CN102372697A - Substituted miazines compound - Google Patents

Substituted miazines compound Download PDF

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CN102372697A
CN102372697A CN2011102208053A CN201110220805A CN102372697A CN 102372697 A CN102372697 A CN 102372697A CN 2011102208053 A CN2011102208053 A CN 2011102208053A CN 201110220805 A CN201110220805 A CN 201110220805A CN 102372697 A CN102372697 A CN 102372697A
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alkyl
substituted
pyrimidine
group
methyl
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黄振华
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Shandong Xuanzhu Pharma Co Ltd
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Shandong Xuanzhu Pharma Co Ltd
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Abstract

The invention belongs to the technical field of medicine, particularly relates to a substituted miazines compound disclosed in a general formula (I) and clinically-acceptable salt thereof, wherein R1, R2, R3, R4, R5, Z or W is defined as in a specification. The invention also relates to a preparation method of the compounds and the application of the compounds in preparing medicines capable of treating and/ or preventing sexual dysfunctions.

Description

Substituted pyrimidines
1, technical field
The invention belongs to medical technical field, be specifically related to substituted pyrimidines or its pharmacy acceptable salt, the preparation method of these compounds, and these compounds treat and/or prevent the purposes in the medicine of sexual dysfunction disease in preparation.
2, background technology
ED (Erectile dysfunction, erective dysfunction) is the modal sexual dysfunction of man, refers to that penis continues can not reach or keep erection to satisfy a kind of disease of sexual life.ED is divided into organic ED, psychological ED and Combination ED.That organic ED can be subdivided into again is vascular, neuropathic, operation and traumatic, incretion etc.Though ED is not fatal, people's quality of life is descended.
Multiple factors such as cardiovascular disorder, mellitus, vascular lesion, ephrosis, sacred disease, endocrinopathy and psychological factor all can cause the generation of ED.The generation that pressure is big in addition, anxiety, compunction, depression, Psychiatric disorders and bad life habits such as smoking, excessive drinking and shortage physical activity such as feel oneself inferior also can cause ED.
The sexual dysfunction symptom appears in the male sex can have a strong impact on normal love life, and patient's self psychology also can be very oppressive.Main negative impact comprises three aspects: 1, love life is discord, and makes the breakdown of a family easily; 2, patient's psychology produces huge variation and burden, makes mental illnesss such as feeling oneself inferior appears in the patient, anxiety; 3, male sexual disorder possibly cause the patient sterile, patient's family is caused have a strong impact on, and also gives the huge strike of family numbers of patients simultaneously.
The treat-ment of ED is a lot, mainly comprises three aspects: periphery pharmacological agent, maincenter pharmacological agent and gene therapy.Periphery pharmacological agent mainly be meant phosphodiesterase 5 suppressor factor (such as: application Virga) has also comprised the application of Papaverine, the sweet cyclase of acid acvator of solubility bird, Rho kinases agonist and local Prostagl E1.Maincenter pharmacological agent then is meant the treatment of medicines such as using dopamine-receptor stimulant, alpha-2 adrenoceptor antagonist, serotonin (5-HT) receptor stimulant, pitocin and ocytocin receptor agonist.Gene therapy is to be this basis, important substance basis of spongy mass unstriated muscle tension adjustment according to ionic channel; Express the plasmid vector hMaxi-K (pVAX-hSLO) of hSlo gene through injection in spongy mass; This plasmid is expressed in the spongy mass unstriated muscle; Produce more potassium-channel, thereby make the spongy mass diastole.
Though it is a lot of to treat the method for ED at present, be that phosphodiesterase-5 (PDE-5) suppressor factor of representative is the line medication of treatment ED with Virga (viagra), also be the treat-ment that favored by the patient.These drug orals absorb, and take easyly, and onset is rapid, determined curative effect.The Virga, Vardenafil and the Tadalafei that have gone on the market have at present all been obtained original market achievement, and wherein, Virga and Tadalafei are respectively the cookle of Pfizer and Li Lai, and visible this type pharmaceutical market is huge.
Clinical application along with the PDE-5 suppressor factor; Some potential safety issues also emerge gradually, and wherein, Virga and Vardenafil are having the inhibiting while to PDE-5; For PDE-6 certain restraining effect is arranged also; And PDE-6 influences amphiblestroid function, so these two medicines can impact people's vision, and is in the majority with the report of Virga especially.Tadalafei has good selectivity to PDE-6; But it has certain restraining effect to PDE-11, though the clinical pharmacology effect of PDE-11 is unknown, but still has potential risks; Have the bibliographical information Tadalafei can cause pain in the back, whether this and PDE-11 have dependency still need investigate.In addition, the transformation period of Tadalafei is very long, and this is easy to make the patient when taking other medicines, to produce drug interaction, share such as nitrate esters medicine and Tadalafei, patient's blood pressure is reduced too much, and then cause life danger.At present, the pharmacologically active of PDE-5 suppressor factor is also satisfied not to the utmost.
This shows that research and development have stronger pharmacologically active, and safe PDE-5 suppressor factor has very important significance.
3, summary of the invention
The invention provides one type of safe compound that treats and/or prevents sexual dysfunction disease, concrete technical scheme is the compound shown in the general formula (I):
Figure BSA00000549944800021
Wherein,
R 1Representative through N be connected on the pyrimidine ring be not substituted or by 1～4 substituted 3～8 yuan of nitrogenous single heterocyclic radical of substituting group;
R 2Representative is not substituted or by 1～4 substituted 5～10 yuan of fragrant cyclic group of substituting group;
R 3Representative is not substituted or by 1～4 substituted C of substituting group 1-6Alkyl is not substituted or by 1～4 the substituted 3-8 member heterocyclic ring containing nitrogen of substituting group C 0-6Alkyl is not substituted or by 1～4 substituted C of substituting group 3-6Naphthenic base C 0-6Alkyl or be not substituted or by 1～4 substituted 5～10 yuan of fragrant cyclic group C of substituting group 0-6The group of alkyl;
R wherein 1, R 2, R 3Described substituting group is selected from halogen atom, cyanic acid, amino, hydroxyl, C 1-6Alkyl, halo C 1-6Alkyl, hydroxyl C 1-6Alkyl, amino C 1-6Alkyl, C 1-6Alkoxyl group, C 1-6Alkyl-carbonyl or C 1-6Alkoxy carbonyl;
R 4Represent Wasserstoffatoms, hydroxyl or C 1-6Alkyl;
Z representative-(CH 2) n-N (R 5)-,-(CH 2) n-O-,-O-(CH 2) n-,-(CH 2) n-CO-N (R 5)-,-N (R 5)-(CH 2) n-,-(CH 2) n-N (R 5)-CO-or-N (R 5)-CO-(CH 2) n-;
W representative-CO-,-N (R 5)-,-N (R 5)-CO-(CH 2) n-or-CO-N (R 5)-(CH 2) n-;
R 5Represent Wasserstoffatoms or C 1-6Alkyl;
N represents 0,1, and 2 or 3.
In the general formula (I), R 1Representative through N be connected on the pyrimidine ring be not substituted or by 1～4 the substituted azetidinyl of substituting group, pyrrolidyl, pyridyl, piperazinyl, morpholinyl, pyrryl or imidazolyl,
Said substituting group is selected from halogen atom, cyanic acid, amino, hydroxyl, C 1-6Alkyl, halo C 1-6Alkyl, hydroxyl C 1-6Alkyl or amino C 1-6Alkyl;
R 1Further be preferably through N and be connected to the following formula group on the pyrimidine ring:
Figure BSA00000549944800031
In the general formula (I), R 2Be preferably and be not substituted or by 1～4 substituted phenyl of substituting group,
Said substituting group is selected from halogen atom, cyanic acid, C 1-6Alkyl, C 1-6Alkoxyl group, halo C 1-6Alkyl or halo C 1-6Alkoxyl group;
R 2Further be preferably
Figure BSA00000549944800032
In the general formula (I), R 3Be preferably 3-8 member heterocyclic ring containing nitrogen base C 0-6Alkyl, 3-8 member heterocyclic ring containing nitrogen base are selected from pyridyl, pyrimidyl, pyrazinyl or 2-nitrogen heterocyclic heptanone;
R 3Further be preferably
Figure BSA00000549944800033
In the general formula (I), R 4Be preferably hydroxyl or methyl.
