CN103183675A - Phosphodiesterase-4 inhibitor - Google Patents
Phosphodiesterase-4 inhibitor Download PDFInfo
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- CN103183675A CN103183675A CN2012105812976A CN201210581297A CN103183675A CN 103183675 A CN103183675 A CN 103183675A CN 2012105812976 A CN2012105812976 A CN 2012105812976A CN 201210581297 A CN201210581297 A CN 201210581297A CN 103183675 A CN103183675 A CN 103183675A
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- 0 *c1cccc(Sc2ccc[n+](O)c2)c1 Chemical compound *c1cccc(Sc2ccc[n+](O)c2)c1 0.000 description 4
- PAMBHVIQMILDFT-UHFFFAOYSA-N CCOC(C1=CN(c2cccc(Sc3ccc[n+]([O-])c3)c2)c2ncccc2C1=O)=O Chemical compound CCOC(C1=CN(c2cccc(Sc3ccc[n+]([O-])c3)c2)c2ncccc2C1=O)=O PAMBHVIQMILDFT-UHFFFAOYSA-N 0.000 description 1
- DSCRLMMBZYEUFT-UHFFFAOYSA-N O=C(C1=CN(c2cccc(Sc3cccnc3)c2)c2ncccc2C1=O)NC1CC1 Chemical compound O=C(C1=CN(c2cccc(Sc3cccnc3)c2)c2ncccc2C1=O)NC1CC1 DSCRLMMBZYEUFT-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention belongs to the technical field of medicines and particularly relates to a phosphodiesterase-4 inhibitor as shown in a general formula (I) and a pharmaceutically acceptable salt, a stereoisomer or a solvent compound thereof. In the formula, R1, R2, R3, R4, R5, R6, R7, R8, R9, R7', R8', R9', L and a ring A are as defined in the specification. The invention further relates to a preparation method for the compound, a pharmaceutical composition with the compound, and an application of the compound and the pharmaceutical composition to preparation of drugs for treating and/or preventing inflammatory diseases, disease symptoms and disease conditions characterized by or related with undesired inflammatory immune reaction and all diseases induced by or related with TNF-alpha (tumor necrosis factor-alpha) and PDE-4 (phosphodiesterase-4) hypersecretion.
Description
Technical field
The present invention relates to inhibitors of phosphodiesterase-4, its pharmacy acceptable salt, its steric isomer or its solvated compounds, their preparation method, the pharmaceutical composition that contains described compound, and described compound and pharmaceutical composition to treat and/or prevent with undesirable inflammatory immune response in preparation be application in the medicine of feature or inflammatory diseases, illness and the state of an illness relevant with undesirable inflammatory immune response and all diseases that brought out by TNF-α and PDE-4 supersecretion or relevant with the PDE-4 supersecretion with TNF-α.
Background technology
Hormone is the compound that a class influences cytoactive by different way.In many cases, hormone is as triggering specific cell reaction and active courier.Yet the many effects that produced by hormone are also not only caused by the special effects of hormone.On the contrary, hormone at first with receptors bind, thereby trigger to discharge second compound, this second compound and then influence cytoactive.In this case, hormone is called the first messenger, and second compound then is called the second messenger.Cyclic amp (adenosine 3 ', 5 '-ring, one phosphoric acid, cAMP or ring AMP) be considered to the second messenger of hormones such as suprarenin, hyperglycemic-glycogenolytic factor, thyrocalcitonin, thyroliberin, lipotropin, lutropin, nor-epinephrine, parathyroid hormone, thyrotropin and Hou Yejiayasu.Therefore, the cAMP mediated cell is to the reaction of hormone, cAMP also mediated cell to the reaction of various neurotransmitters.
(phosphodiesterases PDEs) has the function of second messenger in the hydrolysis cell, cAMP in the degradation of cell, thereby the biochemical action that these second messengers that terminate are conducted to phosphodiesterase.There are 11 kinds of enzymes in PDEs family, wherein the PDE4 enzyme is specific cAMP lytic enzyme, mainly be distributed in inflammatory cell such as airway smooth muscle cells and lymphocyte, scavenger cell, neutrophil leucocyte, eosinophilic granulocyte, basophilic granulocyte, monocyte, epithelial cell and the immunocyte, regulate the level of cAMP in these cells.
The PDE4 inhibitor can suppress the activity of these immunocytes and inflammatory cell, can be used for the treatment of the disease that is caused by inflammation, cause the central nervous system disease that the neuronal damage wound causes as asthma, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, multiple sclerosis, alzheimer disease (AD), Parkinson's disease (PD) and apoplexy etc. by potential inflammation.
Roflumilast (Roflumilast) is the PDE4 inhibitor of first listing.The oral roflumilast of COPD patient can obviously reduce neutrophil leucocyte quantity in the phlegm more than 4 weeks, take more than 6-12 month and can slightly improve pulmonary function, but can not significantly reduce state of an illness acute exacerbation or the quality of making the life better, reason may be that drug side effect has limited its using dosage.
Using a problem that is worth being concerned about of PDE4 inhibitor is its side effect that causes vomitting, and studies show that PDE4 has 4 kinds of hypotype: PDE4A, PDE4B, PDE4C, PDE4D; Wherein, PDE4B is relevant with anti-inflammatory, and PDE4D also has anti-inflammatory action, but relevant with the vomiting reaction of maincenter, and therefore, the PDE4B inhibitor of highly selective will reduce the untoward reaction of vomiting greatly, improves the pharmacological agent window, thereby reaches better result for the treatment of.
Cilomilast (Cilomilast) is a PDE4 inhibitor that stops at phase III because of the vomiting untoward reaction.Studies show that, cilomilast (Cilomilast) is better than 10 times of the activity of PDE4B to the activity of PDE4D, and roflumilast is suitable to the activity of PDE4B and PDE4D, therefore, the active suitable PDE4 inhibitor of design PDE4B and PDE4D, with reducing the side effect of vomiting greatly, improve the pharmacological agent window, reach best medication effect.
Summary of the invention
The invention provides the compound that can be used as the PDE-4 inhibitor shown in the formula (I), its pharmacy acceptable salt, its steric isomer or its solvated compounds:
Wherein, R
1Be hydrogen ,-C (O)-R
a,-S (O)
q-R
a, be not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkyl, the C that is not substituted or is replaced by 1 ~ 3 Q
1-8Alkoxyl group is not substituted or the optional C that is replaced by 1 ~ 3 Q
3-8Cycloalkyl is not substituted or the optional C that is replaced by 1 ~ 3 Q
2-8Thiazolinyl is not substituted or the optional C that is replaced by 1 ~ 3 Q
3-8Alkynyl is not substituted or the optional C that is replaced by 1 ~ 3 Q
6-14Aryl is not substituted or optional 5 ~ 15 yuan of heteroaryls that replaced by 1 ~ 3 Q, or is not substituted or optional 3 ~ 15 yuan of heterocyclic radical C that replaced by 1 ~ 3 Q
1-8Alkyl;
R
2Be hydrogen, be not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkyl, or be not substituted or the optional C that is replaced by 1 ~ 3 Q
3-8Cycloalkyl;
R
3, R
4, R
5And R
6Be hydrogen independently respectively, halogen atom ,-C (O)-R
a,-S (O)
q-R
a, nitro, cyano group ,-NR
aR
a', be not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkyl, or be not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkoxyl group; R
7Be hydrogen, be not substituted or the optional phenyl that is replaced by 1 ~ 3 Q, thienyl, pyriconyl,
The azoles base,
Di azoly, thiazolyl or thiadiazolyl group are not substituted or choose wantonly by pyridyl, pyrimidyl, indyl, quinolyl or the imidazolyl of 1 ~ 3 Q replacement and their oxynitride, are not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkyl, or be not substituted or the optional C that is replaced by 1 ~ 3 Q
3-8Cycloalkyl;
R
7' do not exist, hydrogen, be not substituted or the optional phenyl that is replaced by 1 ~ 3 Q, thienyl, pyriconyl,
The azoles base,
Di azoly, thiazolyl or thiadiazolyl group are not substituted or choose wantonly by pyridyl, pyrimidyl, indyl, quinolyl or the imidazolyl of 1 ~ 3 Q replacement and their oxynitride, are not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkyl, or be not substituted or the optional C that is replaced by 1 ~ 3 Q
3-8Cycloalkyl;
And R
7' for be not substituted or the optional phenyl that is replaced by 1 ~ 3 Q, thienyl, pyriconyl,
The azoles base,
Di azoly, thiazolyl or thiadiazolyl group, or be not substituted or when optional pyridyl, pyrimidyl, indyl, quinolyl or the imidazolyl that is replaced by 1 ~ 3 Q and their oxynitride R
1Be hydrogen ,-C (O)-R
a,-S (O)
q-R
a, be not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkyl is not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkoxyl group is not substituted or the optional C that is replaced by 1 ~ 3 Q
3-8Cycloalkyl is not substituted or the optional C that is replaced by 1 ~ 3 Q
2-8Thiazolinyl is not substituted or the optional C that is replaced by 1 ~ 3 Q
3-8Alkynyl is not substituted or the optional C that is replaced by 1 ~ 3 Q
6-14Aryl, or be not substituted or optional 3 ~ 15 yuan of heterocyclic radical C that replaced by 1 ~ 3 Q
1-8Alkyl;
R
8Be hydrogen, halogen atom, nitro, cyano group ,=N-O-C
1-8Alkyl ,-O-N=C
1-8Alkyl ,-CH (N=NOH)-C
1-8Alkyl ,-NR
aR
a' ,-C (O)-R
a,-C (O) NR
aR
a' ,-NR
aC (O) R
a' ,-S (O)
q-R
a,-S (O)
q-NR
aR
a' ,-NR
a-S (O)
q-R
a' ,-C (O) OR
aGroup, be not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkyl is not substituted or the optional C that is replaced by 1 ~ 3 Q
3-8Cycloalkyl is not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkoxyl group is not substituted or the optional C that is replaced by 1 ~ 3 Q
6-14Aryl is not substituted or optional 5 ~ 15 yuan of heteroaryls that replaced by 1 ~ 3 Q, or is not substituted or optional 3 ~ 15 yuan of heterocyclic radical C that replaced by 1 ~ 3 Q
1-8Alkyl;
R
8' there are not hydrogen, halogen atom, nitro, cyano group ,=N-O-C
1-8Alkyl ,-O-N=C
1-8Alkyl ,-CH (N=NOH)-C
1-8Alkyl ,-NR
aR
a' ,-C (O)-R
a,-C (O) NR
aR
a' ,-NR
aC (O) R
a' ,-S (O)
q-R
a,-S (O)
q-NR
aR
a' ,-NR
a-S (O)
q-R
a' ,-C (O) OR
aGroup, be not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkyl is not substituted or the optional C that is replaced by 1 ~ 3 Q
3-8Cycloalkyl is not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkoxyl group is not substituted or the optional C that is replaced by 1 ~ 3 Q
6-14Aryl is not substituted or optional 5 ~ 15 yuan of heteroaryls that replaced by 1 ~ 3 Q, or is not substituted or optional 3 ~ 15 yuan of heterocyclic radical C that replaced by 1 ~ 3 Q
1-8Alkyl;
R
9Be hydrogen, hydroxyl, halogen atom ,-NR
bR
b', or be not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkyl;
R
9' there are not hydrogen, hydroxyl, halogen atom ,-NR
bR
b', or be not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkyl;
Ring A is phenyl, contains 1 ~ 45 ~ 8 yuan of heteroaryl that are selected from N, S, O, or contains 1 ~ 48 ~ 14 yuan of heterocyclic radical that are selected from N, S, O;
L represents-O-,-S (O)
q-, 1,1-cyclopropane base, carbonyl, vinyl, methylene radical, ethyl, or ethynyl, and when L was ethynyl, ring A can not be phenyl;
Q is selected from 0,1 or 2;
R
a, R
a' be selected from hydrogen, be not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkyl is not substituted or the optional C that is replaced by 1 ~ 3 Q
3-8Cycloalkyl is not substituted or the optional C that is replaced by 1 ~ 3 Q
3-8Cycloalkyl C
1-8Alkyl is not substituted or the optional C that is replaced by 1 ~ 3 Q
6-14Aryl, or be not substituted or optional 3 ~ 15 yuan of heterocyclic radicals that replaced by 1 ~ 3 Q;
Q is selected from hydroxyl, carboxyl, nitro, cyano group, halogen atom, C
1-8Alkyl, C
3-8Cycloalkyl, C
1-8Alkoxyl group, halo C
1-8Alkyl, halo C
1-8Alkoxyl group ,-NR
bR
b' ,-C (O)-R
b,-C (O) NR
bR
b' ,-NR
bC (O) R
b' ,=N-O-C
1-8Alkyl ,-O-N=C
1-8Alkyl ,-S (O)
q-R
b,-S (O)
q-NR
bR
b' ,-NR
b-S (O)
q-R
b', or-C (O) OR
bGroup, R wherein
b, R
b' be respectively hydrogen, C independently
1-8Alkyl, C
3-8Cycloalkyl or C
6-14Aryl.
