CN101087765A - Fused pyrazole derivatives and uses of methods of treatment of metabolic-related disorders thereof - Google Patents
Fused pyrazole derivatives and uses of methods of treatment of metabolic-related disorders thereof Download PDFInfo
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- CN101087765A CN101087765A CN 200580044454 CN200580044454A CN101087765A CN 101087765 A CN101087765 A CN 101087765A CN 200580044454 CN200580044454 CN 200580044454 CN 200580044454 A CN200580044454 A CN 200580044454A CN 101087765 A CN101087765 A CN 101087765A
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Abstract
The present invention relates to certain fused pyrazole derivatives of Formula (Ia), and pharmaceutically acceptable salts thereof, which exhibit useful pharmacological properties, for example, as agonists for the RUP25 receptor. Also provided by the present invention are pharmaceutical compositions containing compounds of the invention, and methods of using the compounds and compositions of the invention in the treatment of metabolic-related disorders, including dyslipidemia, atherosclerosis, coronary heart disease, insulin resistance, type 2 diabetes, Syndrome-X and the like. In addition, the present invention also provides for the use of the compounds of the invention in combination with other active agents such as those belonging to the class of alpha-glucosidase inhibitors, aldose reductase inhibitors, biguanides, HMG-CoA reductase inhibitors, squalene synthesis inhibitors, fibrates, LDL catabolism enhancers, angiotensin converting enzyme (ACE) inhibitors, insulin secretion enhancers, DP receptor antagonists, and the like.
Description
Technical field
The present invention relates to some fused pyrazole derivatives and its pharmaceutically acceptable salt, its (for example) represents useful pharmacological characteristics as the agonist of niacin acceptor (RUP25).The present invention also provides the medical composition that contains one or more compounds of the present invention, and uses compound of the present invention and combination treatment to comprise the method for the metabolic-related disorders of following illness: hyperlipemia, atherosclerosis, coronary heart disease, insulin resistant, diabetes B, X syndromes and similar conditions.In addition, the present invention also provides and purposes such as the The compounds of this invention of other promoting agents combination of those promoting agents that belong to following classification: alpha-glucosidase inhibitor, aldose reductase inhibitor, biguanides, HMG-CoA reductase inhibitor, squalene synthetic inhibitor, Bei Te, LDL katabolism toughener, angiotonin saccharase (ACE) inhibitor, insulin secretion enhancers, thiazolidinedione, DP receptor antagonist and its similar classification.
Background technology
Compound of the present invention is separated agent as lipotropism
In the U.S., atherosclerosis and apoplexy are the first and the 3rd essential factor of masculinity and femininity death.Diabetes B is the public health problem of serious, general and sustainable growth.High level low-density lipoprotein (LDL) cholesterol or low-level high-density lipoprotein (HDL) (HDL) cholesterol are atherosclerosis and the pathological Hazard Factor of relevant cardiovascular independently.High-level in addition blood plasma free fatty acid is relevant with insulin resistant and diabetes B.The strategy of a kind of LDL of reduction cholesterol, rising HDL cholesterol and reduction blood plasma free fatty acid is the steatolysis that suppresses fatty tissue.Described method comprises the hormone-sensitive lipase of adjusting as the lipolysis rate restriction enzyme.The steatolysis agent increases the cell levels of cAMP, and it causes the responsive lipase of activation hormone in adipocyte.On the contrary, the medicament that reduces intracellular cAMP level is separated lipotropism.
In addition, it should be noted that also the increase downward modulation adiponectin of cAMP cell levels is from the secretion of adipocyte [Delporte, people such as ML, Biochem J (2002) July].Blood plasma adiponectin level decline relevant with the metabolic-related disorders that comprises atherosclerosis, coronary heart disease, insulin resistant and diabetes B [Matsuda, people such as M, J Biol Chem (2002) July and the content of wherein being looked back].
Niacin (niacin usp (niacin), Nicotinicum Acidum) is the required water-soluble vitamins of HUMAN HEALTH, growth and breeding; It is the part of vitamin B complex.Niacin also is to be used for one of medicine for the treatment of hyperlipemia the earliest.It is a valuable drug, because it advantageously influences above listed nearly all lipid parameter [Pharmacological Basis of Therapeutics of Goodman and Gilman, editor Harmon JG and Limbird LE, the 36th chapter, Mahley RW and Bersot TP (2001) 971-1002 pages or leaves].In 6 main clinical trials, proved the benefit [Guyton JR (1998) Am J Cardiol82:18U-23U] of niacin in treatment or the atherosis cardiovascular disease of prevention of arterial.Discussed niacin recently and such as the related derivatives [Lorenzen, people such as A (2001) Molecular Pharmacology 59:349-357] of acipimox (acipimox).The structure of other analogues of niacin or derivative and synthetic has been discussed in whole Merck index (Merck Index) (chemistry, medicine and biological encyclopedia) the 10th edition (1983), and the full text of Merck index is incorporated herein by reference.
Niacin may and reduce the hormone-sensitive lipase activity simultaneously and suppress free fatty acids from fatty tissue generation and release by cAMP level in inhibition adenylyl cyclase, the reduction cell.Thereby the active agonist that makes the blood plasma free fatty acid level reduce of downward modulation hormone-sensitive lipase may have therapeutic value.The result who reduces the blood plasma free fatty acid level is dual.At first, it reduces LDL cholesterol and rising HDL cholesterol levels the most at last, does not have and concerns Hazard Factor, thus the danger of the reduction death that back cardiovascular sickness rate causes owing to atheroma forms.Secondly, it will produce the insulin sensitivity that increases in the individuality of suffering from insulin resistant or diabetes B.Unfortunately, niacin is limited by many relevant adverse side effects partly as the purposes of therapeutical agent.These side effects comprise that face is rubescent, free fatty acids resilience and hepatotoxicity.
Reasonable development with novel niacin receptor agonists of less side effect is valuable, but so far its still because of differentiating that on molecular level the niacin acceptor is hindered.In addition, other acceptors of same classification may be present on the surface of adipocyte, and it reduces the hormone sensitive lipase activity similarly by the level that reduces cAMP in the cell, but does not cause that such as the rubescent adverse effect of face, it represents promising novel therapeutic agents target thus.Nearest work prompting niacin may work by specificity GPCR [Lorenzen A waits the people, (2001) MolecularPharmacology 59:349-357 and the content of wherein being looked back].Other work prompting niacins mediate scavenger cell, spleen and may be to the effect [Lorenzen A waits the people, (2002) BiochemicalPharmacology 64:645-648 and the content of wherein being looked back] of adipocyte by specificity GPCR.
Summary of the invention
The present invention relates to compound and its purposes of combination and activation RUP25 acceptor.As used herein, term RUP25 acceptor comprises that being found in gene library (GeneBank) deposits the human nucleic acid sequence of numbering NM_177551 number, is found in gene library and deposits the allelic variation body of NP_808219 number human peptide sequence of numbering and natural generation, Mammals directly to homologue and its recombinant mutant.
An aspect of the present invention relates to some fused pyrazole derivatives by formula (Ia) expression:
Or its pharmaceutically acceptable salt, hydrate or solvate,
Wherein:
X is that N and Z are CR
7, or X is CR
7And Z is N;
R
1And R
4Be selected from the group that forms by following each group independently of one another: H, C
1-6Acyl group, C
1-6Acyloxy, C
2-6Thiazolinyl, C
1-6Alkoxyl group, C
1-6Alkyl, C
1-6Alkylamino, C
1-6Alkyl formamides, C
1-6Alkylthio methane amide, C
2-6Alkynyl, C
1-6Alkyl sulfonamide, C
1-6Alkyl sulphinyl, C
1-6Alkyl sulphonyl, C
1-6Alkylthio, C
1-6Alkyl sulfide urea groups, C
1-6Alkyl urea groups, amino, C
1-6-alkylamidoalkyl, amino-C
1-6-alkyl sulphonyl, C
1-6-alkylthioamide base, C
1-6-alkoxy carbonyl, methane amide, carboxyl, cyano group, C
3-7Cycloalkyl, C
2-6Dialkylamino, C
1-6Dialkylformamide, C
1-6Dialkyl group thioformamide, halogen, C
1-6Halogen alkoxyl group, C
1-6Alkylhalide group, C
1-6Alkylhalide group sulfinyl, C
1-6Alkylhalide group alkylsulfonyl, C
1-6Alkylhalide group sulfenyl, heterocyclic radical, hydroxyl, nitro, sulphonamide and mercaptan;
R
2And R
3Be selected from the group that forms by following each group independently of one another: H, C
1-6Acyl group, C
1-6Acyloxy, C
2-6Thiazolinyl, C
1-6Alkoxyl group, C
1-6Alkyl, C
1-6Alkylamino, C
1-6Alkyl formamides, C
1-6Alkylthio methane amide, C
2-6Alkynyl, C
1-6Alkyl sulfonamide, C
1-6Alkyl sulphinyl, C
1-6Alkyl sulphonyl, C
1-6Alkylthio, C
1-6Alkyl sulfide urea groups, C
1-6Alkyl urea groups, amino, C
1-6-alkylamidoalkyl, amino-C
1-6-alkyl sulphonyl, C
1-6-alkylthioamide base, aryl sulfonyl kia, aryl sulfonyl, artyl sulfo, amidino, C
1-6-alkoxy carbonyl, methane amide, carboxyl, cyano group, C
3-7Cycloalkyl, C
3-7Cycloalkyloxy, C
2-6Dialkylamino, C
1-6Dialkylformamide, C
1-6Dialkyl group thioformamide, C
1-6Dialkyl amide base, C
1-6Dialkyl group thioamides base, halogen, C
1-6Halogen alkoxyl group, C
1-6Alkylhalide group, C
1-6Alkylhalide group sulfinyl, C
1-6Alkylhalide group alkylsulfonyl, C
1-6Alkylhalide group sulfenyl, heterocyclic radical, heterocyclyloxy base, heterocyclic radical alkylsulfonyl, heterocyclic radical carbonyl, heteroaryl, heteroaryl carbonyl, hydroxyl, nitro, C
4-7Oxo-cycloalkyl, phenoxy group, phenyl, sulphonamide, sulfonic acid and mercaptan; Wherein said C
1-6The alkyl substituting group through being selected from the group that is made up of following each group according to circumstances replaces: C
1-6Acyl group, C
1-6Acyloxy, C
1-6Alkoxyl group, C
1-6Alkylamino, C
1-6Alkyl sulphinyl, C
1-6Alkyl sulphonyl, C
1-6Alkylthio, amino, C
1-6-alkoxy carbonyl, methane amide, carboxyl, cyano group, C
3-7Cycloalkyl, C
3-7Cycloalkyloxy, C
2-6Dialkylamino, C
1-6Halogen alkoxyl group, C
1-6Alkylhalide group sulfinyl, C
1-6Alkylhalide group alkylsulfonyl, C
1-6Alkylhalide group sulfenyl, hydroxyl, nitro, phenoxy group and phenyl; Or
R
2And R
3Both carbon of institute's bond form C jointly together with it
3-6Cycloalkyl;
R
5And R
6Be selected from the group that forms by following each group independently of one another: H, C
1-6Acyl group, C
1-6Acyloxy, C
2-6Thiazolinyl, C
1-6Alkoxyl group, C
1-6Alkyl, C
1-6Alkylamino, C
1-6Alkyl formamides, C
1-6Alkylthio methane amide, C
2-6Alkynyl, C
1-6Alkyl sulfonamide, C
1-6Alkyl sulphinyl, C
1-6Alkyl sulphonyl, C
1-6Alkylthio, C
1-6Alkyl sulfide urea groups, C
1-6Alkyl urea groups, amino, C
1-6-alkoxy carbonyl, methane amide, carboxyl, cyano group, C
3-7Cycloalkyl, C
2-6Dialkylamino, C
1-6Dialkylformamide, C
1-6Dialkyl group thioformamide, halogen, C
1-6Halogen alkoxyl group, C
1-6Alkylhalide group, C
1-6Alkylhalide group sulfinyl, C
1-6Alkylhalide group alkylsulfonyl, C
1-6Alkylhalide group sulfenyl, heterocyclic radical, hydroxyl, nitro, sulphonamide and mercaptan; And
R
7Be C
1-6-alkoxy carbonyl, carboxyl or tetrazolium-5-base.
In certain embodiments, R
1And R
4Be cis each other.
Another aspect of the present invention relates to the medical composition that comprises The compounds of this invention and the combination of pharmaceutically acceptable supporting agent.
Another aspect of the present invention relates to and further comprises the medical composition as described herein that one or more are selected from the medicament of the group that is made up of following each thing: alpha-glucosidase inhibitor, aldose reductase inhibitor, biguanides, HMG-CoA reductase inhibitor, squalene synthetic inhibitor, Bei Te, LDL katabolism toughener, angiotonin converting enzyme inhibitor, insulin secretion enhancers, thiazolidinedione and DP receptor antagonist.
Another aspect of the present invention relates to the method for the treatment of metabolic-related disorders, and it comprises to the individuality of this treatment of needs throws and compound of the present invention or its medical composition for the treatment of significant quantity.
Another aspect of the present invention relates to the method that reduces VLDL in the individuality or LDL level, and it comprises to the individuality of described this treatment of needs throws compound of the present invention or its medical composition with the treatment significant quantity.
Another aspect of the present invention relates to the method that reduces serum triglyceride level in the individuality, and it comprises to the individuality of described this treatment of needs throws and compound of the present invention or its medical composition for the treatment of significant quantity.
Another aspect of the present invention relates to the method that reduces serum Lp (a) level in the individuality, and it comprises to the individuality of described this treatment of needs throws and compound of the present invention or its medical composition for the treatment of significant quantity.
Another aspect of the present invention relates to the method for the treatment of metabolic-related disorders, and it comprises to the individuality of this treatment of needs throws and the compound of the present invention and the DP receptor antagonist for the treatment of significant quantity.
Another aspect of the present invention relates to the method for regulating the RUP25 acceptor, and it comprises makes described acceptor contact with compound of the present invention.
Another aspect of the present invention relates to regulates the method for RUP25 acceptor with the treatment metabolic-related disorders in the individuality that needs the RUP25 acceptor to regulate, it comprises makes described acceptor contact with the compound of the present invention of treatment significant quantity.
Another aspect of the present invention relates to compound, and wherein said compound is an agonist.
Another aspect of the present invention relates to compound, and wherein said compound is the part agonist.
Another aspect of the present invention relates to treating needs the atherosis method of the human patients of treatment of atherosclerosis medium sized artery, and it comprises to described patient throws and the compound of the present invention that the treatment atherosclerosis is effectively measured.
Another aspect of the present invention relates to the method for the treatment of hyperlipemia in the human patients that needs the hyperlipemia treatment, and it comprises to described patient's throwing and to treating the effectively compound of the present invention of amount of hyperlipemia.
Another aspect of the present invention relates to the method for HDL in the rising individuality, and it comprises to described individual the throwing and the compound of the present invention for the treatment of significant quantity.
Another aspect of the present invention relates to the compound of the present invention that is used for the mankind or animal body methods of treatment by treatment.
Another aspect of the present invention relates to the compound of the present invention of methods of treatment that is used for the metabolic-related disorders of the mankind or animal body by treatment.
Another aspect of the present invention relates to the purposes that compound of the present invention is used to make the medicine of using for the treatment metabolic-related disorders.
In some embodiments of the invention, described metabolic-related disorders is the illness that is selected from the group that is made up of following each illness: hyperlipemia, atherosclerosis, coronary heart disease, insulin resistant, obesity, glucose dosis tolerata go down, atheromatous disease, hypertension, apoplexy, X syndromes, heart trouble and diabetes B.In certain embodiments, described metabolic-related disorders is hyperlipemia, atherosclerosis, coronary heart disease, insulin resistant and diabetes B.In certain embodiments, described metabolic-related disorders is a hyperlipemia.In certain embodiments, described metabolic-related disorders is an atherosclerosis.In certain embodiments, described metabolic-related disorders is a coronary heart disease.In certain embodiments, described metabolic-related disorders is an insulin resistant.In certain embodiments, described metabolic-related disorders is a diabetes B.
Some embodiments of the present invention relate to wherein, and individuality is mammiferous method.
Some embodiments of the present invention relate to wherein, and Mammals is human method.
Another aspect of the present invention relates to the method for making medical composition, and it comprises makes at least a compound of the present invention mix mutually with pharmaceutically acceptable supporting agent or vehicle.
The application's case is correlated with for the 60/676th, No. 521 with No. the 60/638th, 668, the U.S. of the application in 23 days December in 2004 that is incorporated herein in the mode of incorporating into its full content and the U.S. of application on April 29th, 2005.
The disclosure of this patent continues more to elaborate disclosed these and other aspects of the present invention herein.
Description of drawings
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Embodiment
Scientific and technical literature has adopted a large amount of terms, for the purpose of knowing for making peace, will use in whole patent document as giving a definition.
Agonist should mean and activate such as the acceptor interaction of RUP25 acceptor and with it, and the part of the physiology of initial described acceptor or pharmacological reaction feature.For instance, with receptors bind after, part active cells internal reaction, or enhancing and membrane-bound GTP.
Atherosclerosis is intended to contain the illness of large-scale and medium-sized artery herein, and it causes the carrying out property accumulation in smooth muscle cell inner membrance and lipid.
Chemical group, part or group:
Term " C
1-6Acyl group " expression and the C of carbonyl bond
1-6Alkyl, the definition of wherein said alkyl have and identical definition described herein; Some examples include, but is not limited to: ethanoyl, propionyl, positive butyryl radicals, isobutyryl, secondary butyryl radicals, uncle's butyryl radicals (being pivaloyl group), pentanoyl and its similar group.
Term " C
1-6Acyloxy " represent and the acyl group of Sauerstoffatom bond that wherein said acyl group has and identical definition described herein; Some examples include, but is not limited to: acetoxyl group, propionyloxy, butyryl acyloxy, isobutyl acyloxy, secondary butyryl acyloxy, uncle's butyryl acyloxy and its similar group.
Term " C
2-6Thiazolinyl " expression contains the group of 2 to 6 carbon, wherein has at least one carbon-carbon double bond, and some embodiment are 2 to 4 carbon, and some embodiment have 2 carbon.Term " thiazolinyl " comprises E and Z isomer.In addition, term " thiazolinyl " comprises diene.Therefore, if there be more than one pair of key, then described key can be E or Z, or the mixture of E and Z.The example of thiazolinyl comprises: vinyl, propenyl, allyl group, pseudoallyl, 2-methyl-propenyl, 1-methyl-propenyl, but-1-ene base, but-2-ene base, fourth-3-thiazolinyl, fourth-butadienyl and its similar group.
Term " C
1-6Alkoxyl group " expression is as herein defined directly and the alkyl of Sauerstoffatom bond.Example comprises methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, tert.-butoxy, isobutoxy, sec-butoxy and its similar group.
Term " C
1-6Alkyl " represent to contain the straight or branched carbon-based group of number carbon as represented, for example in certain embodiments, alkyl is " C
1-4Alkyl " and described group contain 1 to 4 carbon.In certain embodiments, alkyl contains 1 to 13 carbon, and some embodiment contain 1 to 2 carbon, and some embodiment contain 1 carbon.The example of alkyl includes, but is not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, sec-butyl and its similar group.
Term " C
1-6Alkyl formamides " the single C of expression and the nitrogen bond of amide group
1-6Alkyl, wherein alkyl has the being seen identical definition with this paper.C
1-6Alkyl formamides can be expressed from the next:
Example includes, but is not limited to N-methylformamide, N-ethyl-formamide, N-n-propyl methane amide, N-sec.-propyl methane amide, N-normal-butyl methane amide, N-sec-butyl methane amide, N-isobutyl-methane amide, N-tert-butylformamide and its similar group.
Term " C
1-6Alkyl sulphinyl " expression and formula-S (O)-the C of sulfoxide group bond
1-6Alkyl, wherein said alkyl have and identical definition described herein.Example includes, but is not limited to methylsulfinyl, ethyl sulfinyl, n-propyl sulfinyl, sec.-propyl sulfinyl, normal-butyl sulfinyl, sec-butyl sulfinyl, isobutyl-sulfinyl, the tertiary butyl and its similar group.
Term " C
1-6Alkyl sulfonamide " refer to following group
C wherein
1-6Alkyl has and identical definition described herein.
Term " C
1-6Alkyl sulphonyl " expression and formula-S (O)
2-the C of sulfuryl bond
1-6Alkyl, wherein said alkyl have and identical definition described herein.Example includes, but is not limited to methyl sulphonyl, ethylsulfonyl, n-propyl alkylsulfonyl, sec.-propyl alkylsulfonyl, normal-butyl alkylsulfonyl, sec-butyl alkylsulfonyl, isobutyl-alkylsulfonyl, tertiary butyl alkylsulfonyl and its similar group.
Term " C
1-6Alkylthio " C of expression and the sulfenyl bond of formula-S-
1-6Alkyl, wherein said alkyl have and identical definition described herein.It (is CH that example includes, but is not limited to the methyl sulfenyl
3S-), ethyl sulfenyl, n-propyl sulfenyl, sec.-propyl sulfenyl, normal-butyl sulfenyl, sec-butyl sulfenyl, isobutyl-sulfenyl, the tertiary butyl and its similar group.
Term " C
1-6The alkylthio methane amide " the single C of expression and the nitrogen bond of thioamides base
1-6Alkyl, wherein alkyl has the definition identical with this paper finding.C
1-6The alkylthio methane amide can be expressed from the next:
Example includes, but is not limited to N-methyl thioformamide, N-ethylenebis dithiocarbamate methane amide, N-n-propyl thioformamide, N-isopropylthio methane amide, N-normal-butyl thioformamide, N-sec-butyl thioformamide, N-isobutyl-thioformamide, N-t-butylthio methane amide and its analogue.
Term " C
1-6The alkyl sulfide urea groups " group of expression-NC (S) N-, wherein one is that two nitrogen are all through identical or different C
1-6Alkyl replaces and alkyl has and identical definition described herein.The example of alkyl sulfide urea groups includes, but is not limited to CH
3NHC (S) NH-, NH
2C (S) NCH
3-, (CH
3)
2N (S) NH-, (CH
3)
2N (S) NH-, (CH
3)
2N (S) NCH
3-, CH
3CH
2NHC (S) NH-, CH
3CH
2NHC (S) NCH
3-and its similar group.
Term " C
1-6The alkyl urea groups " group of expression-NC (O) N-, wherein one is that two nitrogen are all through identical or different C
1-6Alkyl replaces, and wherein alkyl has and identical definition described herein.The example of alkyl urea groups includes, but is not limited to CH
3NHC (O) NH-, NH
2C (O) NCH
3-, (CH
3)
2N (O) NH-, (CH
3)
2N (O) NH-, (CH
3)
2N (O) NCH
3-, CH
3CH
2NHC (O) NH-, CH
3CH
2NHC (O) NCH
3-and its similar group.
Term " C
2-6Alkynyl " represent to contain 2 to 6 carbon and at least one carbon carbon triple-linked group, some embodiment are 2 to 3 carbon, and some embodiment have 2 carbon.The example of alkynyl includes, but is not limited to ethynyl, third-1-alkynyl, 3-Propargyl, fourth-1-alkynyl, 1-methyl-Propargyl, fourth-1,3-diynyl and its similar group.Term " alkynyl " comprises diine.
Term " amino " expression group-NH
2
Term " C
1-6Alkylamidoalkyl " expression and the C as herein defined of NH group bond
1-6Acyl group.C
1-6Alkylamidoalkyl can be expressed from the next:
The example of alkylamidoalkyl includes, but is not limited to-NHCOMe ,-NHCOEt and its similar group.
Term " amino-C
1-6-alkyl sulphonyl " expression and the alkyl sulphonyl as herein defined of NH group bond.Amino-C
1-6-alkyl sulphonyl can be expressed from the next:
Amino-C
1-6The example of-alkyl sulphonyl includes, but is not limited to-NHSO
2Me ,-NHSO
2Et ,-NHSO
2Propyl group and its similar group.