In the general formula (I), R 5Be preferably Wasserstoffatoms or methyl.
In the general formula (I), Z is preferably-CO-N (R 5)-.
In the general formula (I), W is preferably-N (R 5)-CO-CH 2-.
The present invention as the preferred compound of general formula (I) is:
Wherein,
R 1Representative through N be connected on the pyrimidine ring be not substituted or by 1～4 the substituted azetidinyl of substituting group, pyrrolidyl, pyridyl, piperazinyl, morpholinyl, pyrryl or imidazolyl,
Said substituting group is selected from halogen atom, cyanic acid, amino, hydroxyl, C 1-6Alkyl, halo C 1-6Alkyl, hydroxyl C 1-6Alkyl or amino C 1-6Alkyl;
R 2Representative is not substituted or by 1～4 substituted phenyl of substituting group,
Said substituting group is selected from halogen atom, cyanic acid, C 1-6Alkyl, C 1-6Alkoxyl group, halo C 1-6Alkyl or halo C 1-6Alkoxyl group;
R 3Represent 3-8 member heterocyclic ring containing nitrogen base C 0-6Alkyl, 3-8 member heterocyclic ring containing nitrogen base are selected from pyridyl, pyrimidyl, pyrazinyl or 2-nitrogen heterocyclic heptanone;
R 4Represent Wasserstoffatoms, hydroxyl or C 1-6Alkyl;
Z representative-(CH 2) n-N (R 5)-,-(CH 2) n-O-,-O-(CH 2) n-,-(CH 2) n-CO-N (R 5)-,-N (R 5)-(CH 2) n-,-(CH 2) n-N (R 5)-CO-or-N (R 5)-CO-(CH 2) n-;
W representative-CO-,-N (R 5)-,-N (R 5)-CO-(CH 2) n-or-CO-N (R 5)-(CH 2) n-;
R 5Represent Wasserstoffatoms or C 1-6Alkyl;
N represents 0,1, and 2 or 3.
Preferred compound is:
Wherein,
R 1Be selected from through N and be connected to the following formula group on the pyrimidine ring:
Figure BSA00000549944800041
R 2Represent the following formula group:
Figure BSA00000549944800042
R 3Represent the following formula group:
R 4Represent Wasserstoffatoms, hydroxyl or C 1-6Alkyl;
Z representative-(CH 2) n-N (R 5)-,-(CH 2) n-O-,-O-(CH 2) n-,-(CH 2) n-CO-N (R 5)-,-N (R 5)-(CH 2) n-,-(CH 2) n-N (R 5)-CO-or-N (R 5)-CO-(CH 2) n-;
W representative-CO-,-N (R 5)-,-N (R 5)-CO-(CH 2) n-or-CO-N (R 5)-(CH 2) n-;
R 5Represent Wasserstoffatoms or C 1-6Alkyl;
N represents 0,1, and 2 or 3.
Preferred compound is:
Wherein,
R 1Representative through N be connected on the pyrimidine ring be not substituted or by 1～4 the substituted azetidinyl of substituting group, pyrrolidyl, pyridyl, piperazinyl, morpholinyl, pyrryl or imidazolyl,
Said substituting group is selected from halogen atom, cyanic acid, amino, hydroxyl, C 1-6Alkyl, halo C 1-6Alkyl, hydroxyl C 1-6Alkyl or amino C 1-6Alkyl;
R 2Representative is not substituted or by 1～4 substituted phenyl of substituting group,
Said substituting group is selected from halogen atom, cyanic acid, C 1-6Alkyl, C 1-6Alkoxyl group, halo C 1-6Alkyl or halo C 1-6Alkoxyl group;
R 3Represent 3-8 member heterocyclic ring containing nitrogen base C 0-6Alkyl, 3-8 member heterocyclic ring containing nitrogen base are selected from pyridyl, pyrimidyl, pyrazinyl or 2-nitrogen heterocyclic heptanone;
R 4Represent Wasserstoffatoms, hydroxyl or C 1-6Alkyl;
Z representative-CO-N (R 5)-;
W representative-CO-,-N (R 5)-,-N (R 5)-CO-(CH 2) n-or-CO-N (R 5)-(CH 2) n-;
R 5Represent Wasserstoffatoms or methyl;
N represents 0,1, and 2 or 3.
Preferred compound is:
Wherein,
R 1Be selected from through N and be connected to the following formula group on the pyrimidine ring:
Figure BSA00000549944800051
R 2Represent the following formula group:
Figure BSA00000549944800052
R 3Represent the following formula group:
Figure BSA00000549944800053
R 4Represent Wasserstoffatoms, hydroxyl or C 1-6Alkyl;
Z representative-CO-N (R 5)-;
W representative-CO-,-N (R 5)-,-N (R 5)-CO-(CH 2) n-or-CO-N (R 5)-(CH 2) n-;
R 5Represent Wasserstoffatoms or methyl;
N represents 0,1, and 2 or 3.
Preferred compound is:
Wherein,
R 1Representative through N be connected on the pyrimidine ring be not substituted or by 1～4 the substituted azetidinyl of substituting group, pyrrolidyl, pyridyl, piperazinyl, morpholinyl, pyrryl or imidazolyl,
Said substituting group is selected from halogen atom, cyanic acid, amino, hydroxyl, C 1-6Alkyl, halo C 1-6Alkyl, hydroxyl C 1-6Alkyl or amino C 1-6Alkyl;
R 2Representative is not substituted or by 1～4 substituted phenyl of substituting group,
Said substituting group is selected from halogen atom, cyanic acid, C 1-6Alkyl, C 1-6Alkoxyl group, halo C 1-6Alkyl or halo C 1-6Alkoxyl group;
R 3Represent 3-8 member heterocyclic ring containing nitrogen base C 0-6Alkyl, 3-8 member heterocyclic ring containing nitrogen base are selected from pyridyl, pyrimidyl, pyrazinyl or 2-nitrogen heterocyclic heptanone;
R 4Represent Wasserstoffatoms, hydroxyl or C 1-6Alkyl;
Z representative-(CH 2) n-N (R 5)-,-(CH 2) n-O-,-O-(CH 2) n-,-(CH 2) n-CO-N (R 5)-,-N (R 5)-(CH 2) n-,-(CH 2) n-N (R 5)-CO-or-N (R 5)-CO-(CH 2) n-;
W representative-N (R 5)-CO-CH 2-;
R 5Represent Wasserstoffatoms or methyl;
N represents 0,1, and 2 or 3.
Preferred compound is:
Wherein,
R 1Be selected from through N and be connected to the following formula group on the pyrimidine ring:
R 2Represent the following formula group:
Figure BSA00000549944800062
R 3Represent the following formula group:
Figure BSA00000549944800063
R 4Represent Wasserstoffatoms, hydroxyl or C 1-6Alkyl;
Z representative-(CH 2) n-N (R 5)-,-(CH 2) n-O-,-O-(CH 2) n-,-(CH 2) n-CO-N (R 5)-,-N (R 5)-(CH 2) n-,-(CH 2) n-N (R 5)-CO-or-N (R 5)-CO-(CH 2) n-;
W representative-N (R 5)-CO-CH 2-;
R 5Represent Wasserstoffatoms or methyl;
N represents 0,1, and 2 or 3.