The present invention preferably provides as the formula of giving a definition (I) compound, its pharmacy acceptable salt, its steric isomer or its solvated compounds:
Wherein, R
1Be hydrogen ,-C (O)-R
a,-S (O)
q-R
a, be not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkyl is not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkoxyl group is not substituted or the optional C that is replaced by 1 ~ 3 Q
3-8Cycloalkyl is not substituted or the optional C that is replaced by 1 ~ 3 Q
6-14Aryl, or be not substituted or optional 5 ~ 15 yuan of heteroaryls that replaced by 1 ~ 3 Q;
R
2Be hydrogen, or be not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkyl;
R
3, R
4, R
5And R
6Be hydrogen independently respectively, halogen atom ,-C (O)-R
a,-S (O)
q-R
a, nitro, cyano group ,-NR
aR
a', the C that is not substituted or is replaced by 1 ~ 3 substituting group
1-8Alkyl, or be not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkoxyl group; R
7For be not substituted or the optional phenyl that is replaced by 1 ~ 3 Q, thienyl, pyriconyl,
The azoles base,
Di azoly, thiazolyl or thiadiazolyl group, or be not substituted or choose wantonly by pyridyl, pyrimidyl, indyl, quinolyl or the imidazolyl of 1 ~ 3 Q replacement and their oxynitride;
R
7' do not exist, be not substituted or the optional phenyl that is replaced by 1 ~ 3 Q, thienyl, pyriconyl,
Azoles base, two
Azoles base, thiazolyl or thiadiazolyl group, or be not substituted or choose wantonly by pyridyl, pyrimidyl, indyl, quinolyl or the imidazolyl of 1 ~ 3 Q replacement and their oxynitride;
And R
7' for be not substituted or the optional phenyl that is replaced by 1 ~ 3 Q, thienyl, pyriconyl,
The azoles base,
Di azoly, thiazolyl or thiadiazolyl group, or be not substituted or when optional pyridyl, pyrimidyl, indyl, quinolyl or the imidazolyl that is replaced by 1 ~ 3 Q and their oxynitride R
1Be hydrogen ,-C (O)-R
a,-S (O)
q-R
a, be not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkyl is not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkoxyl group is not substituted or the optional C that is replaced by 1 ~ 3 Q
3-8Cycloalkyl, or be not substituted or the optional C that is replaced by 1 ~ 3 Q
6-14Aryl;
R
8Be hydrogen, halogen atom ,-NR
aR
a' ,-C (O)-R
a,-C (O) NR
aR
a' ,-NR
aC (O) R
a' ,-S (O)
q-R
a,-S (O)
q-NR
aR
a' ,-NR
a-S (O)
q-R
a' ,-C (O) OR
aGroup, or be not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkyl;
R
8' there are not hydrogen, halogen atom ,-NR
aR
a' ,-C (O)-R
a,-C (O) NR
aR
a' ,-NR
aC (O) R
a' ,-S (O)
q-R
a,-S (O)
q-NR
aR
a' ,-NR
a-S (O)
q-R
a' ,-C (O) OR
aGroup, or be not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkyl;
R
9Be hydrogen, hydroxyl, halogen atom is not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkyl;
R
9' do not exist, hydrogen, hydroxyl, halogen atom, or be not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkyl;
Ring A is phenyl, contains 1 ~ 4 5-8 unit heteroaryl that is selected from N, S, O, or contains 1 ~ 48 ~ 14 yuan of heterocyclic radical that are selected from N, S, O;
L is-O--S (O)
q-, 1,1-cyclopropane base, carbonyl, methylene radical, ethyl, or ethynyl, and when L was ethynyl, ring A can not be phenyl;
Q is selected from 0,1 or 2;
R
a, R
a' be selected from hydrogen, be not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkyl;
Q is selected from hydroxyl, carboxyl, cyano group, halogen atom, C
1-8Alkyl, C
3-8Cycloalkyl, C
1-8Alkoxyl group, halo C
1-8Alkoxyl group ,-NR
bR
b' ,-C (O)-R
b,-C (O) NR
bR
b' ,-NR
bC (O) R
b' ,-S (O)
q-R
b,-S (O)
q-NR
bR
b' ,-NR
b-S (O)
q-R
b', or-C (O) OR
bGroup, R wherein
b, R
b' be respectively hydrogen or C independently
1-8Alkyl.
The present invention relates to general formula (I) compound, its pharmacy acceptable salt, its steric isomer or its solvated compounds on the other hand,
Wherein, R
1Be hydrogen, methyl, ethyl, propyl group, sec.-propyl, cyclopropyl, cyclobutyl, or cyclopentyl;
R
2Be hydrogen, or methyl;
R
3, R
4, R
5And R
6Be hydrogen independently respectively, methyl, fluorine atom, chlorine atom, or bromine atoms;
R
8, R
9Be hydrogen independently respectively, methyl, fluorine atom, chlorine atom, methyl sulphonyl, or 2-hydroxyl sec.-propyl;
R
7' do not exist;
R
8', R
9' do not exist.
The present invention relates to general formula (I) compound, its pharmacy acceptable salt, its steric isomer or its solvated compounds on the other hand,
Wherein, ring A is phenyl, or contains 1 ~ 3 5-6 unit heteroaryl that is selected from N, S, O;
L is-O--S (O)
q-, 1,1-cyclopropane base, carbonyl, vinyl, methylene radical, ethyl, or ethynyl, and when L was ethynyl, ring A can not be phenyl.
The present invention relates to general formula (I) compound, its pharmacy acceptable salt, its steric isomer or its solvated compounds on the other hand,
Wherein, ring A is phenyl, or contains 1 ~ 3 5-6 unit heteroaryl that is selected from N;
L is-O--S (O)
q-, 1,1-cyclopropane base, carbonyl, vinyl, methylene radical, ethyl, or ethynyl, and when L was ethynyl, ring A can not be phenyl.
The present invention relates to general formula (I) compound, its pharmacy acceptable salt, its steric isomer or its solvated compounds on the other hand,
Wherein, ring A is phenyl, pyrryl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidyl, or pyrazinyl;
L is-O--S (O)
q-, 1,1-cyclopropane base, carbonyl, vinyl, methylene radical, ethyl, or ethynyl, and when L was ethynyl, ring A can not be phenyl.
The present invention relates to general formula (I) compound, its pharmacy acceptable salt, its steric isomer or its solvated compounds on the other hand,
Wherein, L is-O-,-S-, and-S (O)-,-S (O)
2-, 1,1-cyclopropane base, carbonyl, vinyl, methylene radical, or ethynyl, and when L was ethynyl, ring A can not be phenyl.
The present invention relates to general formula (I) compound, its pharmacy acceptable salt, its steric isomer or its solvated compounds on the other hand,
Wherein, L is-O-,-S-, and-S (O)-,-S (O)
2-, 1,1-cyclopropane base, or ethynyl, and when L was ethynyl, ring A can not be phenyl.
The present invention relates to general formula (I) compound, its pharmacy acceptable salt, its steric isomer or its solvated compounds on the other hand,
Wherein, R
7Be pyridyl or their oxynitride.
The present invention relates to general formula (I) compound, its pharmacy acceptable salt, its steric isomer or its solvated compounds on the other hand,
Wherein, R
7Be pyridyl or their oxynitride;
Ring A is phenyl, pyridyl, pyrimidyl, or pyrazinyl;
L is-O-,-S-, and-S (O)-,-S (O)
2-, or ethynyl, and when L was ethynyl, ring A can not be phenyl.
Detailed Description Of The Invention
The example of " halogen atom " of the present invention comprises fluorine atom, chlorine atom, bromine atoms, iodine atom.
" C of the present invention
1-8Alkyl " hydrocarbon that refers to contain 1 ~ 8 carbon atom removes the alkyl of the straight or branched that a hydrogen atom derives; and example includes but not limited to methyl; ethyl; n-propyl; sec.-propyl; normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, the 2-methyl butyl, neo-pentyl, the 1-ethyl propyl, n-hexyl, isohexyl, the 3-methyl amyl, the 2-methyl amyl, the 1-methyl amyl, 3, the 3-dimethylbutyl, 2, the 2-dimethylbutyl, 1, the 1-dimethylbutyl, 1, the 2-dimethylbutyl, 1, the 3-dimethylbutyl, 2, the 3-dimethylbutyl, the 2-ethyl-butyl, 1, the 2-dimethyl propyl, n-heptyl, 2-methyl hexyl, 3-methyl hexyl, 2,2-dimethyl amyl group, 3,3-dimethyl amyl group, 2,3-dimethyl amyl group, 2,4-dimethyl amyl group, the 3-ethyl pentyl group, 2,2,3-trimethylammonium butyl, n-octyl, the 2-methylheptyl, the 3-methylheptyl, the 4-methylheptyl, 2,2-dimethyl hexyl, 3,3-dimethyl hexyl, 2,3-dimethyl hexyl, 2,4-dimethyl hexyl, 2,5-dimethyl hexyl, 3,4-dimethyl hexyl, the 3-ethylhexyl, 2,2,3-tri-methyl-amyl, 2,2, the 4-tri-methyl-amyl, 2,3,3-tri-methyl-amyl, 2,3, the 4-tri-methyl-amyl, 2-methyl-3-ethyl pentyl group, 3-methyl-3-ethyl pentyl group, 2,2,3,3-tetramethyl butyl etc.