Term " C
1-6The alkylthioamide base " expression and the C as herein defined of NH group bond
1-6The sulfo-acyl group.C
1-6The alkylthioamide base can be expressed from the next:
The example of alkylthioamide base includes, but is not limited to-NHCSMe ,-NHCSEt and its similar group.
Term " C
1-6Alkylamino " expression one and the alkyl of amino bond, wherein said alkyl has and identical implication described herein.Some examples include, but is not limited to methylamino-, ethylamino, n-propylamine base, isopropylamino, n-butyl amine base, Zhong Ding amino, isobutyl amino, uncle's fourth is amino and similar group.Some embodiment are " C
1-2Alkylamino ".
Term " aryl " expression contains the aromatics cyclic group of 6 to 10 ring carbon.Example comprises phenyl and naphthyl.
Term " aryl sulfonyl kia " expression and formula-S (O)-the aryl of sulfoxide group bond, wherein said aryl has and identical definition described herein.
Term " aryl sulfonyl " expression and formula-S (O)
2-the aryl of alkylsulfonyl bond, wherein said aryl has and identical definition described herein.
The aryl of the sulfenyl bond of term " arylthio " expression and formula-S-, wherein said aryl has and identical definition described herein.
Term " amidino " refers to the group of following chemical formula:
And in certain embodiments, one or two hydrogen is all through another group displacement.For instance, hydrogen can be through the hydroxyl displacement providing N-hydroxy formamidine base, or a hydrogen can be through the alkyl displacement to provide N-methyl amidino, N-ethyl amidino, N-propyl group amidino, N-butyl amidino and its similar group.
Term " C
1-6-alkoxy carbonyl " expression carboxylic acid C
1-6Alkyl ester, wherein said alkyl as defined herein.Example includes, but is not limited to methoxycarbonyl, ethoxycarbonyl, the third oxygen carbonyl, the different third oxygen carbonyl, butoxy carbonyl, secondary butoxy carbonyl, isobutyl boc, tertbutyloxycarbonyl and its similar group.
Term " methane amide " refers to group-CONH
2
Term " carboxyl " expression group-CO
2H is also referred to as hydroxy-acid group.
Term " cyano group " expression group-CN.
Term " C
3-7Cycloalkyl " expression contains the saturated cyclic group of 3 to 6 carbon, and some embodiment contain 3 to 5 carbon, and some embodiment contain 3 to 4 carbon.Example comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
Term " C
3-7Cycloalkyloxy " represent directly and the cycloalkyl as herein defined of Sauerstoffatom bond.Example comprises ring propoxy-, cyclobutoxy group, cyclopentyloxy and its similar group.
Term " C
2-8Dialkylamino " represent that wherein alkyl has and identical definition described herein through the amino of two identical or different alkyl replacements.C
2-8Dialkylamino can be represented by following group:
Some embodiment comprise C
2-6Dialkylamino, such as-N (C
1-3Alkyl)
2The example of dialkylamino includes, but is not limited to dimethylamino, methyl ethylamino, diethylin, methyl-prop amino, methyl isopropyl is amino and its similar group.
Term " C
1-6The dialkyl amide base " represent and two identical or different alkyl of amide group bond that wherein alkyl has and identical definition described herein.C
1-6The dialkyl amide base can be represented by following group:
C wherein
1-6Have and identical definition described herein.The example of dialkyl amide base includes, but is not limited to-N (CH
3) COCH
3,-N (CH
3) COCH
2CH
3With its similar group.
Term " C
1-6Dialkyl group thioamides base " represent and two identical or different alkyl of thioamides base key knot that wherein alkyl has and identical definition described herein.C
1-6Dialkyl group thioamides base can be represented by following group:
C wherein
1-6Have and identical definition described herein.The example of dialkyl group thioamides base includes, but is not limited to-N (CH
3) CSCH
3,-N (CH
3) CSCH
2CH
3With its similar group.
Term " C
1-6Dialkylformamide " represent and two identical or different alkyl of amide group bond that wherein alkyl has and identical definition described herein.C
1-6Dialkylformamide can be represented by following group:
C wherein
1-6Have and identical definition described herein.The example of dialkylformamide includes, but is not limited to N, dinethylformamide, N-methyl-N-ethyl-formamide, N, N-diethylformamide, N-methyl-N-isopropyl propyl group methane amide and its analogue.
Term " C
1-6The dialkyl group thioformamide " represent and two identical or different alkyl of thioamides base key knot that wherein alkyl has and identical definition described herein.C
1-6Dialkyl group thioformamide base can be represented by following group:
The example of dialkyl group thioformamide includes, but is not limited to N, N-dimethyl thioformamide, N-methyl-N-ethylenebis dithiocarbamate methane amide and its analogue.
Term " C
1-6The halogen alkoxyl group " expression and the alkylhalide group as herein defined of the direct bond of Sauerstoffatom.Example includes, but is not limited to difluoro-methoxy, trifluoromethoxy, 2,2,2-trifluoro ethoxy, five fluorine oxyethyl groups and its similar group.
Term " C
1-6Alkylhalide group " represent that wherein alkyl replaces the alkyl that once extremely replaces fully through halogen, wherein can be by formula C through the alkylhalide group that replaces fully
hL
2h+1Expression, wherein L is the number of halogen and " h " expression carbon atom; When having more than one halogen, then described halogen can be identical or different, and be selected from the group that is made up of F, Cl, Br and I; Should be appreciated that term " alkyl " and " halogen " have the definition identical with this paper finding.In certain embodiments, alkylhalide group is " C
1-4Alkylhalide group " and group contain 1 to 4 carbon, some embodiment contain 1 to 3 carbon, some embodiment contain 1 to 2 carbon, some embodiment contain 1 carbon.When alkylhalide group when halogen atom replaces fully, this paper is called perhaloalkyl radical with this group, the alkyl of an example for replacing fully through fluorine atom, and be called " perfluoroalkyl " in this article.In certain embodiments, the example of alkylhalide group includes, but is not limited to difluoromethyl, methyl fluoride, 2,2,2-three fluoro-ethyls, 2,2-two fluoro-ethyls, 2-fluoro-ethyl, 1,2,2-three fluoro-ethyls, 1,2-two fluoro-ethyls, 1,1-two fluoro-ethyls, 1,1,2-three fluoro-ethyls, 3,3,3-three fluoro-propyl group, 2,2-two fluoro-propyl group, 3,3-two fluoro-propyl group, 3-fluoro-propyl group, 2,3,3-three fluoro-propyl group, 2,3-two fluoro-propyl group, 2,2,3,3,3-five fluoro-propyl group, 2,2,3,3-tetrafluoro-propyl group, 2,2,3-three fluoro-propyl group, 1,2,3,3-tetrafluoro-propyl group, 1,2,3-three fluoro-propyl group, 3,3-two fluoro-propyl group, 1,2,2,3-tetrafluoro-propyl group, 4,4-two fluoro-butyl, 3,3-two fluoro-butyl, 4,4,4-three fluoro-butyl, 3,3-two fluoro-butyl and its similar group.The example of perfluoroalkyl includes, but is not limited to trifluoromethyl, pentafluoroethyl group, seven fluoropropyls, 1,2,2 in certain embodiments, 2-tetrafluoro-1-trifluoromethyl-ethyl and its similar group.
Term " C
1-6The alkylhalide group sulfinyl " expression and formula-S (O)-the alkylhalide group of sulfoxide group bond, wherein said alkylhalide group has and identical definition described herein.
Term " C
1-6The alkylhalide group alkylsulfonyl " expression and formula-S (O)
2-the alkylhalide group of sulfuryl bond, wherein alkylhalide group has and identical definition described herein.
Term " C
1-6The alkylhalide group sulfenyl " represent and the alkylhalide group of the direct bond of sulphur atom that wherein said alkylhalide group has and identical definition described herein.
Term " halogen " or " halogen " expression fluorine, chlorine, bromine or iodine base.
Term " heteroaryl " expression can be the aromatic ring system of monocycle, two fused rings or three fused rings, and wherein the heteroatoms of the group of at least one ring carbon atom through being selected from (but being not limited to) and being made up of O, S and N is replaced, and wherein N can be according to circumstances through H, C
1-4Acyl group or C
1-4Alkyl replaces.The example of heteroaryl include, but is not limited to pyridyl, benzofuryl, pyrazinyl, pyridazinyl, pyrimidyl, triazinyl, quinolyl, benzoxazolyl, benzothiazolyl, 1H-benzimidazolyl-, isoquinolyl, quinazolyl, quinoline quinoline base and its similar group.In certain embodiments, the heteroaryl atom is O, S, NH, and example includes, but is not limited to pyrryl, indyl and its similar group.
Non-aromatic carbocyclic (promptly cycloalkyl or cycloalkenyl group) as herein defined represented in term " heterocyclic radical ", and wherein the heteroatoms of one, two or three ring carbon group through being selected from (but being not limited to) and being made up of O, S, N is replaced, and wherein N can be according to circumstances through H, C
1-4Acyl group or C
1-4Alkyl replaces, and therefore ring carbon atom forms carbonyl or thiocarbonyl group according to circumstances through oxo base or the replacement of sulphur oxo base.Heterocyclic radical is to contain 3,4,5,6 or 7 Yuans ring.The example of heterocyclic radical includes, but is not limited to ethylene imine-1-base, ethylene imine-2-base, azetidine-1-base, azetidine-2-base, azetidine-3-base, piperidines-1-base, piperidin-4-yl, morpholine-4-base, piperazine-1-base, piperazine-4-base, tetramethyleneimine-1-base, tetramethyleneimine-3-base, [1,3]-dioxolane-2-base and its similar group.
The heteroaryl as herein defined that term " heteroaryl carbonyl " expression carbon bond direct and carbonyl (being C=O) is tied.The example of heteroaryl carbonyl include, but is not limited to pyridyl-carbonyl, benzofuryl-carbonyl, pyrazinyl-carbonyl, pyridazinyl-carbonyl, pyrimidyl-carbonyl, triazinyl-carbonyl, quinolyl-carbonyl, benzoxazolyl-carbonyl, benzothiazolyl-carbonyl, 1H-benzimidazolyl--carbonyl, isoquinolyl-carbonyl, quinazolyl-carbonyl, quinoline quinoline base-carbonyl, pyrroles-carbonyl, indyl-carbonyl and its similar group.
The heterocyclic radical as herein defined that term " heterocyclic radical-carbonyl " expression carbon bond direct and carbonyl (being C=O) is tied.In certain embodiments, the ring nitrogen of heterocyclic radical and carbonyl bond form acid amides.Example includes, but is not limited to:
With its analogue.
Term " heterocyclic radical-oxygen base " is represented directly and the heterocyclic radical as herein defined of Sauerstoffatom bond.Example comprises following group:
With its similar group.
Term " heterocyclic radical alkylsulfonyl " expression has the heterocyclic radical as herein defined of ring nitrogen, the direct and SO of wherein said ring nitrogen
2The group bond forms sulphonamide.Example includes, but is not limited to:
With its similar group.
Term " hydroxyl " expression group-OH.
Term " C
4-7Oxo-cycloalkyl " refer to as one of them ring carbon through carbonyl metathetical C defined herein
4-7Cycloalkyl.C
4-7The example of oxo-cycloalkyl includes, but is not limited to 2-oxo-cyclobutyl, 3-oxo-cyclobutyl, 3-oxo-cyclopentyl, 4-oxo-cyclohexyl and its similar group, and can be represented by following structure respectively:
Term " nitro " expression group-NO
2
Term " phenoxy group " refers to group C
6H
5O-.
Term " phenyl " refers to group C
6H
5-.
Term " sulphonamide " refers to group-SO
2NH
2
Term " sulfonic acid " refers to group-SO
3H.
Term " mercaptan " refers to group-SH.
Term " C
1-6The sulfo-acyl group " expression and the C of thiocarbonyl group bond
1-6Alkyl, wherein the definition of alkyl has and identical definition described herein; Some examples include, but is not limited to-CSCH
3,-CSCH
2CH
3,-CSCH
2CH
2CH
3With its similar group.
The term composition should mean the material that comprises at least two kinds of compounds or two kinds of components; For example, and under situation about not limiting, medical composition is the composition that comprises compound of the present invention and pharmaceutically acceptable supporting agent.
The term compound efficacy should mean as opposite with receptors bind avidity, and compound suppresses or the measuring of costimulatory receptor functional capabilities.
Term composing type activated receptor should mean the acceptor that stands the composing type receptor activation.
The mode that term composing type receptor activation should mean outside making acceptor and its endogenous ligand or its chemical equipollent combine makes the acceptor that is in active state stable.
Term contact should mean make indicated part no matter ex vivo system or in vivo flock together in the system.Therefore RUP25 acceptor and compound of the present invention " contacts " to comprise and throw and compound of the present invention, and (for example) contained the sample of cell with compound introducing of the present invention or contained in the more pure preparation of RUP25 acceptor to for example Individual of Humanity with RUP25 acceptor.
The coronary heart disease of wishing this paper contains the little vasoconstrictive illness that comprises to heart supply blood and oxygen.Coronary heart disease is produced by the accumulation of fatty substance and patch usually.When coronary artery shrank, blood can slow down or stop to flowing of heart.Coronary heart disease can cause thoracic cavity pain (stable stenocardia), be short of breath, has a heart attack or other symptoms.
Reduce the decline that is used in reference to measurable amount, and use with term " minimizing ", " reducing ", " falling weak " and " alleviating " synonym.
Wish that diabetes as used in this article contain by the general diagnostic that includes, but is not limited to the diabetes that following listed any method makes: diabetic symptom (for example diuresis, polydipsia, many foods) adds accidental plasma glucose levels more than or equal to 200mg/dl, and no matter wherein accidental plasma glucose is defined as any moment of one day of the selection of time that meals or drinking-water consume; Be less than or equal to 8 hours fasting plasma glucose levels of 126mg/dl; With oral administration and 75g dextrose anhydrous soluble in water after 2 hours, more than or equal to the plasma glucose levels of 200mg/dl.
This paper wishes that phrase lipid metabolism illness includes, but is not limited to hyperlipemia.
This paper wishes that the term hyperlipemia contains any one the illness that comprises in the following illness: the blood plasma free fatty acid level raises, blood plasma cholesterol level raises, the LDL cholesterol levels raises, the HDL cholesterol levels reduces and the plasma triglyceride level raises.
As used herein, phrase need be treated and be referred to that the care-giver (for example is physician, nurse, nursing practitioner etc. under the mankind's situation; Under the situation of the animal that comprises non-human mammal for the animal doctor) individuality or the animal needs of making maybe will be from treating benefited judgement.This judgement is based on comprising because can be through disease, the patient's condition or the illness of compounds for treating of the present invention in care-giver's the areas of expertise, and is individual ill or the various factors of ill knowledge made.In addition, phrase " needs treatment " and also refers to individual " prevention ", and described individuality is made it with ill judgement through the care-giver.In the case, use compound of the present invention with protectiveness or preventative mode.Therefore, " need treatment " refers to care-giver's judgement, and promptly individuality is ill or will be ill, and compound of the present invention can be used for alleviating, inhibition, improvement or preventing disease, the patient's condition or illness.
As used herein, the term individuality refers to any animal, comprises Mammals, for example mouse, rat, other rodents, rabbit, dog, cat, pig, ox, sheep, horse or primate, and be human in one embodiment.
The term that is associated with term " reaction " is opposite when suppressing to refer to not exist with compound, reduces when compound exists or prevents reaction.
Wish that insulin resistant as used in this article contains the general diagnostic of any one insulin resistant of making in many methods, described method includes, but is not limited to: test of intravenously glucose tolerance or fasting insulin horizontal survey.Known between fasting insulin level height and the insulin resistant degree and had good dependency.Therefore, can use the rising of fasting insulin level to be intended to be used to differentiate which normal glucose tolerance (NGT) individuality has insulin resistant as the surrogate markers of insulin resistant.Also can use the diagnosis of euglycemia glucose clamp test carrying out insulin resistant.
Term anti should mean part in conjunction with the acceptor of the acceptor of endogenous form or composing type activated form to agonist, and it suppresses to be lower than active arm's length basis level (observing) or to be reduced combining of GTP and film under the situation that does not have agonist or part agonist by the initial baseline cell internal reaction of the activity form of acceptor.In certain embodiments, when with do not have reverse agonist situation under baseline response when comparing, at the baseline cell internal reaction that has inhibition at least 30% under the reverse agonist situation, suppress at least 50% in other embodiments, and suppress at least 75% in other embodiments.
The term ligand should mean the molecule that the acceptor of endogenous, natural generation is had specific endogenous, natural generation.
This paper wishes that the phrase metabolic-related disorders includes, but is not limited to that hyperlipemia, atherosclerosis, coronary heart disease, insulin resistant, obesity, glucose dosis tolerata go down, atheromatous disease, hypertension, apoplexy, X syndromes, heart trouble and diabetes B.
As used herein, term is regulated and should be meant amount, quality, reaction or the effect that raises or reduce given activity, function or molecule.
As used herein, term " part agonist " for when with acceptor (for example, the RUP25 acceptor) in conjunction with the time active cells internal reaction part, but to compare its degree lower with complete agonist.Owing to compare with complete agonist, the part agonist produces partial reaction, so term part agonist is a relative terms.Should be appreciated that therefore based on the discovery of the complete agonist of novelty, the compound that once was described to complete agonist can be changed into the part agonist subsequently owing to constantly find compounds along with going by.
The term medical composition should mean be used to prevent, the composition of treatment or the control disease state or the patient's condition, it comprises at least a active compound (for example comprising its pharmaceutically acceptable salt, pharmaceutically acceptable solvate and/or the compound of the present invention of hydrate) and at least a pharmaceutically acceptable supporting agent.
Supporting agent that term is pharmaceutically acceptable or vehicle should mean any as the thinner of compound of the present invention or the material of inert substantially of mediator.
As used herein, phrase treatment significant quantity refers to the amount of the active compound or the medical agent that cause biology or drug reaction in tissue, whole body, animal, individuality or the mankind that researchist, animal doctor, doctor or other clinicians look for, and described reaction comprises one or more following situations:
(1) preventing disease, for example may tend to be attacked by a disease, the patient's condition or illness but as yet not experience show the pathology of disease or the individuality of symptom in preventing disease, the patient's condition or illness;
(2) suppress disease, for example experience show the pathology of disease, the patient's condition or illness or the individuality of symptom in suppress disease, the patient's condition or illness (promptly suppressing further developing of pathology and/or symptom); With
(3) improve disease, for example experience show the pathology of disease, the patient's condition or illness or the individuality of symptom in improve disease, the patient's condition or illness (even pathology and/or symptom reverse).
Compound of the present invention
One aspect of the present invention relates to some fused pyrazole derivatives by formula (Ia) expression:
Or its pharmaceutically acceptable salt, hydrate or solvate, wherein X, Z, R
1, R
2, R
3, R
4, R
5And R
6Have with this paper above and hereinafter described identical definition.
One aspect of the present invention relates to some as fused pyrazole derivatives or its pharmaceutically acceptable salt, hydrate or solvate by formula (Ia) expression,
Wherein:
X is that N and Z are CR
7, or X is CR
7And Z is N;
R
1And R
4Be selected from the group that forms by following each group independently of one another: H, C
1-6Acyl group, C
1-6Acyloxy, C
2-6Thiazolinyl, C
1-6Alkoxyl group, C
1-6Alkyl, C
1-6Alkylamino, C
1-6Alkyl formamides, C
1-6Alkylthio methane amide, C
2-6Alkynyl, C
1-6Alkyl sulfonamide, C
1-6Alkyl sulphinyl, C
1-6Alkyl sulphonyl, C
1-6Alkylthio, C
1-6Alkyl sulfide urea groups, C
1-6Alkyl urea groups, amino, C
1-6-alkylamidoalkyl, amino-C
1-6-alkyl sulphonyl, C
1-6-alkylthioamide base, C
1-6-alkoxy carbonyl, methane amide, carboxyl, cyano group, C
3-7Cycloalkyl, C
2-6Dialkylamino, C
1-6Dialkylformamide, C
1-6Dialkyl group thioformamide, halogen, C
1-6Halogen alkoxyl group, C
1-6Alkylhalide group, C
1-6Alkylhalide group sulfinyl, C
1-6Alkylhalide group alkylsulfonyl, C
1-6Alkylhalide group sulfenyl, heterocyclic radical, hydroxyl, nitro, sulphonamide and mercaptan;
R
2And R
3Be selected from the group that forms by following each group independently of one another: H, C
1-6Acyl group, C
1-6Acyloxy, C
2-6Thiazolinyl, C
1-6Alkoxyl group, C
1-6Alkyl, C
1-6Alkylamino, C
1-6Alkyl formamides, C
1-6Alkylthio methane amide, C
2-6Alkynyl, C
1-6Alkyl sulfonamide, C
1-6Alkyl sulphinyl, C
1-6Alkyl sulphonyl, C
1-6Alkylthio, C
1-6Alkyl sulfide urea groups, C
1-6Alkyl urea groups, amino, C
1-6-alkylamidoalkyl, amino-C
1-6-alkyl sulphonyl, C
1-6-alkylthioamide base, aryl sulfonyl kia, aryl sulfonyl, artyl sulfo, amidino, C
1-6-alkoxy carbonyl, methane amide, carboxyl, cyano group, C
3-7Cycloalkyl, C
3-7Cycloalkyloxy, C
2-6Dialkylamino, C
1-6Dialkylformamide, C
1-6Dialkyl group thioformamide, C
1-6Dialkyl amide base, C
1-6Dialkyl group thioamides base, halogen, C
1-6Halogen alkoxyl group, C
1-6Alkylhalide group, C
1-6Alkylhalide group sulfinyl, C
1-6Alkylhalide group alkylsulfonyl, C
1-6Alkylhalide group sulfenyl, heterocyclic radical, heterocyclyloxy base, heterocyclic radical alkylsulfonyl, heterocyclic radical carbonyl, heteroaryl, heteroaryl carbonyl, hydroxyl, nitro, C
4-7Oxo-cycloalkyl, phenoxy group, phenyl, sulphonamide, sulfonic acid and mercaptan; Wherein said C
1-6-alkyl the substituting group through being selected from the group that is made up of following each group according to circumstances replaces: C
1-6Acyl group, C
1-6Acyloxy, C
1-6Alkoxyl group, C
1-6Alkylamino, C
1-6Alkyl sulphinyl, C
1-6Alkyl sulphonyl, C
1-6Alkylthio, amino, C
1-6-alkoxy carbonyl, methane amide, carboxyl, cyano group, C
3-7Cycloalkyl, C
3-7Cycloalkyloxy, C
2-6Dialkylamino, C
1-6Halogen alkoxyl group, C
1-6Alkylhalide group sulfinyl, C
1-6Alkylhalide group alkylsulfonyl, C
1-6Alkylhalide group sulfenyl, hydroxyl, nitro, phenoxy group and phenyl;
R
5And R
6Be selected from the group that forms by following each group independently of one another: H, C
1-6Acyl group, C
1-6Acyloxy, C
2-6Thiazolinyl, C
1-6Alkoxyl group, C
1-6Alkyl, C
1-6Alkylamino, C
1-6Alkyl formamides, C
1-6Alkylthio methane amide, C
2-6Alkynyl, C
1-6Alkyl sulfonamide, C
1-6Alkyl sulphinyl, C
1-6Alkyl sulphonyl, C
1-6Alkylthio, C
1-6Alkyl sulfide urea groups, C
1-6Alkyl urea groups, amino, C
1-6-alkoxy carbonyl, methane amide, carboxyl, cyano group, C
3-7Cycloalkyl, C
2-6Dialkylamino, C
1-6Dialkylformamide, C
1-6Dialkyl group thioformamide, halogen, C
1-6Halogen alkoxyl group, C
1-6Alkylhalide group, C
1-6Alkylhalide group sulfinyl, C
1-6Alkylhalide group alkylsulfonyl, C
1-6Alkylhalide group sulfenyl, heterocyclic radical, hydroxyl, nitro, sulphonamide and mercaptan; And
R
7Be C
1-6-alkoxy carbonyl, carboxyl or tetrazolium-5-base.
Should be appreciated that the present invention contains R
1And R
4Group be each other cis above and hereinafter each compound and general formula.