Preferred compound is:
Wherein,
R 1Representative through N be connected on the pyrimidine ring be not substituted or by 1～4 the substituted azetidinyl of substituting group, pyrrolidyl, pyridyl, piperazinyl, morpholinyl, pyrryl or imidazolyl,
Said substituting group is selected from halogen atom, cyanic acid, amino, hydroxyl, C 1-6Alkyl, halo C 1-6Alkyl, hydroxyl C 1-6Alkyl or amino C 1-6Alkyl;
R 2Representative is not substituted or by 1～4 substituted phenyl of substituting group,
Said substituting group is selected from halogen atom, cyanic acid, C 1-6Alkyl, C 1-6Alkoxyl group, halo C 1-6Alkyl or halo C 1-6Alkoxyl group;
R 3Represent 3-8 member heterocyclic ring containing nitrogen base C 0-6Alkyl, 3-8 member heterocyclic ring containing nitrogen base are selected from pyridyl, pyrimidyl, pyrazinyl or 2-nitrogen heterocyclic heptanone;
R 4Representation hydroxy or methyl;
Z representative-(CH 2) n-N (R 5)-,-(CH 2) n-O-,-O-(CH 2) n-,-(CH 2) n-CO-N (R 5)-,-N (R 5)-(CH 2) n-,-(CH 2) n-N (R 5)-CO-or-N (R 5)-CO-(CH 2) n-;
W representative-CO-,-N (R 5)-,-N (R 5)-CO-(CH 2) n-or-CO-N (R 5)-(CH 2) n-;
R 5Represent Wasserstoffatoms or C 1-6Alkyl;
N represents 0,1, and 2 or 3.
Preferred compound is:
Wherein,
R 1Be selected from through N and be connected to the following formula group on the pyrimidine ring:
Figure BSA00000549944800071
R 2Represent the following formula group:
Figure BSA00000549944800072
R 3Represent the following formula group:
Figure BSA00000549944800081
R 4Representation hydroxy or methyl;
Z representative-(CH 2) n-N (R 5)-,-(CH 2) n-O-,-O-(CH 2) n-,-(CH 2) n-CO-N (R 5)-,-N (R 5)-(CH 2) n-,-(CH 2) n-N (R 5)-CO-or-N (R 5)-CO-(CH 2) n-;
W representative-CO-,-N (R 5)-,-N (R 5)-CO-(CH 2) n-or-CO-N (R 5)-(CH 2) n-;
R 5Represent Wasserstoffatoms or C 1-6Alkyl;
N represents 0,1, and 2 or 3.
" halo " according to the invention is meant by " halogen atom " and replaces that " halogen atom " is meant fluorine atom, chlorine atom, bromine atoms, iodine atom etc.
" C according to the invention 1-6Alkyl " expression straight or branched the alkyl that contains 1-6 carbon atom; like methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec.-butyl, the tertiary butyl, n-pentyl, isopentyl, 2-methylbutyl, neo-pentyl, 1-ethyl propyl, n-hexyl, isohexyl, 3-methyl amyl, 2-methyl amyl, 1-methyl amyl, 3; 3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1; 2-dimethylbutyl, 1; 3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethyl-butyl, 1,2-dimethyl propyl etc.
" C according to the invention 0-6Alkyl " expression singly-bound or C 1-6Alkyl.
" C according to the invention 3-6Naphthenic base " refer to contain the cycloalkyl group of 3-6 carbon atom, like cyclopropyl, cyclobutyl, 1-methyl cyclobutyl, cyclopentyl, cyclohexyl etc.
" C of the present invention 1-6Alkoxyl group " refer to term " C 1-6Alkyl " group that is connected with other structures through Sauerstoffatom, like methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy, sec.-butoxy, pentyloxy, neopentyl oxygen, hexyloxy etc.
" the nitrogenous heteromonocyclic group of 3-8 unit " according to the invention is meant the monocyclic heterocycles base of 3-8 unit nitrogen atom; Can also contain 1-3 heteroatoms; Heteroatoms is selected from O, N and S; Comprise saturated, fractional saturation and whole undersaturated nitrogenous heteromonocyclic group, said " 3-8 member heterocyclic ring containing nitrogen base " can also be further by oxo or sulfo-.
Wherein the instance of " the saturated nitrogenous heteromonocyclic group of 3-8 unit " includes but not limited to ethylenimine base, azetidinyl, Pyrrolidine base, imidazolidyl, pyrazolidyl, piperidyl, piperazinyl, Si Qing oxazolyl, tetrahydrochysene isoxazole base, thiazolidine base, tetrahydrochysene isothiazolyl, morpholinyl, thio-morpholinyl, 2-nitrogen heterocyclic heptanone etc.;
The instance of " the nitrogenous heteromonocyclic group of 3-8 unit of fractional saturation " includes but not limited to 2,3-pyrrolin base, 4,5-glyoxalidine base, 4,5-pyrazoline base etc.;
The instance of " the nitrogenous heteromonocyclic group of whole undersaturated 3-8 units " includes but not limited to pyrryl 、 oxazolyl 、 isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazol radical, 1,2,4-triazol radical, 1; 2,3,4-tetrazyl, 1,2,3; 5-tetrazyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1; 3,5-triazinyl, 1,2,4,5-tetrazine base etc.
" fragrant cyclic group " according to the invention for containing 0-3 the fragrant cyclic group of heteroatomic 5-10 unit, heteroatoms is selected from O, N and S.The fragrance cyclic group comprises and does not contain heteroatomic aryl radical, for example phenyl, naphthyl etc.The fragrance cyclic group also comprises and contains heteroatomic assorted aromatic base, for example pyrroles, pyrrolin, imidazoles, 4,5-glyoxalidine, pyrazoles, 4,5-pyrazoline, 1,2,3-triazoles, 1; 2,4-triazole, tetrazolium, pyridine, pyridazine, pyrimidine, pyrazine, 1,2,3-triazine, 1,2; 4-triazine, 1,3,5-triazines, 1,2,4; 5-tetrazine, furans, thiophene 、 oxazole, 4,5-dihydro-oxazole 、 isoxazole, 4,5-dihydro-isoxazole, 2,3-dihydro-isoxazole, 1,2; 3-oxadiazole, 1,2,5-oxadiazole, thiazole, 4,5-thiazoline, isothiazole, 1,2; 3-thiadiazoles, 1,2,4-thiadiazoles, 1,3,4-thiadiazoles, cumarone, thionaphthene, indoles, isoindole, benzothiazole, benzoglyoxaline, indazole, benzo morpholine, quinoline, isoquinoline 99.9, quinazoline, purine, quinoxaline etc.
Preferred especially compound comprises:
Above-claimed cpd of the present invention can adopt method and/or known other technology of those of ordinary skills of describing in the following flow process to synthesize, but is not limited only to following method:
For simplicity, the present invention uses well-known abbreviation to represent the number of chemical compound, includes but not limited to
THF: THF; TEA: triethylamine; DCM: methylene dichloride; DIPEA:N, the N-diisopropylethylamine; The HOBT:1-hydroxybenzotriazole; MCPBA: metachloroperbenzoic acid.
Reaction equation:
Figure BSA00000549944800111
Reactions step:
Step 1: raw material 2 is added drop-wise in the THF of raw material 1, stirs, again triethylamine is added drop-wise in the reaction soln, continue stirring reaction at ambient temperature, treat that raw material disappears after, vacuum rotary steam is removed solvent, washing, column chromatography purification gets midbody 1.
Step 2: midbody 1 is dissolved among the DMF, and EDC is added drop-wise to reaction flask after HOBT and the raw material 3 usefulness DMF dissolving, stirred overnight at room temperature, and reaction solution adds dichloromethane extraction behind the water, and anhydrous sodium sulfate drying revolves dried after washing, and column chromatography purification gets midbody 2.
Step 3: midbody 2 is dissolved in the methylene dichloride, adds the MCPBA room temperature reaction, and reaction finishes and revolves dried solid; Above-mentioned solid is dissolved with anhydrous THF; Drip several triethylamines and the L-Prolinol is added drop-wise in the reaction flask, room temperature reaction adds the water dichloromethane extraction after revolving dried solution; Anhydrous sodium sulfate drying, post separate the formula I compound.
R in the above reaction equation 1, R 2, R 3, R 4, Z or W such as preamble definition; X 1Be halogen, first sulfydryl, X 2Be halogen, amino, X 3Be carboxyl, amino.
And:
1) works as X 2During=halogen, raw material 2 is R 2-ZH; Work as X 2During=amino, raw material 2 is R 2-COOH or R 2-COCl.
2) work as X 3During=carboxyl, raw material 3 is R 3-NH 2Work as X 3During=amino, raw material 3 is R 3-COOH.
Clinically, formula I compound of the present invention can use with the form of free form or its pharmacy acceptable salt.Formula I compound of the present invention shows alkalescence, can form hydrogen salt with mineral acid or organic acid.