" C of the present invention
1-8Alkoxyl group " refer to above-mentioned " C
1-8Alkyl " group that is connected with main structure by Sauerstoffatom, example includes but not limited to methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy, sec-butoxy, pentyloxy, neopentyl oxygen, hexyloxy, heptan oxygen base, octyloxy etc.
" C of the present invention
3-8Cycloalkyl " refer to contain the cyclic alkyl of 3 ~ 8 carbon atoms, specific examples includes but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group etc.
" C of the present invention
2-8Thiazolinyl " refer to contain carbon-to-carbon double bond; and carbonatoms is the aliphatic alkyl of 2 ~ 8 straight or branched; example includes but not limited to vinyl; the 1-propenyl; the 2-propenyl; the 1-methyl ethylene, the 1-butylene base, crotyl, the 3-butenyl, 1-methyl isophthalic acid-propenyl, 2-methyl isophthalic acid-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, the 1-pentenyl, pentenyl, the 3-pentenyl, the 4-pentenyl, 1-methyl isophthalic acid-butenyl, the 2-methyl-1-butene thiazolinyl, the 3-methyl-1-butene base, 1-methyl-2-butene base, 2-methyl-2-butene base, 3-methyl-2-butene base, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, the 1-hexenyl, the 2-hexenyl, the 3-hexenyl, the 4-hexenyl, the 5-hexenyl, 1-methyl-1-pentene thiazolinyl, 2-methyl-1-pentene thiazolinyl, 3-methyl-1-pentene thiazolinyl, the 4-methyl-1-pentene base, 1-methyl-pentenyl, 2-methyl-pentenyl, 3-methyl-pentenyl, 4-methyl-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-crotyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butylene base, 1,2-dimethyl-crotyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butylene base, 1,3-dimethyl-crotyl, 1,3-dimethyl-crotyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butylene base, 2,3-dimethyl-crotyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butylene base, 3,3-dimethyl-crotyl, 1-ethyl-1-butylene base, 1-ethyl-crotyl, 1-ethyl-3-butenyl, 2-ethyl-1-butylene base, 2-ethyl-crotyl, 2-ethyl-3-butenyl, 1,1,2-trimethylammonium-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl isophthalic acid-propenyl, 1-ethyl-2-methyl-2-propenyl, 1, the 3-divinyl, 1, the 3-pentadiene, 1, the 4-pentadiene, 1, the 4-hexadiene, the 1-heptenyl, the 2-heptenyl, the 3-heptenyl, the 4-heptenyl, the 5-heptenyl, the 6-heptenyl, 1-methyl isophthalic acid-hexenyl, 2-methyl isophthalic acid-hexenyl, 3-methyl isophthalic acid-hexenyl, 4-methyl isophthalic acid-hexenyl, 5-methyl isophthalic acid-hexenyl, 1-methyl-2-hexenyl, 2-methyl-2-hexenyl, 3-methyl-2-hexenyl, 4-methyl-2-hexenyl, 5-methyl-2-hexenyl, 1-methyl-3-hexenyl, 2-methyl-3-hexenyl, 3-methyl-3-hexenyl, 4-methyl-3-hexenyl, 5-methyl-3-hexenyl, 1-methyl-4-hexenyl, 2-methyl-4-hexenyl, 3-methyl-4-hexenyl, 4-methyl-4-hexenyl, 5-methyl-4-hexenyl, 1-methyl-5-hexenyl, 2-methyl-5-hexenyl, 3-methyl-5-hexenyl, 4-methyl-5-hexenyl, 5-methyl-5-hexenyl, 1,1-dimethyl-pentenyl, 1,1-dimethyl-3-pentenyl, 1,1-dimethyl-4-pentenyl, 1,2-dimethyl-1-pentenyl, 2,2-dimethyl-3-pentenyl, 2,2-dimethyl-4-pentenyl, 3,3-dimethyl-1-pentenyl, 3,3-dimethyl-4-pentenyl, 4,4-dimethyl-1-pentenyl, 4,4-dimethyl-pentenyl, the 1-octenyl, the 2-octenyl, the 3-octenyl, the 4-octenyl, the 5-octenyl, the 6-octenyl, 7-octenyl etc.
" C of the present invention
3-8Alkynyl " carbonatoms that refers to contain triple bond is the alkynyl of 3 ~ 8 straight or branched; and specific examples includes but not limited to the 1-proyl; 2-propynyl; the ethyl acetylene base; the 2-butyne base; the 3-butynyl, 3-methyl isophthalic acid-butynyl, the 1-pentynyl, the valerylene base, the 3-pentynyl, 3-methyl-1-pentene alkynyl, 4-methyl-1-pentene alkynyl, 4-methyl-valerylene base, 1-hexin base, 2-hexin base, 3-hexin base, 3-methyl isophthalic acid-hexin base, 3,4-dimethyl-1 hexin base, 1-heptyne base, 2-heptyne base, 3-heptyne base, 4 heptyne bases, 5-heptyne base, 4-methyl isophthalic acid-heptyne base, 1-octyne base, 2-octyne base, 3-octyne base, 4-octyne base, 4-ethyl-1-hexin base etc.
" C of the present invention
6-14Aryl " refer to contain the aromatic group of 6 ~ 14 carbon atoms, comprise 6 ~ 8 yuan of aryl and 8 ~ 14 yuan of fused ring aryl.6 ~ 8 yuan of aryl refer to whole undersaturated aryl, for example phenyl, cyclooctatetraene base etc.8 ~ 14 yuan of fused ring aryl refer to share the formed condensed ring group that to have a ring at least be undersaturated aromatic nucleus of two adjacent carbon atoms each other by two or more ring texturees, comprise 8 ~ 14 yuan of unsaturated fused ring aryl, for example naphthalene, phenanthrene etc., also comprise 8 ~ 14 yuan of fractional saturation fused ring aryl, for example benzo C
3-8Cycloalkyl, benzo C
4-8Cycloalkenyl group, specific examples be as 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetralyl, 1,4-dihydro naphthyl etc.
" 5 ~ 15 yuan of heteroaryls " of the present invention refers to contain 5 ~ 15 annular atomses undersaturated cyclic group with aromaticity of (wherein containing a heteroatoms at least), comprise 5 ~ 8 yuan of heteroaryls, 8 ~ 15 yuan of thick heteroaryls, described heteroatoms has nitrogen, oxygen and sulphur etc., comprises that simultaneously carbon atom, nitrogen-atoms and sulphur atom can be by oxos.
" 5 ~ 8 yuan of heteroaryls " refers to contain 5 ~ 8 annular atomses aromaticity cyclic group of (wherein containing a heteroatoms at least), specific examples include but are not limited to furyl, thienyl, pyrryl, thiazolyl, isothiazolyl, thiadiazolyl group,
Azoles base, different
The azoles base,
Di azoly, imidazolyl, pyrazolyl, 1,2,3-triazoles base, 1,2,4-triazolyl, 1,2,3-
Di azoly, 1,2,4-
Di azoly, 1,2,5-
Di azoly, 1,3,4-
Di azoly, pyridyl, 2-pyridone, 4-pyridone, pyrimidyl, 1,4-Dioxin base, 2H-1,2-
Piperazine base, 4H-1,2-
Piperazine base, 6H-1,2-
Piperazine base, 4H-1,3-
Piperazine base, 6H-1,3-
Piperazine base, 4H-1,4-
Piperazine base, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,3,4-triazinyl, 1,2,4,5-tetrazine base, oxepin base, thia cycloheptatriene base, nitrogen heterocyclic heptantriene base, 1,3-diazacyclo heptantriene base, nitrogen heterocyclic octatetraene base, 1,4-dihydro-1,4-diazacyclo sarohornene, 1,4-dioxane sarohornene etc." 5 ~ 6 yuan of heteroaryls " refers to contain 5 ~ 6 annular atomses aromaticity cyclic group of (wherein containing a heteroatoms at least), and its specific examples is referring to the specific examples of 5 ~ 6 annular atomses in " 5-8 unit heteroaryl ".
8 ~ 15 yuan of thick heteroaryls, refer to contain 8 ~ 15 annular atomses (wherein containing a heteroatoms at least) and share two adjacent atoms each other by two or more ring texturees and couple together the undersaturated condensed ring structure with aromaticity that forms, specific examples includes but not limited to benzofuryl, benzisoxa furyl, benzothienyl, indyl, isoindole, benzo
Azoles base, benzimidazolyl-, indazolyl, benzotriazole base, quinolyl, 2-quinolinone, 4-quinolinone, 1-isoquinolines, isoquinolyl, acridyl, phenanthridinyl, benzo pyridazinyl, phthalazinyl, quinazolyl, quinoxalinyl, phenol piperazine base, pteridine radicals, purine radicals, naphthyridinyl, phenazinyl, phenothiazinyl, benzo three furyls etc.
" 3-15 unit heterocyclic radical " of the present invention refers to contain the first cyclic group of one or more heteroatomic 3-15, and described " heteroatoms " is selected from N, S, O, CO, SO and/or SO
2Deng.Comprise 3-8 unit's heterocyclic radical and 6-15 unit fused heterocycle base.3-8 unit heterocyclic radical refers to contain 3-8 the annular atoms heterocyclic radical of (wherein containing a heteroatoms at least), the first heterocyclic radical of preferred 5-6.Specific examples includes but are not limited to 2,5-dihydro-thiophene base, 4,5-pyrazoline base, 3,4-dihydro-2H-pyranyl, 5,6-dihydro-4H-1,3-
Piperazine base, ethylenimine base, azetidinyl, Thietane base, tetrahydrofuran base, Pyrrolidine base, imidazolidyl, pyrazolidyl, tetrahydrofuran base, 1,4-dioxane base, 1,3-dioxane base, 1,3-dithian base, morpholinyl, piperazinyl etc.
6-15 unit fused heterocycle base, referring to contain 6-15 annular atoms (wherein containing a heteroatoms at least) shares two adjacent atoms each other by two or more ring texturees and couples together the condensed ring structure that forms, the first fused heterocycle base of preferred 6-10, structure as the heterocyclic radical formation of benzo 3-8 unit, the structure that 3-8 unit's heterocyclic radical and 3-8 unit heterocyclic radical form etc., specific examples includes but not limited to: 1,3-dihydro benzo furyl, benzo [d] [1.3] dioxa cyclopentenyl, isoindoline base, chromanyl, 1,2,3, the 4-Pyrrolidine also [3,4-c] pyrroles,
Tetramethylene and Pyrrolidine base, pentamethylene and Pyrrolidine base, azetidine and imidazolidyl,
Deng.
" 8~14 yuan of heterocyclic radicals " of the present invention refers to that annular atoms in above-mentioned " 3~15 yuan of heterocyclic radicals " example is 8~14 yuan specific examples.
" 3~15 yuan of heterocyclic radical C of the present invention
1-8Alkyl " refer to that " 3~15 yuan of heterocyclic radicals " passes through C
1-8The carbon atom of alkyl is connected to the group on the main structure, includes but not limited to pyridin-4-yl methyl, indoles-5-base ethyl etc.
" halo C of the present invention
1-8Alkyl, halo C
1-8Alkoxyl group " in " halo " refer to C
1-8Alkyl, C
1-8One or more hydrogen atom on the carbon atom in the alkoxyl group is replaced by halogen atom, and term " halogen atom " as mentioned before.