Should be appreciated that for clarity sake being described in the combination that some feature of the present invention in the independent embodiment content also can single embodiment provides.On the contrary, for for simplicity, the of the present invention various features that are described in the content of single embodiment also can provide independently or with any suitable sub-portfolio.
As used herein, " be substituted " at least one hydrogen atom of expression chemical group through non-hydrogen substituting group or group displacement.When the chemical group when herein " was substituted ", it can have at the most all replacements of valence state; For example methyl can replace through 1,2 or 3 substituting group, and methylene radical can replace through 1 or 2 substituting group, and phenyl can be through 1,2,3,4 or 5 substituting group replacement etc.In certain embodiments, term " is substituted " and refers to 1,2,3,4,5 or 6 substituting group.In certain embodiments, term " is substituted " and refers to 1,2,3,4 or 5 substituting group.In certain embodiments, term " is substituted " and refers to 1,2,3 or 4 substituting group.In certain embodiments, term " is substituted " and refers to 1,2 or 3 substituting group.In certain embodiments, term " is substituted " and refers to 1 or 2 substituting group.In certain embodiments, term " is substituted " and refers to 1 substituting group.
Should be appreciated that and the compound of understanding formula (Ia) can have one or more chiral centre, and therefore can be used as enantiomer and/or diastereomer and exist.Should be appreciated that the present invention extends and contains all these enantiomers, diastereomer and its mixture, includes, but is not limited to racemic modification.Therefore, one embodiment of the invention are related to the formula (Ia) of R enantiomer and spread all over the compound of the formula of this specification sheets use.In addition, one embodiment of the invention are related to the formula (Ia) of S enantiomer and spread all over the compound of the formula of this specification sheets use.In another embodiment, compound of the present invention has 2 stereochemistry centers and the two is R.In another embodiment, compound of the present invention has 2 stereochemistry centers and the two is S.In another embodiment, compound of the present invention has 3 stereochemistry centers that are R.In another embodiment, compound of the present invention has 3 stereochemistry centers, and wherein two is R, and the 3rd is S.In another embodiment, compound of the present invention has 3 stereochemistry centers, and wherein two is S, and the 3rd is R.Should be appreciated that: unless stated otherwise or show, otherwise formula (Ia) and the compound that spreads all over the formula that this specification sheets uses are intended to represent all indivedual enantiomers and its mixture.
Compound of the present invention can various tautomeric forms exist.For instance, the those skilled in the art should be well understood to tetrazolium can at least two kinds tautomeric forms exist, although and in some formula as herein described a kind of form of expression, should be appreciated that the present invention contains all tautomeric forms; In the mode of explanation, when X is that N and Z are CR
7The time, R wherein
7Be tetrazolium-5-base, then hereinafter show two kinds of possible tautomers of tetrazole ring:
Similarly, should be appreciated that working as X is CR
7, R wherein
7When being N for tetrazolium-5-base and Z, then also can there be tautomer in tetrazole ring.
In addition, the those skilled in the art should be well understood to pyrazole heterocycle also can at least two kinds tautomeric forms exist, although and in formula as herein described a kind of form of expression, should be appreciated that the present invention contains all tautomeric forms.In the mode of explanation, show that hereinafter (when X is N, and Z is CR to two kinds of possible pyrazoles ring tautomers
7The time):
Similarly, when X be CR
7, and can there be tautomer in Z during for N.In addition, should be appreciated that and work as R
7During for tetrazolium-5-basic ring, then also can there be tautomer in the combination of pyrazoles ring and tetrazole ring.Should be appreciated that herein all tautomers that the compound that discloses can exist all are in the category of the present invention.
Should further understand for each tautomer, tautomeric form also can have corresponding nomenclature.Therefore, the present invention includes the various term name of all tautomers and all tautomers.
Some embodiments of the present invention relate to compound, and wherein X is N; Z is CR
7And R
7Be C
1-6-alkoxy carbonyl or carboxyl.
Some embodiments of the present invention relate to compound, and wherein X is N; Z is CR
7And R
7Be carboxyl.Some embodiment can be through the expression of formula (Ic) as described below:
Each variable of its Chinese style (Ic) have with above and hereinafter described identical implication.
Some embodiments of the present invention relate to compound, and wherein X is N; Z is CR
7And R
7Be tetrazolium-5-base.Some embodiment can be through the expression of formula (Ie) as described below:
Each variable of its Chinese style (Ie) have with above and hereinafter described identical implication.
Some embodiments of the present invention relate to compound, and wherein X is CR
7R
7Be C
1-6-alkoxy carbonyl or carboxyl; And Z is N.
Some embodiments of the present invention relate to compound, and wherein X is CR
7R
7Be carboxyl; And Z is N.Some embodiment can be through the expression of formula (Ig) as described below:
Each variable of its Chinese style (Ig) have with above and hereinafter described identical implication.
Some embodiments of the present invention relate to compound, and wherein X is CR
7R
7Be tetrazolium-5-base; And Z is N.Some embodiment can be through the expression of formula (Ii) as described below:
Each variable of its Chinese style (Ii) have with above and hereinafter described identical implication.
Some embodiments of the present invention relate to compound, wherein R
1Be H or halogen.
Some embodiments of the present invention relate to compound, wherein R
1Be H.
Some embodiments of the present invention relate to compound, wherein R
4Be H or halogen.
Some embodiments of the present invention relate to compound, wherein R
4Be H.
Some embodiments of the present invention relate to compound, wherein R
1With R
4Be H.
Some embodiments of the present invention relate to by the represented compound of formula (Ik) as described below:
Each variable of its Chinese style (Ik) have with above and hereinafter described identical implication.
Some embodiments of the present invention relate to compound, wherein R
5Be H or halogen.
Some embodiments of the present invention relate to compound, wherein R
5Be H.
Some embodiments of the present invention relate to compound, wherein R
6Be H or halogen.
Some embodiments of the present invention relate to compound, wherein R
6Be H.
Some embodiments of the present invention relate to compound, wherein R
5With R
6Be H.
Some embodiments of the present invention relate to by the represented compound of formula (Im) as described below:
Each variable of its Chinese style (Im) have with above and hereinafter described identical implication.
Some embodiments of the present invention relate to compound, wherein R
1, R
4, R
5And R
6H respectively does for oneself.Some embodiment can be through the expression of formula (Io) as described below:
Each variable of its Chinese style (Io) have with above and hereinafter described identical implication.
Some embodiments of the present invention relate to compound, wherein R
2And R
3Be selected from independently of one another by H, C
1-6The group that alkyl and halogen are formed; Wherein said C
1-6The alkyl substituting group through being selected from the group that is made up of following each group according to circumstances replaces: C
1-6Acyloxy, C
1-6Alkoxyl group, C
1-6Alkylamino, C
1-6Alkyl sulphinyl, C
1-6Alkyl sulphonyl, C
1-6Alkylthio, amino, C
3-7Cycloalkyloxy, C
2-6Dialkylamino, C
1-6Halogen alkoxyl group, C
1-6Alkylhalide group sulfinyl, C
1-6Alkylhalide group alkylsulfonyl, C
1-6Alkylhalide group sulfenyl, hydroxyl, phenoxy group and phenyl.
Some embodiments of the present invention relate to compound, wherein R
2And R
3Both carbon of institute's bond form C jointly together with it
3-6Cycloalkyl.
Some embodiments of the present invention relate to compound, wherein R
2Be H or C
1-6Alkyl; And R
3Be H, C
1-6Alkyl and halogen; Wherein said C
1-6The alkyl substituting group through being selected from the group that is made up of following each group according to circumstances replaces: C
1-6Acyloxy, C
1-6Alkoxyl group, C
1-6Alkylamino, C
1-6Alkyl sulphinyl, C
1-6Alkyl sulphonyl, C
1-6Alkylthio, amino, C
3-7Cycloalkyloxy, C
2-6Dialkylamino, C
1-6Halogen alkoxyl group, C
1-6Alkylhalide group sulfinyl, C
1-6Alkylhalide group alkylsulfonyl, C
1-6Alkylhalide group sulfenyl, hydroxyl, phenoxy group and phenyl.
Some embodiments of the present invention relate to compound, wherein R
2Be H or C
1-6Alkyl; And R
3Be H, C
2-6Thiazolinyl, C
1-6Alkyl, C
3-7Cycloalkyl, halogen or phenyl; Wherein said C
1-6The alkyl substituting group through being selected from the group that is made up of following each group according to circumstances replaces: C
1-6Alkoxyl group, C
1-6Alkylthio, hydroxyl, phenoxy group and phenyl; Or
R
2And R
3Both carbon of institute's bond form cyclopropyl, cyclopentyl or cyclohexyl jointly together with it.
Some embodiments of the present invention relate to compound, wherein R
2Be H or CH
3And R
3Be H, methyl, ethyl, n-propyl, sec.-propyl, isobutyl-, normal-butyl, n-pentyl, vinyl, methylol, methoxymethyl, benzyl, phenyl, phenoxymethyl, methyl sulfenyl methyl, ethoxyl methyl, cyclopropyl, 1-but-2-ene base or allyl group; Or
R
2And R
3Both carbon of institute's bond form cyclopropyl, cyclopentyl or cyclohexyl jointly together with it.
Some embodiments of the present invention relate to compound, wherein R
2Be H or C
1-6Alkyl; And R
3Be H, C
2-6Thiazolinyl, C
1-6Alkyl, halogen or phenyl; Wherein said C
1-6The alkyl substituting group through being selected from the group that is made up of following each group according to circumstances replaces: C
1-6Alkoxyl group, hydroxyl, phenoxy group and phenyl.
Some embodiments of the present invention relate to compound, wherein R
2Be H or CH
3And R
3Be H, CH
3Or benzyl.
Some embodiments of the present invention relate to compound, wherein R
2Be H or CH
3And R
3Be H, methyl, ethyl, n-propyl, sec.-propyl, isobutyl-, normal-butyl, n-pentyl, vinyl, methylol, methoxymethyl, benzyl, phenyl or phenoxymethyl.
Some embodiments of the present invention relate to compound, wherein:
X is that N, Z are CR
7And R
7Be carboxyl; Or
X is CR
7, R
7Be carboxyl or tetrazyl, and Z is N;
R
1, R
4, R
5And R
6H respectively does for oneself;
R
2Be H or CH
3And
R
3Be H, CH
3Or benzyl; Or
Its pharmaceutically acceptable salt, hydrate or solvate.
Some embodiments of the present invention relate to compound, wherein:
X is N, and Z is CR
7, R wherein
7For carboxyl ,-CO
2Et or tetrazolium-5-base; Or
X is CR
7, R wherein
7For carboxyl ,-CO
2Et or tetrazyl, and Z is N;
R
1, R
4, R
5And R
6H respectively does for oneself;
R
2Be H or CH
3And
R
3Be H, methyl, ethyl, n-propyl, sec.-propyl, isobutyl-, normal-butyl, n-pentyl, vinyl, methylol, methoxymethyl, benzyl, phenyl or phenoxymethyl; Or
Its pharmaceutically acceptable salt, hydrate or solvate.
Some embodiments of the present invention relate to compound, wherein:
X is N, and Z is CR
7, and R
7For carboxyl ,-CO
2Et or tetrazolium-5-base;
R
1, R
4, R
5And R
6H respectively does for oneself;
R
2Be H or CH
3And
R
3Be H, methyl, ethyl, n-propyl, sec.-propyl, isobutyl-, normal-butyl, n-pentyl, vinyl, methylol, methoxymethyl, benzyl, phenyl or phenoxymethyl; Or
Its pharmaceutically acceptable salt, hydrate or solvate.
Some embodiments of the present invention relate to the compound that is selected from the group that is made up of following each thing:
3b, 4,4a, 5-tetrahydrochysene-2H-ring third [3,4] ring penta [1,2-c] pyrazoles-3-formic acid;
1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid; 1-benzyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid; With 1,1-dimethyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid; Or its pharmaceutically acceptable salt, hydrate or solvate.
Some embodiments of the present invention relate to the compound that is selected from the group that is made up of following each thing:
4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene; 1,1-dimethyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene; With 1-benzyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene; Or its pharmaceutically acceptable salt, hydrate or solvate.
Some embodiments of the present invention relate to compound, and the stereochemistry of wherein being appointed as two carbon atoms of 3b and 4a or 1a and 5a is R.
Some embodiments of the present invention relate to compound, and the stereochemistry of wherein being appointed as two carbon atoms of 3b and 4a or 1a and 5a is S.
Some embodiments of the present invention relate to compound, and the stereochemistry of wherein being appointed as two carbon atoms of 1a and 5a is R.
Some embodiments of the present invention relate to compound, and the stereochemistry of wherein being appointed as the carbon atom of 1a is that the stereochemistry of R and the carbon atom of being appointed as 5a is S.
Some embodiments of the present invention relate to compound, and the stereochemistry of wherein being appointed as the carbon atom of 1a is that the stereochemistry of S and the carbon atom of being appointed as 5a is R.
Some embodiments of the present invention relate to compound, and wherein the stereochemistry with the preferred group of being appointed as 1 carbon atom bond is interior type (endo).Should be appreciated that term " preferred group " is by using sequence rule, have and " Cahn; Ingoldand Prelog System " the identical implication that defines, generality for the CIP system is looked back, referring to R.S.Cahn, C.K.Ingold and V.Prelog, Angew.Chem.Internat.Ed.Eng.5,385-415, (1966); With V.Prelog and G.Helmchen, Angew.Chem.Internat.Ed.Eng.21,567-583 (1982).
Some embodiments of the present invention relate to compound, and wherein the stereochemistry with the preferred group of being appointed as 1 carbon atom bond is external form (exo).
In general, interior type and external form term are applicable to R
2And R
3, and (for example) when X be CR
7And when Z is N, can be expressed from the next:
Or when X be N, and Z is CR
7The time, can be expressed from the next:
In general, when X be CR
7And when Z was N, two carbon atoms then being appointed as 3b and 4a were as shown in the formula shown in (IIa):
Should be appreciated that compound of the present invention has wherein R
1And R
4Group relative to each other is the stereochemistry of cis.These compounds can be represented by formula (IIc) and formula (IId) usually:
In certain embodiments, the carbon atom of being appointed as 3b and 4a has the represented stereochemistry title suc as formula (IIc):
In certain embodiments, the carbon atom of being appointed as 3b and 4a has the indicated stereochemistry title suc as formula (IId):
Similarly, when X is N, and Z is CR
7The time, two carbon atoms then being appointed as 1a and 5a are as shown in the formula shown in (IIe):
Should be appreciated that compound of the present invention has wherein R
1And R
4Group relative to each other is the stereochemistry of cis.These compounds can be represented by formula (IIg) and formula (IIh) usually:
In certain embodiments, the carbon atom of being appointed as 1a and 5a has the indicated stereochemistry title suc as formula (IIg):
In certain embodiments, the carbon atom of being appointed as 1a and 5a has the indicated stereochemistry title suc as formula (IIh):
Should be appreciated that for formula (IIc) and the C (3b) (IId) and C (4a) and formula (IIg) and (IIh) in C (1a) and C (5a), actual " R " and " S " title will change according to existing various groups.For instance, in certain embodiments, work as R
1To R
6When being hydrogen, then stereochemistry is for defining suc as formula (IIj) with (IIk):
In certain embodiments, work as R
1, R
2, R
4, R
5And R
6Be hydrogen and R
3For making the carbon atom of described group and C (4) or C (1) directly during the group of bond, then stereochemistry is suc as formula (IIm) and (IIn) and define.R
3Example can be selected from methyl, ethyl, n-propyl, sec.-propyl, isobutyl-, normal-butyl, n-pentyl, vinyl, methylol, methoxymethyl, benzyl, phenyl and phenoxymethyl, or R
3Can be selected from methyl, ethyl, n-propyl, sec.-propyl, isobutyl-, normal-butyl, n-pentyl, vinyl, methylol, methoxymethyl, benzyl, phenyl, phenoxymethyl, methyl sulfenyl methyl, ethoxyl methyl, cyclopropyl, 1-but-2-ene base and allyl group:
Should be appreciated that the present invention contains every other possible stereochemistry and represent and title.
Some embodiments of the present invention relate to as compound represented in the following table 1.
Table 1
In certain embodiments, compound of the present invention relates to the compound in the table 2:
Table 2
In certain embodiments, compound of the present invention relates to the compound in the table 3:
Table 3
In addition, compound of the present invention (for example those compounds seen in the table 1,2 and 3 comprise its diastereomer and enantiomer) is contained its all pharmaceutically acceptable salt, solvate and hydrate especially.
Should be appreciated that the present invention contains each diastereomer, each enantiomer and its mixture of disclosed each compound of this paper and general formula, its specific stereochemistry title with each chiral carbon individually discloses generally seemingly.
For instance, one embodiment of the invention comprise and having (3bS, 4aS) or (1aS, 5aS) stereochemical compound.One embodiment of the invention are to be selected from the group that is made up of following each thing:
(3bS, 4aS)-3b, 4,4a, 5-tetrahydrochysene-2H-ring third [3,4] ring penta [1,2-c] pyrazoles-3-formic acid, (1aS, 5aS)-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene and (1aS, 5aS)-and 1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid.
Similarly, one embodiment of the invention comprise and having (3bR, 4aR) or (1aR, 5aR) stereochemical compound.One embodiment of the invention are to be selected from the group that is made up of following each thing:
(3bR, 4aR)-3b, 4,4a, 5-tetrahydrochysene-2H-ring third [3,4] ring penta [1,2-c] pyrazoles-3-formic acid, (1aR, 5aR)-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene and (1aR, 5aR)-and 1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid.
In another example, one embodiment of the invention comprise having interior-(1aR, 5aS) stereochemical compound.One embodiment of the invention are to be selected from the group that is made up of following each thing:
In-(1aR, 5aS)-1-methyl isophthalic acid a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid, in-(1aR, 5aS)-and 1-isobutyl--1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid, in-(1aR, 5aS)-1-butyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid, in-(1aR, 5aS)-1-methyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene, in-(1aR, 5aS)-and 1-ethyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene, in-(1aR, 5aS)-1-amyl group-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid, in-(1aR, 5aS)-1-propyl group-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene, in-(1aR, 5aS)-and 1-propyl group-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid, in-(1aR, 5aS)-1-isobutyl--4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene, in-(1aR, 5aS)-1-methoxymethyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid, in-(1aR, 5aS)-and 1-ethyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid, in-(1aR, 5aS)-1-phenyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene, in-(1aR, 5aS)-1-benzyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene, in-(1aR, 5aS)-and 1-benzyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid, in-(1aR, 5aS)-1-benzyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate, in-(1aR, 5aS)-1-phenyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate, in-(1aR, 5aS)-and 1-phenyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid, in-(1aR, 5aS)-1-amyl group-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene, in-(1aR, 5aS)-1-butyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene, in-(1aR, 5aS)-1-ethyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate, in-(1aR, 5aS)-1-methyl isophthalic acid a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate, in-(1aR, 5aS)-and 1-amyl group-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate, in-(1aR, 5aS)-1-sec.-propyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene, in-(1aR, 5aS)-1-phenoxymethyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene, in-(1aR, 5aS)-1-sec.-propyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid, in-(1aR, 5aS)-and 1-vinyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate, in-(1aR, 5aS)-1-vinyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid, in-(1aR, 5aS)-4-(2H-tetrazolium-5-yl)-1-vinyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene, in-(1aR, 5aS)-1-ethyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate, in-(1aR, 5aS)-and 1-methoxymethyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate, in-(1aR, 5aS)-1-methoxymethyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene, in-(1aR, 5aS)-1-methylol-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate, in-(1aR, 5aS)-1-methylol-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid and interior-(1aR, 5aS)-[4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-1-yl]-methyl alcohol.
Another embodiment of the present invention is to be selected from the group that is made up of following each thing: interior-(1aR, 5aS)-1-methyl sulfenyl methyl isophthalic acid a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid, in-(1aR, 5aS)-and 1-ethoxyl methyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid, in-(1aR, 5aS)-1-cyclopropyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid, in-(1aR, 5aS)-1-cyclopropyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene, in-(1aR, 5aS)-and 1-vinyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid, in-(1aR, 5aS)-4-(2H-tetrazolium-5-yl)-1-vinyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene, in-(1aR, 5aS)-1-Spirocyclopropyl-1 a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid, in-(1aR, 5aS)-and 1-Spirocyclopropyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene, in-(1aR, 5aS)-(E)-1-but-2-ene base-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid, in-(1aR, 5aS)-(Z)-and 1-but-2-ene base-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid, in-(1aR, 5aS)-(E)-1-propenyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene, in-(1aR, 5aS)-(Z)-1-propenyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene, in-(1aR, 5aS)-1-methoxymethyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid, in-(1aR, 5aS)-and 1-methoxymethyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene, in-(1aR, 5aS)-1-phenoxymethyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid, in-(1aR, 5aS)-spiral shell [1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-1,1 '-pentamethylene]-4-formic acid, in-(1aR, 5aS)-5-(spiral shell-[1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-1,1 '-pentamethylene]-the 4-yl)-the 1H-tetrazolium, in-(1aR, 5aS)-spiral shell [1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-1,1 '-hexanaphthene]-4-formic acid, in-(1aR, 5aS)-5-(spiral shell-[1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-1,1 '-hexanaphthene]-the 4-yl)-the 1H-tetrazolium, in-(1aR, 5aS)-1-allyl group-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid, in-(1aR, 5aS)-1-allyl group-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene and interior-(1aR, 5aS)-and 1-cyclopropyl methyl isophthalic acid a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid.
Should be appreciated that as described herein have outer-(1aR, 5aS), interior-(1aS, 5aR) and outer-(1aS, 5aR) stereochemical compound can be write in a similar manner.
In certain embodiments, compound of the present invention has following structure:
Or its pharmaceutically acceptable salt, solvate or hydrate.
In certain embodiments, compound of the present invention has following structure:
Or its pharmaceutically acceptable salt, solvate or hydrate.
In certain embodiments, compound of the present invention has following structure:
Or its pharmaceutically acceptable salt, solvate or hydrate.
In certain embodiments, compound of the present invention has following structure:
Or its pharmaceutically acceptable salt, solvate or hydrate.
In certain embodiments, compound of the present invention has following structure:
Or its pharmaceutically acceptable salt, solvate or hydrate.
In certain embodiments, compound of the present invention has following structure:
Or its pharmaceutically acceptable salt, solvate or hydrate.
In certain embodiments, compound of the present invention has following structure:
Or its pharmaceutically acceptable salt, solvate or hydrate.
In certain embodiments, compound of the present invention has following structure:
Or its pharmaceutically acceptable salt, solvate or hydrate.
In certain embodiments, compound of the present invention has following structure:
Or its pharmaceutically acceptable salt, solvate or hydrate.
In certain embodiments, compound of the present invention has following structure:
Or its pharmaceutically acceptable salt, solvate or hydrate.
In certain embodiments, compound of the present invention has following structure:
Or
Or its pharmaceutically acceptable salt, solvate or hydrate.
In certain embodiments, compound of the present invention has following structure:
Or its pharmaceutically acceptable salt, solvate or hydrate.
In certain embodiments, compound of the present invention has following structure:
Or its pharmaceutically acceptable salt, solvate or hydrate.
In certain embodiments, compound of the present invention has following structure:
Or
Or its pharmaceutically acceptable salt, solvate or hydrate.
In certain embodiments, compound of the present invention has following structure:
Or its pharmaceutically acceptable salt, solvate or hydrate.
In certain embodiments, compound of the present invention has following structure:
Or its pharmaceutically acceptable salt, solvate or hydrate.
In certain embodiments, compound of the present invention has following structure:
Or its pharmaceutically acceptable salt, solvate or hydrate.
In certain embodiments, compound of the present invention has following structure:
Or its pharmaceutically acceptable salt, solvate or hydrate.
Chemistry of the present invention
The synthesis program for preparing compound of the present invention
Some embodiments of the present invention relate to the synthetic method of the novel fused pyrazole of preparation formula (Ia).Various initial substances according to these novel methods utilize various synthetic methods commercially available or that be easy to be familiar with by the those skilled in the art to prepare can easily prepare compound of the present invention.In institute's general description synthetic, unless otherwise indicated, otherwise the substituting group of institute's mark has and identical definition described herein hereinafter.