Formula I compound of the present invention or its pharmacy acceptable salt can exist with a kind of optically active isomer form owing to there is unsymmetrical carbon, and therefore, the present invention also comprises these optically active isomers and composition thereof.
Formula I compound of the present invention or its pharmacy acceptable salt can be formed pharmaceutical composition with one or more pharmaceutical carriers.Said pharmaceutical composition can be processed clinically the conventional formulation that uses, can be oral or mode such as administered parenterally be applied to the patient who needs this treatment.Like tablet, particle, capsule, powder, injection, inhalation, sublingual administration preparation, syrup, gel, ointment, suppository, lotion, nasal cavity drop, sprays, preparation capable of permeating skin etc.These preparations can pass through ordinary method, add pharmaceutical carrier such as vehicle, tamanori, moistening agent, disintegrating agent, thickening material etc. and are prepared from.
Formula I compound of the present invention or its pharmacy acceptable salt have the activity of better inhibited PDE-5 (phosphodiesterase-5), can be used for preventing and/or treating the sexual function erection problem.
Below further set forth the beneficial effect of The compounds of this invention, but should this be interpreted as that The compounds of this invention only has following beneficial effect through external pharmacologically active experiment.
The external pharmacologically active of experimental example The compounds of this invention
Zymetology experiment (enzyme assay)
Trial-product: part of compounds of the present invention, its chemical name and preparation method see preparation embodiment;
Experimental technique: accurately take by weighing trial-product, add the DMSO dissolving, fully mixing is made into 10 μ M.Then with DMSO with above-mentioned mother liquor stepwise dilution to 3.163 μ m, 1 μ m, 0.316 μ m, 100nm, 31.6nm, 10.0nm, 3.164nm, 1.0nm, 0.316nM, 0.1nM.
Caliper Mobility-Shift PDE Assay (electrophoretic migration test):
Respectively at adding buffered soln (100mM Hepes pH 7.5,5mM MgCl in 96 orifice plates 2, 0.002%Brij-35) substrate iFL-cGMP (4 μ M) and above-mentioned each concentration compound of dilution, the blank hole does not add compound.Multiple hole (each concentration repeats twice).Hatch for some time, add 40ng PDE-5A, 30 ℃ hatch 60min after, 100mM Hepes; PH 7.5,0.1%CR-3,0.015%Brij; 30mM Disodium EDTA termination reaction, electrophoretic separation detects substrate and product, Caliper ' s Reviewer computed in software transformation efficiency.
Experimental result and conclusion:
Table 1 The compounds of this invention is to the restraining effect of PDE-5A
Figure BSA00000549944800121
Visible by table 1, The compounds of this invention all has better inhibited activity to PDE-5A, can be used for preventing and/or treating the sexual function erection problem.
4, embodiment
The specific embodiment of form is described in further detail foregoing of the present invention by the following examples.But should this scope that is interpreted as the above-mentioned theme of the present invention only not limited to following examples.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
The preparation of embodiment 1 3-chloro-4-methoxybenzylamine
Figure BSA00000549944800131
(1) preparation of 3-chloro-4-methoxyl group benzylalcohol
Figure BSA00000549944800132
(1g 5mmol) is dissolved in the 30mL dry THF, under-10～-20 ℃, slowly adds LiAlH with 3-chloro-4-methoxyl methyl benzoate 4(0.38g, 10mmol), the TLC monitoring was reacted after 2 hours, with the cancellation of 4-5%NaOH solution, added 500mL ETHYLE ACETATE, and creaming is arranged, and suction filtration revolves steaming, gets 3-chloro-4-methoxyl group benzylalcohol 0.78g, yield 91%.
(2) preparation of 4-azido-methyl-2-chlorine anisole
Figure BSA00000549944800133
With 3-chloro-4-methoxyl group benzylalcohol (200mg 1.16mmol) is dissolved in the 20mL dry THF, under 0 ℃, slowly add successively DBU (210mg, 1.28mmol) and DPPA (320mg; 1.16mmol), TLC monitoring, react about 3 hours after; Stopped reaction, add an amount of saturated NaCl solution after, use ethyl acetate extraction; Revolve steaming, get 4-azido-methyl-2-chlorine anisole 140mg, yield 59% behind the post excessively.
(3) preparation of 3-chloro-4-methoxybenzylamine
Figure BSA00000549944800134
(280mg 1.42mmol) is dissolved in the 40mL dry THF, adds Ph with 4-azido-methyl-2-chlorine anisole 3P (558mg, 2.13mmol) after, add about 10mL water again, in 80 ℃ of refluxed, the TLC monitoring, react about 3 hours after, stopped reaction, add an amount of saturated NaCl solution after, with the THF extraction, revolve steaming, get 3-chloro-4-methoxybenzylamine 158mg, yield 64% after crossing post.
The preparation of embodiment 2 (S)-4-(3-chloro-4-methoxybenzyl amido)-2-[2-(methylol) Pyrrolidine-1-yl]-6-methyl-N-(pyrimidine-2-methyl) pyrimidine-5-ethanamide (compound 1)
Figure BSA00000549944800141
(1) preparation of 4-(3-chloro-4-methoxybenzyl amido)-6-methyl-2-(first sulfydryl) pyrimidine-5-carboxylic acid's ethyl ester
With 4-chloro-6-methyl-2-(first sulfydryl) pyrimidine-5-carboxylic acid's ethyl ester (700mg, 2.8mmol), triethylamine (2mL) is dissolved in the 50mL anhydrous tetrahydro furan; Ice bath slowly adds 3-chloro-4-methoxybenzylamine down, and (486mg 2.8mmol), stirred 12 hours under the room temperature; Concentration of reaction solution; Add ethyl acetate extraction, concentrate brown solid 4-(3-chloro-4-methoxybenzyl amido)-6-methyl-2-(first sulfydryl) pyrimidine-5-carboxylic acid's ethyl ester 970mg, yield 91%.
(2) 4-(3-chloro-4-methoxybenzyl amido)-6-methyl-2-(first sulfydryl) pyrimidine-5-carboxylic acid's preparation
Figure BSA00000549944800143
(3-chloro-4-methoxybenzyl amido)-(970mg 2.5mmol) is dissolved in the 10mL ethanol 6-methyl-2-(first sulfydryl) pyrimidine-5-carboxylic acid's ethyl ester, adds 10%NaOH solution (10mL) then with 4-; Stirring reaction spends the night under the room temperature, drips Hydrogen chloride and transfers pH=5, with dichloromethane extraction (3 * 50mL); Merge organic layer; Anhydrous sodium sulfate drying revolves dried brown solid 4-(3-chloro-4-methoxybenzyl amido)-6-methyl-2-(first sulfydryl) pyrimidine-5-carboxylic acid 800mg, yield 89%.
(3) preparation of 4-(3-chloro-4-methoxybenzyl amido)-6-methyl-2-(first sulfydryl)-N-(pyrimidine-2-methyl) pyrimidine ethanamide
With 4-(3-chloro-4-methoxybenzyl amido)-6-methyl-2-(first sulfydryl) pyrimidine-5-carboxylic acid (800mg, 2.3mmol), EDC (475mg; 2.5mmol), HOBT (427mg, 2.5mmol); (251mg 2.3mmol) is dissolved in the 10mL THF stirred overnight at room temperature to 2-amine methylpyrimidine; Reaction solution adds dichloromethane extraction behind the water; Anhydrous sodium sulfate drying revolves dried back and gets faint yellow solid 4-(3-chloro-4-methoxybenzyl amido)-6-methyl-2-(first sulfydryl)-N-(pyrimidine-2-methyl) pyrimidine ethanamide 685mg, yield 67% for several times with petroleum ether.
(4) preparation of 4-(3-chloro-4-methoxybenzyl amido)-6-methyl-2-(methylsulfonyl)-N-(pyrimidine-2-methyl) pyrimidine ethanamide
Figure BSA00000549944800151
With 4-(3-chloro-4-methoxybenzyl amido)-6-methyl-2-(first sulfydryl)-N-(pyrimidine-2-methyl) pyrimidine ethanamide (180mg; 0.4mmol) be dissolved in the 10mL methylene dichloride; Add MCPBA (83mg; 0.48mmol) room temperature reaction 3 hours, reaction finishes and revolves dried brown solid 4-(3-chloro-4-methoxybenzyl amido)-6-methyl-2-(methylsulfonyl)-N-(pyrimidine-2-methyl) pyrimidine ethanamide, does not add purification and directly is used for next step reaction.