More specifically, the present invention relates to be selected from following one group of compound:
The invention still further relates to the method for preparation formula defined above (I) compound, reaction equation is as follows, but is not limited only to following method:
Step 1: the preparation of compound a
Raw material 1 is dissolved in the thionyl chloride, adds an amount of DMF(N, dinethylformamide), heating, reaction finishes, and concentrates, and gets compound a.
Step 2: the preparation of compound b
Compound a is dissolved in the toluene, adds (E)-3-dimethyl amido ethyl propenoate, triethylamine, heated and stirred, concentrated and purified, get compound b.
Step 3: the preparation of compound c
Compound b is dissolved among the DMF, adds raw material 2, stirring at room adds alkali, heats up and stirs, and extraction concentrates and separates out compound c.
Step 4: the preparation of compound d
Compound c is dissolved in tetrahydrofuran (THF) and the methyl alcohol, adds the methanol solution of KOH, react under the high temperature.Transfer pH with hydrochloric acid, the suction filtration solid, filtration cakes torrefaction gets compound d.
Step 5: the preparation of Verbindung
Compound d is dissolved in the methylene dichloride, adds triethylamine and chloroformic acid isopropyl ester under the low temperature, low-temp reaction for some time, add raw material 3 and triethylamine then, stirring reaction under the room temperature, washing, concentrate Verbindung.
Step 6: the preparation of formula (I) compound
Verbindung and raw material 4 are dissolved in the DMSO(dimethyl sulfoxide (DMSO)) in, add catalyzer, cuprous iodide and appropriate bases, microwave reaction under the high temperature, extraction after reaction finishes, purifies and separates gets formula (I) compound.
In the above reaction formula, radicals R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
7', R
8', R
9', L, ring A as mentioned before, X is halogen atom.
The above-mentioned arbitrary compound pharmacy acceptable salt of the present invention refers to comprise organic acid salt, inorganic acid salt, organic alkali salt, inorganic base salts by the salt of pharmaceutically acceptable, non-toxic bases or acid preparation.Organic acid salt comprises the salt of formic acid, acetic acid, Phenylsulfonic acid, phenylformic acid, tosic acid, camphorsulfonic acid, citric acid, methylsulfonic acid, ethyl sulfonic acid, propanesulfonic acid, fumaric acid, glyconic acid, L-glutamic acid, isethionic acid, lactic acid, toxilic acid, oxysuccinic acid, amygdalic acid, glactaric acid, pamoic acid, pantothenic acid, succsinic acid, tartrate etc.Inorganic acid salt comprises the salt of Hydrogen bromide, spirit of salt, nitric acid, sulfuric acid, phosphoric acid etc.Organic alkali salt comprises primary, the second month in a season and tertiary amine, be substituted amine and comprise naturally occurring replacement amine, cyclammonium and basic ion exchange resin, be selected from trimethyl-glycine, caffeine, choline, N, the salt of N '-dibenzyl-ethylenediamin, diethylamine, 2-diethylin ethanol, 2-dimethylamino-ethanol, thanomin, quadrol, N-ethyl-morpholine, N-ethylpiperidine, meglumine, glucosamine, Hai Baming, isopropylamine, methylglucosamine, morpholine, piperazine, piperidines, PROCAINE HCL, PHARMA GRADE, purine, Theobromine, triethylamine, Trimethylamine 99, tripropyl amine, Trometamol etc.The salt of natural amino acid salt such as glycine, L-Ala, Xie Ansuan, leucine, Isoleucine, nor-leucine, tyrosine, Gelucystine, halfcystine, methionine(Met), proline(Pro), oxyproline, Histidine, ornithine, Methionin, arginine, Serine etc.Inorganic base salts comprises the salt of ammonium and lithium, sodium, potassium, calcium, magnesium, zinc, barium, aluminium, iron, ketone, ferrous, manganese, bivalent manganese etc.The salt that is solid form can exist with the solvated compounds form, for example the form of hydrate.
The compounds of this invention contains one or more asymmetric centers, thereby can be used as racemic modification and racemic mixture, single enantiomer, non-enantiomer mixture and single diastereomer.The compounds of this invention has asymmetric center, and each will independently produce two optical isomers this class asymmetric center, and scope of the present invention comprises all possible optical isomer and non-enantiomer mixture and pure or partial-purified compound.The present invention includes all stereoisomeric forms in any ratio of these compounds.
Compound of the present invention unless stated otherwise, the present invention includes cis-isomeride and trans-isomer(ide) if contain olefinic double bonds.
Compound of the present invention can exist with tautomeric forms, and it has the tie point of different hydrogen by one or more double-bond shifts.For example, ketone and its enol form are the keto-enol tautomerism bodies.Each tautomer and composition thereof all is included in the compound of the present invention.
Compound, its pharmacy acceptable salt, its steric isomer shown in the logical formula I can be the solvated compounds forms.Solvated compounds is under the situation of hydrate, and hydration can be finished in preparation process or can be utilized the water absorbability of original anhydrous product to carry out gradually.
Another object of the present invention is treatment with undesirable inflammation immune response is feature or undesirable inflammation immune response relevant inflammatory disease, illness or the state of an illness and that brought out with the PDE4 supersecretion by TNF-α or relevant with the PDE4 supersecretion with TNF-α all diseases and the method for the state of an illness, and this method comprises described individual formula (I) compound that uses the treatment significant quantity.
Another object of the present invention is the method for the treatment of the inflammation state of an illness and immunity illness in the individuality that needs is arranged, and this method comprises described individual formula (I) compound that uses the treatment significant quantity.
The preferred inflammation state of an illness and immunity illness are selected from asthma, bronchial asthma, chronic obstructive pulmonary disease, allergic rhinitis, the eosinophilic granuloma, ephritis, rheumatoid arthritis, cystic fibrosis, chronic bronchitis, multiple sclerosis, Crohn disease, psoriasis, urticaria, adult vernal conjunctivitis, respiratory distress is comprehensively demonstrate,proved, rheumatoid spondylitis, osteoarthritis, urarthritis, uveitis, anaphylaxis conjunctivitis, inflammatory bowel disease, ulcerative colitis, eczema, atopic dermatitis and chronic inflammatory diseases.Allergic inflammatory diseases preferably.
Further preferably be selected from the inflammation state of an illness of lung, joint, eye, intestines, skin and heart or the inflammatory state of an illness and the immunity illness of immunity illness.
Further preferably be selected from the inflammatory conditions of bronchial asthma, ephritis and allergic rhinitis.
Another object of the present invention is the method that alleviates the inflammation of the organ or tissue that gets involved, and this method comprises to the formula of organ or tissue's delivery treatments significant quantity (I) compound.
The pharmaceutical composition of the arbitrary compound of the present invention, its pharmacy acceptable salt, its steric isomer or its solvated compounds and one or more pharmaceutical carriers and/or thinner can be applied to the patient who needs this treatment in the mode of oral or inhalation-type drug administration.
Can be made into conventional oral solid formulation when being applied to the patient who needs this treatment in oral mode, as tablet, capsule, pill, granule etc.; Also can be made into oral liquid, as oral solution, oral suspensions, syrup etc.Tablet means disk shape that medicine and suitable auxiliary materials and mixing compacting form or the solid preparation of special-shaped sheet, based on oral ordinary tablet, other has lozenge, Sublingual tablet, mouth paster, chewable tablet, dispersible tablet, fuse, effervescent tablet, slow releasing tablet, controlled release tablet and enteric coated tablet etc.Capsule means medicine or is added with the auxiliary material filling in Capsules or is sealed in solid preparation in the soft capsule material, according to its dissolving and release characteristics, can be divided into hard capsule (being commonly referred to as capsule), soft capsule (capsule and pill), slow releasing capsule, controlled release capsule and enteric coated capsule etc.Pill means that medicine evenly mixes with the auxiliary material that suits, and the spherical or near-spherical solid preparation so that proper method is made comprises dripping pill, sugar-pill, piller etc.Granule means that medicine and suitable auxiliary material make the dried particles shape preparation with certain particle size, can be divided into soluble particles (being commonly referred to as particle), mix suspension grain, effervescent granule, enteric coated particles, slow-releasing granules and controlled release granule etc.Oral solution means that medicine dissolution makes for oral clarified liq preparation in suitable solvent.Oral suspensions means the insoluble solid pharmaceutical, is dispersed in the liquid medium, makes for oral suspension body preparation, also comprises dry suspensoid or dense suspension.Syrup means the dense aqueous sucrose solution that contains medicine.
When making oral preparations, can add suitable weighting agent, tackiness agent, disintegrating agent, lubricant etc.Weighting agent commonly used comprises starch, Icing Sugar, calcium phosphate, calcium sulfate two water things, dextrin, Microcrystalline Cellulose, lactose, pregelatinized Starch, N.F,USP MANNITOL etc.; Typical binders comprises Xylo-Mucine, PVP – K30, hydroxypropylcellulose, starch slurry, methylcellulose gum, ethyl cellulose, hypromellose, gelling starch etc.; Disintegrating agent commonly used comprises dry starch, polyvinylpolypyrrolidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose etc.; Conventional lubricants comprises Magnesium Stearate, talcum powder, sodium lauryl sulphate, micropowder silica gel etc.
When being applied to the patient who needs this treatment in the mode of inhalation-type drug administration, be that formula (I) compound is sent with the form of pressurised aerosol.After homogenize, preferably with the micronization of formula (I) compound, for example in lactose, glucose, higher fatty acid, dioctyl sodium sulfosuccinate or most preferably in carboxymethyl cellulose micronization so that most of particle reaches 5 μ m or littler granularity.For sucking preparation, aerosol can be mixed with the gaseous state or the liquid propellent that are used for the dispersed activity material.Can use sucker or spraying gun.
The compounds of this invention has the following advantages:
(1) The compounds of this invention, its steric isomer of its pharmacy acceptable salt or its solvated compounds have better inhibited activity and anti-inflammatory action;
(2) The compounds of this invention, its steric isomer of its pharmacy acceptable salt or its solvated compounds demonstrate good biologically stable;
(3) The compounds of this invention preparation technology is simple, and medicine purity height, steady quality are easy to carry out large-scale commercial production.
Below further set forth the beneficial effect of The compounds of this invention by external pharmacological evaluation, but this should be interpreted as that The compounds of this invention only has following beneficial effect.
The external pharmacologically active of experimental example The compounds of this invention
Trial-product: part of compounds of the present invention, self-control, its chemical name and structural formula are as be shown in the examples.
Contrast medicine: MK-0873, self-control.
Experimental technique: Lance cAMP Assay:
Accurately take by weighing trial-product, add the DMSO dissolving, fully mixing is made into 100 μ M.Be 1 μ M with DMSO with above-mentioned mother liquor dilution then, 4 times are diluted to 0.0038nM then.