A kind of can be used for preparing X wherein be N and Z be the method utilization of compound of the present invention of C-tetrazolium-5-base derived from the intermediate of the cyclic ketones of formula (A) illustrated among the following text response flow process I:
Flow process I
Can be at alkali and polar solvent (such as (but being not limited to) C
1-6Alkanol, methyl alcohol, ethanol, butanols, amylalcohol, hexanol, 2-methyl cellosolve, Virahol, THF, DMF and its similar solvent) exist down, by cyclic ketones and formula (C (O) OR that makes formula (A)
10)
2Dialkyl oxalate (R wherein
10Be C
1-6Alkyl) ketone ester of reacting generating (B) comes the compound of preparation formula (Ia).Appropriate base comprises: alkali metal alcoholates, for example first sodium oxide, ethoxyquin sodium, ethoxyquin potassium, uncle's fourth potassium oxide and its similar alkali metal alcoholates; Alkali metal amide (that is basic metal-NR,
11, R wherein
11Be C
1-6Alkyl or silylation-C
1-6-alkyl), for example LDA, two (trimethyl silane) Lithamide, two (trimethyl silane) sodium amide, two (trimethyl silane) potassium amide and its similar alkali.Under conditions suitable, make ketone ester (B) and the pyrazoles ester of hydrazine reaction with production (C), can use through protection or without the hydrazine of protecting.According to circumstances, can protect pyrazoles with its similar group by (for example) benzyl.Subsequently, use the known method of those skilled in the art, for example in polar solvent in room temperature to the temperature of the boiling point of described solvent, described ester is transformed the acid amides of an accepted way of doing sth (D) with ammonia treatment.Acid amides (D) with such as the pure ground of the dehydrated reagent of phosphoryl chloride, Vanadium Pentoxide in FLAKES, thionyl chloride, trifluoroacetic anhydride and its analogue or in such as the non-protonic solvent of acetonitrile, DMF and its similar solvent reaction to produce nitrile (E).Nitrile (E) (is N with triazo-compound
3) or such as sodium azide, repeatedly potassium nitride, TMS azide (that is (CH,
3) SiN
3) and the repeatedly nitrogen equipollent reaction of its analogue with the compound of production (Ia), wherein X is that N and Z are C-tetrazolium-5-base.In some instances, in suitable solvent, comprise for example AlCl such as DMF and its similar solvent
3, ZnBr
2Can be useful with the existence of the lewis acid (Lewis acid) of its analogue.
(wherein X is that N and Z are C-CO to other compounds of the present invention
2H or Z are that N and X are C-CO
2H) can prepare by respective acids from intermediate C through lithium hydroxide, sodium hydroxide, potassium hydroxide, trimethyl silicane alkanoic acid potassium or its analogue hydrolysis accepted way of doing sth (Ic).Described method following be that N and Z are C-CO about X wherein
2The embodiment of H is illustrated.
Similar approach can be C-CO about X wherein also
2H and Z are that the embodiments of the invention of N are illustrated.
(wherein Z is that N and X are C-tetrazyl or C-CO to compound of the present invention
2H or C-CO
2-C
1-6-alkyl) can use ketone (F) to prepare in the similar fashion described in the flow process I as mentioned.
Can be by handling, by making the Cyclopropanated compound for preparing ketone (F) of suitable cyclopentenol with suitable carbene or such as the class carbene generation reagent of (but being not limited to) ethylidene periodide and zinc ethyl, methylene bromide and sodium hydroxide and its analogue.Known method in the field under using can be with R
2And R
3Directly introduce ketone (F) or introduce and to be subsequently converted to R
2And R
3The group of group is (promptly by R
12And R
13Expression) suitable replacement selects carbene or class carbene to produce reagent.Can cyclopentanol be oxidized to cyclic ketones by oxygenant such as chloro-chromic acid pyrrole ingot, perrhenic acid tetrapropyl ammonium and its similar oxygenant.This method is described as follows.
Can handle through suitable 1 of suitable replacement such as the highly basic of tetramethyl-piperazine lithium, LDA, hexamethyldisilazane lithium, hexamethyldisilazane sodium, hexamethyldisilazane potassium and its similar alkali, 2-epoxy-5,6-alkene prepares compound so that alcohol (M) to be provided, referring to people such as Hodson, J.Am.Chem.Soc.2004,126,8664.Subsequently, can use oxygenant that alcohol is changed into ketone (L) such as (but being not limited to) chloro-chromic acid pyrrole ingot, perrhenic acid tetrapropyl ammonium and its analogue.
Can use open method (Schaus, S.E.; Brandes, B.D.; Larrow, J.F.; Tokunga, M.; Hansen, K.B.; Gould, A.E.; Furrow, M.E.; Jacobsen, E.N.J.Am.Chem.Soc.2002,124,1307) resolve by the kinetics hydrolysis of epoxide (G) and to prepare chirality of the present invention (non-racemize) compound.
Perhaps, can by in suitable cyclopentenone, add by the iodate trimethyl sulfoxide with as the appropriate base of sodium hydride, potassium hydride KH and its analogue react the negatively charged ion that is produced and prepare other and be substituted ketone (L).
Describe herein and can be used for preparing the another kind of method of compound of the present invention (wherein X or Z are C-tetrazolium-5-yl).This method allows need not to use under the situation of a plurality of steps or azide reagent, selects directly to introduce tetrazolium-5-base.This method illustrates that in following flow process wherein X is N, and Z is C-tetrazolium-Ji:
In the presence of alkali, use tetrazolium (P) to change into diketone (O) through the ketone (A) of suitable replacement, wherein PG is appropriate protection group or metallic cation.The appropriate base that is used for described reaction is for dissolving in solvent, and can remove proton from cyclopentanone, but otherwise do not participate in the alkali of described reaction.Strong organic bases is especially to be suitable for, such as DBU, DBN, tetramethyl guanidine or such as sodium alkoxide or alkanol magnesium and the especially alkali or the alkaline earth metal alkali of fourth potassium oxide.Suitable leaving group (being LG) comprise can be under the situation of the stability that does not influence tetrazolium (P) or gained diketone (O) the metathetical group, some examples comprise ester (C
1-4Alkoxyl group or be substituted benzyloxy).Suitable solvent comprises dimethyl formamide (DMF), N,N-DIMETHYLACETAMIDE (DMAC), methyl-sulphoxide (DMSO), N-Methyl pyrrolidone (NMP) and HMPT and tetrahydrofuran (THF) (THF).In same reaction or as the additional step after separating, use hydrazine that diketone (O) is changed into tetrazolium (Q).Then remove protecting group to produce compound of the present invention.
Similar fashion can be that C-tetrazolium-5-base and Z are that the embodiments of the invention of N are illustrated about X wherein also.
Various organic group used herein transforms and protecting group can the many programs except that mentioned above be carried out.For being found in (for example) Smith, M.B. and March in order to the reference of other synthesis programs of the preparation disclosed intermediate of this paper or compound, J., Advanced Organic Chemistry waits the people, the 5th edition, Wiley-Interscience (2001); Larock, R.C., Comprehensive Organic Transformations, A Guide to Functional GroupPreparations waits the people, second edition, VCH Publishers, Inc. (1999) or Wuts, P.G.M.; Greene, T.W.; Protective Groups in Organic synthesis waits the people, the third edition, and John Wiley and Sons, (1999), all threes all are incorporated herein by reference.
Can pass through currently known methods, for example separate diastereo-isomerism salt and discharge the optical activity amine compound, or separate diastereo-isomerism salt and with acid treatment release acid racemic mixture is become the optical purity enantiomer subsequently with optical active alkali with alkaline purification with optical activity acid.Become the other method of optical purity enantiomer to be based on chromatography on optical activity matrix or the chiral support mesotomy.Therefore by the fractional crystallization of (for example) d-or l-(tartrate, mandelate or camsilate), some racemic compound of the present invention can be split into its optical antipode.By making compound of the present invention and form diastereo-isomerism acid amides or ester, separate and with the detachable compound of the present invention of posthydrolysis by substep recrystallize, chirality chromatography or similar approach such as the optically active amines of (but being not limited to) (+) or (-) α-Jia Jibianji amine, pure and mild its analogue of (+) or (-) α-Jia Jibianji or alcohol reaction.
Can use the known additive method that is used to split optical isomer of those skilled in the art, and described method should be conspicuous for those skilled in the art.These methods comprise J.Jaques, and A.Collet and S.Wilen are in " Enantiomers, Racemates, and Resolutions " John Wiley and Sons, the method for being discussed among the New York (1981).
Should be appreciated that chemistry as herein described is representational and does not wish to be limited by any way.
Method and purposes
Compound of the present invention is applicable to the generation that suppresses free fatty acids.In addition, compound of the present invention is applicable to that the generation that suppresses free fatty acids produces lower substantially simultaneously or do not have the rubescent side effect of measurable face in some instances.The rubescent normally relevant side effect of face with throwing and nicotine.When known method (method of being showed in such as example 7) is measured in the field under using, can not cause vasodilation usually up to the compound of the present invention of about 300 mpk dosage.
In certain embodiments, compare with the nicotine of dose,equivalent basically, compound of the present invention is gone up substantially and can not caused in individuality that measurable face is rubescent.In other embodiments, compare with the nicotine of dose,equivalent basically, compound of the present invention causes that in individuality to be lower than about face measured of 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5% or 1% rubescent.
Compound of the present invention can be regulated the activity of RUP25 acceptor.Term " adjusting " means the ability that increases or reduce receptor active.In certain embodiments, contact with any one or more compound as herein described by making the RUP25 acceptor, compound of the present invention can be used for regulating in the method for RUP25 acceptor.In other embodiments, compound of the present invention can be used for regulating in the method for RUP25 acceptor to treat metabolic-related disorders in the individuality of this adjusting of needs, and described method comprises makes acceptor contact with the compound of the formula (Ia) of treatment significant quantity.In certain embodiments, compound of the present invention increases the activity of RUP25 acceptor.In other embodiments, compound of the present invention is the agonist of RUP25 acceptor.As used herein, term " agonist " refers to stimulate (i.e. activation) medicament as the receptor active of RUP25 acceptor.In certain embodiments, compound of the present invention is the part agonist of RUP25 acceptor.
Another aspect of the present invention relates to the method for the treatment of metabolic-related disorders, and it comprises the compound of throwing and treating the formula (Ia) of significant quantity to the individuality of this treatment of needs.
Another aspect of the present invention relates to the method for HDL in the rising individuality, and it comprises to the described individual compound of throwing and treating the formula (Ia) of significant quantity.
Another aspect of the present invention relates to the compound that is used for the formula (Ia) of the mankind or animal body methods of treatment by treatment as described herein.
Another aspect of the present invention relates to the compound of formula (Ia) of the methods of treatment of the metabolic-related disorders that is used for the mankind or animal body by treatment as described herein.
Another aspect of the present invention relates to the compound of the formula (Ia) of the methods of treatment that is used for the mankind or animal body metabolic-related disorders by treatment as described herein, and wherein said metabolic-related disorders is to be selected from the group that is made up of following each illness: hyperlipemia, atherosclerosis, coronary heart disease, insulin resistant, obesity, glucose dosis tolerata go down, atheromatous disease, hypertension, apoplexy, X syndromes, heart trouble and diabetes B.
Another aspect of the present invention relates to the compound of the formula (Ia) of the methods of treatment that is used for the mankind or animal body metabolic-related disorders by treatment as described herein, and wherein said metabolic-related disorders is to be selected from the group that is made up of following each illness: hyperlipemia, atherosclerosis, coronary heart disease, insulin resistant and diabetes B.
Another aspect of the present invention relates to the compound that is used for the formula (Ia) of the mankind or animal body treatment of atherosclerosis method by treatment as described herein.
Another aspect of the present invention relates to as described herein by treatment be used for the raising compound of formula (Ia) of HDL method of the mankind or animal body.
Another aspect of the present invention relates to the purposes that formula as described herein (Ia) compound is used for being manufactured on the medicine that the treatment metabolic-related disorders uses.
Another aspect of the present invention relates to the purposes that formula as described herein (Ia) compound is used for being manufactured on the medicine that the treatment metabolic-related disorders uses, and described metabolic-related disorders is to be selected from the group that is made up of following each illness: hyperlipemia, atherosclerosis, coronary heart disease, insulin resistant, obesity, glucose dosis tolerata go down, atheromatous disease, hypertension, apoplexy, X syndromes, heart trouble and diabetes B.
Another aspect of the present invention relates to the purposes that formula as described herein (Ia) compound is used for being manufactured on the medicine that the treatment atherosclerosis uses.
Another aspect of the present invention relates to formula as described herein (Ia) compound and is used for being manufactured on the purposes of the medicine that individual HDL uses of raising.
Some embodiments of the present invention relate to the method for the treatment of metabolic-related disorders.In certain embodiments, the illness of the group that is made up of following each illness of described metabolic-related disorders: hyperlipemia, atherosclerosis, coronary heart disease, insulin resistant, obesity, glucose dosis tolerata go down, atheromatous disease, hypertension, apoplexy, X syndromes, heart trouble and diabetes B.In certain embodiments, described metabolic-related disorders is hyperlipemia, atherosclerosis, coronary heart disease, insulin resistant and diabetes B.In certain embodiments, described metabolic-related disorders is a hyperlipemia.In certain embodiments, described metabolic-related disorders is an atherosclerosis.In certain embodiments, described metabolic-related disorders is a coronary heart disease.In certain embodiments, described metabolic-related disorders is an insulin resistant.In certain embodiments, described metabolic-related disorders diabetes B.
In some embodiment about method of the present invention, described individuality is a Mammals.In other embodiments, described Mammals is the people.
Another aspect of the present invention relates to the method for making medical composition, and it comprises makes formula as described herein (Ia) compound mix with pharmaceutically acceptable supporting agent or make up.
Composition of the present invention
Some embodiments of the present invention comprise the medical composition that comprises according to the compound of formula (Ia) and pharmaceutically acceptable supporting agent combination.
Some embodiments of the present invention comprise the method for making medical composition, and it comprises to make according at least a compound of the disclosed any compound embodiment of this paper and mixes with pharmaceutically acceptable supporting agent.
Can make described active compound and liquid or finely powdered solid carriers or both uniform mixing with required ratio usually by any appropriate method, and then (if needs) the gained mixture formed desired shape prepare prescription.
Can use such as tackiness agent, weighting agent, can accept the conventional excipients of wetting agent, compressing tablet lubricant and disintegrating agent at the tablet that is used for oral administration and capsule.The liquid preparation that is used for oral administration can be solution, emulsion, waterborne suspension or oily suspensions and syrupy form.Perhaps the per os preparation can be the form of dry powder, can be with itself and water or another suitable liquid mediator reprovision before using.Can in liquid preparation, add other additives such as suspension agent or emulsifying agent, non-aqueous mediator (comprising edible oil), sanitas and seasonings and tinting material.Can be by compound of the present invention be dissolved in the suitable liquid mediator, before filling,, and seal suitable bottle or the peace bottle prepares non-through the intestines formulation with the solution filtration sterilization.These only prepare a few examples of many proper methods of formulation for being used to of having known in the affiliated field.
Use the known technology of those skilled in the art compound of the present invention can be deployed into medical composition.Except that supporting agent referred to above, suitable pharmaceutically acceptable supporting agent is known in affiliated field, for example referring to Remington, The Science and Practice of Pharmacy waits the people, the 20th edition, 2000, Lippincott Williams﹠amp; Wilkins, (editor: Gennaro, people such as A.R.).
Although may be in substituting purposes, the compound that in treatment of the present invention, uses can be undressed or the form of pure chemistry material throw with, but preferably provide compound or " activeconstituents " with the medicine prescription that further comprises pharmaceutically acceptable supporting agent or the form of composition.Therefore one aspect of the present invention is contained and is comprised pharmaceutically acceptable supporting agent and at least a medical composition that makes up according to the compound of formula (Ia).
The invention provides and comprise compound of the present invention or its pharmaceutically acceptable salt, hydrate or solvate medicine prescription together with one or more pharmaceutically acceptable supporting agents.Described supporting agent is palpus " can accept " on the implication compatible with other compositions of prescription, and can not be excessively unfavorable to its recipient.
Medicine prescription comprises and is suitable for per os, rectum, intranasal, part (comprising oral cavity and hypogloeeis), vagina or non-through intestines (comprising intramuscular, subcutaneous and intravenously) dispensing or to be suitable for sucking, be blown into or those prescriptions of the form of transdermal patch dispensing.Transdermal patch distributes medicine with controllable rate by the medicine that is used to absorb with the minimum effective means oblatio of drug degradation amount.Usually, transdermal patch comprises waterproof stratum basale, single pressure sensitive adhesive layer and has the removable protective layer of release liner.One of ordinary skill in the art should be appreciated that and understand the technology that is suitable for making required effective transdermal patch based on those skilled in the art's needs.
Therefore compound of the present invention can be made into the form of medicine prescription and its unit dosage together with conventional adjuvant, supporting agent or thinner and can be used as with this form and all is used for the solid such as tablet or filled capsules that per os uses, or such as solution, suspension, emulsion, elixir, gel or through the capsular liquid of its filling; The suppository form that is used for rectal administration; Or be used for the non-aseptic injectable solution form of using through intestines (comprising subcutaneous).These medical compositions and its unit dosage can comprise the conventional ingredient of conventional ratio, have or do not have extra active compound or composition, and these unit dosage can contain and the suitable any suitable effective amount of actives of per daily dose scope of the employing of being scheduled to.
For oral administration, medical composition can be the form of (for example) tablet, capsule, suspension or liquid.Medical composition is preferably with the dosage unit form manufacturing of the activeconstituents that contains specified quantitative.The example of these dose units is capsule, tablet, pulvis, granule or suspension, and it has the conventional additives such as lactose, N.F,USP MANNITOL, W-Gum or yam starch; Tackiness agent such as crystalline cellulose, derivatived cellulose, gum arabic, W-Gum or gelatin; Disintegrating agent such as W-Gum, yam starch or carboxymethyl-sodium cellulosate; With lubricant such as talcum powder or Magnesium Stearate.Described activeconstituents also can be used as wherein can use (for example) normal saline solution, dextrose or water as the composition of suitable pharmaceutically acceptable supporting agent by inject throw with.
Compound of the present invention or its pharmaceutically acceptable salt, hydrate or solvate can be used as the activeconstituents in the medical composition, especially as RUP25 receptor agonists/part agonist.Term " activeconstituents " defines in the context of " medical composition ", and it should mean and it has been generally acknowledged that that " non-active ingredient " of medical benefit can't be provided basically is relative, and the component of the medical composition of main pharmacological effect is provided.
Dosage can extensively change in the limit when using compound of the present invention, and as usual and the physician is known, under each individual instances, it should be fit to individual state.Its situation according to the character of (for example) institute desire treatment disease and seriousness, patient, the compound that adopts or the morbid state for the treatment of be acute or chronic or except that compound of the present invention, whether throw with other active compounds and decide.Representative dosage of the present invention include, but is not limited to about 0.001mg to about 5000mg, about 0.001mg to about 2500mg, about 0.001mg to about 1000mg, 0.001mg about 500mg, 0.001mg about 250mg, about 0.001mg to 100mg, about 0.001mg about 50mg and about 0.001mg about 25mg extremely extremely extremely extremely.Especially when thinking relatively in a large number, can throw in the daytime and multidose, for example 2,3 or 4 dosage.Decide on individuality, and when patient's physician or care-giver think fit, depart from dosage as herein described up or down and can be necessary.
The amount of the activeconstituents that requirement is used for the treatment of or its pharmaceutically acceptable salt, hydrate or solvate will be not only changes with selected specific salts but also with the character of dosing way, the patient's condition for the treatment of and patient age and situation.Therefore, institute's usage quantity is the most at last according to attending doctor or clinician's judgement.In general, it will be understood by one of ordinary skill in the art that the in vivo data how to obtain are extrapolated to the alternate model system, for example are extrapolated to the mankind from animal model in a model system.Usually, animal model includes, but is not limited to the rodent diabetes model described in example 1 hereinafter; The atherosis model of rat artery described in example 2 hereinafter; Or the in vivo animal Atherosclerosis Model described in example 5 hereinafter.In some cases, these extrapolations can be only based on such as Mammals and be preferably the weight of the animal model that another human animal compares.Yet more generally, these extrapolations and not only based on weight differential but are incorporated multiple factor into.Representative factor comprises patient's type, age, weight, sex, diet and medical conditions, severity of disease, dosing way, pharmacology Consideration, such as the pharmacokinetics and the toxicology overview of activity, effect, the specific compound that adopts, whether utilize drug delivery system, the morbid state for the treatment of be acute or chronic, whether outside compound of the present invention also throwing and other active compounds as the part of combination treatment.Select to be used for dosage regimen according to the multiple factor of all cited as mentioned factors with the compound of the present invention and/or the composition therapeuticing disease patient's condition.Therefore, the actual dosage regimen that is adopted can extensively change, and therefore can depart from preferred modes, and the those skilled in the art will be appreciated that dosage and the dosage regimen that can test outside these typical ranges, and if suitably, then it can be used in the method for the present invention.
Can single dose or provide required dosage expediently as separate doses with appropriate intervals (for example with every day twice, three times, sub-dosage more than four times or four times) dispensing.Sub-dosage itself can be further divided into the dispensing at (for example) many discrete loose intervals.Especially when thinking when be fit to throwing with relative big amount, that per daily dose can be divided into is some (for example 2,3 or 4), and part is offerd medicine.Decide on individual state,, then may necessity depart from indicated per daily dose up or down if suitably.
Compound of the present invention can multiple per os and non-through the intestines formulation throw with.Apparent for the those skilled in the art, following formulation can comprise as the compound of the present invention of active ingredient or the pharmaceutically acceptable salt of compound of the present invention.
For from compound medical composition of the present invention, pharmaceutically acceptable supporting agent can be solid or liquid.But the solid form preparation comprises pulvis, tablet, pill, capsule, cartridge bag, suppository and discrete particles.Solid carriers can be one or more materials that also can be used as thinner, perfume compound, solubilizing agent, lubricant, suspension agent, tackiness agent, sanitas, tablet disintegrant or capsule closure material.
In pulvis, supporting agent is and finely powdered active ingredient blended finely powdered solid mutually.
In tablet, active ingredient is mixed mutually with the supporting agent with necessary viscosifying power with proper ratio and is pressed into desired shape and size.
Pulvis and tablet can contain the active compound of different quantities per-cent.Representative amount can contain 0.5% to about 95% active compound in pulvis or the tablet; Yet the skilled worker should know that this extraneous amount is necessary.The suitable supporting agent of pulvis and tablet is magnesiumcarbonate, Magnesium Stearate, talcum powder, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose gum, Xylo-Mucine, low melt wax, theobroma oil and its similar supporting agent.
Terms " formulation " be intended to comprise active compound with as the prescription that the capsule closure material of capsular supporting agent is provided, in capsule, having or do not having under the situation of supporting agent, described active ingredient is surrounded by supporting agent, therefore associates with active ingredient as the capsule closure material of supporting agent.Similarly, comprise cartridge bag and suck agent.Tablet, pulvis, capsule, pill, cartridge bag and suck agent and can be used as the solid form that is suitable for oral administration.
For preparation suppository, at first melt low melt wax, and active ingredient is dispersed in wherein by stirring such as the mixture of glycerin fatty acid ester or theobroma oil.Then in the mould with fusing uniform mixture impouring suitable size, make its cooling and and then solidify.
The prescription that is suitable for vaginal dosing can also contain these forms as the hysterophore that is known as suitable supporting agent in the affiliated field, sanitary tampons, emulsifiable paste, gel, paste, foam, spraying except that activeconstituents provide.
