtain the compound of the reference example 7-2 to 7-7 of table 9.
Reference example 8-1 to 8-7
With 260 milligrams of 4-amino-4-methyl piperidines (method with the US5821240 record is synthetic), 2 milliliters of suspension of the ethanol that 237 milligrams of 2-chloropyrimide and salt of wormwood are 858 milligrams stir in 50 ℃ and earn 12 hours.Reaction mixture is injected water, use chloroform extraction.With the saturated aqueous common salt cleaning and with behind the anhydrous sodium sulfate drying, underpressure distillation removes and desolvates with extraction liquid.With resistates silicon gel rapid column chromatography (solvent: chloroform-methanol-ammoniacal liquor (300: 10: 1)) make with extra care, obtain 259 milligrams of 4-amino-4-methyl-N-(2-pyrimidyl) piperidines (the reference example 8-1 of table 9).
In addition, use corresponding starting compound, with above-mentioned same mode, obtain the compound of the reference example 8-2 to 8-7 of table 9.
Reference example 8-8 to 8-21
Use 4-amino-4-methoxyl methyl piperidines (reference example 6-3 (2)) and corresponding starting compound,, obtain the compound of the reference example 8-8 to 8-15 of table 9 to handle with the same mode of above-mentioned reference example 8-1.
In addition, use 4-amino-4-hydroxymethyl piperidine 2 hydrochlorides (reference example 6-4) and corresponding starting compound, handle in the same way, obtain the compound of the reference example 8-16 to 8-21 of table 9.
Reference example 8-22 to 8-23
In the suspension of 15 milliliters of the tetrahydrofuran (THF)s of 897 milligrams of t-4-t-butoxycarbonyl amino-4-methylol-r-1-hexahydroaniline (reference example 6-2) 1.00 grams and N-ethoxycarbonyl phthalimides, add 0.86 milliliter of triethylamine, then in 50 ℃ of coffees heat 5 hours.In reaction solution, add entry, use ethyl acetate extraction then.After organic layer cleaned with saturated sodium bicarbonate aqueous solution and saturated aqueous common salt, use anhydrous sodium sulfate drying, remove by underpressure distillation and desolvate, obtain N-tertbutyloxycarbonyl-1-methylol-t-4-phthalimide-r-1-hexahydroaniline 1.47 and restrain.In the solution of 10 milliliters in two alkane of this compound 1.44 grams, add 10 milliliters of 4N hydrochloric acid/two alkane, then in stirring at room 3 hours.Reaction mixture is diluted leaching crystallization then with ether.The crystallization that obtains is cleaned with ether, obtain 1-methylol-t-4-phthalimide-r-1-hexahydroaniline (the reference example 8-22 of table 9) 1.03 grams.
In addition, with the above-mentioned compound that similarly obtains the reference example 8-23 of table 9.
Reference example 8-24
(1) with N-tertbutyloxycarbonyl-anti-form-1,500 milligrams of 4-cyclohexanediamine, the solution that the 15 milliliters-chloroform of toluene that 623 milligrams of 2-brooethyl ethyl benzoates and triethylamine are 354 milligrams is 1.5 milliliters was in 100 ℃ of heating 5 hours.After the cooling, add entry, use ethyl acetate extraction.After organic layer cleaned with saturated aqueous common salt, use anhydrous sodium sulfate drying, underpressure distillation is except that desolvating then.Resistates is refining by silicon gel rapid column chromatography, obtains 400 milligrams of N-tertbutyloxycarbonyl-trans-4-(1-ketone group-2-indolinyl) hexahydroaniline.
(2) in the solution of 10 milliliters in two alkane of 380 milligrams of compounds that obtains in above-mentioned (1), add 10 milliliters in 4N HCl/ two alkane, then in stirring at room 5 hours.After reaction solution concentrated,, obtain 298 milligrams of trans-4-(1-ketone group-2-iso-dihydro-indole-group) cyclohexylamine hydrochlorides (the reference example 8-24 of table 9) with resistates ether wet-milling.
Reference example 8-25 to 8-31
With N-tertbutyloxycarbonyl-anti-form-1, the solution that the chloroform that 500 milligrams of 4-cyclohexanediamine and 3-nitrophthalide acid anhydrides are 540 milligrams is 15 milliliters refluxed 1 hour.After the cooling, add 756 milligrams of carbonyl dimidazoles, then in stirring at room 15 hours.In reaction solution, add entry, use chloroform extraction then.After organic layer cleaned with saturated aqueous common salt, remove with anhydrous sodium sulfate drying and underpressure distillation and to desolvate.Resistates is refining by silicon gel rapid column chromatography, obtain 900 milligrams of N-tertbutyloxycarbonyl-trans-4-(1, the 3-diketo-different diindyl quinoline of 4-nitro-2-base) hexahydroaniline.
In the suspension of 10 milliliters in the two alkane of 885 milligrams of this compounds, add 10 milliliters of 4N HCl two alkane solution, then in stirring at room 5 hours.By reaction solution is concentrated, and, obtain 700 milligrams of trans-4-(1, the 3-diketo-different diindyl quinoline of 4-nitro-2-base) cyclohexylamine hydrochlorides (the reference example 8-25 of table 9) with resistates ether wet-milling.
In addition, use corresponding starting compound, obtain the compound of the reference example 8-26 to 8-31 of table 9 with the same manner.
Reference example 8-32
In methylene dichloride 20 ml solns of 0.303 milliliter of chlorination trimellitic acid 1,2-anhydride 1.5 gram and methyl alcohol, in ice-cooled 1.49 milliliters of the triethylamines that add down, and in stirring at room 3 hours.In reaction solution, add entry, use chloroform extraction then.With the organic layer anhydrous sodium sulfate drying, except that desolvating, obtain 4-methoxycarbonyl anhydride phthalic acid 1.81 grams by underpressure distillation.Replace 3-nitrophthalide acid anhydrides as raw material with this compound, to obtain trans-4-(1,3-diketo-5-methoxycarbonyl-2-iso-dihydro-indole-group) cyclohexylamine hydrochloride (the reference example 8-32 of table 9) with the same mode of above-mentioned reference example 8-25.
Reference example 8-33 to 8-34
In the solution of 10 milliliters of the methylene dichloride of chlorination trimellitic acid 1,2-anhydride 1.0 gram, in ice-cooled 577 milligrams of 354 milligrams of tetramethyleneimine and the triethylamines that add down, and in stirring at room 2 hours.In reaction solution, add entry, use chloroform extraction then.With the organic layer anhydrous sodium sulfate drying, except that desolvating, obtain 4-(1-pyrrolidyl) carbonyl anhydride phthalic acid 1.09 grams by underpressure distillation.Replace 3-nitrophthalide acid anhydrides as raw material with this compound,, obtain trans-4-[1,3-diketo-5-(1-pyrrolidyl) carbonyl-2-iso-dihydro-indole-group to handle with the same mode of above-mentioned reference example 8-25] cyclohexylamine hydrochloride (the reference example 8-33 of table 9).
In addition, in above-mentioned same mode, obtain the compound of the reference example 8-34 of table 9.