Add 2.5 μ L substrate 20nM cAMP, 50nL Compound D MSO solution in 384 orifice plates, add 2.5 μ L PDE enzyme (PDE4B1 0.18nM, PDE4D3 0.024nM) damping fluid (1 * HBSS, 5mM Hepes pH 7.4,3mM MgCl again
2, 0.1%BSA) behind the incubated at room 90min, add 5 μ L Alexa
Behind the 647-anti cAMP antibody incubation 30min, add after 10 μ L detection reagent hatch 60min, 665nm detects its LANCE signal, calculates inhibiting rate by following formula, calculates IC by inhibiting rate with XLfit
50Value.
Inhibiting rate=[signal value (MAX)-signal value (sample)] * 100/[signal value (MAX)-signal value (MIN)]
Annotate: MAX: not enzyme-added blank; MIN: the blank that does not add compound.
Experimental result and conclusion:
Table 1 The compounds of this invention is to PDE-4B1, the IC of PDE-4D3
50Value
Table 2 The compounds of this invention is to PDE-4B1, the IC of PDE-4D3
50Value
Table 3 The compounds of this invention is to PDE-4B1, the IC of PDE-4D3
50Value
Table 4 The compounds of this invention is to PDE-4B1, the IC of PDE-4D3
50Value
Table 5 The compounds of this invention is to PDE-4B1, the IC of PDE-4D3
50Value
Conclusion: by table 1-5 as seen, The compounds of this invention is suitable with the contrast medicine to inhibition activity and the anti-inflammatory action of PDE-4B1, PDE-4D3; And the same compound of the present invention is more or less the same to the inhibition activity of PDE-4B1 and PDE-4D3, the generation of vomiting side reaction in the time of can effectively reducing clinical application.
Embodiment
The embodiment of form is described in further detail foregoing of the present invention by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following examples.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
Embodiment 1 N-cyclopropyl-4-oxo-1-(3-(pyridin-3-yl oxygen base) phenyl)-1,4-dihydro-1,8-naphthyridines-3-methane amide (compound
1) preparation
(1) preparation of 2-chloro-3-pyridine acyl chlorides
With 2-chloro-3-pyridine carboxylic acid (15g 0.095mol) is dissolved in the thionyl chloride, adds DMF(N, dinethylformamide) (0.5mL), 70 ℃ were reacted 3 hours, concentrating under reduced pressure, and cooling is separated out, and gets product (13g, productive rate 78%).
(2) preparation of 2-(2-chloronicotinoyl base)-3-(dimethyl amido) ethyl propenoate
With 2-chloro-3-pyridine acyl chlorides (10g, 0.057mol) be dissolved in the toluene (200mL), add the TEA(triethylamine) (10.5g, 0.10mol), (E)-and 3-dimethyl amido ethyl propenoate (10g, 0.07mol), 90 ℃ were reacted 3 hours down, use the DCM(methylene dichloride) and the water extraction, the separation and purification of recycle silicon plastic column chromatography gets product (13g, productive rate 81%).
(3) 1-(3-bromophenyl)-4-oxo-1,4-dihydro-1, the preparation of 8-naphthyridines-3-ethyl formate
In 2-(2-chloronicotinoyl base)-3-(dimethyl amido) ethyl propenoate (7g 0.025mol) is dissolved in DMF(200mL), add m-bromoaniline (4.2g; 0.024mol) stirred 12 hours under the room temperature, add water and dichloromethane extraction, concentrating under reduced pressure; residuum is dissolved in DMF(200mL) in; add salt of wormwood (7g, 0.05mol), 90 ℃ of stirring reactions 5 hours; add water and dichloromethane extraction; concentrating under reduced pressure is separated out, and gets product (5.2g, productive rate 56%).
(4) 1-(3-bromophenyl)-4-oxo-1,4-dihydro-1, the preparation of 8-naphthyridines-3-formic acid
With 1-(3-bromophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridines-3-ethyl formate (2.1g, 5.6mmol) be dissolved in the mixing solutions (100mL) of tetrahydrofuran (THF) and methyl alcohol, add and be dissolved with KOH(potassium hydroxide) (70 ℃ were reacted 4 hours down for 2.5g, methanol solution 44.6mmol).With salt acid for adjusting pH value to 5, suction filtration, filter residue is got product (1.5g, productive rate 78%) through drying under reduced pressure.
(5) 1-(3-bromophenyl)-N-cyclopropyl-4-oxo-1,4-dihydro-1, the preparation of 8-naphthyridines-3-methane amide
With 1-(3-bromophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridines-3-formic acid (2.0g, 5.8mmol) be dissolved in the methylene dichloride (100mL) ,-15 ℃ add down triethylamine (1.2g, 0.012mol) and isopropyl chlorocarbonate (0.85g, 6.9mmol),-15 ℃ were reacted 4 hours down, and concentrating under reduced pressure is dissolved in DCM(100mL with residuum) in,-5 ℃ add triethylamine (1g, 9.9mmol), cyclopropylamine (0.285g, 5.0mmol), stirring reaction is 12 hours under the room temperature, washing, concentrating under reduced pressure gets product (1.5g, productive rate 67%).
(6) N-cyclopropyl-4-oxo-1-(3-(pyridin-3-yl oxygen base) phenyl)-1,4-dihydro-1, the preparation of 8-naphthyridines-3-methane amide
With 1-(3-bromophenyl)-N-cyclopropyl-4-oxo-1,4-dihydro-1,8-naphthyridines-3-methane amide (200mg, 0.52mmol), the 3-pyridone (60mg, 0.63mmol), 2-oxocyclopentyl ethyl formate (20mg, 0.13mmol), cuprous iodide (40mg, 0.21mmol), cesium carbonate (400mg, 1.3mmol) be dissolved in the DMSO(dimethyl sulfoxide (DMSO)) and (20mL) in, 90 ℃ of following microwave reactions 4 hours.Water and DCM extraction, organic phase preparation separate product (21mg, productive rate 10%).
Molecular formula: C
23H
18N
4O
3Molecular weight: 398.41 LC-MS:399.2 (M+H)
+
1H-NMR(400MHz,CDCl
3)δ:9.75(s,1H),9.01(s,1H),8.80(dd,1H),8.71(dd,1H),8.51(d,1H),8.43(d,1H),7.56(t,1H),7.48-7.42(m,2H),7.35-7.31(m,1H),7.22-7.18(m,2H),7.10-7.09(m,1H),2.99-2.97(m,1H),0.88-0.83(m,2H),0.69-0.65(m,2H).
Embodiment 2 3-((change by 3-(3-(cyclopropyl formamyl)-4-oxo-1,8-naphthyridines-1 (4H)-yl) phenoxy group) pyridine 1-oxide compound
The oxynitride of compound 1) preparation
Will be by the N-cyclopropyl-4-oxo-1-(3-(pyridin-3-yl oxygen base) phenyl)-1 of embodiment 1 preparation gained, 4-dihydro-1, (the 0.6g of 8-naphthyridines-3-methane amide, 1.5mmol) and metachloroperbenzoic acid (m-CPBA) (778mg, 4.5mmol) be dissolved in DCM(200mL) in, 40 ℃ of reactions 3 hours down.After reaction finishes, wash with water, dichloromethane extraction is got organic phase, anhydrous sodium sulfate drying, and the rotary evaporation desolventizing, (methylene dichloride: methyl alcohol=50:1) separation and purification gets product (100mg, productive rate 16%) to residuum with silica gel column chromatography.
Molecular formula: C
23H
18N
4O
4Molecular weight: 414.41LC-MS:415.2 (M+H)
+
1H-NMR(400MHz,CDCl
3)δ:9.75(s,1H),9.02(s,1H),8.79(dd,1H),8.75(dd,1H),8.16(s,1H),8.02(d,1H),7.60(m,1H),7.50-7.47(m,1H),7.32-7.30(m,1H),7.28-7.23(m,2H),7.21-7.20(m,1H),7.04-7.02(m,1H),3.02-2.95(m,1H),0.88-0.84(m,2H),0.69-0.65(m,2H).
Embodiment 3 N-cyclopropyl-4-oxo-1-(3-(pyridin-3-yl sulfenyl) phenyl)-1,4-dihydro-1,8-naphthyridines-3-methane amide (compound
2) preparation
(1) preparation of 3-nitro thiophenol
(20g 65mmol) is dissolved in the tetrahydrofuran (THF) (200mL) with 1,2-two (3-nitrophenyl) disulphanes, under 0 ℃ of condition, dropwise add sodium borohydride (8g, 211mmol), behind the room temperature reaction 10 hours, use the dilute hydrochloric acid cancellation, the ethyl acetate dilution is washed with saturated sodium-chloride, get organic phase, anhydrous sodium sulfate drying, rotary evaporation desolventizing get product (10g, productive rate 99%).
(2) preparation of 3-((3-nitrophenyl) sulfenyl) pyridine
Under nitrogen protection; with cuprous bromide (758mg; 5.3mmol), 2-oxo naphthenic acid ethyl ester (1.8mg, 10.6mmol) and cesium carbonate (33g 0.1mol) is dissolved in the dimethyl sulfoxide (DMSO) (100mL); after the stirring at room 0.5 hour; add the 3-nitro thiophenol (8g, 52mmol) and the 3-iodine pyridine (13g, 63mmol); under 110 ℃ of conditions, stirred 5 hours.After reaction finished, cooling was filtered, and removes dimethyl sulfoxide (DMSO), residuum is dissolved in the ethyl acetate washing, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, and residuum usefulness silica gel column chromatography (sherwood oil: ethyl acetate=3:1) must product (7g, productive rate 60%).
(3) preparation of 3-(pyridin-3-yl sulfenyl) aniline
3-((3-nitrophenyl) sulfenyl) pyridine (6g, 26mmol) and Pd/C(1g) is dissolved in the methyl alcohol, in the hydrogen system, stirring at room 3 hours.Filter, the rotary evaporation desolventizing gets product (5g, productive rate 95%).
(4) preparation of 2-chloronicotinoyl chloride
(60g 0.38mol) is dissolved in the sulfur oxychloride (400mL), under 70 ℃ of conditions, stirs 3 hours, and the rotary evaporation desolventizing gets product (56g, productive rate 84%) with the 2-chlorine apellagrin.
(5) preparation of 2-(2-chloronicotinoyl base)-3-(dimethylamino) ethyl propenoate
(56g in toluene 0.32mol) (500mL) solution, adds triethylamine (96g to being dissolved with the 2-chloronicotinoyl chloride, 0.95mol), 3-(dimethylamino) ethyl propenoate (81.5g, 0.57mmol), mixed solution is under 90 ℃ of conditions, stirred 2 hours, after rotary evaporation is removed toluene, with ethyl acetate dilution, washing, anhydrous sodium sulfate drying, rotary evaporation goes out desolventizing, and (sherwood oil: ethyl acetate=10:1) separation and purification gets product (60g, productive rate 66%) to residuum with silica gel column chromatography.
(6) preparation of 2-(2-chloronicotinoyl base)-3-((3-(pyridin-3-yl sulfenyl) phenyl) amino) ethyl propenoate
(6.6g is 23.3mmol) and in 3-(pyridin-3-yl sulfenyl) aniline (3.9g 19.3mmol) is dissolved in DMF(30mL) with 2-(2-chloronicotinoyl base)-3-(dimethylamino) ethyl propenoate; mixed solution stirred 5 hours at ambient temperature, added salt of wormwood (5.3g; 38.4mmol), under 90 ℃ of conditions, stirred 3 hours; dilute with ethyl acetate; wash with water, merge organic layer, concentrating under reduced pressure obtains crude product; get product (5g, productive rate 53%) with re-crystallizing in ethyl acetate again.