Liquid form preparation comprises solution, suspension and emulsion, for example water or water-propylene glycol solution.For instance, non-ly can be formulated into solution in the polyoxyethylene glycol aqueous solution through the enteral administration liquid preparation.Can use suitable dispersant or wetting agent and suspension agent to allocate the injectable formulation of sterile injectable water-based for example or oily suspensions according to known technology.Sterile injectable preparation also can be in nontoxic non-ly can accept sterile injectable solution or suspension in thinner or the solvent through intestines, for example is the solution in the 1,3 butylene glycol.Adoptablely accept mediator and solvent is water, Ringer's solution (Ringer ' s solution) and isotonic sodium chlorrde solution.In addition, adopt aseptic, fixed oil as solvent or suspension medium usually.For this purpose, can adopt any gentle fixed oil, comprise synthetic single or two glyceryl ester.In addition, find to can be used in the injectable formulation such as oleic lipid acid.
Therefore, can be used for non-through intestines dispensing (for example by injection, for example by fast injection or transfusion continuously) and can infuse or the unit dosage that added in the multi-dose container of sanitas provides through allotment according to compound of the present invention in peace bottle, pre-filled syringe, small volume.Described composition can be these forms as the suspension in oiliness or aqueous vehicles, solution or emulsion, and can contain the blender such as suspension agent, stablizer and/or dispersion agent.Perhaps, described activeconstituents can be by the aseptic separation of sterile solid or the powder form that obtains by freeze-drying from solution, its before use with the suitable mediator reprovision of the water of for example aseptic, pyrogen-free matter.
Can be by active ingredient is water-soluble and optionally add suitable tinting material, seasonings, stablizer and thickening material and prepare and be suitable for the aqueous solution that per os uses.
Can be by being suitable for the waterborne suspension that per os uses the finely powdered active ingredient is scattered in to make in the water such as natural or synthetical glue, resin, methylcellulose gum, Xylo-Mucine or other cohesive materials of knowing suspension agent.
The preparation that also comprises solid form, wish before the use its change into rapidly liquid absorption member with oral administration with.These liquid forms comprise solution, suspension and emulsion.Except that active ingredient, these preparations also can contain tinting material, seasonings, stablizer, buffer reagent, artificial and natural sweeteners, dispersion agent, thickening material, solubilizing agent and its analogue.
For through the epidermis topical administration, compound according to the present invention can be formulated into ointment, emulsifiable paste or lotion, or is deployed into transdermal patch.
Ointment and emulsifiable paste can (for example) be allocated with water-based or oleaginous base under the situation of adding suitable thickening material and/or gelifying agent.Lotion can water-based or the oleaginous base allotment, and in general it will also contain one or more emulsifying agents, stablizer, dispersion agent, suspension agent, thickening material or tinting material.
Be suitable for that the prescription of topical administration comprises in mouth: suck agent, it is generally comprised within the promoting agent in the seasonings matrix (usually sucrose and gum arabic or tragacanth); Lozenge, it is included in such as the activeconstituents in the inert base of gelatin and glycerine or sucrose and gum arabic; With gargle agent, it is included in the activeconstituents in the suitable liquid supporting agent.
By for example usual manner solution or suspension directly are applied to nasal cavity with dropper, suction pipe or spraying.Can be single or the multiple doses form prescription is provided.Under the latter's of dropper or suction pipe situation, its can by the patient throw with suitably, the solution or the suspension of pre-determined volume realize.Under the situation of spraying, it can be realized by the mode of (for example) metering atomisation pump.
In respiratory tract dispensing also can be by the pressurized bag with suitable propelling agent, provide the mode of the aerosol formulations of activeconstituents to realize.If with the compound of formula (Ia) or the medical composition that comprises it as aerosol throw with, for example as the intranasal aerosol or by suck to throw with, then it can use (for example) spraying, atomizer, pump sprayer, suction apparatus, metered dose inhaler or Diskus to carry out.Be used to throw with medical form and can prepare by the known method of affiliated field person's technician as the compound of the formula (Ia) of aerosol.For its preparation, for example can use typical additives (for example benzyl alcohol or other suitable preservatives, the absorption enhancer that is used to strengthen biological usability, solubilizing agent, dispersion agent and other reagent) and suitably the time propelling agent commonly used (for example comprise carbonic acid gas, CFC and its analogue such as Refrigerant 12, trichlorofluoromethane or dichloro tetrafluoro ethane), solution or dispersion liquid in the compound Yu Shui of employing formula (Ia), water/alcohol mixture or the suitable normal saline solution solution.Aerosol also can suitably contain the tensio-active agent such as Yelkin TTS.By metering valve may command drug dose is provided.
Comprise in the prescription of filling a prescription in the nose that to what respiratory tract was offerd medicine compound should have (for example) 10 micron number magnitudes or littler small particle size usually be intended for.This particle diameter can obtain by known mode in the affiliated field, for example obtains by micronization.When needs, can adopt to be suitable for providing the prescription that continues release of active ingredients.
Or form that can dry powder provides activeconstituents, for example with in such as lactose, starch, such as the powder mixture form of the compound in the suitable pulvis matrix of the starch derivative of Vltra tears and polyvinylpyrrolidone (PVP).Expediently, the pulvis supporting agent should form gel in nasal cavity.Dust composition can provide by unit dosage, for example with the capsule or the filter cylinder form of gelatin, or provides with the blister pack form that pulvis can the suction dispensing.
Pharmaceutical preparation preferably is unit dosage.With this form, preparation is further divided into the unitary dose of the active ingredient that contains appropriate amount.Described unit dosage can be the encapsulation preparation, and described encapsulation contains the preparation of discrete magnitude, such as package tablet, capsule and the pulvis in bottle or peace bottle.Unit dosage self also can be capsule, tablet, cartridge bag or sucks agent, or it can be any unit dosage that is packing forms of proper number.
The tablet or the capsule that are used for oral administration are preferred compositions with the liquid that is used for the intravenously dispensing.These tablets and capsule contain the 0.001mg that has an appointment usually to about 1000mg, about 0.001mg about 500mg or the about 0.001mg compound of the formula (Ia) of about 250mg extremely extremely.
Compound of the present invention can be converted into " prodrug ".Term " prodrug " refers in affiliated field known particular chemical base group modification and when throwing when individual, these groups carry out bio-transformation so that the compound of parent compound to be provided.Therefore prodrug can be considered and contains one or more and use to change or to eliminate the compound of the present invention of the special-purpose nontoxic blocking group of compound characteristic in interim mode.In general, utilize " prodrug " method to promote oral absorption.Expound adequately in T.Higuchi and V.Stella, " Pro-drugs as Novel Delivery Systems; " the A.C.S.Symposium Series, Deng the people, the 14 volume and Bioreversible Carriers in Drug Design, Edward B.Roche compiles, AmericanPharmaceutical Association and Pergamon Press, provide in 1987, both all are incorporated herein by reference.
Combination treatment
Although compound of the present invention can be used as independent active medical agent (that is, monotherapy) throw with, it also can be used in combination (combination treatment) with other medical agents, such as being used for the treatment of disease/patient's condition as herein described/illness.Therefore, another aspect of the present invention comprises the method for the treatment of metabolic-related disorders, its comprise to the individuality of this treatment of needs throw with the compound of the present invention of the treatment significant quantity of one or more other medical agents combinations as herein described.
Can comprise with the suitable medical agent that compound of the present invention is used in combination: antiobesity agent, such as apo-B-secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitor, MCR-4 agonist, cholecystokinin-A (CCK-A) agonist, thrombotonin and noradrenalin reuptake inhibithors (for example, Reductil (sibutramine)), parasympathomimetic agent, β
3The adrenoceptor agonist, Dopamine HCL agonist (for example bromocriptine (bromocriptine)), the melanotropin receptor analogs, cannabin(e) 1 receptor antagonist [SR141716:N-(piperidines-1-yl)-5-(4-chloro-phenyl-)-1-(2 for example, the 4-dichlorophenyl)-4-methyl isophthalic acid H-pyrazole-3-formamide], melanocyte aggegation hormone antagonist, leptin (lepton) (OB albumen), the leptin analogue, the leptin receptor agonist, the plain antagonist of galanin, lipase inhibitor (is moored Si Tating (tetrahydrolipstatin) such as the tetrahydrochysene Buddhist nun, be Xenical (Orlistat)), anoretic (such as to bell toad element (bombesin) agonist), neuropeptide-Y antagonist, the Protirelin agent, the male sterone of dehydrogenation table or its analogue, glucocorticoid receptor agonist or antagonist, plain (orexin) receptor antagonist of appetizing, the conjugated protein antagonist of urotensin (urocortin), glucagon-like peptide-1 receptor agonists, the ciliary nerves somatomedin is (such as available from RegeneronPharmaceuticals, Inc., Tarrytown, NY and Procter﹠Gamble Company, Cincinnati, the Axokine of OH
TM), human cavy associated protein (AGRP), stomach internal hormone receptor antagonist, histamine 3 receptor antagonists or oppositely agonist, neuromedin U receptor agonists, the neural plain anoretic (for example PHENTERMINE (phntermine), Mazindol (mazindol) and its analogue) of quasiorthogonal sense and appetite-inhibiting agent (for example Bupropion (bupropion)).
Those skilled in the art known or according to this disclosure its other comprise the antiobesity agent of medicament hereinafter described with easy to understand.
In certain embodiments, antiobesity agent is selected from the group that is made up of following each thing: Xenical, Reductil, bromocriptine, ephedrine (ephedrine), leptin and false racephedrine (pseudoephedrine).In another embodiment, compound of the present invention and combination treatment and exercise and/or realizable go on a diet combine throw with.
The category that should be appreciated that the combination treatment of compound of the present invention and other antiobesity agents, anoretic, appetite-inhibiting agent and related agents is not limited to above cited those therapies, and comprises in principle with any treating the useful medical agent of overweight and obese individuals or any combination of medical composition.
Except that antiobesity agent, can be included in useful medicament in the concurrent illness of treatment with other suitable medical agents that compound of the present invention is used in combination.These treatment of conditions comprise use under known one or more the medical agent that belongs to the following drug categories of mentioning (but being not limited to) in the field: sulfonylurea, MAG is for anti-(meglifinide), biguanides, alpha-glucosidase inhibitor, peroxisome proliferation body activated receptor-γ (peroxisome proliferators-activatedreceptor-γ) (being PPAR-γ) agonist, Regular Insulin, insulin analog, the HMG-CoA reductase inhibitor, cholesterol-the reduction medicine (for example, Bei Te, it comprises: fenofibrate (Fenofibrate), bezafibrate (Bezafibrate), gemfibrozil (Gemfibrozil), chlorine Bei Te (Clofibrate) and its analogue; Bile acid chelating agent, it comprises QUESTRAN (cholestyramine), colestipol (colestipol) and its analogue; And nicotine), anti-platelet agents (for example acetylsalicylic acid (aspirin) and adenosine diphosphate (ADP) receptor antagonist, it comprises: clopidogrel (clopidogrel), Ticlopidine (ticlopidine) and its analogue), angiotonin converting enzyme inhibitor, angiotonin II receptor antagonist and adiponectin (adiponectin).According to an aspect of the present invention, compound of the present invention can use with medical agent or the drug regimen that belongs to one or more drug categories cited herein.
The category that should be appreciated that the combination treatment of compound of the present invention and other medical agents is not limited to above and those hereinafter cited combination treatments, and comprises in principle with any the useful medical agent of the treatment disease, the patient's condition or the illness that are associated with metabolic-related disorders or any combination of medical composition.
Some embodiments of the present invention comprise the disease that treatment is as described herein, the method of the illness or the patient's condition, it comprises to the individuality of this treatment of needs throws and the treatment significant quantity that combines at least a medical agent that is selected from the group that is made up of following each thing or the compound of the present invention of dosage: sulfonylurea, MAG is for anti-, biguanides, alpha-glucosidase inhibitor, peroxisome proliferation body activated receptor-γ (being PPAR-γ) agonist, Regular Insulin, insulin analog, the HMG-CoA reductase inhibitor, cholesterol-the reduction medicine (for example, Bei Te, it comprises: fenofibrate, bezafibrate, gemfibrozil, chlorine Bei Te and its analogue; Bile acid chelating agent, it comprises QUESTRAN, colestipol and its analogue; And nicotine), anti-platelet agents (for example acetylsalicylic acid and adenosine diphosphate (ADP) receptor antagonist, it comprises: clopidogrel, Ticlopidine and its analogue), angiotonin converting enzyme inhibitor, angiotonin II receptor antagonist and adiponectin.In certain embodiments, medical composition further comprises one or more medicaments that is selected from the group that is made up of following each thing: alpha-glucosidase inhibitor, aldose reductase inhibitor, biguanides, HMG-CoA reductase inhibitor, squalene synthetic inhibitor, Bei Te, LDL katabolism toughener, angiotonin converting enzyme inhibitor, insulin secretion enhancers, thiazolidinedione and DP receptor antagonist.
One aspect of the present invention is contained the medical composition that comprises at least a The compounds of this invention as described herein.In certain embodiments, described medical composition further comprises one or more reagent that is selected from the group that is made up of (for example) following each thing: alpha-glucosidase inhibitor, aldose reductase inhibitor, biguanides, HMG-CoA reductase inhibitor, squalene synthetic inhibitor, Bei Te, LDL katabolism toughener, angiotonin converting enzyme inhibitor, insulin secretion enhancers and thiazolidinedione.
Can comprise alpha-glucosidase inhibitor in conjunction with the suitable medical agent that compound of the present invention uses.Alpha-glucosidase inhibitor belongs to the drug categories such as the digestive ferment of α-Dian Fenmei, maltin, limit dextrinase, sucrase etc. in competitive inhibition pancreas and/or the small intestine.But blood glucose levels is slowed down, eliminates or reduced in addition to the retroactive inhibition of alpha-glucosidase inhibitor by the digestion that postpones starch and sugar.The representative example of some alpha-glucosidase inhibitors comprises acarbose (acarbose), N-(1,3-dihydroxyl-2-propyl group) known alpha-glucosidase inhibitor in well ridge Valiolamine (valiolamine) (popular name, voglibose (voglibose)), miglitol (miglitol) and the affiliated field.
Can comprise sulfonylurea in conjunction with the suitable medical agent that compound of the present invention uses.Sulfonylurea (SU) is by promoting Regular Insulin from pancreatic beta cell excretory medicine via the transmission of the SU acceptor in cytolemma insulin secretion signal.The example of sulfonylurea comprises known other sulfonylureas in U26452 (glyburide), Glipizide (glipizide), glimepiride (glimepiride) and the affiliated field.
It is anti-to comprise that MAG replaces in conjunction with the suitable medical agent that compound of the present invention uses.It is the benzoic acid derivative of representing the novel class of insulin secretagogue that MAG replaces anti-.These medicament target postprandial hyperglycemia diseases, and reducing HbA
1cThe effect suitable with sulfonylurea showed in the aspect.MAG comprises that for anti-example known other MAGs are for anti-in Nuo Helong (repaglinide), nateglinide (nateglinide) and the affiliated field.
Can comprise biguanides in conjunction with the suitable medical agent that compound of the present invention uses.Biguanides representative stimulates the anaerobism glycolysis-, increase susceptibility to Regular Insulin in perienchyma, suppress from intestinal absorption glucose, to suppress liver glucose newborn and suppress the drug categories of Fatty Acid Oxidation.The example of biguanides comprises known biguanides in phenformin (phenformin), N1,N1-Dimethylbiguanide (metformin), butyl biguanides (buformin) and the affiliated field.
Can comprise alpha-glucosidase inhibitor in conjunction with the suitable medical agent that compound of the present invention uses.Digestive ferment in alpha-glucosidase inhibitor competitive inhibition pancreas and/or the small intestine such as α-Dian Fenmei, maltin, limit dextrinase, sucrase etc.But blood glucose levels is slowed down, eliminates or reduced in addition to the retroactive inhibition of alpha-glucosidase inhibitor by the digestion that postpones starch and sugar.The example of alpha-glucosidase inhibitor comprises known alpha-glucosidase inhibitor in acarbose, N-(1,3-dihydroxyl-2-propyl group) well ridge Valiolamine (popular name, voglibose), miglitol and the affiliated field.
Can comprise peroxisome proliferation body activated receptor-γ (being PPAR-γ) agonist in conjunction with the suitable medical agent that compound of the present invention uses.Peroxisome proliferation body activated receptor-γ agonist is represented active nuclei acceptor PPAR-γ and therefore is adjusted in the compounds category of insulin replies genetic transcription related in the generation of control glucose, transportation and the utilization.The medicament of described classification also promotes to regulate fatty acid metabolism.The example of PPAR-γ agonist comprises Avandia (rosiglitazone), pioglitazone (pioglitazone), carries Si Liezha (tesaglitazar), known PPAR-γ agonist in Mi Tuolie ketone (netoglitazone), GW-409544, GW-501516 and the affiliated field.
Can comprise the DP receptor antagonist in conjunction with the suitable medical agent that compound of the present invention uses.The DP receptor antagonist comprises those DP receptor antagonists that are described in WO01/79169, WO03/062200, WO01/66520, WO03/022814, WO03/078409, WO2004/103370, EP 1305286, WO02/094830 and its similar document.Other representative DP agonist compounds are found among the WO04/103370.The examples for compounds that is particularly useful for selectivity antagonism DP acceptor comprises following compound:
Comprise its pharmaceutically acceptable salt, solvate and hydrate.Can come synthetic compound AB according to illustrated description among September 13 calendar year 2001 disclosed WO01/66520A1; Can come synthetic compound AC according to illustrated description among on March 20th, the 2003 disclosed WO03/022814A1; And can come synthetic compound AD and AE according to illustrated description among on September 25th, the 2003 disclosed WO03/078409.
Can comprise the HMG-CoA reductase inhibitor in conjunction with the suitable medical agent that compound of the present invention uses.The HMG-CoA reductase inhibitor is to belong to by suppressing the medicament that also is called statin (Statin) compound that hydroxymethyl glutaryl base CoA (HMG-CoA) reductase enzyme reduces the drug categories of blood cholesterol levels.The HMG-CoA reductase enzyme is the rate limiting enzyme in the cholesterol biosynthesizing.Statin reduces serum LDL concentration by the activity that raises ldl receptor, and is responsible for LDL is removed from blood.The representative example of some statin compounds comprises rosuvastatin (rosuvastatin), Pravastatin (pravastatin) and its sodium salt, simvastatin (simvastatin), lovastatin (lovastatin), atorvastatin (atorvastatin), fluvastatin (fluvastatin), Cerivastatin (cerivastatin), pitavastatin (pitavastatin), known HMG-CoA reductase inhibitor in " super he spit of fland (superstatin) " of BMS and the affiliated field.
Can comprise angiotonin saccharase (ACE) inhibitor in conjunction with the suitable medical agent that compound of the present invention uses.The angiotonin converting enzyme inhibitor belongs to by suppressing the drug categories that the angiotonin saccharase partly reduces blood glucose levels and brings high blood pressure down.The example of angiotonin converting enzyme inhibitor comprises captopril (captopril), enalapril (enalapril), alacepril (alacepril), delapril (delapril), Ramipril (ramipril), lisinopril (lisinopril), imidapril (imidapril), benazepril (benazepril), SQ-29852 (ceronapril), Yipingshu (cilazapril), enalaprilat (enalaprilat), fosinopril (fosinopril), good fortune Puli (moveltopril) not, perindopril (perindopril), quinapril (quinapril), spirapril (spirapril), temocapril (temocapril), known angiotonin converting enzyme inhibitor in Trolapril (trandolapril) and the affiliated field.
Can comprise angiotonin II receptor antagonist in conjunction with the suitable medical agent that compound of the present invention uses.Angiotonin II receptor antagonist target vascular therapy shrinks plain II receptor subtype 1 (being AT1) and proof has useful effect to hypertension.The example of angiotonin II receptor antagonist comprises known angiotonin II receptor antagonist in losartan (losartan) (with its potassium salt form) and the affiliated field.
Other comprise one or more medical agents that use the drug categories of being mentioned below known belonging to (but being not limited to) in the affiliated field to one or more treatment of diseases cited herein: islet amyloid sample peptide (amylin) agonist (for example tripro-amylin (pramlintide)); insulin secretagogue (GLP-1 agonist for example; insulin secretion accelerating peptide-4 (exendin-4); Regular Insulin regulator (insulinotropin) (NN2211); depeptidyl peptidase inhibitors (for example NVP-DPP-728); acyl-CoA cholesterol acetyltransferase inhibitor (ezetimibe (ezetimibe) for example; Yi Fusimibei (eflucimibe) and its similar compound); cholesterol absorption inhibitor (ezetimibe for example; Pamaqueside (pamaqueside) and its similar compound); cholestery ester transfer protein inhibitors (for example, CP-529414; JTT-705; CETi-1; open up sand and blow rich (torcetrapib) and its similar compound); microsomal triglyceride transfer protein inhibitor (for example Yi Miputate (implitapide) and its similar compound); Cholesterol Regulating Agents (for example NO-1886 and its similar compound); bile acide conditioning agent (for example GT103-279 and its similar compound); inhibitor for squalene synthetic enzyme and 11 beta-HSD 1 inhibitors.
The squalene synthetic inhibitor belongs to by suppressing the drug categories that reduces blood cholesterol levels of synthesizing of squalene.The example of squalene synthetic inhibitor comprises (S)-α-[two [2,2-dimethyl-1-oxopropoxy) methoxyl group] phosphoryl]-3-phenoxy group benzene butane sulfonic acid, known squalene synthetic inhibitor in monopotassium salt (BMS-188494) and the affiliated field.
According to the present invention, combination can be used in the following manner: active ingredient out of the ordinary is mixed with pharmaceutically acceptable supporting agent as indicated above, vehicle, tackiness agent, thinner etc. all or independently, and with described mixture as medical composition per os or non-oral administration with use.When compound of the present invention throw as combination treatment with another active compound and the time, the independent medical composition that described therapeutical agent can be formulated at the same time or different time provides, or described therapeutical agent can be used as single composition and provides.
According to the present invention, compound of the present invention can prepare in the following manner with the combination of medical agent: active ingredient out of the ordinary is mixed with pharmaceutically acceptable supporting agent as described herein, vehicle, tackiness agent, thinner etc. all or independently, and with described mixture as medical composition per os or non-oral administration with.When the mixture of compound of the present invention or compound throw as combination treatment with another active compound and the time, the independent medical composition that described therapeutical agent can be formulated at the same time or different time provides, or described therapeutical agent can be used as single independent composition and provides.
Tagged compound and calibration method
Another target of the present invention relate to formula (Ia) and relative formula through radiolabeled compound, described compound is not only applicable to radiophotography and is applicable in vitro with in vivo examine and determine, with the PUP25 in location and the quantitative tissue sample (comprising the mankind) with by suppressing the receptor ligand through the combination discriminating RUP25 of radiolabeled compound.Another target of the present invention comprises that comprising these novel RUP25 through radiolabeled compound examines and determine.
The present invention contain through the subclass of isotope-labeled formula (Ia) and any this paper (such as, but not limited to) compound of formula (Ia) to (Io).The compound of " isotropic substance " or " through radio-labeling " is to be different from the fact of the atomic substitutions of the atomic mass of common (being natural existence) atomic mass of finding of occurring in nature or total mass number or total mass number or replacement through having except that one or more atom, those compounds that are equal to the disclosed compound of this paper.The suitable radioactive nuleus that can incorporate compound of the present invention into includes, but is not limited to
2H (also being written as D, deuterium),
3H (also being written as T, tritium),
11C,
13C,
14C,
13N,
15N,
15O,
17O,
18O,
18F,
35S,
36Cl,
82Br,
75Br,
76Br,
77Br,
123I,
124I,
125I and
131I.Described radioactive nuleus can be incorporated into and described application-specific should be depended on through radiolabeled compound through radiolabeled compound.For instance, in vitro RUP25 mark and competition calibrating, incorporate into
3H,
14C,
82Br,
125I,
131I,
35S or compound the most suitable usually.Use for radiological imaging,
11C,
18F,
125I,
123I,
124I,
131I,
75Br,
76Br or
77Br is the most suitable usually.
Should be appreciated that " through radio-labeling " or " tagged compound " is the compound of the present invention of having incorporated at least one radioactive nuleus into; In certain embodiments, described radioactive nuleus be selected from by
3H,
14C,
125I,
35S and
82The group that Br forms.