Reference example 8-35
(1) is suspended in the suspension of 150 milliliters of methylene dichloride at trans-(4-benzyloxycarbonyl amino) hexanaphthene-1-carboxylic acid 15.00 grams, added 5.92 milliliters of thionyl chloride and reflux 4 hours.With the reaction solution concentrating under reduced pressure, add the operation secondary of methylene dichloride and concentrating under reduced pressure, obtain trans-4-(benzyloxycarbonyl amino) hexahydrobenzoic acid muriate.
(2) compound that above-mentioned (1) is obtained is dissolved in 70 milliliters of methylene dichloride and gets solution, in the ice-cooled aqueous solution that drips 120 milliliters in 60 milliliters-water of strong aqua down.After 30 minutes, the precipitation that leaching is separated out after water, 2-propyl alcohol and isopropyl ether clean, obtains trans-4-(benzyloxycarbonyl amino)-1-hexanaphthene carboxylic acid amides 14.17 grams in stirring at room.
(3) add 5.54 milliliters of thionyl chloride in 140 milliliters of suspension of acetonitrile of compound 7.00 grams that obtain in above-mentioned (2), and reflux 30 minutes.Behind the reaction solution concentrating under reduced pressure, add acetonitrile, in concentrating under reduced pressure gained residual solid, add diisopropyl ether again, obtain trans-4-(benzyloxycarbonyl amino)-1-hexanaphthene formonitrile HCN 6.14 grams by leaching.
(4) compound 1.20 grams that obtain at above-mentioned (3) item are suspended in the suspension of 24 milliliters of ethanol, feed hydrogen chloride gas down in the cooling of ice-salt, till the temporary transient dissolving of starting compound and separating out precipitation once again.In stirring at room 14 hours, concentrating under reduced pressure added saturated sodium bicarbonate aqueous solution in the resistates that obtains then, uses the chloroform extraction secondary then with this reaction solution.With the extraction liquid anhydrous sodium sulfate drying, obtain trans-4-(benzyloxycarbonyl amino) hexanaphthene-1-imidic acid ethyl ester 0.93 gram by concentrating under reduced pressure.
(5) 929 milligrams of compounds that obtains in above-mentioned (4) are dissolved in the solution of 1 milliliter in 6 milliliters-water of ethanol, add 163 milligrams of ammonium chlorides and in stirring at room 9 hours.With the reaction solution concentrating under reduced pressure, add the operation secondary of toluene and concentrating under reduced pressure.In the residual solid that obtains, add 20 milliliters of 0.3 milliliter-ether of ethanol, obtain 859 milligrams of trans-4-(benzyloxycarbonyl amino)-1-hexanaphthene amitraz hydrochloride by leaching.
(6) compound that above-mentioned (5) are obtained (500 milligrams) is as initial substance, method (Schmidi.H according to people such as Schmidt, W.et al., J.Hetrocycl.Chem., 24 volumes, 1305 pages, 1987), with the reaction of oxyethyl group ethylidene propane dinitrile, obtain anti-form-1-(benzyloxycarbonyl amino)-4-(4-amino-5-cyanopyrimidine-2-yl) hexanaphthene (186 milligrams).
(7) 174 milligrams of compounds that obtains in above-mentioned (6) are suspended in the suspension of 7 milliliters of acetonitriles, add iodate three silicomethanes, 282 microlitres down and in stirring at room 1 hour in ice-cooled.In reaction solution, add frozen water, after cleaning with chloroform, in water layer, add salt of wormwood and make saturated, use chloroform extraction then 3 times.With the extraction liquid anhydrous sodium sulfate drying,, obtain 105 milligrams of trans-4-(4-amino-5-cyanopyrimidine-2-yl) hexahydroaniline (the reference example 8-35 of table 9) by concentrating under reduced pressure.
Reference example 8-36
With trans-4-(benzyloxycarbonyl amino)-1-hexanaphthene amitraz hydrochloride (compound of reference example 8-35 (5)) (348 milligrams) as initial substance; method (J.Cliem.Soc. according to people such as Libman; 2305 pages; nineteen fifty-two) with the Acetyl Acetone reaction; obtain anti-form-1-benzyloxycarbonyl amino-4-(4,6-dimethyl pyrimidine-2-yl) hexanaphthene (220 milligrams).This compound (205 milligrams) with the mode iodate trimethyl silane processing same with reference example 8-35 (7), is obtained 129 milligrams of trans-4-(4,6-dimethyl pyrimidine-2-yl) hexahydroaniline (the reference example 8-36 of table 9).
Reference example 8-37 to 8-39
With N-tertbutyloxycarbonyl-anti-form-1,500 milligrams of 4-cyclohexanediamine, 1,326 milligrams of 4-dichlorobutane, 805 milligrams in salt of wormwood, the mixture of 70 milligrams of sodium iodides and alcohol-water (8 milliliters-2 milliliters) stirred 12 in 90 ℃.In reaction solution, add entry, use chloroform extraction then.Extraction liquid is cleaned with saturated aqueous common salt, behind anhydrous sodium sulfate drying, concentrating under reduced pressure.The resistates that obtains is made with extra care by silicon gel rapid column chromatography (solvent: chloroform-methanol-ammoniacal liquor=100/5/0.5 is to 100/10/0.5), obtains 453 milligrams of N-tertbutyloxycarbonyl-trans-4-(1-pyrrolidyl) hexahydroaniline.
By being handled, this compound deprotection under acidic conditions obtains trans-4-(1-pyrrolidyl) hexahydroaniline (the reference example 8-37 of table 9).
In addition, with above-mentioned same mode, obtain the compound of the reference example 8-38 to 8-39 of table 9.
Reference example 8-40
With trans-4-(t-butoxycarbonyl amino) hexahydrobenzoic acid 10 grams, 2-chloro-3-aminopyridine 7.93 grams, 1-(3-dimethylamine propyl)-3-ethyl-carbodiimide hydrochloride 10.2 grams, 4-dimethylamino pyridine 65 gram and N, the mixture that dinethylformamide is 180 milliliters was in stirring at room 15 minutes.After in this reaction solution, adding sodium bicarbonate aqueous solution furnishing alkalescence, use ethyl acetate extraction.Extraction liquid water and saturated aqueous common salt are cleaned, and behind anhydrous sodium sulfate drying, underpressure distillation removes and desolvates, and obtains trans-4-t-butoxycarbonyl amino-N-(2-chloro-3-pyridyl) hexanaphthene carboxylic acid amides.
Reference example 8-41
With 500 milligrams of trans-4-t-butoxycarbonyl amino-N-(2-chloro-3-pyridyl) hexanaphthene carboxylic acid amides (reference example 8-40)), 2, two (the 4-methoxyphenyls)-1 of 4-, 3-two sulphur-2,4-diphosphine (diphosphetane)-2, the mixture that 858 milligrams of 4-disulphide and tetrahydrofuran (THF) are 10 milliliters stirred 18 hours in 60 ℃.Behind the filtering insolubles, filtrate decompression is concentrated.The resistates that obtains is by silicon gel rapid column chromatography (solvent: chloroform-methanol 50: 1) refining.