(7) 4-oxo-1-(3-(pyridin-3-yl sulfenyl) phenyl)-1,4-dihydro-1, the preparation of 8-naphthyridines-3-formic acid
With 4-oxo-1-(3-(pyridin-3-yl sulfenyl) phenyl)-1,4-dihydro-1,8-naphthyridines-3-ethyl formate (2g, 5mmol) and potassium hydroxide (840mg 15mmol) is dissolved in the mixing solutions (15mL) of second alcohol and water, under 60 ℃ of conditions, stirs 5 hours.Cooling, to 5-6, ethyl acetate extraction is got organic layer to mixed solution with 2N salt acid for adjusting pH value, and with the saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, rotary evaporation go out desolventizing and get product (1.7g, productive rate 91%).
(8) N-cyclopropyl-4-oxo-1-(3-(pyridin-3-yl sulfenyl) phenyl)-1,4-dihydro-1, the preparation of 8-naphthyridines-3-methane amide
Under 0 ℃ of condition, to being dissolved with 4-oxo-1-(3-(pyridin-3-yl sulfenyl) phenyl)-1,4-dihydro-1, (1.7g is in dichloromethane solution 4.5mmol) for 8-naphthyridines-3-formic acid, add triethylamine (910mg, 9mmol) and isobutyl chlorocarbonate (685mg, 5mmol), stirring at room 1 hour, dropwise add cyclopropylamine (285mg, 5mmol), stirring at room 3 hours is diluted with methylene dichloride, washing, the saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, (methylene dichloride: methyl alcohol=20:1) separation and purification gets product (1.5g, productive rate 80%) to residuum with silica gel column chromatography.
Molecular formula: C
23H
18N
4O
2S molecular weight: 414.48 LC-MS:415.1 (M+H)
+
1H-NMR(400MHz,CDCl
3)δ:9.75(s,1H),9.02(s,1H),8.79(dd,1H),8.75(dd,1H),8.16(s,1H),8.02(d,1H),7.6(d,1H),7.50-7.47(m,1H),7.32-7.30(m,1H),7.28-7.23(m,2H),7.21-7.20(m,1H),7.04-7.02(m,1H),3.02-2.95(m,1H),0.88-0.84(m,2H),0.69-0.65(m,2H).
Embodiment 4 3-((3-(3-(cyclopropyl formamyl-4-oxo-1,8-naphthyridines-1 (4H)-yl) phenyl) sulfenyl) pyridine 1-oxide compound
The preparation of (oxynitride of compound 2)
(1) preparation of 3-iodine pyridine 1-oxide compound
With the 3-iodine pyridine (1g, 5.0mmol) and metachloroperbenzoic acid (1.6g 9.3mmol) is dissolved in the methylene dichloride (10mL), and room temperature reaction spends the night.Dilute with water, dichloromethane extraction is got organic layer, uses anhydrous sodium sulfate drying, and the rotary evaporation desolventizing gets crude product (1g, productive rate 90%), not purifiedly is directly used in next step reaction.
(2) preparation of 3-((3-nitrophenyl) sulfenyl) pyridine 1-oxide compound
Under nitrogen protection; with cuprous bromide (64mg; 0.45mmol), 2-oxo naphthenic acid ethyl ester (152mg, 0.9mmol) and cesium carbonate (2.9g 9mmol) joins in the dimethyl sulfoxide (DMSO) (20mL); after mixed solution stirs 0.5 hour at ambient temperature; add 3-iodine pyridine 1-oxide compound (1g, 4.5mmol) and the 3-nitro thiophenol (706mg, 4.5mmol); mixed solution stirred 5 hours under 110 ℃ of conditions.Cooling is filtered, and removes dimethyl sulfoxide (DMSO), the residuum acetic acid ethyl dissolution, washing, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, (sherwood oil: ethyl acetate=3:1) separation and purification gets product (600mg, productive rate 55%) to residuum with silica gel column chromatography.
(3) preparation of 3-((3-aminophenyl) sulfenyl) pyridine 1-oxide compound
3-((3-nitrophenyl) sulfenyl) pyridine 1-oxide compound (600mg, 2.4mmol) and Pd/C(100mg) is dissolved in the tetrahydrofuran (THF) (20mL), in the hydrogen system, room temperature reaction 3 hours.After reaction finishes, filter, the rotary evaporation desolventizing gets product (500mg, productive rate 95%).
(4) 3-(preparation of (3-(3-(ethoxy acetyl)-4-oxo-1,8-naphthyridines-1 (4H)-yl) phenyl) sulfenyl) pyridine 1-oxide compound
With 2-(2-chloronicotinoyl base)-3-(dimethylamino) ethyl propenoate (340mg; 1.2mmol) and 3-((3-aminophenyl) sulfenyl) pyridine 1-oxide compound (220mg; 1.0mmol) be dissolved in DMF(10mL) in; behind the room temperature reaction 3 hours; add salt of wormwood (276mg; 2mmol), under 90 ℃ of conditions, reacted 3 hours.After reaction finished, with the ethyl acetate dilution, washing was associated with several one-tenth, and concentrating under reduced pressure gets crude product, gets product (460mg) with re-crystallizing in ethyl acetate again.
(5) 3-(preparation of (3-(3-carboxyl-4-oxo-1,8-naphthyridines-1 (4H)-yl) phenyl) sulfenyl) pyridine 1-oxide compound
With 3-((3-(3-(ethoxy acetyl)-4-oxo-1; 8-naphthyridines-1 (4H)-yl) phenyl) pyridine 1-oxide compound (470mg sulfenyl); 1.1mmol) and potassium hydroxide (185mg 3.3mmol) is dissolved in the mixing solutions (7mL) of second alcohol and water, stirs under 60 ℃ of conditions 5 hours.Cooling, mixed solution 2N salt acid for adjusting pH value to 5 ~ 6, dichloromethane extraction.Get organic layer, use anhydrous sodium sulfate drying, the rotary evaporation desolventizing gets product (300mg, productive rate 70%).
(6) the 3-((preparation of 3-(3-(cyclopropyl formamyl-4-oxo-1,8-naphthyridines-1 (4H)-yl) phenyl) sulfenyl) pyridine 1-oxide compound
To being dissolved with 3-((3-(3-carboxyl-4-oxo-1,8-naphthyridines-1 (4H)-yl) phenyl) pyridine 1-oxide compound (210mg sulfenyl), 0.54mg) methylene dichloride (10mL) solution in, add triethylamine (109mg, 1.08mmol) and the chloroformic acid peopentyl ester (89mg 0.59mmol), adds amino-cyclopropane (34mg after 2 hours, 0.59mmol), continued room temperature reaction 2 hours.After reaction finishes, the rotary evaporation desolventizing, (methylene dichloride: methyl alcohol=20:1) separation and purification gets product (200mg, productive rate 86%) to residuum with silica gel column chromatography
Molecular formula: C
23H
18N
4O
3S molecular weight: 430.48 LC-MS:431.2 (M+H)
+
1H-NMR(400MHz,CDCl
3)δ:9.75(s,1H),9.02(s,1H),8.78~8.81(m,2H),8.20(s,1H),8.04~8.06(m,1H),7.59~7.64(m,3H),7.27~7.49(m,2H),7.21~7.22(m,2H),2.97~3.00(m,1H),0.76~0.89(m,2H),0.67~0.69(m,2H).
Embodiment 5 N-cyclopropyl-4-oxo-1-(3-(pyridin-3-yl sulfinyl) phenyl)-1,4-dihydro-1,8-naphthyridines-3-methane amide (is changed
Compound 3) preparation
Will be by the N-cyclopropyl-4-oxo-1-(3-(pyridin-3-yl sulfenyl) phenyl)-1 of embodiment 3 preparation gained, 4-dihydro-1, (100mg 0.24mmol) is dissolved in the mixing solutions of methylene dichloride and water 8-naphthyridines-3-methane amide, adds potassium hydrogen persulfate composite salts 2KHSO
5KHSO
4K
2SO
4(Oxone) (223g, 0.36mmol), stirring at room 5 hours is separated organic layer, uses the saturated sodium-chloride water washing, anhydrous Na
2SO
4Drying, (methylene dichloride: methyl alcohol=20:1) separation and purification gets product (50mg) to the recycle silicon plastic column chromatography.
Molecular formula: C
23H
18N
4O
3S molecular weight: 430.48 LC-MS:431.1 (M+H)
+
1H-NMR(400MHz,CDCl
3)δ:9.72(s,1H),8.97(s,1H),8.90(s,1H),8.79(m,1H),8.75(m,1H),8.65(m,1H),8.04(d,1H),7.84-7.71(m,3H),7.57-7.46(m,3H),3.00-2.96(m,1H),0.89-0.84(m,2H),0.69-0.65(m,2H).
Embodiment 6 N-cyclopropyl-4-oxo-1-(3-(pyridin-3-yl alkylsulfonyl) phenyl)-1,4-dihydro-1,8-naphthyridines-3-methane amide (chemical combination
Thing 4) preparation
To the N-cyclopropyl-4-oxo-1-(3-(pyridin-3-yl sulfenyl) phenyl)-1 that is dissolved with by embodiment 3 preparation gained, 4-dihydro-1, (100mg in methylene dichloride 0.24mmol) and the mixing solutions of water, adds 2KHSO to 8-naphthyridines-3 acrylic acid ethyl ester
5KHSO
4K
2SO
4(Oxone) (223mg, 0.36mmol), stirring at room 5 hours is separated organic layer, uses the saturated sodium-chloride water washing, anhydrous sodium sulfate drying, (methylene dichloride: methyl alcohol=20:1) separation and purification gets product (50mg) to the recycle silicon plastic column chromatography.
Molecular formula: C
23H
18N
4O
4S molecular weight: 446.48 LC-MS:447.2 (M+H)
+
1H-NMR(400MHz,CDCl
3)δ:9.70(s,1H),9.20(s,1H),8.96(s,1H),8.80~8.86(m,2H),8.64~8.66(m,1H),8.65(d,1H),8.25(d,1H),8.10~8.15(m,1H),7.68~7.79(m,2H),7.49~7.53(m,2H),2.98~2.99(m,1H),0.84~0.89(m,2H),0.67~0.70(m,2H).
Embodiment 7 3-((3-(3-(cyclopropyl formamyl-4-oxo-1,8-naphthyridines-1 (4H)-yl) phenyl) alkylsulfonyl) pyridine 1-oxide compound
The preparation of (oxynitride of compound 4)
N-cyclopropyl-4-oxo-the 1-(3-(pyridin-3-yl alkylsulfonyl) phenyl)-1 that will be prepared by embodiment 6; 4-dihydro-1; 8-naphthyridines-3-methane amide (300mg; 0.67mmol) and metachloroperbenzoic acid (m-CPBA) (407mg; 2mmol) be dissolved in the methylene dichloride (20mL), mixed solution stirred 10 hours at ambient temperature.After reaction finished, with methylene dichloride dilution, washing, saturated sodium-chloride water washing, anhydrous sodium sulfate drying, rotary evaporation desolventizing, (methylene dichloride: methyl alcohol=20:1) separation and purification got product (50mg, productive rate 16%) to residuum with silica gel column chromatography.