(5) (S)-preparation of 4-(3-chloro-4-methoxybenzyl amido)-2-[2-(methylol) Pyrrolidine-1-yl]-6-methyl-N-(pyrimidine-2-methyl) pyrimidine-5-ethanamide
Figure BSA00000549944800152
Above-mentioned preparation 4-(3-chloro-4-methoxybenzyl amido)-6-methyl-2-(methylsulfonyl)-N-(pyrimidine-2-methyl) pyrimidine ethanamide is dissolved with anhydrous THF, drip several triethylamines, get L-Prolinol (40mg; 0.4mmol) be added drop-wise in the reaction flask; Room temperature reaction 3 hours adds the water dichloromethane extraction, anhydrous sodium sulfate drying after revolving dried solution; Post separates (methylene dichloride: methyl alcohol=10: 1) get white solid 9.6mg, yield 4.8%.
Molecular formula: C 24H 28ClN 7O 3Molecular weight: 497.98 mass spectrums (m/e): 498.2 (M+H)
1H-NMR(400M，CDCl 3)：δ1.62(m，1H)，1.91(m，2H)，2.12(m，1H)，2.50s，3H)，3.64(m，1H)，3.72(d，1H)，3.78(m，1H)，3.89(s，3H)，4.25(t，1H)，4.59(s，2H)，4.86(s，2H)，6.87(d，1H)，6.98(t，1H)，7.20(t，2H)，7.38(d，1H)，8.13(s，1H)，8.64(d，2H).
The preparation of embodiment 3 (S)-4-(3-chloro-4-methoxy benzamide)-2-[2-(methylol) Pyrrolidine-1-yl]-N-(pyrimidine-2-methyl) pyrimidine-5-ethanamide (compound 2)
(1) 4-(3-chloro-4-methoxy benzamide)-2-(first sulfydryl) pyrimidine-5-carboxylic acid's preparation
Figure BSA00000549944800162
(1.86g 9mmol) is dissolved in pyridine, takes by weighing 4-amino-2-(first sulfydryl) pyrimidine-5-carboxylic acid (1.67g with 3-chloro-4-methoxy benzoyl chloride; 9mmol) be added in the pyridine solution, 90 ℃ of stirring heating were reacted 18 hours; Pour in the Hydrogen chloride dichloromethane extraction, anhydrous sodium sulfate drying after being returned to room temperature into; Revolve and do, leach pale solid 4-(3-chloro-4-methoxy benzamide)-2-(first sulfydryl) pyrimidine-5-carboxylic acid 200mg, yield 6.3% to there being deposition to separate out.
(2) preparation of 4-(3-chloro-4-methoxy benzamide)-2-(first sulfydryl)-N-(pyrimidine-2-methyl) pyrimidine-5-ethanamide
Figure BSA00000549944800163
With 4-(3-chloro-4-methoxy benzamide)-(198mg 0.56mmol) is dissolved among the 10mL DMF 2-(first sulfydryl) pyrimidine-5-carboxylic acid, takes by weighing EDC (120mg; 0.63mmol), HOBT (94mg, 0.56mmol); (92mg is 0.85mmol) with being added drop-wise to reaction flask, stirred overnight at room temperature after the DMF dissolving for 2-amine methylpyrimidine; Reaction solution adds dichloromethane extraction behind the water; Anhydrous sodium sulfate drying revolves dried back and gets faint yellow solid 4-(3-chloro-4-methoxy benzamide)-2-(first sulfydryl)-N-(pyrimidine-2-methyl) pyrimidine-5-ethanamide 180mg, yield 72% for several times with petroleum ether.
(3) preparation of 4-(3-chloro-4-methoxy benzamide)-2-(methylsulfonyl)-N-(pyrimidine-2-methyl) pyrimidine-5-ethanamide
With 4-(3-chloro-4-methoxy benzamide)-2-(first sulfydryl)-N-(pyrimidine-2-methyl) pyrimidine-5-ethanamide (180mg; 0.4mmol) be dissolved in the 10mL methylene dichloride; Add MCPBA (83mg; 0.48mmol) room temperature reaction 3 hours, reaction finishes and revolves dried brown solid 4-(3-chloro-4-methoxy benzamide)-2-(methylsulfonyl)-N-(pyrimidine-2-methyl) pyrimidine-5-ethanamide, does not add purification and directly is used for next step reaction.
(4) (S)-preparation of 4-(3-chloro-4-methoxy benzamide)-2-[2-(methylol) Pyrrolidine-1-yl]-N-(pyrimidine-2-methyl) pyrimidine-5-ethanamide
Above-mentioned preparation 4-(3-chloro-4-methoxy benzamide)-2-(methylsulfonyl)-N-(pyrimidine-2-methyl) pyrimidine-5-ethanamide is dissolved with anhydrous THF, drip several triethylamines, get L-Prolinol (40mg; 0.4mmol) be added drop-wise in the reaction flask; Room temperature reaction 3 hours adds the water dichloromethane extraction, anhydrous sodium sulfate drying after revolving dried solution; Post separates (PE: EA=1: 2) get white solid 22mg, yield 11%.
Molecular formula: C 23H 24ClN 7O 4Molecular weight: 497.93 mass spectrums (m/e): 498.2 (M+H)
1H-NMR(400M，CDCl 3)：δ1.98(m，1H)，2.02(m，2H)，2.21(m，1H)，3.71(m，3H)，3.90(d，1H)，3.99(s，3H)，4.58(t，1H)，4.88(d，2H)，5.46(m，1H)，7.04(d，1H)，7.30(t，1H)，7.68(s，1H)，7.98(d，1H)，8.12(s，1H)，8.77(m，3H)，12.91(s，1H).
The preparation of embodiment 4 (S)-4-(3-chloro-4-methoxybenzyl amido)-6-hydroxyl-2-[2-(methylol) Pyrrolidine-1-yl]-N-(pyrimidine-2-methyl) pyrimidine-5-ethanamide (compound 3)
Figure BSA00000549944800173
(1) 4-chloro-6-(3-chloro-4-methoxybenzyl amido)-2-(first sulfydryl) pyrimidine-5-carboxylic acid's preparation
Figure BSA00000549944800181
(2.48g 14.5mmol) is added drop-wise to 4,6-two chloro-2-methylthio groups-5-pyrimidinecarboxylic acid (3.46g with 3-chloro-4-methoxybenzylamine; 14.5mmol) THF (69mL) in, stirred 3 minutes, the 5.9mL triethylamine is added drop-wise in the reaction soln; Continue to stir at ambient temperature 3 hours; After treating that raw material disappears, vacuum rotary steam is removed solvent, obtains white solid 4-chloro-6-(3-chloro-4-methoxybenzyl amido)-2-(first sulfydryl) pyrimidine-5-carboxylic acid 6g; Need not pass through any purifying, directly drop in next step reaction.
(2) 4-(3-chloro-4-methoxybenzyl amido)-6-methoxyl group-2-(first sulfydryl) pyrimidine-5-carboxylic acid's preparation
Figure BSA00000549944800182
6g 4-chloro-6-(3-chloro-4-methoxybenzyl amido)-2-(first sulfydryl) pyrimidine-5-carboxylic acid's bullion that the reaction of last step is obtained is dissolved in the 69mL methyl alcohol; 7.8g new system sodium methylate is added in this reaction soln reflux 24 hours, cooling; Add an amount of pasty state sodium sulfate with the excess sodium methoxide cancellation; Filter, revolve driedly, obtain white solid 4-(3-chloro-4-methoxybenzyl amido)-6-methoxyl group-2-(first sulfydryl) pyrimidine-5-carboxylic acid's bullion 8g.