The coarse crystallization that obtains is suspended in 5 milliliters of the ethanol, added 10 milliliters of 4N-ethanol solution hydrochlorides and reflux 1.5 hours.After the ethanol underpressure distillation removed, resistates is soluble in water, and clean with ether.After in water layer, adding salt of wormwood and furnishing alkalescence, use chloroform extraction.Extraction liquid water and saturated aqueous common salt are cleaned, behind anhydrous sodium sulfate drying, except that desolvating, obtain 195 milligrams of trans-4-(thiazole is [5,4-b] pyridine-2-yl also) hexahydroaniline (the reference example 8-41 of table 9) by underpressure distillation.
Reference example 8-42
Trans-4-(benzyloxycarbonyl amino) hexahydrobenzoic acid and 2-amino phenol to handle with the same mode of above-mentioned reference example 8-40, are obtained trans-4-benzyloxycarbonyl amino-N-(2-hydroxyphenyl) hexanaphthene carboxylic acid amides.
With 300 milligrams of this compounds, right-286 milligrams of toluenesulphonic acids pyridine , 6 milliliters of methyl alcohol and 1, the mixture heating up that the 2-methylene dichloride is 6 milliliters refluxed 48 hours.In this reaction solution, add entry and ethyl acetate and separate organic layer.Extraction liquid is cleaned with saturated aqueous common salt, and behind anhydrous sodium sulfate drying, underpressure distillation removes and desolvates.Resistates is by silicon gel rapid column chromatography (solvent: chloroform) refining.
With 150 milligrams of this compounds, the mixture that 10% palladium/30 milligrams in carbon and methyl alcohol are 7.5 milliliters stirred 2 hours in hydrogen atmosphere (1 air pressure) and under the room temperature.The elimination catalyzer obtains 63 milligrams of trans-4-(benzo [d] [1,3] azoles-2-yl) hexahydroaniline (the reference example 8-42 of table 9) by concentrated filtrate.
Reference example 8-43
(1) sodium borohydride 0.74 gram is suspended in 35 milliliters of the tetrahydrofuran (THF)s, in the ice-cold boron trifluoride diethyl coordination compound that adds therein down.Down its stirring after 30 minutes, is restrained the solution that is dissolved in 90 milliliters of tetrahydrofuran (THF)s in ice-cold trans-4-(benzyloxycarbonyl amino) hexahydrobenzoic acid 3.60 that adds down in ice-cold., after 2 hours reaction solution is added in the frozen water in stirring at room, and use chloroform extraction.Extraction liquid water and saturated aqueous common salt are cleaned, and with behind the anhydrous sodium sulfate drying, underpressure distillation removes and desolvates.Resistates is suspended in the diisopropyl ether, obtains N-carbobenzoxy-(Cbz)-trans-4-(methylol) hexahydroaniline by leaching.
(2) in methylene dichloride 35 ml solns that compound 1.95 restrains and dimethyl sulfoxide (DMSO) 1.45 restrains that above-mentioned (1) obtains, add 0.81 milliliter of oxalyl chloride in-78 ℃.In-45 ℃ stir 2 hours after, be cooled to-78 ℃, add methylene dichloride 5 ml solns of triethylamine 5.62 grams then, stirred 2 hours after being warming up to room temperature.With the reaction solution water, aqueous hydrochloric acid and saturated aqueous common salt clean, and with behind the anhydrous sodium sulfate drying, underpressure distillation removes and desolvates.Resistates is by analysing (solvent: hexane-ethyl acetate=4: 1) refining trans-4-(benzyloxycarbonyl amino) hexanaphthene formaldehyde that obtains with silicon gel layer.
(3) in methylene dichloride 4 ml solns of thionyl chloride 512 microlitres, the solution in 4 milliliters of the ice-cold methylene dichloride that splashes into down pyridine 568 microlitres adds compound 1.53 grams that above-mentioned (2) obtain then.Reaction mixture in stirring at room after 1 hour, is added 715 milligrams of 2-amino-benzylamines, add the solution of 15 milliliters in the water of 961 milligrams of sodium acetates then.In stirring at room after 1 hour, methylene dichloride is removed in underpressure distillation with reaction mixture.In residual mixture, add 10% aqueous sodium hydroxide solution with furnishing alkalescence.After 30 minutes, use chloroform extraction in stirring at room.Extraction liquid water and saturated aqueous common salt are cleaned, and with behind the anhydrous sodium sulfate drying, underpressure distillation removes and desolvates.With the resistates and 2 that obtains, 3-two chloro-5,6-dicyano-1, the mixture that 4-benzoquinones 2.66 gram and toluene are 75 milliliters was in stirring at room 14 hours.Reaction mixture is diluted with chloroform, use the 10%-aqueous sodium hydroxide solution, water and saturated aqueous common salt clean successively, and with behind the anhydrous sodium sulfate drying, underpressure distillation removes and desolvates.Resistates is by silicon gel rapid column chromatography (solvent: chloroform) refining.Once again the resistates that obtains is suspended in the mixed solvent of isopropyl ether-hexane, and the precipitation separated out of leaching.
362 milligrams of this compounds are dissolved in 7 milliliters of the acetonitriles, under ice-cold, splash into trimethyl silane iodide 427 microlitres, and in stirring at room 15 minutes.After in reaction mixture, adding methyl alcohol and water, clean with chloroform.After in water layer, adding salt of wormwood furnishing alkalescence, use chloroform extraction.Extraction liquid water and saturated aqueous common salt are cleaned and with behind the anhydrous sodium sulfate drying, underpressure distillation removes and desolvates, and obtains 220 milligrams of trans-4-(quinazoline-2-yl) hexahydroaniline (the reference example 8-43 of table 9).
Reference example 8-44
Trans-4-(benzyloxycarbonyl amino) hexahydrobenzoic acid and 3-(aminomethyl carbonyl) pyridine to handle with the same mode of above-mentioned reference example 8-40, are obtained trans-4-benzyloxycarbonyl amino-N-(3-pyridine carbonyl methyl) hexanaphthene carboxylic acid amides.
With 600 milligrams of this compounds, Phosphorus Oxychloride 283 microlitres and N, the mixture that dinethylformamide is 9 milliliters was in stirring at room 1 hour.Reaction mixture is injected water, after sodium bicarbonate aqueous solution furnishing alkalescence, use ethyl acetate extraction.Extraction liquid water and saturated aqueous common salt are cleaned, and with behind the anhydrous sodium sulfate drying, underpressure distillation removes and desolvates.Resistates is suspended in the ether, then the precipitation separated out of leaching.
With 350 milligrams of this compounds, the mixture that 10% palladium/70 milligrams in carbon and methyl alcohol are 17.5 milliliters stirred 20 hours in hydrogen atmosphere (1 air pressure) and under the room temperature.The elimination catalyzer concentrates filtrate, obtains trans-4-[5-(3-pyridyl)-1,3- azoles-2-yl] 211 milligrams of hexahydroaniline (the reference example 8-44 of table 9).