More of the present inventionly be applicable to the calibrating of compound and/or substrate tissue distribution through isotope-labeled compound.In certain embodiments, radioactive nuleus
3H and/or
14The C isotropic substance is applicable to these research.In addition, with (promptly such as deuterium
2H) some treatment advantage (for example, in vivo the transformation period increases or the reduction of dosage demand) that can provide by than the greater metabolic stability generation is provided higher isotope, and therefore can be preferred in some cases.Of the present invention through isotope-labeled compound usually can through with flow process above and the similar following program of disclosed program in the example hereinafter, by preparing without isotope-labeled reagent to replace through isotope-labeled reagent.Hereinafter discuss the synthetic method that other are suitable for.In addition, should be appreciated that all atoms of indicating all can be the isotropic substance of the most common existence of these atoms or the most rare radio isotope or the active isotropic substance of non-radioactive in compound of the present invention.
The synthetic method of incorporating radio isotope into organic compound is applicable to compound of the present invention and knows in affiliated field.These synthetic methods of for example radioactive level of tritium being incorporated into the target molecule are as follows:
A. produce the high specific acitivity product usually with tritium gas catalytic reduction-this program, and need halogenation or unsaturated precursor.
B. with boron hydrogen [
3H] to change sodium reduction-this program quite cheap and need contain precursor such as the reducible functional group of aldehyde, ketone, lactone, ester and its similar group.
C. with hydrogen [
3H] change lithium aluminium reducing-this program the product of theoretical maximum specific activity is provided.It also needs to contain the precursor such as the reducible functional group of aldehyde, ketone, lactone, ester and its similar group.
D. tritium gas exposes mark-this program and relates to the precursor that contains exchangeable protons is exposed in the tritium gas.
E. use methyl-iodide [
3H] N-methylate-adopt usually this program with by with the high specific acitivity methyl-iodide (
3H) handle suitable precursor prepare O-methyl or N-methyl (
3H) product.This method makes that usually specific activity is higher, for example about 70-90 Ci/mmol.
Will
125The synthetic method that the activity level of I is incorporated the target molecule into comprises:
A. sandmeyer reaction (Sandmeyer) and its similar reaction-this program change into diazonium salt such as a tetrafluoro borate with aryl or heteroaryl amine, and then use Na
125I convert it into through
125The compound of I mark.Representative program is by Zhu, and D.-G. and co-worker are reported in J.Org.Chem.2002, and 67, among the 943-948.
B. adjacent
125Iization phenol-this program allows to incorporate at the ortho position of phenol
125I, it is by Collier, and T.L. and co-worker be at J.Labeled Compd Radiopharm.1999, and 42, report among the S264-S266.
C. aryl and heteroaryl bromide with
125I exchange-this method is generally two step method.First step [is Pd (Ph for using (for example) Pd catalyzed reaction
3P)
4] or by aryl or heteroaryl lithium at trialkyltin halogenide or six alkyl, two tin [for example, (CH
3)
3SnSn (CH
3)
3] exist down, aryl or heteroaryl bromide are changed into corresponding trialkyltin intermediate.Representative program is by Bas, and M.-D. and co-worker are reported in J.Labeled Compd Radiopharm.2001, and 44, among the S280-S282.
Formula (Ia) can be used for differentiating/assess in the screening calibrating of compound through radio-labeling RUP25 compound.In general, can assess the ability that compound (being test compounds) new synthetic or that differentiate reduces " formula (Ia) through radiolabeled compound " and RUP25 receptors bind.Therefore, test compounds is directly relevant with its binding affinity to the competition binding ability of RUP25 acceptor with " formula (Ia) through radiolabeled compound ".
Of the present invention through tagged compound and RUP25 receptors bind.In one embodiment, described have an IC that is lower than about 500 μ M through tagged compound
50, in another embodiment, described have an IC that is lower than about 100 μ M through tagged compound
50, in another embodiment, described have an IC that is lower than about 10 μ M through tagged compound
50, in another embodiment, described have an IC that is lower than about 1 μ M through tagged compound
50, and in another embodiment, described have an IC that is lower than about 0.1 μ M through the mark inhibitor
50
Especially based on the review of this disclosure, the those skilled in the art should be obviously other purposes of the acceptor that discloses and method.
The step that it should be understood that method of the present invention need not to carry out the number of times of any given number or carries out with any particular order.The examination of the present invention be used for the explanation and and unrestriced following example after, other targets of the present invention, advantage and novel feature are to it will be apparent to those skilled in the art that.
Example
For illustration purposes and be not to provide following example with restrictive one.Based on the disclosure of this paper, one of ordinary skill in the art can design equivalence calibrating and method, and it all forms part of the present invention.
Example 1
The rodent diabetes model
Developed the diabetes B rodent model relevant with obesity and insulin resistant.Be physiopathology and the test candidate therapeutic compound understand disease, developed such as the db/db of mouse and ob/ob[referring to Diabetes (1982) 31:1-6] and genetic model [Diabetes (1983) 32:830-838 of the fa/fa of zucker rat; Annu Rep SankyoRes Lab (1994) 46:1-57].The homozygote animal C57BL/KsJ-db/db mouse of being developed by Jackson Lab (Jackson Laboratory) is the mouse [J Clin Invest (1990) 85:962-967] of obesity, hyperglycemia, Regular Insulin excessive secretion and insulin resistant, and heterozygote is thin and normoglycemic.In the db/db model, mouse is along with the age is carried out sexual development insulin deficit disease, its be when sugar level is not subjected to enough controlling in human diabetes B late stage common observed feature.Because this model is similar to human diabetes B model, so the activity of testing compound of the present invention, it includes, but is not limited to reduce plasma glucose and triglyceride level.Zucker (fa/fa) rat is serious obesity, Regular Insulin excessive secretion and insulin resistant { Coleman, Diabetes (1982) 31:1; E Shafrir in DiabetesMellitus, H Rifkin and D Porte, the Jr volume [Elsevier Science Publishing Co, New York waits the people, the 4th edition, (1990), wait the people, the 299-340 page or leaf] }, and fa/fa sudden change can be rat equipollent [people such as Friedman, Cell (1992) 69:217-220 of Muridae db sudden change; People such as Truett, Proc Natl Acad Sci USA (1991) 88:7806].Tubby (tub/tub) mouse is characterised in that obesity, moderate insulin resistant and hyperinsulinemia, does not have remarkable hyperglycemia [people such as Coleman, Heredity (1990) 81:424].
The present invention is contained in use compound reduction of the present invention arbitrary or whole rodent diabetes model above, in suffering from other preferred metabolic-related disorders or lipid metabolism illness human or mentioned above of diabetes B, or insulin resistant in mammiferous model based on other and hyperglycemia.To test plasma glucose and insulin level and include, but is not limited to blood plasma free fatty acid and other factors of triglyceride level.
The active in vivo calibrating of compound hyperglycemia of the present invention
Under 22 ℃ and 50% relative humidity, the obese diabetes mouse (db/db) of stable breeding under standard laboratory conditions (7-9 mouse/cage) genetic modification is (male, and keep the food of ad libitum access Purina rodent diet and random tap water age in 7-9 week).Before the treatment, collect blood and use one touch type basic type glucose monitoring system (One Touch Basic Glucose Monitor System) (Lifescan) to measure blood glucose concentration from the tail vein of each animal.Use plasma glucose levels between the mouse between the 250mg/dl to 500mg/dl.Each treatment group by through distributing in case 7 mouse that average glucose level equates in each group during the research beginning form.By little osmotic pump, use isoflurane anesthesia to insert to the administration of db/db mouse, to provide compound of the present invention, normal saline solution or uncorrelated compound to mouse through subcutaneous (s.c.).Regularly from tail vein extract blood sample and analyzing blood glucose concn thereafter.Use the significant difference (relatively with the group of compound treatment of the present invention and the group of handling with normal saline solution) between student t-test (Student t-test) evaluation group.
Example 2
The mouse Atherosclerosis Model
Proved that lacking mouse by the adiponectin of rejecting the apm 1 gene generation tends to suffer from atherosclerosis and be the mouse of insulin resistant.Described mouse also is the appropriate model [J Biol Chem (2002) July and wherein cited reference, the disclosure of described document all is incorporated herein by reference for Matsuda, people such as M] of ischemic heart disease.
Under 22 ℃ and 50% relative humidity, stable breeding under standard laboratory conditions (7-9 mouse/cage) adiponectin is rejected mouse.By little osmotic pump, use isoflurane anesthesia to insert to the mouse administration, to provide compound of the present invention, normal saline solution or uncorrelated compound to mouse through subcutaneous (s.c.).Mensuration thickens and ischemic heart disease with the new intima of the separate groups of mice that different time is put to death at interval.Use the significant difference (relatively with the group of compound treatment of the present invention and the group of handling with normal saline solution) between the student t-testing evaluation group.
Example 3
Biological activity in vitro
According to following scheme utilization through improved Flash Plate
TMAdenylyl cyclase cover group (New England Nuclear; Catalog number (Cat.No.) SMP004A) directly differentiates candidate compound as the agonist of hRUP25.Term hRUP25 comprises that being found in gene pool deposits the numbering human nucleotide sequence of NM_177551 and gene pool and deposit the allelic variation body of the human peptide sequence of numbering NP 808219 and natural generation, Mammals directly to homologue and its recombinant mutant.
Collect with the expression vector stable transfection of coding hRUP25 and the Chinese hamster ovary celI of under the condition that allows the coded hRUP25 acceptor of cell surface expression, cultivating from flask by non-enzymatic mode.Wash described cell and resuspending in the calibrating damping fluid of described manufacturers with PBS.Use hemocytometer and trypanblue exclusion method (Trypan blue exclusion) living cell counting, and cell concn is adjusted to 2 * 10
6Individual cells/ml.According to the explanation of manufacturers preparation and keep the cAMP standard substance and detect damping fluid (11ml detect comprise in the damping fluid 2 μ Ci tracer agents [
125I]-cAMP (100 μ l)).With cumulative concentration (3 microlitres/hole; Final calibrating concentration 12 μ M) will be added in its hole out of the ordinary (being preferably the hole of 96 orifice plates) according to the candidate compound of above differentiating (, then at room temperature thawing) as freezing.In these holes, make an addition to 100,000 cells in the 50 μ l calibrating damping fluid, and then at room temperature the mixture light shaking was cultivated 30 minutes.After the cultivation, add 100 μ l to each hole and detect damping fluid, then cultivated 2-24 hour.Use " Prot.#31 " (according to explanation of manufacturers) at Wallac MicroBeta
TMIn the plate reader plate is counted.
Compounds more of the present invention have about 25 μ M or the EC below the 25 μ M in the full cell method of cAMP
50
Example 4: biological activity in vitro
35S-GTP γ S is in conjunction with calibrating:
In Wallac Scintistrip plate with calibrating damping fluid (100mM HEPES, 100mM NaCl and 10mMMgCl
2PH 7.4) dilute by the stably express nAChR of Chinese hamster ovary (CHO)-K1 cell preparation or the film of vehicle Control (7 microgram/calibrating), and, add subsequently with about 10 minutes of the pre-cultivation of the test compounds of in the calibrating damping fluid that contains 40 μ M GDP (final [GDP] is 10 μ M), diluting
35S-GTP γ S to 0.3nM.For avoiding potential compound precipitation, at first in 100%DMSO, prepare all compounds, and, in calibrating, obtain the ultimate density of 3%DMSO then with the dilution of calibrating damping fluid.Make in conjunction with carrying out 1 hour, then at room temperature with 4000 rpm with centrifugal 15 minutes of plate, and in the TopCount scintillometer, count subsequently.Carry out the nonlinear regression analysis of binding curve with GraphPad Prism.
Membrane prepare
Material:
CHO-K1 cell culture medium: F-12 Kaighn improvement cell culture medium with G418 of 10%FBS, 2mM L-glutaminate, 1mM Sodium.alpha.-ketopropionate and 400 μ g/mL;
Knifing damping fluid: 20mM HEPES
10mM?EDTA，pH?7.4
Wash the film damping fluid: 20mM HEPES
0.1mM?EDTA，pH?7.4
Proteinase inhibitor mixed solution: P-8340 (Sigma, St.Louis, MO)
Program:
Cell culture medium is detached 15cm
2Plate is with cold PBS washing of 5mL and sucking-off.
Add 5mL knifing damping fluid and scraping cell.Scrape is transferred in the 50mL centrifuge tube.Add 50mL proteinase inhibitor mixed solution.
Under 4 ℃ with 20, centrifugal 17 minutes of 000rpm.
Sucking-off supernatant liquor and centrifugal resuspending washed in the film damping fluid in 30mL.Add 50 μ L proteinase inhibitor mixed solutions.
Under 4 ℃ with 20, centrifugal 17 minutes of 000rpm.
With supernatant liquor sucking-off from centrifugal of film.Can with centrifugal-80 ℃ down freezing with standby or its can use immediately.
Calibrating
Material:
Guanosine 5 '-bisphosphate sodium salt (GDP, Sigma-Aldrich catalog number (Cat.No.) 87127);
Guanosine 5 '-[γ
35S] thio triphosphates salt, triethyl ammonium salt ([
35S] GTP γ S, Amersham Biosciences catalog number (Cat.No.) SJ1320, about 1000 Ci/mmol);
96 holes flicker plate (Perkin-Elmer#1450-501);
Binding buffer liquid: 20mM HEPES, pH 7.4
100mM?NaCl
10mM?MgCl
2
The GDP damping fluid: binding buffer liquid adds GDP, in the scope of 0.4 μ M to 40 μ M, and new system before the calibrating.
Program:
(always examining and determine volume=100 μ L/ holes)
25 μ L have or do not have the GDP damping fluid (therefore final GDP 10 μ M-use 40 μ M stock solutions) of compound;
The film (0.4mg protein/milliliter) of 50 μ L in binding buffer liquid;
25 μ L in binding buffer liquid [
35S] GTP γ S.This is by add 5 μ l[in 10mL binding buffer liquid (this damping fluid does not have GDP)
35S] GTP γ S stock solution and making.
The compound plate (daughter board has the 2mM compound of 5 μ L in 100%DMSO) of the desire of thawing screening.
By 1: 50 the 2mM diluted chemical compound is become 40 μ M with 245 μ L GDP damping fluids, wherein DMSO is 2%.Thaw on ice and to freeze the film fritter.
Use POLYTRON PT3100 (probe PT-DA 3007/2 is set at 7000rpm) that film is simply homogenized until becoming suspension.Measure membrane protein concentration by Bradford (Bradford) calibrating.In binding buffer liquid, film is diluted to the protein concn (annotate: finally examining and determine concentration is 20 micrograms/hole) of 0.40mg/ml.
The compound of 25 μ L in the GDP damping fluid added in every hole in the flicker plate.
50 μ L films are added in every hole in the flicker plate.
At room temperature cultivated in advance 5-10 minute.
Add 25 μ L through the dilution [
35S] GTP γ S.At room temperature earthquake device (Lab-Line type #1314, concussion is set at 4) is gone up and was cultivated 60 minutes.
Stopping calibrating in 20 minutes by centrifugal plate under 2500rpm under 22 ℃ with the sealing of plate coverture.
On TopCount NXT scintillometer, read-the 35S scheme.
Some compound of the present invention has EC in about 10-100 μ M scope at functional in vitro GTP γ S in conjunction with calibrating
50More favourable compound of the present invention has the EC in about 1-10 μ M scope in this calibrating
50Value.More favourable compound has the EC that is lower than about 1 μ M in this calibrating
50Value.
Example 5
Animal model in vivo
A kind of effectiveness of compound of the present invention is in prevention and treats in high total cholesterol/HDL-cholesterol ratio and the relative illness as medical agent; it can reduce total cholesterol/HDL-cholesterol ratio in the pig model in vivo by compound; rising HDL-cholesterol, or protect it to avoid atherosclerotic activity to prove.Because therefore pig model is used as animal model with pig than most other animal models more approaching reflection anthropophysiologies (especially lipid metabolism).Provided herein and nonrestrictive illustrative is pig model in vivo.
In 50 days, (body weight 25.5 ± 4kg) is raised with what the standard food that is supplemented with 2% cholesterol and 20% tallow was formed and is rich in saturated fatty acid and is rich in food (1kg food/35kg pig is heavy) [people such as Royo T, European Journal of Clinical Investigation (2000) 30:843-52 of cholesterol (SFA-CHO) to Yorkshire albefaction pig (Yorkshire albino pig); Its disclosure all is incorporated herein by reference].Saturated and unsaturated fatty acids ratio in normal pig food is changed into 1.12 the SFA-CHO food from 0.6.Animal is divided into 2 groups, and one group (n=8) raises with SFA-CHO food and with placebo treatment, and one group (n=8) raises with SFA-CHO food and with compound treatment (3.0mg kg
-1).Control animal raised with standard food last 50 days.Begin to gather in back 50 days blood sample at baseline (after the animals received 2 days) and diet.The analyzing blood lipid.Put to death animal and check.
Perhaps, aforementioned analysis comprises a plurality of groups, and each group is all with the compound treatment of various dose.Preferred described dosage is to be selected from the group that is made up of following each dosage: 0.1mg kg
-1, 0.3mg kg
-1, 1.0mg kg
-1, 3.0mg kg
-1, 10mg kg
-1, 30mg kg
-1With 100mg kg
-1Perhaps, aforementioned analysis is carried out at a plurality of time points.Preferred described time point is to be selected from the group that is made up of 10 weeks, 20 weeks, 30 weeks, 40 weeks and 50 weeks.
The HDL-cholesterol
With blood collecting in trisodium citrate (3.8%, 1: 10).Centrifugal (1200g, 15 minutes) back obtains blood plasma and handles rapidly.(NY USA) measures total cholesterol, HDL-cholesterol and LDL-cholesterol for Eastman Kodak Company, Rochester to use automatic analyser Kodak Ektachem DT system.Solution dilution with manufacturers's supply has the sample that parameter value is higher than scope, and then analyzes again.Measure total cholesterol/HDL-cholesterol ratio.Between group, the HDL-cholesterol levels is compared.Between group, total cholesterol/HDL-cholesterol ratio is compared.
When throwing, adopt the indication that the HDL-cholesterol raises or total cholesterol/HDL-cholesterol ratio descends and has aforementioned effectiveness as compound with compound.
Atherosclerosis
With chest and the complete removal of abdominal aorta, vertically open along abdominal surface, and after cutting the sample that is used for tissue examination and lipid composition and study on the synthesis, be fixed in the neutral buffered formalin from chest and abdominal aorta standard location.After fixing, whole Aorta with sudan (Sudan IV) dyeing, and is flatly pegged, and with computerized image analysis system (Image Pro Plus; Media Cybernetics, Silver Spring, the TV photographic camera that MD) is connected obtain digitized video relates to the Aorta surface of atherosclerotic lesion with mensuration percentage ratio [people such as Gerrity RG, Diabetes (2001) 50:1654-65; People such as Cornhill JF, Arteriosclerosis, Thrombosis, and VascularBiology (1985) 5:415-26; Its disclosure all is incorporated herein by reference].Percentage ratio to the Aorta surface that relates to atherosclerotic lesion between group compares.
When throwing with compound, the indication of adopting the decline of the Aorta surface percentage ratio that relates to atherosclerotic lesion to have aforementioned effectiveness as compound.
Example 6
The receptors bind calibrating
Except that method as herein described, the mode of another assessment test compounds is by the binding affinity of mensuration with the RUP25 acceptor.The calibrating of this type need usually the RUP25 acceptor through radiolabeled ligand.Do not use the known ligand of RUP25 acceptor and its radio-labeling, the compound of formula (Ia) can labelled with radioisotope and is used for assessing the calibrating of the affinity of test compounds and RUP25 acceptor.
Formula (Ia) can be used for differentiating/assess in the screening calibrating of compound through radio-labeling RUP25 compound.In general, can assess the ability that compound (being test compounds) new synthetic or that differentiate reduces " formula (Ia) through radiolabeled compound " and RUP25 receptors bind.Therefore, test compounds and " formula (Ia) through radio-labeled compound " or relevant in conjunction with the ability of RUP25 acceptor directly combines the RUP25 acceptor with it affinity through the competition of radio-labeling RUP25 ligand.
Measure the calibrating scheme of RUP25 receptors bind
The preparation of A.RUP25 acceptor
Make 293 cell (human kidneys with human RUP25 acceptor of 10 μ g and 60 μ l lipofection agent (Lipofectamine) (every 15cm dish) transient transfection, ATCC) growth 24 hours (75% merges) in dish, change substratum simultaneously, and it is shifted out with 10 milliliters/dish Hepes-EDTA damping fluid (20mM Hepes+10 mM EDTA, pH 7.4).With 17,000rpm (JA-25.50 rotor) was with cell centrifugation 20 minutes in Beckman Coulter whizzer.Subsequently with centrifugal resuspending in 20mM Hepes+1mM EDTA (pH 7.4), and it is homogenized, and recentrifuge with 50ml Dounce homogenizer.After removing supernatant liquor, store centrifugal down until being used in conjunction with calibrating at-80 ℃.When being used to examine and determine, on ice film being thawed 20 minutes, and then add 10mL and cultivate damping fluid (20mM Hepes, 1mM MgCl
2, 100mM NaCl, pH 7.4).Make the film vortex with Brinkmann PT-3100 Polytron homogenizer it be homogenized 15 seconds with the thick film fritter of resuspending and being set at 6 times.Use the calibrating of BRL Bradford protein to measure membrane protein concentration.
B. in conjunction with calibrating
For total binding, with cumulative volume be 50 μ l warp suitably the film of dilution (to contain 50 mM Tris HCl (pH7.4), 10mM MgCl
2With 1mM EDTA; The proteinic calibrating damping fluid dilution of 5-50 μ g) is added in the 96 hole polypropylene microtiter plates, then adds 100 μ l calibrating damping fluid and 50 μ l through radiolabeled RUP25 ligand.For non-specific binding, add 50 μ l but not 100 μ l calibrating damping fluid, and, add the cold RUP25 of 50 μ l, 10 μ M again adding 50 μ l before radiolabeled RUP25 ligand.Then at room temperature plate is cultivated 60-120 minute.Filter assaying table by micro plate device (Microplate Devices) GF/C Unifilter screen plate, then stop association reaction with cold 50mM Tris HCl (pH 7.4) washing that contains 0.9%NaCl with Brandell 96 orifice plate collectors.Then seal the screen plate bottom, in each hole, add 50 μ l Optiphase Supermix, the sealing plate top, and in Trilux MicroBeta scintillometer, plate is counted.For compound competition research, in appropriate well, add 100 μ l through the test compounds of suitably dilution but not add 100 μ l calibrating damping fluid, then add 50 μ l through radiolabeled RUP25 ligand.
C. calculate
At first at 1 μ M and 0.1 μ M and then verification test compound in selected concentration range, so that intermediate value dosage will cause about 50% inhibition (that is IC, of radiation-RUP25 ligand bonded
50).The specificity of no test compounds is in conjunction with (B
o) be total binding (B
T) deduct the poor of non-specific binding (NSB), and specificity is that displacement is in conjunction with (B (B) in conjunction with (having test compounds) similarly
D) deduct the poor of non-specific binding (NSB).By inhibited reaction curve (%B/B
oLogit-log figure to the concentration of test compounds) determines IC
50
By Cheng and Prustoff transformation calculations K
i:
K
i＝IC
50/(1+[L]/K
d)
Wherein [L] is the concentration of employed radiation-RUP25 ligand in calibrating, and K
dDissociation constant for independent radiation-RUP25 ligand of measuring under the identical combination condition.
D. substitute in conjunction with calibrating procedure
3The H-niacin is in conjunction with the competition calibrating.