Molecular formula: C
23H
18N
4O
5S molecular weight: 462.48 LC-MS:463.1 (M+H)
+
1H-NMR(400MHz,CDCl
3)δ:9.74(s,1H),8.98(s,1H),8.83(d,1H),8.71~8.72(m,2H),8.31(d,1H),8.11~8.13(m,2H),7.81~7.85(m,1H),7.74~7.77(m,2H),7.44~7.54(m,2H),2.97~3.00(m,1H),0.85~0.90(m,2H),0.66~0.70(m,2H).
Embodiment 8 N-cyclopropyl-4-oxo-1-(2-(pyridin-3-yl ethynyl) pyrimidine-4-yl)-1,4-dihydro-1,8-naphthyridines-3-methane amide
The preparation of (compound 6)
(1) 1-(2-chloropyrimide-4-yl)-4-oxo-1,4-dihydro-1, the preparation of 8-naphthyridines-3-ethyl formate
With 4-oxo-1,4-dihydro-1 in the 8-naphthyridines-3-ethyl formate (10.9g 0.05mol) is dissolved in DMF(100mL), reacts after 30 minutes, and add sodium hydride (2.4g 0.1mol), adds 2,4-dichloro pyrimidine after 2 hours in batches.Reaction is stirred and is spent the night, and adds water (3mL cancellation.Reaction mixture is used DCM(200mL * 3) and salt solution (200mL) extraction, the organic phase anhydrous sodium sulfate drying that merges, vacuum decompression concentrates, (sherwood oil: ethyl acetate=2:1 ~ methylene dichloride: methyl alcohol=20:1) separation and purification obtains solid product (1.35g, productive rate 8.3%) to silica gel column chromatography.
(2) 1-(2-iodine pyrimidine-4-yl)-4-oxo-1,4-dihydro-1, the preparation of 8-naphthyridines-3-ethyl formate
With 1-(2-chloropyrimide-4-yl)-4-oxo-1,4-dihydro-1, (2.2g 6.65mmol) is dissolved in 40% the hydroiodic acid HI (10mL) 8-naphthyridines-3-ethyl formate, and room temperature reaction stirs and spends the night.Reaction finishes, and regulates pH ≈ 9-10 with ammoniacal liquor, uses DCM(100mL * 3 then) extract three times, anhydrous sodium sulfate drying, the rotary evaporation desolventizing obtains solid product (1.2g, productive rate 43%).
(3) 4-oxo-1-(2-(pyridin-3-yl ethynyl) pyrimidine-4-yl)-1,4-dihydro-1, the preparation of 8-naphthyridines-3-ethyl formate
With 1-(2-iodine pyrimidine-4-yl)-4-oxo-1,4-dihydro-1,8-naphthyridines-3-ethyl formate (1.2g, 2.84mmol), the 3-ethynyl pyridine (0.35g, 3.41mmol), cuprous iodide (0.16g, 0.85mmol), Pd (pph
3)
2Cl
2In ([1,1'-two (diphenylphosphine) ferrocene] palladium chloride) (0.6g 0.85mmol) and TEA(0.72g, 7.1mmol) is dissolved in DMF(10mL), stirred overnight at room temperature.Mixture extracts with DCM, the saturated nacl aqueous solution washing, and anhydrous sodium sulfate drying, (methylene dichloride: methyl alcohol=100:1 ~ 25:1) separation and purification obtains solid product (0.5g, productive rate 44%) to silica gel column chromatography.
(4) 4-oxo-1-(2-(pyridin-3-yl ethynyl) pyrimidine-4-yl)-1,4-dihydro-1, the preparation of 8-naphthyridines-3-formic acid
With the LiOH(lithium hydroxide) (0.84g 0.02mol) is dissolved in methyl alcohol (5mL) solution, adds 4-oxo-1-(2-(pyridin-3-yl ethynyl) pyrimidine-4-yl)-1,4-dihydro-1,8-naphthyridines-3-carboxylic acid, ethyl ester (0.6g, 1.5mmol), spend the night by the stirring at room reaction.Aqueous hydrochloric acid with 10% is regulated pH ≈ 3-4.Mixed solution extracts with DCM, and vacuum decompression concentrates and obtains solid product (0.54g, productive rate 97%).
(5) N-cyclopropyl-4-oxo-1-(2-(pyridin-3-yl ethynyl) pyrimidine-4-yl)-1,4-dihydro-1, the preparation of 8-naphthyridines-3-methane amide
With 4-oxo-1-(2-(pyridin-3-yl ethynyl) pyrimidine-4-yl)-1,4-dihydro-1,8-naphthyridines-3-formic acid (0.54g, 1.46mmol) be dissolved in DCM(5mL), add the chloroformic acid tert-butyl ester (0.2g, 1.46mmol) and TEA(0.18g, 1.76mmol), mixture stirring at room 3 hours is directly used in next step reaction without purification.
In reaction mixture, add cyclopropylamine (0.17g, 2.92mmol), stirred overnight at room temperature, reaction mixture washs with saturated nacl aqueous solution, anhydrous sodium sulfate drying, vacuum decompression concentrates, and (methylene dichloride: methyl alcohol=100:1 ~ 30:1) separation and purification gets product (0.12g, productive rate 20%) to silica gel column chromatography.
Molecular formula: C
23H
16N
6O
2Molecular weight: 408.41 LC-MS:409.2 (M+H)
+
1H-NMR(400MHz,CDCl
3)δ:8.99(s,1H),8.60(s,1H),8.56(s,1H),8.44(s,1H),8.42(s,1H),8.36(s,1H),7.93(s,1H),7.40(s,1H),7.27(s,1H),7.17(s,1H),3.12(s,1H),1.02-0.92(m,5H)
Embodiment 9 3-((4-(3-(cyclopropyl formamyl)-4-oxo-1,8-naphthyridines-1 (4H)-yl) pyrimidine-2-base) ethynyl) pyridine 1-
The preparation of oxide compound (oxynitride of compound 6)
N-cyclopropyl-4-oxo-the 1-(2-(pyridin-3-yl ethynyl) pyrimidine-4-yl)-1 that will be prepared by embodiment 8,4-dihydro-1, and 8-naphthyridines-3-methane amide (0.15g, 0.367mmol) and m-CPBA(0.127g, 0.735mmol) be dissolved in DCM(5mL) in, stirred overnight at room temperature.Reaction mixture washs with saturated nacl aqueous solution, anhydrous sodium sulfate drying, and (methylene dichloride: methyl alcohol=100:1 ~ 20:1) separation and purification gets product (0.06g) to silica gel column chromatography.
Molecular formula: C
23H
16N
6O
3Molecular weight: 424.41 LC-MS:425.2 (M+H)
+
1H-NMR(400MHz,CDCl
3)δ:8.99(s,1H),8.59(s,1H),8.56(s,1H),8.44(s,1H),8.34(s,1H),8.22(s,1H),7.50(s,1H),7.29(s,1H),7.20(s,1H),7.17(s,1H),3.15(s,1H),1.14-0.74(m,5H).
With reference to above-mentioned preparation method, can also prepare following compound:
Claims (13)
1. lead to compound, its pharmacy acceptable salt, its steric isomer or its solvated compounds shown in the formula I:
Wherein, R
1Be hydrogen ,-C (O)-R
a,-S (O)
q-R
a, be not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkyl, the C that is not substituted or is replaced by 1 ~ 3 Q
1-8Alkoxyl group is not substituted or the optional C that is replaced by 1 ~ 3 Q
3-8Cycloalkyl is not substituted or the optional C that is replaced by 1 ~ 3 Q
2-8Thiazolinyl is not substituted or the optional C that is replaced by 1 ~ 3 Q
3-8Alkynyl is not substituted or the optional C that is replaced by 1 ~ 3 Q
6-14Aryl is not substituted or optional 5 ~ 15 yuan of heteroaryls that replaced by 1 ~ 3 Q, or is not substituted or optional 3 ~ 15 yuan of heterocyclic radical C that replaced by 1 ~ 3 Q
1-8Alkyl;
R
2Be hydrogen, be not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkyl, or be not substituted or the optional C that is replaced by 1 ~ 3 Q
3-8Cycloalkyl;
R
3, R
4, R
5And R
6Be hydrogen independently respectively, halogen atom ,-C (O)-R
a,-S (O)
q-R
a, nitro, cyano group ,-NR
aR
a', be not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkyl, or be not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkoxyl group;
R
7Be hydrogen, be not substituted or the optional phenyl that is replaced by 1 ~ 3 Q, thienyl, pyriconyl,
The azoles base,
Di azoly, thiazolyl or thiadiazolyl group are not substituted or choose wantonly by pyridyl, pyrimidyl, indyl, quinolyl or the imidazolyl of 1 ~ 3 Q replacement and their oxynitride, are not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkyl, or be not substituted or the optional C that is replaced by 1 ~ 3 Q
3-8Cycloalkyl;
R
7' do not exist, hydrogen, be not substituted or the optional phenyl that is replaced by 1 ~ 3 Q, thienyl, pyriconyl,
The azoles base,
Di azoly, thiazolyl or thiadiazolyl group are not substituted or choose wantonly by pyridyl, pyrimidyl, indyl, quinolyl or the imidazolyl of 1 ~ 3 Q replacement and their oxynitride, are not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkyl, or be not substituted or the optional C that is replaced by 1 ~ 3 Q
3-8Cycloalkyl;
And R
7' for be not substituted or the optional phenyl that is replaced by 1 ~ 3 Q, thienyl, pyriconyl,
The azoles base,
Di azoly, thiazolyl or thiadiazolyl group, or be not substituted or when optional pyridyl, pyrimidyl, indyl, quinolyl or the imidazolyl that is replaced by 1 ~ 3 Q and their oxynitride R
1Be hydrogen ,-C (O)-R
a,-S (O)
q-R
a, be not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkyl is not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkoxyl group is not substituted or the optional C that is replaced by 1 ~ 3 Q
3-8Cycloalkyl is not substituted or the optional C that is replaced by 1 ~ 3 Q
2-8Thiazolinyl is not substituted or the optional C that is replaced by 1 ~ 3 Q
3-8Alkynyl is not substituted or the optional C that is replaced by 1 ~ 3 Q
6-14Aryl, or be not substituted or optional 3 ~ 15 yuan of heterocyclic radical C that replaced by 1 ~ 3 Q
1-8Alkyl;
R
8Be hydrogen, halogen atom, nitro, cyano group ,=N-O-C
1-8Alkyl ,-O-N=C
1-8Alkyl ,-CH (N=NOH)-C
1-8Alkyl ,-NR
aR
a' ,-C (O)-R
a,-C (O) NR
aR
a' ,-NR
aC (O) R
a' ,-S (O)
q-R
a,-S (O)
q-NR
aR
a' ,-NR
a-S (O)
q-R
a' ,-C (O) OR
aGroup, be not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkyl is not substituted or the optional C that is replaced by 1 ~ 3 Q
3-8Cycloalkyl is not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkoxyl group is not substituted or the optional C that is replaced by 1 ~ 3 Q
6-14Aryl is not substituted or optional 5 ~ 15 yuan of heteroaryls that replaced by 1 ~ 3 Q, or is not substituted or optional 3 ~ 15 yuan of heterocyclic radical C that replaced by 1 ~ 3 Q
1-8Alkyl;
R
8' there are not hydrogen, halogen atom, nitro, cyano group ,=N-O-C
1-8Alkyl ,-O-N=C
1-8Alkyl ,-CH (N=NOH)-C
1-8Alkyl ,-NR
aR
a' ,-C (O)-R
a,-C (O) NR
aR
a' ,-NR
aC (O) R
a' ,-S (O)
q-R
a,-S (O)
q-NR
aR
a' ,-NR
a-S (O)
q-R
a' ,-C (O) OR
aGroup, be not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkyl is not substituted or the optional C that is replaced by 1 ~ 3 Q
3-8Cycloalkyl is not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkoxyl group is not substituted or the optional C that is replaced by 1 ~ 3 Q
6-14Aryl is not substituted or optional 5 ~ 15 yuan of heteroaryls that replaced by 1 ~ 3 Q, or is not substituted or optional 3 ~ 15 yuan of heterocyclic radical C that replaced by 1 ~ 3 Q
1-8Alkyl;
R
9Be hydrogen, hydroxyl, halogen atom ,-NR
bR
b', or be not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkyl;
R
9' there are not hydrogen, hydroxyl, halogen atom ,-NR
bR
b', or be not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkyl;
Ring A is phenyl, contains 1 ~ 45 ~ 8 yuan of heteroaryl that are selected from N, S, O, or contains 1 ~ 4 8~14 yuan of heterocyclic radical that are selected from N, S, O;
L represents-O-,-S (O)
q-, 1,1-cyclopropane base, carbonyl, vinyl, methylene radical, ethyl, or ethynyl, and when L was ethynyl, ring A can not be phenyl;
Q is selected from 0,1 or 2;
R
a, R
a' be selected from hydrogen, be not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkyl is not substituted or the optional C that is replaced by 1 ~ 3 Q
3-8Cycloalkyl is not substituted or the optional C that is replaced by 1 ~ 3 Q
3-8Cycloalkyl C
1-8Alkyl is not substituted or the optional C that is replaced by 1 ~ 3 Q
6-14Aryl, or be not substituted or optional 3 ~ 15 yuan of heterocyclic radicals that replaced by 1 ~ 3 Q;
Q is selected from hydroxyl, carboxyl, nitro, cyano group, halogen atom, C
1-8Alkyl, C
3-8Cycloalkyl, C
1-8Alkoxyl group, halo C
1-8Alkyl, halo C
1-8Alkoxyl group ,-NR
bR
b' ,-C (O)-R
b,-C (O) NR
bR
b' ,-NR
bC (O) R
b' ,=N-O-C
1-8Alkyl ,-O-N=C
1-8Alkyl ,-S (O)
q-R
b,-S (O)
q-NR
bR
b' ,-NR
b-S (O)
q-R
b', or-C (O) OR
bGroup, R wherein
b, R
b' be respectively hydrogen, C independently
1-8Alkyl, C
3-8Cycloalkyl or C
6-14Aryl.