Reference example 8-45 to 8-56
With 4-t-butoxycarbonyl amino-4-methylcyclohexanone (compound of reference example 6-1 (3)) and corresponding starting compound (amine compound); exist down in sodium triacetoxy borohydride; after the reaction that stirring at room made in 16 hours; carry out acid treatment to remove protecting group (tertbutyloxycarbonyl), can obtain the compound of the reference example 8-45 to 8-56 of table 9.
Reference example 8-57 to 8-59
300 milligrams of t-4-t-butoxycarbonyl amino-4-methyl-r-1-hexahydroaniline (compound that above-mentioned reference example 6-1 (5) item obtains) are dissolved in the mixed solvent of 2 milliliters of tetrahydrofuran (THF)s and 0.5 milliliter of Formalin solution, add 418 milligrams of sodium triacetoxy borohydrides then therein and in stirring at room after 16 hours, add 10% aqueous sodium hydroxide solution, then with chloroform extraction and use anhydrous sodium sulfate drying.After underpressure distillation removed and desolvates, (solvent: made with extra care by chloroform-methanol-ammoniacal liquor (50: 1: 0.1 → 10: 1: 0.1) by the silicon gel filtration chromatography for resistates.
This compound stirred 8 hours in 2 milliliters of 2 milliliters in 4N hydrochloric acid-two alkane and ethanol after, reaction solution is concentrated, add 10% aqueous sodium hydroxide solution, with chloroform extraction and with behind the anhydrous sodium sulfate drying, underpressure distillation removes and desolvates, and obtains 55 milligrams of t-4-dimethylin-1-methyl-r-1-hexahydroaniline (the reference example 8-57 of table 9).
In addition, obtain the compound of the reference example 8-58 to 8-59 of table 9 with the same manner.
Reference example 9-1 to 9-3
In the solution of 10 milliliters of the methylene dichloride of three surpalites 1.04 gram,, and it was stirred 15 minutes in the solution of 10 milliliters of the ice-cooled methylene dichloride that adds 1.4 milliliters of N-ethoxycarbonyl piperazine 1.59 grams and triethylamines down.
Therein in the solution of 10 milliliters of the ice-cold methylene dichloride that adds down 0.77 milliliter of 4-t-butoxycarbonyl amino piperidinyl-1 .00 gram and triethylamine, then whole night in stirring at room.Reaction solution is added in the frozen water, use chloroform extraction then.Extraction liquid is cleaned with saturated aqueous common salt, and with after the dried over mgso, underpressure distillation removes and desolvates.Resistates is by silicon gel rapid column chromatography (solvent: ethyl acetate: hexane=4: 1) make with extra care, obtain 4-t-butoxycarbonyl amino-1-(4-ethoxycarbonyl-1-piperazinyl) carbonyl piperidines 0.94 gram.
This compound 0.60 gram is dissolved in 6 milliliters of the methylene dichloride, adds 2 milliliters of trifluoroacetic acids and in stirring at room 3 hours.The solvent underpressure distillation is removed, and resistates is by NH silicon gel rapid column chromatography (solvent: chloroform-methanol=100: 1) make with extra care, obtain 4-amino-1-(4-ethoxycarbonyl-1-piperazinyl) carbonyl piperidines (the reference example 9-1 of table 10) 0.42 gram.
In addition, use 4-t-butoxycarbonyl amino piperidines and corresponding starting compound,, obtain the compound of the reference example 9-2 to 9-3 of table 10 to handle with above-mentioned same mode.
Reference example 9-4 to 9-5
(1) in the suspension of 27 milliliters of potassium hydroxide aqueous solution (4 gram KOH/10 ml water) and ether, under ice-cold, splashes into the N-nitrosomethylurea.After dripping end, divide the ether layer that extracts reaction solution, add potassium hydroxide, placed refrigerator then 3 hours.In the diethyl ether solution of this diazomethane, add trans-4-(benzyloxycarbonyl amino) hexahydrobenzoic acid muriate (compound that reference example 8-35 (1) obtains) 2.00 gram slowly, then in stirring at room 2 hours.The crystallization that leaching is separated out is cleaned by ether, obtains N-carbobenzoxy-(Cbz)-trans-4-(diazonium ethanoyl) hexahydroaniline 1.63 grams.
(2) 800 milligrams of compounds that obtains in above-mentioned (1) are suspended in the suspension of 8 milliliters in two alkane, add the aqueous solution (100 milligrams/1 milliliter) of morpholine and Silver Nitrate, in stirring at room 1 hour, stir 30 minutes in 60 ℃ then.After making reaction solution return room temperature, add entry, and use ethyl acetate extraction.Extraction liquid water and saturated aqueous common salt are cleaned successively, behind anhydrous sodium sulfate drying, concentrating under reduced pressure.The resistates that obtains is suspended in the ether, and the precipitation separated out of leaching obtains 741 milligrams of N-carbobenzoxy-(Cbz)-trans-4-(morpholine carbonyl methyl) hexahydroaniline then.
This compound (350 milligrams) and 10% palladium/70 milligrams of suspension that are suspended in 4 milliliters of methyl alcohol of carbon under nitrogen atmosphere, were stirred 3 hours in room temperature and normal pressure.The elimination catalyzer concentrates filtrate, obtains trans-4-(morpholine carbonyl methyl) hexahydroaniline (the reference example 9-4 of table 10).
In the solution that the methylene dichloride of compound 1.00 grams that (3) obtain in above-mentioned (1) is 10 milliliters, in ice-cold 10 milliliters of the 1N hydrochloric acid diethyl ether solutions that add down, then in stirring at room 4 hours.In reaction solution, add saturated sodium bicarbonate aqueous solution, use chloroform extraction then.Extraction liquid is cleaned with saturated aqueous common salt, and behind anhydrous sodium sulfate drying, concentrating under reduced pressure obtains N-carbobenzoxy-(Cbz)-trans-4-(chloracetyl) hexahydroaniline.
With the mixing solutions of 6 milliliters of this compound (400 milligrams) morpholine 1.12 gram and methylene dichloride one night of stirring at room.In reaction solution, add entry and use chloroform extraction.Extraction liquid is water and saturated aqueous common salt cleaning in regular turn, behind anhydrous sodium sulfate drying, and concentrating under reduced pressure.The resistates that obtains is suspended in the ether, and the precipitation that leaching is separated out obtains 417 milligrams of N-carbobenzoxy-(Cbz)-trans-4-(morpholine methyl carbonyl) hexahydroaniline.
This compound and 10% palladium/72 milligrams of suspension that are suspended in 4 milliliters of methyl alcohol of carbon under nitrogen atmosphere, were stirred 1 hour in room temperature and normal pressure.The elimination catalyzer concentrates filtrate, obtains-trans-4-(morpholine methyl carbonyl) hexahydroaniline (the reference example 9-5 of table 10).
Reference example 9-5 to 9-7
According to document (Johnston et al., J.Med.Chem, 1971,14 volumes, the the 600th to 614 page) record method, synthesis of trans-4-aminocyclohexane carboxylic acid, ethyl ester hydrochloride (reference example 9-6) and cis-4-aminocyclohexane carboxylic acid, ethyl ester hydrochloride (reference example 9-7).