(3) preparation of 4-(3-chloro-4-methoxybenzyl amido)-6-methoxyl group-2-(first sulfydryl)-N-(pyrimidine-2-methyl) pyrimidine-5-ethanamide
Figure BSA00000549944800183
4g is gone up 2-methylthio group-4-methoxyl group-6-(3-chloro-4-methoxyl group) benzene methanamine base-5-pyrimidinecarboxylic acid bullion that the step reaction obtains is dissolved among the 100mL DMF, in this solution, be sequentially added into 2-amine methylpyrimidine (0.78g, 7.2mmol); HATU (3.46g, 9.2mmol), 3mL TEA; Stirred overnight at room temperature after reactant disappears, adds 300mL water in reaction system; With ethyl acetate extraction three times (3 * 200mL), next with saturated salt solution washing ethyl acetate solution, drying; Revolve dried; Residual solids is crossed column purification, obtains white solid 4-(3-chloro-4-methoxybenzyl amido)-6-methoxyl group-2-(first sulfydryl)-N-(pyrimidine-2-methyl) pyrimidine-5-ethanamide 1.4g, three step total recoverys 21%.
(4) preparation of 4-(3-chloro-4-methoxybenzyl amido)-6-methoxyl group-2-(methylsulfonyl)-N-(pyrimidine-2-methyl) pyrimidine-5-ethanamide
Figure BSA00000549944800191
With 4-(3-chloro-4-methoxybenzyl amido)-6-methoxyl group-2-(first sulfydryl)-N-(pyrimidine-2-methyl) pyrimidine-5-ethanamide (1g; 2.2mmol) be dissolved among the 10mL DCM, next (662mg 3.8mmol) added in the reaction soln stirring at room 1 hour with m-CPBA; After treating that substrate disappears; Revolve the dried 4-of obtaining (3-chloro-4-methoxybenzyl amido)-6-methoxyl group-2-(methylsulfonyl)-N-(pyrimidine-2-methyl) pyrimidine-5-ethanamide, this product need not pass through any aftertreatment, directly applies to next step.
(5) (S)-preparation of 4-(3-chloro-4-methoxybenzyl amido)-2-[(2-methylol) Pyrrolidine-1-yl]-6-methoxyl group-N-(pyrimidine-2-methyl) pyrimidine-5-ethanamide
Figure BSA00000549944800192
The product that a last step is obtained is dissolved in the 10mL THF; Add an amount of triethylamine and be alkalescence until reaction soln, and dropping L-Prolinol (250mg, 2.47mmol); Stirring at room 1 hour; Revolve driedly, cross post (methylene dichloride: methyl alcohol=10: 1) obtain (S)-4-(3-chloro-4-methoxybenzyl amido)-2-[(2-methylol) Pyrrolidine-1-yl]-6-methoxyl group-N-(pyrimidine-2-methyl) pyrimidine-5-ethanamide 800mg, yield 71%.
(6) (S)-preparation of 4-(3-chloro-4-methoxy benzamide)-2-[2-(methylol) Pyrrolidine-1-yl]-N-(pyrimidine-2-methyl) pyrimidine-5-ethanamide
Figure BSA00000549944800193
With (S)-4-(3-chloro-4-methoxybenzyl amido)-2-[(2-methylol) Pyrrolidine-1-yl]-6-methoxyl group-N-(pyrimidine-2-methyl) pyrimidine-5-ethanamide (300mg; 0.58mmol) be dissolved in the 1.2g pyridine hydrochloride; 90 ℃ were reacted 1 hour; Be cooled to room temperature, (methylene dichloride: methyl alcohol=10: 1) purifying obtains white solid (S)-4-(3-chloro-4-methoxy benzamide)-2-[2-(methylol) Pyrrolidine-1-yl]-N-(pyrimidine-2-methyl) pyrimidine-5-ethanamide 90mg, yield 31% to cross post.
Molecular formula: C 23H 26ClN 7O 4Molecular weight: 499.95 mass spectrums (m/e): 500.2 (M+H)
1H-NMR(400M，CDCl 3)：δ1.68(m，1H)，1.83(m，2H)，2.02(m，1H)，2.64(s，1H)，3.52(m，1H)，3.67(d，1H)，3.74(m，1H)，3.80(s，3H)，3.81(m，1H)，4.54(s，2H)，4.84(d，2H)，6.87(d，1H)，7.17(t，2H)，7.34(s，1H)，8.73(d，2H)，10.37(br?s，1H)，10.77(br?s，1H).
The preparation of embodiment 5 (S)-N-[4-(3-chloro-4-methoxybenzyl amido)-2-[(2-methylol) Pyrrolidine-1-yl] pyrimidine-5-yl]-2-(pyrimidine-2-base) ethanamide (compound 4)
Figure BSA00000549944800201
(1) preparation of 2-chloro-N-(3-chloro-4-methoxy-benzyl)-5-nitro-pyrimidine-4-amine
Figure BSA00000549944800202
With 2,5 two chloro-4-nitro-pyrimidines (1.93g, 10mmol), N; (4.3mL 25mmol) is dissolved in the 50mL anhydrous tetrahydro furan N diisopropylethylamine, and ice bath slowly adds 3-chloro-4 methoxybenzylamines (1.72g down; 10mmol), stirred 12 hours concentration of reaction solution under the room temperature; Add ethyl acetate extraction, concentrate 2-chloro-N-(3-chloro-4-methoxy-benzyl)-5-nitro-pyrimidine-4-amine red solid 3.0g, yield 91.4%.
(2) (S)-[1-[4-(3-chloro-4-methoxybenzyl the amido)-5-nitro-pyrimidine-2-yl] Pyrrolidine-2-yl] preparation of methyl alcohol
Figure BSA00000549944800203
With 2-chloro-N-(3-chloro-4-methoxy-benzyl)-5-nitro-pyrimidine-4-amine (3.0g, 9.14mmol), N; (4.0mL 22.8mmol) is dissolved in the 60mL anhydrous tetrahydro furan N diisopropylethylamine, and ice bath slowly adds L-Prolinol (1.11g down; 11mmol), stirred 3 hours concentration of reaction solution under the room temperature; Add ethyl acetate extraction, concentrate red solid (S)-[1-[4-(3-chloro-4-methoxybenzyl amido)-5-nitro-pyrimidine-2-yl] Pyrrolidine-2-yl] methyl alcohol 3.26g, yield 88.6%.
(3) (S)-preparation of 1-[[5-amino-4-(3-chloro-4-methoxybenzyl amido) pyrimidine-2-base] Pyrrolidine-2-yl] methyl alcohol
Figure BSA00000549944800211
With (S)-[1-[4-(3-chloro-4-methoxybenzyl amido)-5-nitro-pyrimidine-2-yl] Pyrrolidine-2-yl] (1.92g 5mmol) is dissolved in the 15mL absolute ethyl alcohol methyl alcohol, adds the Hydrogen chloride of 40mL 4N then; (stirring is 24 hours under the room temperature for 1.4g, 25mmol) iron powder in ice bath slowly adding down; Reaction finishes, and adds solution of potassium carbonate, stirs 10 minutes; Regulate PH to 10, add dichloromethane extraction, concentrate; Column chromatography (DCM: MeOH=1: 10) get red solid (S)-1-[[5-amino-4-(3-chloro-4-methoxybenzyl amido) pyrimidine-2-base] Pyrrolidine-2-yl] methyl alcohol 0.72g, yield 41.1%.
(4) (S)-preparation of N-[[4-(3-chloro-4-methoxybenzyl amido)-2-[(2-methylol) Pyrrolidine-1-yl]] pyrimidine-5-yl]-2-(pyrimidine-2-base) ethanamide
Figure BSA00000549944800212
With (S)-1-[[5-amino-4-(3-chloro-4-methoxybenzyl amido) pyrimidine-2-base] Pyrrolidine-2-yl] methyl alcohol (0.363g, 1mmol), EDC (0.23g; 1.2mmol) and HOBt (0.112g 1.2mmol) is dissolved in the 30mL THF, and ice bath adds down slowly 2-pyrimidine acetate (0.138g; 1mmol); Stirred under the room temperature 10 hours, and concentrated and revolve driedly, add dichloromethane extraction; Column chromatography (DCM: MeOH=1: 20) get red solid (S)-N-[[4-(3-chloro-4-methoxybenzyl amido)-2-[(2-methylol) Pyrrolidine-1-yl]] pyrimidine-5-yl]-2-(pyrimidine-2-base) ethanamide 0.12g, yield 25.8%.