The CHO-KI cell preparation of use stably express nAChR is used for the film of binding analysis.Make cell (contain 10%FBS (GIBCO at growth medium, #10438-026), 1mg/ml G418 (GIBCO, #10131-027) and the F-12 Kaighn improved culture medium (ATCC of 1XPen-Strep (Sigma P-0871), grow to about 80% #30-2004)) and merge, collect and under 4 ℃ centrifugal 10 minutes with 12000 X g by scraping.Cell fritter resuspending in collecting in the damping fluid (pH 7.4 for 20mM HEPES, 10mM EDTA), and was burst with 4 * 10 seconds it is homogenized to be set at 5 12mm Polytron homogenizer.Under 4 ℃ with 2000 X g with centrifugal 10 minutes of molten born of the same parents' thing removing undissolved cell and nuclear, and under 4 ℃, with 39000 X g with centrifugal 45 minutes of gained supernatant liquor to obtain centrifugal of film.Gained fritter resuspending in lavation buffer solution (20mM HEPES, 0.1mM EDTA, pH 7.4), was burst with 3 * 10 seconds it is homogenized to be set at 4 12mm Polytron, and under 4 ℃, centrifugal again 45 minutes with 39000 X g.Centrifugal resuspending of gained is stored in the liquid nitrogen in lavation buffer solution and before use.Use Pierce BCA protein checking method to measure membrane protein concentration in this preparation as standard substance with BSA.
3The junction at equilibrium of H-niacin is combined in the 96 hole polypropylene boards and carries out.Reaction contains 140 μ L, and (20mM HEPES, pH 7.4,1mM MgCl with the calibrating damping fluid
2, and 0.01%CHAPS; 15-30 μ g membrane protein/calibrating) Xi Shi film, (the compound stock solution is in 100%DMSO to the test compounds that 20 μ L dilute with the calibrating damping fluid; Final DMSO concentration in the calibrating is 0.25%) and 40 μ L, 250 nM tritiate nicotine ([5,6-
3H]-niacin: AmericanRadiolabeled Chemicals, Inc., 20 μ M are in ethanol; Final alcohol concn is 1.5% in each calibrating).In the presence of 250 μ M un-marked niacins, measure non-specific binding.Mix under the room temperature after 3-4 hour, use the Packard collector by Packard Unifilter GF/C plate filtering reaction, and with the ice-cold binding buffer liquid washing of 8 * 200 μ L.With the plate dried overnight and use PerkinElmer band as GF/C plate design with its back seal.In each hole, add 40 μ LPerkinElmer Microscint-20 scintillation solutions, the sealing top, and in Packard TopCount scintillometer analysis plates.
Calculate among the C as mentioned.
Some compound of the present invention exists
3The H-niacin is in conjunction with having the EC of about 10 μ M to about 100 μ M scopes in the competition calibrating
50More favourable compound of the present invention has the EC of about 1 μ M to about 10 μ M scopes in this calibrating
50Value.More favourable compound has the EC that is lower than about 1 μ M in this calibrating
50Value.
Example 7: vasodilation (flushing), detect by laser-Doppler (Laser Doppler)
Program-use 10 mg/ml/kg vetanarcol (Nembutal sodium) are anaesthetized male C57B16 mouse (about 25g).When throwing, itself and Sodital narcotic are injected jointly with antagonist.After 10 minutes, animal is positioned under the laser, and ear is rolled over backward to expose facies ventralis.Laser placed the ear center and focus to the intensity (about 4.5cm on ear usually) of 8.4-9.0V.With 50 * 50 image formats, at interval, 60 images and 20 seconds time lags are collected with moderate resolving power initial data automatically.By injection test compounds is thrown with to the peritonaeum space behind the 10th image.Think that image 1-10 is the baseline of animal, and with the regular mean value that changes into the baseline average intensity of data.
Material and method-laser-Doppler Pirimed PimII; Nicotine (Sigma); Sodital (Abbott labs).
Example 8: the in vivo free fatty acids in the male Sprague-Daly rat of inhibition insertion conduit produces
To carrying out non-esterified free fatty acids (NEFA) calibrating from the serum of living, obtain the free-moving rat.The jugular vein conduit is implanted in the jugular vein by operation, and animal was recovered after operation 48 hours at least.Calibrating precontract 16 hours is removed food from animal.Extract about 200 μ l blood from conduit, and it represents baseline NEFA serum sample.Throw and medicine to indivedual rats through intraperitoneal (IP) with various concentration, and then extract 200 μ l blood from conduit at some instruction time that other NEFA analyze.Explanation (Wako Chemicals, USA according to manufacturers; NEFA C) carries out the NEFA calibrating, and measure the free-fat acid concentration by the regression analysis of known standard curve (scope of known free fatty acids).Use Excel and PrismGraph analytical data.
Example 9
Synthetic selected compound of the present invention
It is synthetic with it to further specify compound of the present invention by following example.Provide following example further defining the present invention, but be not the details that the present invention is limited to these examples.Above and compound hereinafter described be according to CS ChemDraw Ultra 7.0.1 version or AutoNom 2000 names.Use common name in some instances, should be appreciated that, the those skilled in the art should approve these common name.In general, for the example that is hereinafter provided, the preceding standard symbol " (±) " that is located immediately at chemical name is used in reference to racemic mixture.The chemical name of example unless otherwise indicated, otherwise the chemical structure of being showed in the example only provides for illustration purposes, and be not to be used for restriction.
Chemistry: record proton magnetic resonance (PMR) on the Bruker Avance-400 of the Varian Mercury Vx-400 that is equipped with 4 nuclear automatic switchover probes and z gradient or outfit QNP (four nuclear probes) or BBI (the reverse probe in broadband) and z gradient (
1HNMR) spectrum.Provide chemical shift with for referencial use with PPM (ppm) with the residual solvent signal.Use following NMR abbreviation: s=is unimodal, d=doublet, two groups of doublets of dd=, two groups of triplets of dt=, t=triplet, q=quartet, m=multiplet, br=broad peak.Use Emyrs Synthesizer (Personal Chemistry) to carry out microwave radiation.At silica gel 60 F
254(Merck) go up execution thin-layer chromatography (TLC), go up at PK6F silica gel 60A 1mm plate (Whatman) and carry out preparation type thin-layer chromatography (preparation type TLC), and use Kieselgel 60,0.063-0.200mm (Merck) is at the enterprising line pipe column chromatography of silica gel tubing string.On the Buchi Rotary Evaporators, evaporate in a vacuum.During filtering, uses palladium diatomite 545
_
LCMS specification: 1) PC:HPLC-pump: LC-10AD VP, Shimadzu Inc.; HPLC central controller: SCL-10A VP, Shimadzu Inc; UV-detector: SPD-10A VP, Shimadzu Inc; Automatic sampler: CTCHTS, PAL, Leap Scientific; Mass spectrograph: have the API 150EX in Turbo ionspray source, AB/MDS Sciex; Software: Analyst 1.2.2) Mac:HPLC-pump: LC-8A VP, Shimadzu Inc; HPLC central controller: SCL-10A VP, Shimadzu Inc; UV-detector: SPD-10A VP, Shimadzu Inc; Automatic sampler: 215 liquid processing systems (Liquid Handler), Gilson Inc; Mass spectrograph: have the API 150EX in Turbo ionspray source, AB/MDS Sciex; Software: Masschrom 1.5.2.
Example 9.1: preparation (1aR, 5aR)-(+)-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene (compound 4)
Steps A: the preparation dicyclo [3.1.0] oneself-2-alcohol
By at-78 ℃, (50.7g, (2.5M in hexane, 143mL 358mmol) produce LiTMP 359mmol) to add n-Butyl Lithium in the stirred solution in t-BuOMe (1.0 L) to TMP.Through 45 minutes faint yellow LiTMP solution is slowly to warm to 0 ℃.Under 0 ℃, in the stirred solution of (R)-2-fourth-3-thiazolinyl-oxyethane (17.6g, 179mmol, Schaus, people such as S.E, J.Am.Chem.Soc.2002,124,1307) in t-BuOMe (500mL), dropwise added LiTMP solution by sleeve pipe through 15 minutes.At ambient temperature the gained mixture is stirred 18h, then end with MeOH (40mL).It is 600mL that reaction is concentrated into cumulative volume, and with HCl (the 1N aqueous solution, 3 * 350mL) and salt solution (300mL) washing soln.With organism through MgSO
4Drying, filter and concentrate (90mmHg, 25 ℃ of bath temperatures) with the dicyclo [3.1.0] that obtains being faint yellow oily oneself-2-alcohol.Dicyclo [3.1.0] oneself-spectroscopic data of 2-alcohol and the data in literature Hodgson that is reported, D.M.; Chung, Y.K.; Paris, J.-M.J.Am.Chem.Soc.2004,126,8664 is similar.
Step B: the preparation dicyclo [3.1.0] oneself-2-ketone
At ambient temperature with TPAP (1.88g, 5.35mmol) be added into dicyclo [3.1.0] oneself-2-alcohol (10.5g, 107mmol), NMO (25.1g, 214mmol) and Powdered 4_ MS (20g) in CH
2Cl
2In the stirred solution (500mL).Mixture is stirred 2.5h, and (80cm * 12cm) filters, and with Et by silica gel
2O/CH
2Cl
2(1: 1) elution.In a vacuum (100mmHg, 25 ℃ of bath temperatures) carefully evaporate organic solvent with obtain dicyclo [3.1.0] oneself-2-ketone.Spectroscopic data with before to racemize-dicyclo [3.1.0] oneself-data (Newman-Evans, R.H. that 2-ketone is reported; Simon, R.J.; Carpenter, B.K.J.Org.Chem.1990,55,695) similar.
Step C: preparation 1a, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate
In room temperature at N
2Down, to dicyclo [3.1.0] oneself-2-ketone (9.24g, 96.1mmol) and oxalic acid diethyl ester (14.7g, 101mmol) solution of interpolation KOt-Bu in THF in the solution in EtOH (250mL) (106mL 1M solution, 106mmol).To react and stir 3.5h, make an addition to during stirring hydrazine hydrochloride in the water (40mL) (7.90g, 115mmol).At room temperature reaction mixture is stirred 20h, and be acidified to the pH value and be about 3 by adding HCl (the 6N aqueous solution).Remove volatile matter in a vacuum and with EtOAc (500mL) and H
2O (500mL) dilution gained solid.Separate each layer and with EtOAc (300mL) strip aqueous.To wash with salt solution (400mL) through the organism of combination, through MgSO
4Thick oil is filtered and be condensed into to drying, its warp
1H NMR is determined as the ester of about 75-80% pure (w/w).Need not to be further purified, title compound is directly used in next reaction (aminolysis).
1H?NMR(400MHz，CDCl
3)：δ?10.55(1H，bs)，4.32(2H，q，J＝6.8Hz)，2.96(1H，dd，J＝16.8，6.0Hz)，2.80(1H，d，J＝17.2Hz)，2.23-2.13(2H，m)，1.35(3H，t，J＝7.2Hz)，1.15(1H，m)，0.34(1H，m)。
13C APTNMR (part) (100MHz, CDCl
3): δ makes progress: 127.4,61.2,26.8,16.8; Downwards: 23.0,15.4,14.5.HPLC/MS:Discovery
_C18 tubing string (5 μ, 50 * 2.1mm), gradient: 5%v/v CH in the water (containing 1%v/v TFA)
3CN (containing 1%v/v TFA) 99%v/v CH to the water
3CN, 0.75 ml/min, t
r=1.62 minutes, ESI
+=193.1 (M+H).
Step D: preparation 1a, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-benzoic acid amides
(14.2g 73.9mmol) adds the ammonium hydroxide (28%NH of Yu Shuizhong in the solution in diox (140mL) to the ester of step C
3, 750mL).Mixture is placed the heat-resisting bottle of 1000mL, and at room temperature on the concussion dish, shake 22h.In a vacuum mixture being concentrated into cumulative volume is 100mL, obviously produces faint yellow precipitation this moment.Filtering mixt and with H
2O (2 * 100mL) washing solids.Further drying solid obtain the being white in color 1a of solid state in a vacuum, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-benzoic acid amides [HPLC/MS:Discovery
_C18 tubing string (5 μ, 50 * 2.1mm), gradient: 5%v/v CH in the water (containing 1%v/v TFA)
3CN (containing 1%v/v TFA) 99%v/v CH to the water
3CN, 0.75 ml/min, t
r=1.09 minutes, ESI
+=164.0 (M+H)].
Step e: preparation 2-benzyl-1a, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-nitrile
With the acid amides of step D (9.38g, 57.9mmol) be partially dissolved in the diox (150mL) and add NaOH (the 5N aqueous solution, 23.0mL, 115mmol), then add bromotoluene (10.3g, 60.2mmol).The mixture clarification that slowly becomes, and at room temperature will react and stir 20h.Make the mixture acidifying become the pH value to be about 2 by adding HCl (the 6N aqueous solution), and be concentrated into drying in a vacuum.With NaHCO
3(saturated aqueous solution, 100mL) and H
2O (100mL) washing gained faint yellow solid.Further drying solid obtain the being white in color benzyl product of solid state in a vacuum, 2-benzyl-1a, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-benzoic acid amides.
At N
2Under the atmosphere dry DMF (50mL) feed-in is equipped with in the flask of drying tube.Flask is cooled to 0 ℃, and through 2 minutes period dropwise add thionyl chloride (4.84mL, 66.5mmol).Behind the restir 10 minutes, use feed hopper to add 2-benzyl-1a, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-benzoic acid amides (14.0g, 55.3mmol) suspension in DMF (90mL) through 5 minutes.Mixture is slowly to warm to room temperature and stirred 20 minutes, add thionyl chloride (3.05mL, 41.9mmol) aqueous premix in DMF (20mL) this moment again.Restir be will react 20 minutes, and thionyl chloride (6.0mL, 82.5mmol) second aqueous premix in DMF (20mL) added.To react restir 15 minutes, and add NaHCO
3(saturated aqueous solution 50mL), then adds H
2O (100mL).Mixture was stirred 10 minutes, and be concentrated in a vacuum near dry.With EtOAc (350mL) and H
2O (250mL) dilutes resistates.Separate each layer and with EtOAc (250mL) strip aqueous.Will through the combination organism with NaHCO
3(saturated aqueous solution, 400mL) and salt solution (400mL) washing, through MgSO
4Drying is filtered and is concentrated obtaining being the 2-benzyl-1a of brown solid shape, and 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-nitrile.
1H?NMR(400MHz，CDCl
3)：δ?7.37(3H，m)，7.25(2H，m)，5.31(1H，d，J＝14.8Hz)，5.24(1H，d，J＝14.8Hz)，2.86，(1H，dd，J＝16.4，6.4Hz)，2.72(1H，d，J＝16.0Hz)，2.19(1H，m)，1.87(1H，m)，1.07(1H，m)，0.32(1H，m)。
13C APT NMR (100MHz, CDCl
3): δ makes progress: 154.4,135.3,130.0,118.9,114.3,55.9,26.2,16.9; Downwards: 129.2,128.6,128.1,24.2,14.4.HPLC/MS:Discovery
_C18 tubing string (5 μ, 50 * 2.1mm), gradient: 5%v/v CH in the water (containing 1%v/v TFA)
3CN (containing 1%v/v TFA) 99%v/v CH to the water
3CN, 0.75 ml/min, t
r=2.23 minutes, ESI
+=236.1 (M+H).
Step F: preparation 2-benzyl-4-(2H-tetrazolium-5-yl)-1a, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene
To 2-benzyl-1a, 2,5,5a-tetrahydrochysene-1H-2, (11.1g 47.2mmol) adds ZnBr in the solution in DMF (125mL) to 3-diaza-ring third [a] pentalene-4-nitrile
2(18.4g 70.6mmol), then adds NaN
3(12.2g, 188mmol).With mixture heating up to 120 ℃, and at N
2Stir 18h under the atmosphere.Reaction is cooled to room temperature and removes DMF in a vacuum.Thick resistates is diluted with EtOAc (200mL) and HCl (the 3N aqueous solution, about 100mL) and stirred 10 minutes.Separate each layer, and with EtOAc (150mL) strip aqueous.Will through the combination organism (the 1M aqueous solution, 2 * 250mL) wash and abandon organic layer with NaOH.With 6N HCl alkaline water is acidified to the pH value and is about 2, and with EtOAc (2 * 250mL) extractions.Extract is washed with salt solution (150mL), through MgSO
42-benzyl-4-(2H-tetrazolium-5-the yl)-1a to obtain being the light brown solid state is filtered and concentrated to drying, and 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene.
1HNMR(400MHz，MeOD)：δ?7.33(5H，m)，5.42(1H，d，J＝14.8Hz)，5.35(1H，d，J＝15.2Hz)，3.01(1H，dd，J＝16.4，6.4Hz)，2.88(1H，d，J＝17.6Hz)，2.28(1H，m)，2.11(1H，M)，1.14(1H，m)，0.33(1H，m)。HPLC/MS:Alltech
_Prevail C18 tubing string (5 μ, 50 * 4.6mm), gradient: 5%v/v CH in the water (containing 1%v/v TFA)
3CN (containing 1%v/v TFA) 99%v/v CH to the water
3CN, 3.5 ml/min, t
r=2.14 minutes, ESI
+=279.3 (M+H).
Step G: preparation (1aR, 5aR)-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene (compound 4)
At room temperature the air bubbling is passed through 2-benzyl-4-(2H-tetrazolium-5-yl)-1a, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene (10.4g, 37.4mmol) and KOt-Bu (374mL 1M THF solution, 374mmol) stirred solution in DMSO (300mL) lasts 20h.Remove residue THF in a vacuum, and reaction is acidified to pH=2 by adding HCl (the 3M aqueous solution).In a vacuum mixture is concentrated near dry.With resistates be dissolved in HCl (the 1N aqueous solution, 250mL) in and with EtOAc (5 * 250mL) extraction.With organism through MgSO
4Drying is filtered and is concentrated.With product purification, and, material (form of MeOH solution) converts it into ammonium salt by being filled on the tubing string that contains BondesilSCX SPE resin (about 250g).With MeOH (200mL) washover pipe to remove not in conjunction with impurity.Use 2N NH
3/ MeOH (about 200mL) elution product.The concentrated alkaline eluant, the ammonium salt of the compound 4 of the solid state that obtains being white in color.
1H?NMR(400MHz，MeOD)：δ?3.02(1H，dd，J＝16.4，6.0Hz)，2.90(1H，d，J＝16.0Hz)，2.19(2H，m)，1.17(1H，m)，0.33(1H，m)。HPLC/MS:Discovery
_C18 tubing string (5 μ, 50 * 2.1mm), gradient: 5%v/v CH in the water (containing 1%v/v TFA)
3CN (containing 1%v/v TFA) 99%v/v CH to the water
3CN, 0.75 ml/min, t
r=1.21 minutes, ESI
+=189.0 (M+H).[α]
25 D+35.7(c?0.39，MeOH)。
Example 9.2: preparation (±)-1,1-dimethyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene (compound 7)
Steps A: (±)-2-(4-methylpent-3-thiazolinyl)-oxyethane
At room temperature (1.000g, 10mmol) (10g, 102mmol) (0.057g 0.086mmol) stirs 24 hours together with Zhan catalyzer 1 with 2-methyl but-2-ene with 2-(fourth-3-thiazolinyl) oxyethane in the sealing scintillation vial.Under reduced pressure remove solvent, and through 2-(4-methylpent-3-thiazolinyl) oxyethane of tubing string chromatography (0-10%EtOAc/ normal hexane/silicon-dioxide) purifying resistates to obtain being colorless oil.
1H?NMR(CDCl
3)：δ?5.2-5.1(m，1H)，2.95-2.88(m，1H)，2.75(dd，1H?J
1＝5.0，J
2＝4.1)，2.48(dd，1H?J
1＝5.0，J
2＝2.8)，2.15(2H，q，J＝7.4)，1.70(s，3H)，1.63(s，3H)，1.60-1.50(m，2H)。
Step B: the preparation (±)-6,6-dimethyl-dicyclo [3.1.0] oneself-2-alcohol
With 2,2,6, (9.70g 69mmol) is dissolved among the MTBE (100mL) and is cooled to-78 ℃ the 6-tetramethyl piperidine.(43mL, 1.6M in normal hexane 69mmol), and make gained solution stir 30 minutes down at-78 ℃ to careful interpolation n-Butyl Lithium.By sleeve pipe yellow solution is transferred to 2-(4-methyl-penta-3-thiazolinyl)-oxyethane (4.33g through interpolation in 30 minutes, 34.3mmol) in MTBE (30mL) through the cooling (0 ℃) solution in, make it be slowly to warm to room temperature, and under argon gas, stirred 18 hours.Then solution is added in the 1M aqueous hydrochloric acid (50mL), and it further is extracted among the MTBE (200mL).Under reduced pressure, remove solvent, by tubing string chromatography (0-40%EtOAc/ normal hexane, silicon-dioxide) purifying gained oily matter.Obtain yellow oily (±)-6,6-dimethyl-dicyclo [3.1.0] oneself-2-alcohol.
1H?NMR(CDCl
3)：δ?4.15-4.10(m，1H)，2.10-2.00(m，1H)，1.90-1.80(m，1H)，1.80-1.70(m，1H)，1.62(br?s，O
H)，1.56(ddd，1H，J
1＝12.9，J
2＝9.5，J
3＝2.9)，1.48(br?s，1H)，1.14(dd，1H，J
1＝6.3，J
2＝1.2)，0.99(s，3H)，0.93(s，3H)。
Step C: the preparation (±)-6,6-dimethyl-dicyclo [3.1.0] oneself-2-ketone
(3.11g is 26.5mmol) with perrhenic acid tetrapropyl ammonium (VII) (0.280g, 0.796mmol) cold (0 ℃) solution in DCM (40mL) to prepare the N-methylmorpholine N-oxide compound that contains 4_ molecular sieve (about 0.3g).Dropwise add (±)-6,6-dimethyl-dicyclo [3.1.0] oneself-(1.67g, the 13.3mmol) solution in DCM (10mL) makes the solution temperature to room temperature to 2-alcohol, and stirs 1 hour under argon gas.By silicon-dioxide embolism filtering solution, under reduced pressure remove solvent, and by tubing string chromatography (0-100%DCM/ normal hexane, silicon-dioxide) purifying gained oily matter.Obtain brown oily 6,6-dimethyl-dicyclo [3.1.0] oneself-2-ketone.
1H?NMR(CDCl
3)：δ?2.35-2.15(m，2H)，2.10-2.00(m，1H)，1.97-1.85(m，2H)，1.66(d，1H，J＝4.7)，1.16(s，3H)，1.12(s，3H)。
Step D: preparation (±)-1,1-dimethyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate
At room temperature with (±)-6,6-dimethyl-dicyclo [3.1.0] oneself-2-ketone (1.49g, 12.0mmol), oxalic acid diethyl ester (2.46g, 16.8mmol) and uncle's fourth potassium oxide (18.0mL, 1M in THF, 18.0mmol) stirring 2 hours in ethanol (40mL).By LCMS (m/z (ES
+): 247[M+Na]
+, 225[M+H]
+) observe required (6,6-dimethyl-2-oxygen-dicyclo [3.1.0] oneself-the 3-yl)-oxygen-ethyl acetate, but it is without separation.(0.168g 24.4mmol), and is heated to 80 ℃ with solution and lasts 18 hours to make an addition to hydrazine monohydrochloride in the water (2.0mL).Under reduced pressure remove solvent, and with in the gained oily matter impouring 0.1M aqueous hydrochloric acid (30mL), and it is extracted among the DCM (200mL).Under reduced pressure remove solvent, and pass through tubing string chromatography (0-50%EtOAc/ normal hexane, silicon-dioxide) purifying resistates to obtain faint yellow oily (±)-1,1-dimethyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate, it is leaving standstill after coagulation.M/z (ES
+): 243[M+Na]
+, 221[M+H]
+, 175[M-OEt]
+ 1H NMR (CD
3OD): δ 4.4-4.3 (m, 2H, OCH
2), 2.90 (dd, 1H, J
1=17.5, J
2=6.9), 2.65 (d, 1H, J=17.5), 2.1-2.0 (m, 1H), 1.95 (t, 1H, J=12.9), 1.37 (td, J
1=7.1, J
2=2.0), 1.13 (s, 3H, outer-C
H 3), 0.74 (d, 3H, J=2.0, interior-C
H 3).