Reference example 9-8 to 9-12
In the solution of 6 milliliters of the tetrahydrofuran (THF)s of 873 milligrams of trans-4-(t-butoxycarbonyl amino) hexalin 1.0 gram and benzyl bromides, add 204 milligrams of 60% sodium hydrides slowly, and and then add 0.5 milliliter of dimethyl sulfoxide (DMSO) after, stirred 2 hours in 70 ℃.Reaction mixture is injected water, and use chloroform extraction.Extraction liquid water and saturated aqueous common salt are cleaned, and behind anhydrous sodium sulfate drying, underpressure distillation removes and desolvates.With resistates with the silicon gel filtration chromatography (solvent: hexane-ethyl acetate (4: 1)) refining, be suspended in the powder crystallization that obtains in ethyl acetate-hexane mixing solutions and leaching and obtain anti-form-1-t-butoxycarbonyl amino-4-(benzyloxy) hexanaphthene.
In the alcohol suspension of this compound, add 2N hydrochloric acid-two alkane solution, obtain trans-4-(benzyloxy) cyclohexylamine hydrochloride (reference example 9-8) in stirring at room 18 hours and deprotection.
In addition, use corresponding starting compound, with above-mentioned same mode, obtain the compound of the reference example 9-9 to 9-12 of table 10.
Reference example 9-13
204 milligrams of N-tertbutyloxycarbonyl-trans-4-(2-propylene-1-base oxygen base) hexahydroaniline (compound of reference example 9-11) are dissolved in 1.0 milliliters of the methyl alcohol.Add 44 milligrams of 10% palladiums/carbon, under non-pressurized nitrogen atmosphere, in stirring at room 2 days.Behind the elimination catalyzer, distillation removes and desolvates, and adds 10% aqueous sodium hydroxide solution in resistates, use chloroform extraction, and with behind the anhydrous sodium sulfate drying, underpressure distillation removes and desolvates, and obtains 102 milligrams of trans-4-(propoxy-) hexahydroaniline (the reference example 9-13 of table 10).
Reference example 9-14 to 9-29
(1) sodium borohydride 9.33 gram is suspended in 200 milliliters of the tetrahydrofuran (THF)s, in the ice-cold boron trifluoride diethyl coordination compound that adds therein down.In ice-cold down it is stirred 30 minutes after, in the solution of 150 milliliters of the ice-cold tetrahydrofuran (THF)s that adds trans-4-(t-butoxycarbonyl amino) hexahydrobenzoic acid 40 grams down., after 4 hours reaction solution is added in the frozen water in stirring at room, and use chloroform extraction.Extraction liquid water and saturated aqueous common salt are cleaned, and with behind the anhydrous sodium sulfate drying, underpressure distillation removes and desolvates.Resistates is recrystallization from ethyl acetate-hexane, obtains N-tertbutyloxycarbonyl-trans-(methylol) hexahydroaniline 20 grams.
(2) compound and the corresponding starting compound that uses above-mentioned (1) to obtain in the mode same with reference example 9-8, obtains the compound of the reference example 9-14 to 9-29 of table 10.
Reference example 9-30 to 9-33
(1) in the methylene dichloride suspension of trans-4-(t-butoxycarbonyl amino) hexalin 5.00 grams, restrains and stirred 10 minutes in 0 ℃ of 4.86 milliliters of triethylamine of interpolation and methylsulfonyl chloride 3.09.In reaction solution, add water and use ethyl acetate extraction.With the extraction liquid water, saturated sodium bicarbonate aqueous solution and saturated aqueous common salt clean, and with behind the anhydrous sodium sulfate drying, underpressure distillation removes and desolvates.Resistates is suspended in ethyl acetate-isopropyl ether mixed solvent, obtains trans-4-t-butoxycarbonyl amino cyclohexyl methanesulfonates 6.19 grams by leaching.
(2) in the solution of 10 milliliters of the dimethyl formamides of 2-thiol group pyridine-5-carbonitriles, in ice-cooled 60% sodium hydride, 0.818 gram that adds down, and in stirring at room 1 hour.Add compound 2.00 grams that above-mentioned (1) obtains therein, put cold making and get back to room temperature in 80 ℃ of stirrings 8 hours in the back whole night in stirring at room.Add entry and ethyl acetate in reaction solution, separate organic layer, with the extraction liquid aqueous sodium hydroxide solution, water and saturated aqueous common salt clean successively and with behind the anhydrous sodium sulfate drying, underpressure distillation removes and desolvates.With resistates silicon gel rapid column chromatography (solvent: ethyl acetate-hexane (1: 6)) make with extra care, obtain cis-1-t-butoxycarbonyl amino-4-(5-cyano group-2-pyridine sulfenyl) hexanaphthene 0.977 gram.
This compound 0.977 gram is dissolved in chloroform, adds 4 milliliters of 4N-hydrochloric acid two alkane solution, and in stirring at room 4 hours.After the adding small amount of methanol makes the object crystallization in reaction solution, solvent is concentrated into dried.Resistates is suspended in methyl alcohol: in the mixed solvent of diisopropyl ether,, obtain cis-4-(5-cyano group-2-pyridine sulfenyl) hexahydroaniline (the reference example 9-30 of table 10) 0.787 gram by leaching.
In addition, use corresponding starting compound, to obtain the compound of the reference example 9-31 to 9-33 of table 10 with above-mentioned same mode.
Reference example 10-1
(1) 5-nitro isoindoline 42.8 gram being added to wet chemical (salt of wormwood 108 grams, 200 milliliters in water) suspension in, in the solution of 200 milliliters of 0 ℃ of ethyl acetate that dripped 31.2 milliliters of chloracetyl chlorination things through 1 hour.Behind 0 ℃ of restir 45 clock, the leaching precipitate.The solid that obtains carried out activated carbon treatment in ethyl acetate after,, obtain 2-chloracetyl-5-nitro isoindoline by recrystallization.
(2) will contain the compound that obtains in above-mentioned (1) 1.21 grams, N-tertbutyloxycarbonyl-anti-form-1, the N of 4-cyclohexanediamine 1.07 grams and salt of wormwood 1.39 grams, 10 milliliters of dinethylformamides were in stirring at room 20 hours.Reaction solution is injected the solid that water and leaching are separated out, after washing and the drying, with silicon gel filtration chromatography (solvent: chloroform-methanol=98: 2 to 95: 5) make with extra care, obtain N-tertbutyloxycarbonyl-trans-4-[(5-nitro-2-iso-dihydro-indole-group) carbonyl methylamino] hexahydroaniline.284 milligrams of this compounds are dissolved in 3 milliliters of trifluoroacetic acids and in stirring at room 2 hours.With the reaction solution concentrating under reduced pressure, resistates with 10% sodium hydroxide furnishing alkalescence after, use chloroform extraction.Extraction liquid with anhydrous sodium sulfate drying and concentrating under reduced pressure, is obtained trans-4-[(5-nitro-2-iso-dihydro-indole-group) the carbonyl methylamino] hexahydroaniline (reference example of table 11 (10-1).