Molecular formula: C 23H 26ClN 7O 3Molecular weight: 483.95 mass spectrums (m/e): 484.2 (M+H)
1H-NMR(400M，CDCl 3)：δ1.64(m，1H)，1.87(m，2H)，2.07(m，1H)，3.52(m，2H)，3.70(m，2H)，3.89(s，3H).4.10(s，2H)，4.16(m，1H)，4.64(m，2H)，6.68(m，1H)，6.88(d，1H)，7.15(t，1H)，7.22(d，1H)，7.38(s，1H)，7.67(m，1H)，8.22(m，1H)，8.41(s，2H).
The preparation of embodiment 6 (S)-2-[2-(amine methyl) Pyrrolidine-1-yl]-4-(3-chloro-4-methoxybenzyl amido)-N-(pyrimidine-2-base methyl) pyrimidine-5-ethanamide (compound 5)
Figure BSA00000549944800213
(1) preparation of 4-(3-chloro-4-methoxybenzyl amido)-2-(first sulfydryl) pyrimidine-5-carboxylic acid's ethyl ester
With 4-chloro-2-(first sulfydryl) pyrimidine-5-carboxylic acid's ethyl ester (5.0g, 21.55mmol), 3-chloro-4-methoxybenzylamine (4.0g; 23.4mmol) and triethylamine (4.35g 43.1mmol) is dissolved among the 100mL DCM, stirs under the room temperature 10 hours; Wash three times; Organic layer is dry, concentrate brown solid 4-(3-chloro-4-methoxybenzyl amido)-2-(first sulfydryl) pyrimidine-5-carboxylic acid's ethyl ester 6.0g, yield 76%.
(2) 4-(3-chloro-4-methoxybenzyl amido)-2-(first sulfydryl) pyrimidine-5-carboxylic acid's preparation
Figure BSA00000549944800222
With 4-(3-chloro-4-methoxybenzyl amido)-2-(first sulfydryl) pyrimidine-5-carboxylic acid's ethyl ester (6.0g, 16.3mmol) and sodium hydroxide (1.14g 28.57mmol) is dissolved among 10mL water and 30mL methyl alcohol and the 30mL THF, the reaction 10 hours down of 60 ℃ of reaction solutions.Drip Hydrogen chloride and transfer pH=4, filter, solid is used methanol wash, dry white solid 4-(3-chloro-4-methoxybenzyl amido)-2-(first sulfydryl) pyrimidine-5-carboxylic acid 4.2g, the yield 76% of getting.
(3) preparation of 4-(3-chloro-4-methoxybenzyl amido)-2-(first sulfydryl)-N-(pyrimidine-2-base methyl) pyrimidine ethanamide
Figure BSA00000549944800223
With 4-(3-chloro-4-methoxybenzyl amido)-2-(first sulfydryl) pyrimidine-5-carboxylic acid (1.0g, 2.95mmol), 2-amine methylpyrimidine (570mg; 5.22mmol) and HATU (898mg 6.96mmol) is dissolved among the 60mL DMF, drips DIEA (152mg; 1.2mmol); 60 ℃ of stirred overnight, reaction solution add dichloromethane extraction behind the water, anhydrous sodium sulfate drying; Revolve and do the back solid through silicagel column separation (methylene dichloride: methyl alcohol=50: 1) get faint yellow solid 4-(3-chloro-4-methoxybenzyl amido)-2-(first sulfydryl)-N-(pyrimidine-2-base methyl) pyrimidine ethanamide 350mg, yield 26%.
(4) preparation of 4-(3-chloro-4-methoxybenzyl amido)-2-(methylsulfonyl)-N-(pyrimidine-2-base methyl) pyrimidine ethanamide
Figure BSA00000549944800231
4-(3-chloro-4-methoxybenzyl amido)-2-(first sulfydryl)-N-(pyrimidine-2-base methyl) pyrimidine ethanamide (150mg; 0.35mmol) be dissolved in the 5mL methylene dichloride; (reaction finishes and uses water washing for 110mg, 0.35mmol) room temperature reaction 30min to add MCPBA; Dichloromethane extraction; Organic layer is dry, revolves to do after silicagel column separates (methylene dichloride: methyl alcohol=50: 1) get yellow solid 4-(3-chloro-4-methoxybenzyl amido)-2-(methylsulfonyl)-N-(pyrimidine-2-base methyl) pyrimidine ethanamide 100mg, yield 72%.
(5) (S)-preparation of 2-[2-(amine methyl) Pyrrolidine-1-yl]-4-(3-chloro-4-methoxybenzyl amido)-N-(pyrimidine-2-base methyl) pyrimidine-5-ethanamide
Figure BSA00000549944800232
(100mg 0.22mmol) with anhydrous THF dissolving, drips several triethylamines with 4-(3-chloro-4-methoxybenzyl amido)-2-(methylsulfonyl)-N-(pyrimidine-2-base methyl) pyrimidine ethanamide; (40mg 0.4mmol) is added drop-wise in the reaction flask, room temperature reaction 3 hours to get the L-2-aminomethyl pyrrolidine; Add the water dichloromethane extraction after revolving dried solution; Anhydrous sodium sulfate drying, post separate (methylene dichloride: methyl alcohol=10: 1) get white solid 38mg, yield 36%.
Molecular formula: C 23H 27ClN 8O 2Molecular weight: 482.97 mass spectrums (m/e): 483.2 (M+1)
1H?NMR(400M，CDCl 3)：δ12.05(br?s，1H)，9.32(s，2H)，8.74(s，2H)，8.44(s，1H)，7.77(m，1H)，7.36(s，1H)，7.19(m，2H)，6.88(d，1H)，4.79(s，2H)，4.57(s，2H)，4.33(s，1H)，3.89(s，3H)，3.75(m，1H)，3.55(m，1H)，3.35(m，1H)，2.28(m，1H)，1.88-1.92(m，4H).
The preparation of embodiment 7 (S)-4-(3-chloro-4-methoxybenzyl amido)-2-[2-(methylol) tetramethyleneimine-1-yl]-N-methyl-N-(pyrimidine-2-base methyl) pyrimidine-5-ethanamide (compound 6)
(1) preparation of 4-(3-chloro-4-methoxybenzyl amido)-N-methyl-2-(first sulfydryl)-N-(pyrimidine-2-base methyl) pyrimidine ethanamide
(380mg 1.13mmol) is dissolved among the 40mL DMF, adds HATU (644mg with 4-(3-chloro-4-methoxybenzyl amido)-2-(first sulfydryl) pyrimidine-5-carboxylic acid; 1.69mmol), DIEA (437mg, 3.39mmol); After stirring 15min, add N-methyl isophthalic acid-(pyrimidine-2-base) methylamine (153mg, 1.24mmol) stirred overnight at room temperature; Reaction solution adds dichloromethane extraction behind the water; Anhydrous sodium sulfate drying revolves and does the back solid through silicagel column separation (methylene dichloride: methyl alcohol=60: 1) get faint yellow solid 4-(3-chloro-4-methoxybenzyl amido)-N-methyl-2-(first sulfydryl)-N-(pyrimidine-2-base methyl) pyrimidine ethanamide 202mg, yield 41%.
(2) preparation of 4-(3-chloro-4-methoxybenzyl amido)-N-methyl-2-(methylsulfonyl)-N-(pyrimidine-2-base methyl) pyrimidine ethanamide
Figure BSA00000549944800242
(202mg 0.46mmol) is dissolved among the 40mLTHF 4-(3-chloro-4-methoxybenzyl amido)-N-methyl-2-(first sulfydryl)-N-(pyrimidine-2-base methyl) pyrimidine ethanamide, adds MCPBA (88mg; 0.51mmol) room temperature reaction 3 hours; Reaction finishes and uses water washing, dichloromethane extraction, and organic layer is dry; Revolve dried yellow solid, this product directly is used for next step reaction without purifying.