2. compound as claimed in claim 1, its pharmacy acceptable salt, its steric isomer or its solvated compounds:
Wherein, R
1Be hydrogen ,-C (O)-R
a,-S (O)
q-R
a, be not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkyl is not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkoxyl group is not substituted or the optional C that is replaced by 1 ~ 3 Q
3-8Cycloalkyl is not substituted or the optional C that is replaced by 1 ~ 3 Q
6-14Aryl, or be not substituted or optional 5 ~ 15 yuan of heteroaryls that replaced by 1 ~ 3 Q;
R
2Be hydrogen, or be not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkyl;
R
3, R
4, R
5And R
6Be hydrogen independently respectively, halogen atom ,-C (O)-R
a,-S (O)
q-R
a, nitro, cyano group ,-NR
aR
a', the C that is not substituted or is replaced by 1 ~ 3 substituting group
1-8Alkyl, or be not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkoxyl group;
R
7For be not substituted or the optional phenyl that is replaced by 1 ~ 3 Q, thienyl, pyriconyl,
The azoles base,
Di azoly, thiazolyl or thiadiazolyl group, or be not substituted or choose wantonly by pyridyl, pyrimidyl, indyl, quinolyl or the imidazolyl of 1 ~ 3 Q replacement and their oxynitride;
R
7' do not exist, be not substituted or the optional phenyl that is replaced by 1 ~ 3 Q, thienyl, pyriconyl,
The azoles base,
Azoles base, thiazolyl or thiadiazolyl group, or be not substituted or choose wantonly by pyridyl, pyrimidyl, indyl, quinolyl or the imidazolyl of 1 ~ 3 Q replacement and their oxynitride;
And R
7' for be not substituted or the optional phenyl that is replaced by 1 ~ 3 Q, thienyl, pyriconyl,
The azoles base,
Di azoly, thiazolyl or thiadiazolyl group, or be not substituted or when optional pyridyl, pyrimidyl, indyl, quinolyl or the imidazolyl that is replaced by 1 ~ 3 Q and their oxynitride R
1Be hydrogen ,-C (O)-R
a,-S (O)
q-R
a, be not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkyl is not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkoxyl group is not substituted or the optional C that is replaced by 1 ~ 3 Q
3-8Cycloalkyl, or be not substituted or the optional C that is replaced by 1 ~ 3 Q
6-14Aryl;
R
8Be hydrogen, halogen atom ,-NR
aR
a' ,-C (O)-R
a,-C (O) NR
aR
a' ,-NR
aC (O) R
a' ,-S (O)
q-R
a,-S (O)
q-NR
aR
a' ,-NR
a-S (O)
q-R
a' ,-C (O) OR
aGroup, or be not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkyl;
R
8' there are not hydrogen, halogen atom ,-NR
aR
a' ,-C (O)-R
a,-C (O) NR
aR
a' ,-NR
aC (O) R
a' ,-S (O)
q-R
a,-S (O)
q-NR
aR
a' ,-NR
a-S (O)
q-R
a' ,-C (O) OR
aGroup, or be not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkyl;
R
9Be hydrogen, hydroxyl, halogen atom is not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkyl;
R
9' do not exist, hydrogen, hydroxyl, halogen atom, or be not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkyl;
Ring A is phenyl, contains 1 ~ 4 5-8 unit heteroaryl that is selected from N, S, O, or contains 1 ~ 48 ~ 14 yuan of heterocyclic radical that are selected from N, S, O;
L is-O--S (O)
q-, 1,1-cyclopropane base, carbonyl, methylene radical, ethyl, or ethynyl, and when L was ethynyl, ring A can not be phenyl;
Q is selected from 0,1 or 2;
R
a, R
a' be selected from hydrogen, be not substituted or the optional C that is replaced by 1 ~ 3 Q
1-8Alkyl;
Q is selected from hydroxyl, carboxyl, cyano group, halogen atom, C
1-8Alkyl, C
3-8Cycloalkyl, C
1-8Alkoxyl group, halo C
1-8Alkoxyl group ,-NR
bR
b' ,-C (O)-R
b,-C (O) NR
bR
b' ,-NR
bC (O) R
b' ,-S (O)
q-R
b,-S (O)
q-NR
bR
b' ,-NR
b-S (O)
q-R
b', or-C (O) OR
bGroup, R wherein
b, R
b' be respectively hydrogen or C independently
1-8Alkyl.
3. compound as claimed in claim 2, its pharmacy acceptable salt, its steric isomer or its solvated compounds:
Wherein, R
1Be hydrogen, methyl, ethyl, propyl group, sec.-propyl, cyclopropyl, cyclobutyl, or cyclopentyl;
R
2Be hydrogen, or methyl;
R
3, R
4, R
5And R
6Be hydrogen independently respectively, methyl, fluorine atom, chlorine atom, or bromine atoms;
R
8, R
9Be hydrogen independently respectively, methyl, fluorine atom, chlorine atom, methyl sulphonyl, or 2-hydroxyl sec.-propyl;
R
7' do not exist;
R
8', R
9' do not exist.
4. as each described compound of claim 1 ~ 3, its pharmacy acceptable salt, its steric isomer or its solvated compounds:
Wherein,
Ring A is phenyl, or contains 1 ~ 3 5-6 unit heteroaryl that is selected from N, S, O;
L is-O--S (O)
q-, 1,1-cyclopropane base, carbonyl, vinyl, methylene radical, ethyl, or ethynyl, and when L was ethynyl, ring A can not be phenyl.
5. compound as claimed in claim 4, its pharmacy acceptable salt, its steric isomer or its solvated compounds:
Wherein,
Ring A is phenyl, or contains 1 ~ 3 5-6 unit heteroaryl that is selected from N;
L is-O--S (O)
q-, 1,1-cyclopropane base, carbonyl, vinyl, methylene radical, ethyl, or ethynyl, and when L was ethynyl, ring A can not be phenyl.
6. compound as claimed in claim 5, its pharmacy acceptable salt, its steric isomer or its solvated compounds:
Wherein,
Ring A is phenyl, pyrryl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidyl, or pyrazinyl;
L is-O--S (O)
q-, 1,1-cyclopropane base, carbonyl, vinyl, methylene radical, ethyl, or ethynyl, and when L was ethynyl, ring A can not be phenyl.
7. as each described compound of claim 1 ~ 3, its pharmacy acceptable salt, its steric isomer or its solvated compounds:
Wherein,
L is-O-,-S-, and-S (O)-,-S (O)
2-, 1,1-cyclopropane base, carbonyl, vinyl, methylene radical, or ethynyl, and when L was ethynyl, ring A can not be phenyl.
8. compound as claimed in claim 7, its pharmacy acceptable salt, its steric isomer or its solvated compounds:
Wherein,
L is-O-,-S-, and-S (O)-,-S (O)
2-, 1,1-cyclopropane base, or ethynyl, and when L was ethynyl, ring A can not be phenyl.
9. as each described compound of claim 1 ~ 3, its pharmacy acceptable salt, its steric isomer or its solvated compounds:
Wherein, R
7Be pyridyl or their oxynitride.
10. as each described compound of claim 1 ~ 3, its pharmacy acceptable salt, its steric isomer or its solvated compounds:
Wherein,
R
7Be pyridyl or their oxynitride;
Ring A is phenyl, pyridyl, pyrimidyl, or pyrazinyl;
L is-O-,-S-, and-S (O)-,-S (O)
2-, or ethynyl, and when L was ethynyl, ring A can not be phenyl.
12. as the pharmaceutical composition of each described compound of claim 1 ~ 11, its pharmacy acceptable salt, its steric isomer or its solvated compounds and one or more pharmaceutical carriers and/or thinner, be pharmaceutically acceptable arbitrary formulation.
13. as the application in the medicine that for the preparation for the treatment of with undesirable inflammatory immune response is feature or inflammatory diseases, illness and the state of an illness relevant with undesirable inflammatory immune response and all diseases that brought out by TNF-α and PDE-4 supersecretion or relevant with the PDE-4 supersecretion with TNF-α of each described compound of claim 1 ~ 11, its pharmacy acceptable salt, its steric isomer or its solvated compounds.
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