Reference example 10-2 to 10-13
With N-tertbutyloxycarbonyl-anti-form-1,4-cyclohexanediamine 1 gram, 632 milligrams of 3-pyridine carboxylic acids, the N that 1-ethyl-3-(3-dimethylamine propyl) carbodiimide 1.07 gram and I-hydroxybenzotriazole are 757 milligrams, the solution that dinethylformamide is 10 milliliters was in stirring at room 24 hours.In reaction mixture, add saturated sodium bicarbonate aqueous solution and use ethyl acetate extraction.With the saturated aqueous common salt cleaning and with behind the anhydrous sodium sulfate drying, underpressure distillation removes and desolvates with extraction liquid.Resistates is cleaned with ether, obtain N-tertbutyloxycarbonyl-trans-4-(3-pyridine carbonylamino) hexahydroaniline.The mixture of 13 milliliters of this compound 1.27 grams and 15% hydrochloric acid-ethanolic soln was stirred 2 hours in 50 ℃.After the cooling, leach precipitate, clean, obtain trans-4-(3-pyridine carbonylamino) hexahydroaniline 2 hydrochlorides (the reference example 10-2 of table 11) 1.12 grams with ether.
In addition, use corresponding starting compound, obtain the compound of the reference example 10-3 to 10-4 of table 11 in the same way.
In addition, use t-or c-4-t-butoxycarbonyl amino-4-methyl-r-1-hexahydroaniline (compounds of reference example 6-1 (5) or (6)) and corresponding starting compound, in the same way, obtain the compound (hydrochloride of generation can be handled with wet chemical, and makes episome) of the reference example 10-5 to 10-10 of table 11.
In addition, use t-or c-4-t-butoxycarbonyl amino-4-methylol-r-1-hexahydroaniline (reference example 6-2) and corresponding starting compound, in the same way, obtain the compound (hydrochloride of generation can be handled with wet chemical, and makes episome) of the reference example 10-11 to 10-13 of table 11.
Reference example 10-14 to 10-17
(1) in the solution of 160 milliliters of the methylene dichloride of 10.55 milliliters of 4-(t-butoxycarbonyl amino) pimelinketone 16.93 gram and N-methylbenzylamines, adds sodium triacetoxy borohydride 19.08 grams down and in stirring at room 14 hours in ice-cooled.Reaction solution is diluted with sodium bicarbonate aqueous solution, and use ethyl acetate extraction.Extraction liquid water and saturated aqueous common salt are cleaned and with behind the anhydrous sodium sulfate drying, underpressure distillation removes and desolvates.Be suspended in the hexane resistates that obtains and leaching.This mother liquor is concentrated.Resistates NH-silica gel column chromatography (solvent: hexane-ethyl acetate (97: 3 to 83: 17)) make with extra care, then by resistates being suspended in the hexane and leaching, and merge with previous filter taker, obtain N '-benzyl-N-tertbutyloxycarbonyl-N '-methyl-anti-form-1,4-cyclohexanediamine 13.55 grams.
These compound 13.53 grams and palladium hydroxide-carbonyl 2.00 are restrained the suspension that is suspended in methyl alcohol, under normal pressure and room temperature, carried out catalytic hydrogenation 5 hours.Elimination catalyzer and filtrate decompression is concentrated obtains N-tertbutyloxycarbonyl-N '-methyl-anti-form-1,4-cyclohexanediamine 9.93 grams.
(2) compound that above-mentioned (1) is obtained is 500 milligrams, 326 milligrams of 2-pyrazine carboxylic acids, 355 milligrams of I-hydroxybenzotriazoles, O-benzotriazole-1-base-N, N, N ', 997 milligrams of N '-tetramethyl-urea hexafluorophosphate, N-methylmorpholine 578 microlitres and N, the mixture that dinethylformamide is 11 milliliters was in stirring at room 14 hours.In reaction solution, add entry, add saturated sodium bicarbonate aqueous solution then, use ethyl acetate extraction then.With the extraction liquid saturated sodium bicarbonate aqueous solution, water and saturated aqueous common salt clean, and remove with underpressure distillation behind the anhydrous sodium sulfate drying and desolvate.
The resistates that obtains is suspended in diisopropyl ether, gets N-tertbutyloxycarbonyl-N '-methyl-N '-(2-pyrazine carbonyl)-anti-form-1,4-cyclohexanediamine by leaching.
Next, 420 milligrams of this compounds are dissolved in 6 milliliters in the two alkane, add 5 milliliters in 4N hydrochloric acid-two alkane and in stirring at room 15 hours.Reaction solution is diluted with ether, and the precipitation that leaching is separated out obtains powder by the ether cleaning.The aqueous solution that the gained powder is water-soluble is saturated and use chloroform extraction with salt of wormwood.With extraction liquid with anhydrous sodium sulfate drying after, underpressure distillation removes desolvates, and obtains N-methyl-N-(2-pyrazine carbonyl)-anti-form-1,4-cyclohexanediamine (the reference example 10-14 of table 11).
In addition, use compound and the corresponding starting compound (carboxylic acid cpd) in (1), obtain, to obtain the compound of the reference example 10-15 to 10-17 of table 11 with above-mentioned same mode.
Reference example 10-18 to 10-20
At N-tertbutyloxycarbonyl-N '-methyl-anti-form-1, in the dichloromethane solution of 500 milligrams of 4-cyclohexanediamine (reference example 10-14 (1)) and triethylamine 763 microlitres, add methanesulfonyl chloride 254 microlitres, and in stirring at room 14 hours.In reaction solution, add entry and saturated sodium bicarbonate aqueous solution, use ethyl acetate extraction then.With the extraction liquid saturated sodium bicarbonate aqueous solution, water and saturated aqueous common salt clean, and with behind the anhydrous sodium sulfate drying, underpressure distillation removes and desolvates.The resistates that obtains is suspended in diisopropyl ether, gets N-tertbutyloxycarbonyl-N '-methyl-N '-methylsulfonyl-anti-form-1, the 4-cyclohexanediamine by leaching.Then,, obtain N-methyl-N-methylsulfonyl-anti-form-1,4-cyclohexanediamine (the reference example 10-18 of table 11) with the salt acid treatment of this compound.
In addition, use corresponding starting compound (muriate), with above-mentioned same mode, obtain the compound of the reference example 10-19 to 10-20 of table 11.
To table 11, is (in the table, " Me " represent methyl, in addition MSAPCI (m/z) expression mass analysis value (atmospheric pressure chemical ionization massspectrum) in the table) such as chemical structural formula transitivity values of showing the compound of the foregoing description and reference example at following table 1.