(3) (S)-preparation of 4-(3-chloro-4-methoxybenzyl amido)-2-[2-(methylol) tetramethyleneimine-1-yl]-N-methyl-N-(pyrimidine-2-base methyl) pyrimidine-5-ethanamide
Figure BSA00000549944800243
To go up a step product and be dissolved among the anhydrous THF of 30mL, add L-dried meat ammonia alcohol (62mg, 0.51mmol), DIEA (119mg, 0.92mmol), the LC-MS monitoring, react about 12 hours after, stopped reaction.Revolve do after, with the DCM extraction, organic layer is dry, concentrate after silicagel column separate (DCM: MeOH=50: 1) product 102mg, yield 44%.
Molecular formula: C 24H 28ClN 7O 3Molecular weight: 497.98 mass spectrums (m/e): 498.2 (M+1)
1H?NMR(400M，CDCl 3)：δ8.54(m，2H)，8.05(m，1H)，7.64(m，1H)，7.37(s，1H)，7.22(d，1H)，7.18(t，1H)，6.87(d，1H)，5.30(m，2H)，4.90(m，2H)，4.24(m，1H)，3.89(s，3H)，3.55-3.73(m，?4H)，3.12(s，3H)，2.11(m，1H)，1.91(m，2H)，1.62(m，1H).
The preparation of embodiment 8 (S)-4-(3-chloro-4-methoxybenzyl amido)-2-[2-(methylol) azetidine-1-yl]-N-(pyrimidine-2-base methyl) pyrimidine-5-ethanamide (compound 7)
With 4-(3-chloro-4-methoxybenzyl amido)-2-(methylsulfonyl)-N-(pyrimidine-2-base methyl) pyrimidine ethanamide (200mg, (100mg 1.15mmol) is dissolved in 5mL THF 0.45mmol) to change butane-2-base methyl alcohol with azepine; The dropping triethylamine (184mg, 1.35mmol), room temperature reaction 5 hours; Add water and use dichloromethane extraction; Anhydrous sodium sulfate drying, post separate (methylene dichloride: methyl alcohol=40: 1) get white solid 35mg, yield 17%.
Molecular formula: C 22H 24ClN 7O 3Molecular weight: 469.92 mass spectrums (m/e): 470.2 (M+1)
1H?NMR(400M，DMSO)：δ9.20(m，1H)，8.81(m，1H)，8.75(d，2H)，8.49(s，1H)，7.38(t，2H)，7.36(d，1H)，7.07(d，1H)，4.56(d，2H)，4.44(d，2H)，4.43(m，1H)，3.92(m，2H)，3.89(s，3H)，3.67(m，2H)，2.25(m，2H).
The preparation of embodiment 9 (S)-4-(3-chloro-4-methoxybenzyl amido)-2-(2-ethyl pyrrolidine-1-yl)-N-(pyrimidine-2-base methyl) pyrimidine-5-ethanamide (compound 8)
Figure BSA00000549944800252
With 4-(3-chloro-4-methoxybenzyl amido)-2-(methylsulfonyl)-N-(pyrimidine-2-base methyl) pyrimidine ethanamide (250mg, 0.56mmol), DIEA (0.22mL; 1.12mmol) be dissolved in 30mL DCM, drip the 2-ethyl pyrrolidine (120mg, 0.6mmol) room temperature reaction spends the night; Add the water dichloromethane extraction; Anhydrous sodium sulfate drying, post separate (methylene dichloride: methyl alcohol=20: 1) get white solid 100mg, yield 37.1%.
Molecular formula: C 24H 28ClN 7O 2Molecular weight: 481.98 mass spectrums (m/e): 482.0 (M+1)
1H?NMR(400M，CDCl 3)：δ9.05(m?1H)，8.73(d，2H)，8.45(s，1H)，7.33(m，2H)，7.24(t，1H)，7.22(m，1H)，6.85(d，1H)，4.79(d，2H)，4.60(m，2H)，3.92(m，1H)，3.88(s，3H)，3.65(m，2H)，0.83-1.95(m，9H).
With reference to above-mentioned preparation method, can also prepare following compound:
Figure BSA00000549944800261
。

Claims (9)

1. compound or its pharmacy acceptable salt shown in the logical formula I:
Wherein,
R 1Representative through N be connected on the pyrimidine ring be not substituted or by 1～4 substituted 3～8 yuan of nitrogenous single heterocyclic radical of substituting group;
R 2Representative is not substituted or by 1～4 substituted 5～10 yuan of fragrant cyclic group of substituting group;
R 3Representative is not substituted or by 1～4 substituted C of substituting group 1-6Alkyl is not substituted or by 1～4 the substituted 3-8 member heterocyclic ring containing nitrogen of substituting group C 0-6Alkyl is not substituted or by 1～4 substituted C of substituting group 3-6Naphthenic base C 0-6Alkyl or be not substituted or by 1～4 substituted 5～10 yuan of fragrant cyclic group C of substituting group 0-6The group of alkyl;
R wherein 1, R 2, R 3Described substituting group is selected from halogen atom, cyanic acid, amino, hydroxyl, C 1-6Alkyl, halo C 1-6Alkyl, hydroxyl C 1-6Alkyl, amino C 1-6Alkyl, C 1-6Alkoxyl group, C 1-6Alkyl-carbonyl or C 1-6Alkoxy carbonyl;
R 4Represent Wasserstoffatoms, hydroxyl or C 1-6Alkyl;
Z representative-(CH 2) n-N (R 5)-,-(CH 2) n-O-,-O-(CH 2) n-,-(CH 2) n-CO-N (R 5)-,-N (R 5)-(CH 2) n-,-(CH 2) n-N (R 5)-CO-or-N (R 5)-CO-(CH 2) n-;
W representative-CO-,-N (R 5)-,-N (R 5)-CO-(CH 2) n-or-CO-N (R 5)-(CH 2) n-;
R 5Represent Wasserstoffatoms or C 1-6Alkyl;
N represents 0,1, and 2 or 3.
2. compound as claimed in claim 1 or its pharmacy acceptable salt:
Wherein,
R 1Representative through N be connected on the pyrimidine ring be not substituted or by 1～4 the substituted azetidinyl of substituting group, pyrrolidyl, pyridyl, piperazinyl, morpholinyl, pyrryl or imidazolyl,
Said substituting group is selected from halogen atom, cyanic acid, amino, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halo C 1-6Alkyl, hydroxyl C 1-6Alkyl or amino C 1-6Alkyl;
R 2Representative is not substituted or by 1～4 substituted phenyl of substituting group,
Said substituting group is selected from halogen atom, cyanic acid, C 1-6Alkyl, C 1-6Alkoxyl group, halo C 1-6Alkyl or halo C 1-6Alkoxyl group;
R 3Represent 3-8 member heterocyclic ring containing nitrogen base C 0-6Alkyl, 3-8 member heterocyclic ring containing nitrogen base are selected from pyridyl, pyrimidyl, pyrazinyl or 2-nitrogen heterocyclic heptanone.
3. compound as claimed in claim 2 or its pharmacy acceptable salt:
Wherein, R 1Be selected from through N and be connected to the following formula group on the pyrimidine ring:
R 2Represent the following formula group:
Figure FSA00000549944700022
R 3Represent the following formula group:
Figure FSA00000549944700023
4. like each described compound of claim 2-3 or its pharmacy acceptable salt:
Wherein, Z representative-CO-N (R 5)-;
R 5Represent Wasserstoffatoms or methyl.
5. like each described compound of claim 2-3 or its pharmacy acceptable salt:
Wherein, W representative-N (R 5)-CO-CH 2-;
R 5Represent Wasserstoffatoms or methyl.
6. like each described compound of claim 2-3 or its pharmacy acceptable salt:
Wherein, R 4Representation hydroxy or methyl.
7. like each described compound of claim 1-3 or its pharmacy acceptable salt, said compound is selected from:
Figure FSA00000549944700024
Figure FSA00000549944700031
8. contain the pharmaceutical prepn of the described compound of the arbitrary claim of claim 1～7 or its pharmacy acceptable salt, it is characterized in that comprising one or more pharmaceutical carriers.
9. treat and/or prevent the application in the medicine of sexual dysfunction disease like the described compound of the arbitrary claim of claim 1～7 or its pharmacy acceptable salt in preparation.
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CN103483323B (en) * 2013-08-23 2016-01-20 苏州永健生物医药有限公司 Ai Wanafei
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