Table 1
Table 1 (continuing)
Table 1 (continuing)
Table 1 (continuing)
Table 1 (continuing)
Table 1 (continuing)
Table 1 (continuing)
Table 1 (continuing)
Table 1 (continuing)
Table 1 (continuing)
Table 1 (continuing)
Table 1 (continuing)
Table 2
Table 3
Table 4
Table 4 (continuing)
Table 5
Table 5 (continuing)
Table 5 (continuing)
Table 5 (continuing)
Table 6
Table 7
Table 8
Table 9
Table 9 (continuing)
Table 9 (continuing)
Table 9 (continuing)
Table 9 (continuing)
Table 9 (continuing)
Table 10
Table 10 (continuing)
Table 10 (continuing)
Table 11
Table 11 (continuing)
Claims (34)
1. the salt of permitting on the aliphatic nitrogenous 5-membered ring compounds shown in the general formula [I] or its pharmacology:
In the formula:
A represents-CH
2-or-S-;
B represents CH or N;
R
1Expression H, low-carbon alkyl, hydroxyl low-carbon alkyl or low-carbon alkoxy low-carbon alkyl;
X represent singly-bound ,-CO-,-Alk-CO-,-COCH
2-,-Alk-O-,-O-CH
2-,-SO
2-,-S-,-COO-,-CON (R
3)-,-Alk-CON (R
3)-,-CON (R
3) CH
2-,-Alk-CON (R
3) CH
2-,-COCH
2N (R
3)-,-SO
2N (R
3)-or-NHCH
2-, in each definition of above-mentioned X, the key table of right-hand member shows and B bonded key,
R
3Expression hydrogen atom or low-carbon alkyl, and
Alk represents the low-carbon (LC) alkylidene group;
R
2Expression is selected from (1), the group in (2) and (3):
(1) replacement or unsubstituted cyclic group, this cyclic group partly is
(i) monocycle or dicyclo alkyl, or
(ii) monocycle or bicyclic heterocyclic radical;
(2) amino that replaces by 1 to 2 the identical or different substituting group that is selected from replacement or unsubstituted low-carbon alkyl; And
(3) low-carbon alkyl, carboxyl low-carbon alkyl, low-carbon alkoxy, low-carbon (LC) thiazolinyl, the low-carbon alkyl that replaces by low-carbon alkoxy, phenoxy group, the low-carbon alkyl or the phenyl low-carbon (LC) thiazolinyl that replace by phenoxy group;
But when X is singly-bound, R
2The base of above-mentioned for being selected from (1) and (2), in addition, X is-CO-in, B is N.
2. the salt of permitting on the aliphatic nitrogenous 5-membered ring compounds shown in the general formula [I-e] or its pharmacology:
In the formula:
A represents-CH
2-or-S-;
B represents CH or N;
R
1Expression H, low-carbon alkyl, hydroxyl low-carbon alkyl or low-carbon alkoxy low-carbon alkyl;
X
4The expression singly-bound ,-Alk-CO-,-COCH
2-,-Alk-O-,-O-CH
2-,-SO
2-,-S-,-COO-,-CON (R
3)-,-Alk-CON (R
3)-,-CON (R
3) CH
2-,-Alk-CON (R
3) CH
2-,-COCH
2N (R
3)-,-SO
2N (R
3)-or-NHCH
2-, at above-mentioned X
4Each definition in, the key table of right-hand member shows and B bonded key,
R
3Expression hydrogen atom or low-carbon alkyl, and
Alk represents the low-carbon (LC) alkylidene group;
R
23Expression is selected from the group of (1) and (2):
(1) replacement or unsubstituted cyclic group, this cyclic group partly is
(i) monocycle or dicyclo alkyl, or
(ii) monocycle or bicyclic heterocyclic radical;
(2) amino that replaces by 1 to 2 the identical or different substituting group that is selected from replacement or unsubstituted low-carbon alkyl.
3. compound according to claim 1, wherein, R
2Following for being selected from (1), the group of (2) and (3):
(1) have or do not have and be selected from following A and organize substituent 1 to 3 identical or different substituent cyclic group, this cyclic group partly is:
(i) monocycle or dicyclo alkyl, or
(ii) monocycle or bicyclic heterocyclic radical;
(2) amino that replaces of the substituting group that " replaces or unsubstituted low-carbon alkyl " by 1 to 2 identical or different being selected from by the substituting group that is selected from cyano group, low-carbon alkoxy, phenyl and 6 yuan of aromatic heterocycles of nitrogenous monocyclic;
(3) low-carbon alkyl, carboxyl low-carbon alkyl, low-carbon alkoxy, low-carbon (LC) thiazolinyl, the low-carbon alkyl that is replaced by low-carbon alkoxy, phenoxy group, the low-carbon alkyl or the phenyl low-carbon (LC) thiazolinyl that replace by phenoxy group;
A organizes substituting group:
Halogen atom, cyano group, nitro, amino, ketone group, low-carbon alkyl, low-carbon alkoxy, lower alkanes acyl group, low-carbon (LC) carbalkoxy, low-carbon (LC) alkoxycarbonyl amido, low carbon naphthene acyl group, halo low-carbon alkyl, halo low-carbon alkyl carbonyl, the 6 yuan of aromatic heterocycles of carbonyl, nitrogenous monocycle that replaced by 5 to 6 yuan of aliphatics heterocyclic radicals of nitrogenous monocyclic, monocyclic aryl, the aryl lower alkanes carbonyl amino, lower alkanes sulfenyl and the amino-sulfonyl that replace by monocyclic aryl.
4. compound according to claim 1, wherein, R
2Be replacement or unsubstituted cyclic group, and this cyclic group partly following for being selected from (i), (ii) reach group (iii):
(i) the monocycle alkyl of carbon number 3 to 7,
(ii) contain 1 to 2 heteroatomic monocyclic heterocycles base from nitrogen-atoms, Sauerstoffatom and sulphur atom, selecting, and
(iii) contain 1 to 3 heteroatoms from nitrogen-atoms, Sauerstoffatom and sulphur atom, selecting, and condense the bicyclic heterocyclic radical that forms by 25 to 7 yuan of rings.
5. compound according to claim 4, wherein, R
2For having or do not have 1 to 3 identical or different substituent cyclic group, this cyclic group is partly for being selected from following group:
Phenyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, pyrrolidyl, imidazolidyl, pyrazolidyl, the tetrahydrofuran base, the thiacyclopentane base, pyrrolinyl, imidazolinyl, pyrazolinyl, pyrryl, imidazolyl, pyrazolyl, triazolyl, tetrazyl, furyl, azoles base, different azoles base, the di azoly, thienyl, thiazolyl, isothiazolyl, thiadiazolyl group, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyranyl, tetrahydro pyridyl, the dihydrogen dazin base, perhydro azepine , perhydro sulphur azepine , indolinyl, iso-dihydro-indole-group, indyl, indazolyl, pseudoindoyl, benzimidazolyl-, benzothiazolyl, the benzoxazol base, benzo two azoles bases, benzothienyl, benzofuryl, the thienopyridine base, thiazole and pyridyl, pyrrolopyridinyl, pyrrolin and pyridyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolyl, phthalazinyl, the cinnolines base, chromanyl, different chromanyl and naphthyridinyl, and they part or all is saturated cyclic group.
6. compound according to claim 5, wherein R2 is for having or do not have substituent cyclic group, and this cyclic group is partly for being selected from following group:
Phenyl, cyclohexyl, cyclopropyl, pyrrolidyl, imidazolidyl, pyrazolidyl, pyrryl, imidazolyl, pyrazolyl, furyl, azoles base, different azoles base, thienyl, thiazolyl, isothiazolyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, iso-dihydro-indole-group, indolinyl, thiazole and pyridyl, pyrrolopyridinyl, pyrrolin and pyridyl, the benzoxazol base, quinolyl, isoquinolyl, quinazolyl, pseudoindoyl and indyl, and they part or all is saturated cyclic group.
7. compound according to claim 6, wherein R
2For having or do not have substituent cyclic group, this cyclic group is partly for being selected from the group of piperidyl, piperazinyl, morpholinyl, indolinyl, iso-dihydro-indole-group and thiazole and pyridyl.
8. according to each described compound in the claim 3 to 7, wherein, R
2For having or not having the following A of being selected from ' substituent 1 to 3 the identical or different substituent cyclic group of group, this cyclic group is partly for being selected from the group of piperidyl, piperazinyl, morpholinyl, indolinyl, iso-dihydro-indole-group and thiazole and pyridyl;
A ' group substituting group is:
Ketone group, lower alkanes acyl group, low carbon naphthene acyl group, low-carbon (LC) carbalkoxy and the carbonyl that replaces by nitrogenous aliphatics heterocyclic radical.
9. according to each described compound in the claim 2 to 8, wherein, B is CH, and X is a singly-bound, R
2Be following formula:
(1) of expression is by replacement or unsubstituted monocycle or bicyclic nitrogen-containing heterocyclic base, or (2) are by the amino of 1 to 2 the substituting group replacement that is selected from replacement or unsubstituted low-carbon alkyl.
10. compound according to claim 2, wherein B is CH, and X is a singly-bound, and A is-CH
2-and R
1Be hydrogen atom or low-carbon alkyl.
11. compound according to claim 3, wherein, B is CH, and X is a singly-bound, and A is-CH
2-and R
1Be hydrogen atom or low-carbon alkyl.
12. compound according to claim 4, wherein, B is CH, and X is a singly-bound, and A is-CH
2-and R
1Be hydrogen atom or low-carbon alkyl.
13. compound according to claim 5, wherein, B is CH, and X is a singly-bound, and A is-CH
2-and R
1Be hydrogen atom or low-carbon alkyl.
14. compound according to claim 6, wherein, B is CH, and X is a singly-bound, and A is-CH
2-and R
1Be hydrogen atom or low-carbon alkyl.
15. compound according to claim 7, wherein, B is CH, and X is a singly-bound, and A is-CH
2-and R
1Be hydrogen atom or low-carbon alkyl.
16. compound according to claim 8, wherein, B is CH, and X is a singly-bound, and A is-CH
2-and R
1Be hydrogen atom or low-carbon alkyl.
17. compound according to claim 9, wherein, B is CH, and X is a singly-bound, and A is-CH
2-and R
1Be hydrogen atom or low-carbon alkyl.
18. compound according to claim 2, wherein, B is CH, and X is a singly-bound, and A is-S-and R
1Be hydrogen atom or low-carbon alkyl.
19. according to the salt of permitting on each described compound or its pharmacology in the claim 1 to 18, wherein, B is CH, and has the following part structure:
20. one kind is selected from the salt of permitting on following group compound or its pharmacology:
(S)-and 2-cyano group-1-[t-4-(4-ethanoyl-1-piperazinyl)-1-methyl-r-1-cyclohexylamino] acetyl-pyrrole alkane;
(S)-and 2-cyano group-1-[is trans-4-(1,3-diketo-2-iso-dihydro-indole-group) cyclohexylamino] and acetyl-pyrrole alkane;
(S)-and 2-cyano group-1-[is trans-4-morpholine and cyclohexylamino] and acetyl-pyrrole alkane; And
(S)-and 2-cyano group-1-[is trans-4-(thiazole is [5,4-b] pyridine-2-yl also) cyclohexylamino] and acetyl-pyrrole alkane.
21. method for preparing the salt of permitting on the aliphatic nitrogenous 5-membered ring compounds shown in the general formula [I] or its pharmacology, it is characterized in that, make the compound or its salt reaction shown in compound shown in the general formula (II) and the general formula [III], and as required its resultant is prepared as the salt of permitting on the pharmacology
R in the formula
1, R
2, A and B have and following identical meaning,
In the formula, A represents-CH
2-or-S-, and Z
1The expression reactive group,
In the formula:
A represents-CH
2-or-S-;
B represents CH or N;
R
1Expression H, low-carbon alkyl, hydroxyl low-carbon alkyl or low-carbon alkoxy low-carbon alkyl;
X represent singly-bound ,-CO-,-Alk-CO-,-COCH
2-,-Alk-O-,-O-CH
2-,-SO
2-,-S-,-COO-,-CON (R
3)-,-Alk-CON (R
3)-,-CON (R
3) CH
2-,-Alk-CON (R
3) CH
2-,-COCH
2N (R
3)-,-SO
2N (R
3)-or-NHCH
2-,
In each definition of above-mentioned X, the key table of right-hand member record shows and B bonded key,
R
3Expression hydrogen atom or low-carbon alkyl, and
Alk represents the low-carbon (LC) alkylidene group;
R
2Expression is selected from (1), the group of (2) and (3):
(1) replacement or unsubstituted cyclic group, this cyclic group partly is
(i) monocycle or dicyclo alkyl, or
(ii) monocycle or bicyclic heterocyclic radical;
(2) amino that replaces by 1 to 2 the identical or different substituting group that is selected from replacement or unsubstituted low-carbon alkyl; And
(3) low-carbon alkyl, carboxyl low-carbon alkyl, low-carbon alkoxy, low-carbon (LC) thiazolinyl, the low-carbon alkyl that replaces by low-carbon alkoxy, phenoxy group, the low-carbon alkyl or the phenyl low-carbon (LC) thiazolinyl that replace by phenoxy group;
But when X is singly-bound, R
2The group of above-mentioned for being selected from (1) and (2), in addition, X is-during CO-, B is N.
22. one kind is suppressed the active method of DPP IV, is to use arbitrary described compound in the claim 1 to 20:
23. treatment of diseases or prevention method are to arbitrary described compound in the claim 1 to 20 of patient's effective dosage.
24. treatment of diseases according to claim 23 or prevention method, wherein, disease is to estimate the disease that can improve morbid state by suppressing the DPP IV activity.
25. treatment of diseases according to claim 23 or prevention method, wherein, this disease is diabetes.
26. treatment of diseases according to claim 23 or prevention method, wherein, this disease is a diabetes B.
27. the purposes of arbitrary described compound in the claim 1 to 20 is that the inhibitor as DPP IV uses.
28. the purposes of arbitrary described compound is to use as the medicinal activity composition in the claim 1 to 20.
29. the purposes of arbitrary described compound is the preparation that is used for medicine in the claim 1 to 20.
30. according to claim 28 or 29 described purposes, wherein, this medicine is for improving the treatment of diseases of morbid state by expection behind the inhibition DPP IV or preventing with medical.
31. according to claim 28 or 29 described purposes, wherein, this medicine is treatment of diabetes or prevention medicine.
32. according to claim 28 or 29 described purposes, wherein, this medicine is the treatment or the prevention medicine of diabetes B.
33. a medical composition is to contain in the claim 1 to 20 arbitrary described compound as effective constituent.
34. medical composition according to claim 33 is an inhibitors of dipeptidyl IV.
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