Step e: preparation (±)-1,1-dimethyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-benzoic acid amides
With (±)-1,1-dimethyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate (1.280g, 5.81mmol) be dissolved in the methanol solution (60mL) of 7 M ammonia in the sealed flask, and be heated to 100 ℃ and last 18 hours.Collect gained suspension to obtain paste solid 1,1-dimethyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-benzoic acid amides through vacuum filtration.From mother liquor, remove solvent, and by preparation HPLC purifying resistates, further to obtain paste solid (±)-1,1-dimethyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-benzoic acid amides.m/z?(ES
+)：192[M+H]
+，175[M-NH
2]
+；
1H?NMR(CD
3OD)：δ?2.9-2.65(m，1H)，2.55(t，1H，J＝19.9)，2.0-1.8(m，2H)，1.03(s，3H)，0.63(s，3H)。
Step F: preparation (±)-1,1-dimethyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-nitrile
Dissolving (±)-1 in THF (150mL), 1-dimethyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-benzoic acid amides (0.532g, 2.79mmol), and the interpolation trifluoroacetic anhydride (0.936g, 4.46mmol).At room temperature under argon gas with gained solution stirring 1 hour.Add ethyl acetate (50mL), and under reduced pressure remove solvent.The faint yellow oily thing of gained is dissolved among the DCM (100mL),, and under reduced pressure removes solvent with saturated sodium bicarbonate aqueous solution (40mL) washing.The gained white solid is dissolved in formation suspension among the DCM (20mL), and filters (±)-1 to obtain being the pale solid shape, 1-dimethyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-nitrile.m/z?(ES
+)：174[M+H]
+。
Step G: preparation (±)-1,1-dimethyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene (compound 7)
In the heavy wall Glass tubing with (±)-1,1-dimethyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-nitrile (0.184g, 1.06mmol) and dibrominated zinc (0.500g, 2.22mmol) and sodium azide (0.300g 4.62mmol) is dissolved in 1 together, in the 4-diox (10 mL).Under microwave radiation, gained solution is heated to 200 ℃ and lasts 1 hour.In solution impouring 1M aqueous hydrochloric acid (10mL), and it is extracted in the ethyl acetate (50mL).Under reduced pressure remove solvent, and through (±)-1 of preparation HPLC purifying gained oily matter with the solid state that obtains being white in color, 1-dimethyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene.m/z(ES
+)：217[M+H]
+，189[M-N
2+H]
+；
1H?NMR(CD
3OD)：δ?2.87(dd，1H，J
1＝16.5，J
2＝5.6)，2.67(dd，1H，J
1＝16.5，J
2＝0.8)，2.1-2.0(m，2H)，1.08(s，3H)，0.69(s，3H)。
Example 9.3: preparation (±)-1,1-dimethyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid (compound 6)
At room temperature with (±)-1,1-dimethyl-1a, 3,5,5a-tetrahydrochysene-1H-2, (0.0390g is 0.177mmol) in methyl alcohol: THF: stirred 18 hours in 1 M lithium hydroxide aqueous solution 1: 5: 1 solution (14mL) for 3-diaza-ring third [a] pentalene-4-ethyl formate.Under reduced pressure remove solvent, in 1 M aqueous hydrochloric acid (5mL), dissolve resistates, and it is extracted in the ethyl acetate (40mL).Under reduced pressure remove solvent, and through preparation HPLC purifying resistates to obtain white solid.M/z (ES
+): 215[M+Na]
+, 193[M+H]
+, 175[M-OH]
+ 1H NMR (CD
3CN): δ 2.91 (dd, 1H, J
1=17.4, J
2=6.8), 2.66 (d, 1H, J=17.4), 2.11 (dd, 1H, J
1=6.3, J
2=1.2), 2.05-1.95 (m, 1H), 1.19 (s, 3H, outer-C
H 3), 0.77 (d, 3H, J=2.0, interior-C
H 3).
Example 9.4: preparation (±)-outer-1-benzyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene (compound 8)
(5-phenyl-penta-3-thiazolinyl)-oxyethane is initial with (E)-2-, with to mode synthetic compound 8 similar described in the example 9.2.As characterizing the intermediate of individual steps shown in hereinafter.
Steps A: (±)-outer-6-benzyl-dicyclo [3.1.0] oneself-2-alcohol
To prepare title compound to mode similar described in the example 9.2 step B.
1H NMR (CDCl
3): δ 7.35-7.25 (m, 2H), 7.25-7.15 (m, 3H), 4.25 (d, 1H, J=4.7), 2.54 (d, 2H, J=6.9), 2.00-1.85 (m, 1H), 1.74 (dd, 1H, J
1=12.5, J
2=8.0), 1.65-1.50 (m, 1H), 1.45-1.35 (m, 1H), 1.35-1.30 (m, 1H), 0.71 (septet, 1H, J=3.3).Contain 15% (±)-Nei-6-benzyl-dicyclo [3.1.0] oneself-2-alcohol.
Step B:(±)-outer-6-benzyl-dicyclo [3.1.0] oneself-2-ketone
To prepare title compound to mode similar described in the example 9.2 step C.
1H?NMR(CDCl
3)：δ7.35-7.28(m，2H)，7.25-7.20(m，3H)，2.78(dd，1H，J
1＝14.9，J
2＝6.1)，2.60(dd，1H，J
1＝14.9，J
2＝7.2)，2.20-2.10(m，1H)，2.10-2.00(m，4H)，1.74(dd，1H，J
1＝5.2，J
2＝2.4)，1.65-1.55(m，1H)。Contain 15% (±)-Nei-6-benzyl-dicyclo [3.1.0] oneself-2-ketone.
Step C:(±)-outer-1-benzyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate
To prepare title compound to mode similar described in the example 9.2 step D.
1H NMR (CD
3OD): δ 7.35-7.10 (m, 5H), 4.31 (q, 2H, J=7.1, OC
H 2), 2.97 (dd, 1H, J
1=17.2, J
2=6.2), and 2.90-2.75 (m, 2H), 2.59 (dd, 1H, J
1=15.0, J
2=7.5), 2.20-2.15 (m, 1H), 2.15-2.05 (m, 1H), 1.34 (t, 3H, J=7.1), 1.00 (septet, 1H, J=3.5).Contain 15% (±)-Nei-1-benzyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate.MS?m/z?(ES
+)：305[M+Na]
+，283[M+H]
+，237[M-OEt]
+。
Step D:(±)-outer-1-benzyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-benzoic acid amides
To prepare title compound to mode similar described in example 9.2 step e.
1H?NMR(CD
3OD)：δ?7.4-7.1(m，5H)，2.95(dd，1H，J
1＝16.5，J
2＝5.4)，2.87(d，1H，J＝15.6)，2.8-2.6(m，2H)，2.25-2.15(m，2H)，1.05-0.90(m，1H)。Contain 15% (±)-Nei-1-benzyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-benzoic acid amides.MS?m/z?(ES
+)：276[M+Na]
+，254[M+H]
+，237[M-NH
2]
+。
Step e: (±)-outer-1-benzyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-nitrile
To prepare title compound to mode similar described in example 9.2 step F.MS?m/z?(ES
+)：236[M+H]
+。Contain 15% (±)-Nei-1-benzyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-nitrile.
Step F: (±)-outer-1-benzyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene (compound 8)
To prepare title compound to mode similar described in the example 9.2 step G.
1H?NMR(CD
3OD)：δ?7.6-7.5(m，4H)，7.5-7.4(m，1H)，3.29(dd，1H，J
1＝16.2，J
2＝6.0)，3.18(d，1H，J＝16.2)，3.01(dd，1H，J
1＝14.7，J
2＝6.6)，2.90(dd，1H，J
1＝14.7，J
2＝7.4)，2.55-2.45(m，2H)，1.35-1.25(m，1H)。MSm/z?(ES
+)：301[M+H]
+，279[M+H]
+，251[M-N
2+H]
+。
Example 9.5: preparation (±)-outer-1-benzyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid (compound 5)
Use with mode similar described in the example 9.3 by (±)-outward-1-benzyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate synthetic compound 5.MS m/z (ES
+): 277[M+Na]
+, 255[M+H]
+, 237[M-OH]
+ 1H NMR (CD
3CN): δ 7.3-7.1 (m, 5H), 2.83 (dd, 1H, J
1=17.0, J
2=5.8), 2.66 (d, 1H, J=17.0), 2.57 (dd, 2H, J
1=7.0, J
2=4.2), 2.05-1.95 (m, 2H), 0.82 (septet, 1H, J=3.5).Contain 15% (±)-Nei-1-benzyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid.
Example 9.6: preparation (±)-3b, 4,4a, 5-tetrahydrochysene-2H-ring third [3,4] ring penta [1,2-c] pyrazoles-3-formic acid (compound 1)
Steps A: the preparation dicyclo [3.1.0] oneself-3-ketone
At 0 ℃, N
2Under the atmosphere, use syringe pump to cyclopentenes-4-alcohol (5.0g, 59.5mmol) and Et
2(12.4mL 121mmol) added CH to Zn through 30 minutes in the solution in DCM (25mL)
2I
2(9.76mL, 121mmol).Sluggish temperature to room temperature and stirring spent the night, during stirring mixture is opened wide and slowly ends by adding rare HCl (50mL) to air.Mixture is diluted and filtration with EtOAc (100mL).Separate organic layer, with H
2O (100mL) and salt solution (100mL) washing.With organism through MgSO
4Oily matter is filtered and be condensed into to drying, and (gradient: the 30%EtOAc of the 10%EtOAc in the hexane to the hexane) purifying is to obtain being clarification buttery ring propyl alcohol through silica gel chromatography for described oily matter.
At room temperature alcohol (from above) is dissolved among the DCM (250mL), and continues with alkali alumina (10g) and PCC (15.2g, 70.6mmol) processing.After stirring 18h, use DCM/Et
2O (3: 1) has diatomaceous silicagel pad filtering solution as eluant by the top.Move down in vacuum (250 millibars, 20 ℃ of bath temperatures) and to desolventize, and under decompression (100 millibars) by the underpressure distillation purified product to obtain being clarification buttery ketone.
1H?NMR(CDCl
3，400?MHz)：δ?2.60(2H，m)，2.16(2H，d，J＝20.0?Hz)，1.54(2H，m)，0.90(1H，dt，J＝6.0，1.6Hz)，-0.05(1H，dt，J＝6.0，4.0Hz)。
Step B: preparation (±)-3b, 4,4a, 5-tetrahydrochysene-1H-ring third [3,4] ring penta [1,2-c] pyrazoles-3-ethyl formate
Use dicyclo [3.1.0] oneself-3-ketone to be to prepare title ester to mode similar described in the example 9.1 step C.
Step C: preparation (±)-3b, 4,4a, 5-tetrahydrochysene-2H-ring third [3,4] ring penta [1,2-c] pyrazoles-3-formic acid (compound 1)
At room temperature (43mg is 0.23mmol) in THF (2mL) and H to ester
2Add LiOHH in the solution among the O (1mL)
2O (38mg, 0.90mmol).Reaction is heated to 55 ℃ lasts 1.5 h.After being cooled to room temperature, mixture is acidified to pH=1 with HCl (the 6 N aqueous solution).By anti-phase HPLC purifying [Phenomenex
_Luna C18 tubing string (10 μ, 250 * 21.2mm), gradient: 5% (v/v) CH in the water (containing 1%v/v TFA)
3CN (containing 1%v/v TFA) 95% (v/v) CH to the water
3CN, 20 ml/min, λ=214nm] free acid of the solid state that obtains being white in color after the freeze-drying.
HPLC/MS:Alltech
_Prevail C18 tubing string (5 μ, 50 * 4.6 mm), gradient: 5%v/v CH in the water (containing 1%v/v TFA)
3CN (containing 1%v/v TFA) 99%v/v CH to the water
3CN, 3.5 ml/min, t
r=1.24 minutes, ESI
+=165.0 (M+H).
Example 9.7: preparation (±)-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene (compound 2)
Use racemize 2-fourth-3-thiazolinyl-oxyethane, to prepare compound 2 to mode similar described in the example 9.1.
Example 9.8: preparation (±)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid (compound 3)
At room temperature to corresponding (±)-ester (50mg, 0.26mmol) add in the solution in the Yu diox (1mL) NaOH (the 1 N aqueous solution, 2mL).To react to stir and spend the night, and be acidified to pH=1 with HCl (the 6N aqueous solution).By anti-phase HPLC purifying [Phenomenex
_Luna C18 tubing string (10 μ, 250 * 21.2mm), gradient: 5% (v/v) CH in the water (containing 1%v/v TFA)
3CN (containing 1%v/v TFA) 95% (v/v) CH to the water
3CN, 20 ml/min, λ=214nm] free acid of the solid state that obtains being white in color after the freeze-drying.HPLC/MS:Discovery
_C18 tubing string (5 μ, 50 * 2.1mm), gradient: 5%v/v CH in the water (containing 1%v/v TFA)
3CN (containing 1%v/v TFA) 99%v/v CH to the water
3CN, 0.75 ml/min, t
r=1.09 minutes, ESI
+=164.1 (M+H).
Example 9.9: preparation intermediate (±)-6,6-two chloro-spiral shells [dicyclo [3.1.0] hexane-2,2 '-[1,3] dioxolane]
At room temperature to 1,4-two oxa-s-spiral shell [4.4] ninth of the ten Heavenly Stems-(25.23g is 0.20mol) in CHCl for 6-alkene
3(200mL) and CH
2Cl
2Add 3-ethyl benzyl ammonium chloride (100mg) and 50%NaOH solution (200mL) in the solution (200mL).Under 45 ℃ with this solution vigorous stirring 3 days.With H
2O (300mL) diluted reaction mixture and with CHCl
3(2 * 150mL) extractions.Concentrate the organic layer that is made up in a vacuum, and through SiO
2Tubing string chromatography (0-50%CH in the hexane
2Cl
2) the purifying resistates to be to obtain being the title compound of colourless liquid shape.
1H?NMR(400?MHz，CDCl
3)：δ4.06-3.93(m，4H)，2.25-2.01(m，5H)，1.89-1.83(m，1H)。
Example 9.10: preparation intermediate (±)-outer-6-chloro-spiral shell [dicyclo [3.1.0] hexane-2,2 '-[1,3] dioxolane] and (±)-Nei-6-chloro-spiral shell [dicyclo [3.1.0] hexane-2,2 '-[1,3] dioxolane]
At room temperature to (±)-6,6-two chloro-spiral shells [dicyclo [3.1.0] hexane-2,2 '-[1,3] dioxolane] (17.0g, 81mmol) and KOH (28.0g, 0.5mol) add in the solution in EtOH (200mL) Zn (62.8g, 0.96mol).Under vigorous stirring in 80 ℃ of following reacting by heating mixture overnight.After reaction mixture is cooled to room temperature, filter, and (47.27mL 0.5mol) handles filtrate with diacetyl oxide under ice bath by Celite pad.After concentrating in a vacuum, with residue extracted to hexane (300mL), and with H
2O (2 * 150mL) and salt solution (150 mL) washing.SiO
2Tubing string chromatography (20-70%CH in hexane
2Cl
2) obtain outward-muriate and interior-muriate.
Outward-muriate:
1H NMR (400 MHz, CDCl
3): δ 4.07-3.90 (m, 4 H), 2.94 (t, 1H, J=1.9Hz) 1.95-1.90 (m, 2H), 1.88-1.74 (m, 2H), 1.68-1.62 (m, 1H), 1.45-1.36 (m, 1H).
In-muriate:
1H NMR (400 MHz, CDCl
3): δ 4.02-3.91 (m, 4 H), 3.42 (t, 1H, J=7.5Hz) 2.22-2.12 (m, 1H), 2.05-1.74 (m, 5H).
Example 9.11: outside preparation intermediate (±)-Nei-6-chloro--6-methyl-spiral shell [dicyclo [3.1.0] hexane-2,2 '-[1,3] dioxolane]
To (±)-6, (6.50 g 31.1mmol) dropwise add tert-butyl lithium (37.32mmol, 21.95mL 1.7 M n-heptane solutions) to 6-two chloro-spiral shells [dicyclo [3.1.0] hexane-2,2 '-[1,3] dioxolane] in the solution in THF (140mL) under-100 ℃.After 20 minutes, (2.33mL 37.32mmol), and makes it be slowly to warm to room temperature dropwise to add methyl iodide in solution.Product is extracted in the normal hexane.Under reduced pressure remove solvent.SiO
2Tubing string chromatography (0-20%EtOAc/ normal hexane) obtains being the buttery title compound.
1H?NMR(400MHz，CDCl
3)：δ?4.01-3.91(m，4?H)，2.20-2.07(m，2H)，1.96-1.82(m，2H).1.63(dd，1H，J
1＝6.8Hz，J
2＝5.3Hz)，1.61(s，3H)，1.54(dd，1H，J
1＝7.6Hz，J
2＝1.0Hz)。
Example 9.12: preparation intermediate (±)-6-methylene radical-spiral shell [dicyclo [3.1.0] hexane-2,2 '-[1,3] dioxolane]
(2.50g 13.25mmol) adds KO in the solution in DMSO (40mL) to (±)-6-chloro-6-methyl-spiral shell [dicyclo [3.1.0] hexane-2,2 '-[1,3] dioxolane]
tBu solution (1.0M in THF, 15.9mL).Under 60 ℃ with the solution heated overnight.After reaction mixture is cooled to room temperature, product is extracted in the normal hexane.Under reduced pressure remove solvent.SiO
2Tubing string chromatography (14-25%EtOAc/ normal hexane) obtains being the buttery title compound.
1H?NMR(400MHz，CDCl
3)：δ?5.55(s，1H)，5.42(t，1H，J＝1.0Hz)，4.08-3.91(m，4H)，2.07-1.97(m，2H)，1.90-1.84(m，2H)，1.65-1.54(m，2H)。
Example 9.12a: preparation intermediate (±)-6-Spirocyclopropyl-spiral shell [dicyclo [3.1.0] hexane-2,2 '-[1,3] dioxolane]
(1.52g is 10mmol) in Et to (±)-6-methylene radical-spiral shell [dicyclo [3.1.0] hexane-2,2 '-[1,3] dioxolane]
2Solution among the O (20mL) and in Et
2CH among the O
2N
2Add Pd (OAc) in (about 5mmol)
2(about 20mg).At room temperature in solution, dropwise made an addition to Et again through 1 hour
2CH among the O
2N
2(about 45mmol).After concentrating, SiO
2Tubing string chromatography (the 50-90%CH in the hexane
2Cl
2) obtain product (±)-6-Spirocyclopropyl-spiral shell [dicyclo [3.1.0] hexane-2,2 '-[1,3] dioxolane].
1H?NMR(400MHz，CDCl
3)：4.02-3.94(m，1H)，3.92-3.86(m，3H)，1.96-1.89(m，1H)，1.75-1.62(m，5H)，0.82-0.86(m，2H)，0.79-0.76(m，1H)，0.73-0.70(m，1H)。
Example 9.13: in the preparation-be substituted intermediate
General reaction process:
At room temperature in the solution of 4,4 '-two-tertiary butyl-biphenyl (5 equivalent) in THF, add the lithium line (5 equivalent) that is cut into small shreds.Under 0 ℃,, and be cooled to-78 ℃ with solution vigorous stirring 6 h.(±)-Nei type or the single muriate of external form (1 equivalent) that are dissolved among the THF are added in the blackish green solution.After 10 minutes, in solution, dropwise add electrophilic reagent (5 equivalent), it is slowly to warm to room temperature, and with hexane through the vigorous stirring/saturated NH of the rapid impouring of gained solution in ice bath
4In the Cl solution mixture.Concentrate separated organic layer, SiO
2In the tubing string chromatography obtains-be substituted product.
Example 9.13a:(±)-outer-6-methyl-spiral shell [dicyclo [3.1.0] hexane-2,2 '-[1,3] dioxolane]
1H?NMR(400MHz，CDCl
3)：δ?4.05-3.87(m，4H)，1.90-1.80(m，1H)，1.76(dd，1H，J
1＝12.3Hz，J
2＝8.0Hz)，1.61(dd，1H，J
1＝13.8Hz，J
2＝8.4Hz)，1.45(ddd，1H，J
1＝13.8Hz，J
2＝11.8Hz，J
3＝8.2Hz)，1.18-1.14(m，1H)，1.10(ddd，1H，J
1＝6.1Hz，J
2＝2.9Hz，J
3＝1.1Hz)，1.00(d，3H，J＝6.0Hz)，0.88(qdd，1H，J
1＝6.0Hz，J
2＝3.0Hz，J
3＝3.0Hz)。
Example 9.13b:(±)-Nei-6-methyl-spiral shell [dicyclo [3.1.0] hexane-2,2 '-[1,3] dioxolane]
1H?NMR(400MHz，CDCl
3)：δ?3.98-3.88(m，4H)，2.10-2.00(m，1H)，1.91(dd，1H，J
1＝14.3Hz，J
2＝10.7Hz)，1.69(ddd，1H，J
1＝13.2Hz，J
2＝9.3Hz，J
3＝1.4Hz)，1.59-1.45(m，2H)，1.38(ddd，1H，J
1＝8.6Hz，J
2＝6.5Hz，J
3＝1.3Hz)，1.15(d，3H，J＝6.6Hz)，0.97(qdd，1H，J
1＝6.6Hz，J
2＝7.5Hz，J
3＝7.5Hz)。
Example 9.13c:(±)-Nei-6-ethyl-spiral shell [dicyclo [3.1.0] hexane-2,2 '-[1,3] dioxolane]
1HNMR(400MHz，CDCl
3)：δ?3.99-3.88(m，4H)，2.09-1.91(m，2H)，1.73-1.50(m，4H)，1.45-1.35(m，2H)，1.15(t，3H，J＝7.4Hz)，0.78(qdd，1H，J
1＝7.4Hz，J
2＝7.5Hz，J
3＝7.5Hz)。
Example 9.13d:(±)-Nei-6-formyl radical-spiral shell [dicyclo [3.1.0] hexane-2,2 '-[1,3] dioxolane]
1H?NMR(400MHz，CDCl
3)：δ?9.60(d，1H，J＝6.3Hz)，4.05-3.93(m，4H)，2.34-2.19(m，2H)，2.15-2.06(m，3H)，1.91-1.76(m，2H)。
Example 9.13e:(±)-outer-6-formyl radical-spiral shell [dicyclo [3.1.0] hexane-2,2 '-[1,3] dioxolane]
1H?NMR(400MHz，CDCl
3)：δ?9.27(d，1H，J＝4.0Hz)，4.08-4.02(m，1H)，3.99-3.91(m，3H)，2.13-1.99(m，4H)，1.90(dd，1H，J
1＝12.7Hz，J
2＝8.0Hz)，1.72(dd，1H，J
1＝14.0Hz，J
2＝8.7Hz)，1.59-1.50(m，1H)。
Example 9.14: preparation intermediate (±)-Nei-6-vinyl-spiral shell [dicyclo [3.1.0] hexane-2,2 '-[1,3] dioxolane]
At room temperature (2.55g 7.14mmol) adds n-Butyl Lithium (7.14mmol, 4.46mL 1.6 M solution in hexane) in the solution in THF (40mL) to the Diethylaminoethyl triphenyl phosphonium.Behind the 2h, at room temperature (1.0g, 5.95mmol) solution in 8mL THF is added in the reaction mixture, and its stirring is spent the night with interior-6-formyl radical-spiral shell [dicyclo [3.1.0] hexane-2,2 '-[1,3] dioxolane].Product is extracted in the normal hexane.Under reduced pressure remove solvent.SiO
2Tubing string chromatography (0-20%EtOAc/ normal hexane) obtains being the buttery title compound.
1H?NMR(400MHz，CDCl
3)：δ?5.87(ddd，1H，J
1＝17.0Hz，J
2＝10.2Hz，J
3＝8.6Hz)，5.30(ddd，1H，J
1＝17.0Hz，J
2＝2.0?Hz，J
3＝1.0Hz)，5.18(ddd，1H，J
1＝10.2Hz，J
2＝2.0Hz，J
3＝1.0Hz)，4.00-3.88(m，4H)，2.12-2.02(m，1H)，1.90(dd，1H，J
1＝14.5Hz，J
2＝10.3Hz)，1.80-1.56(m，5H)。
Example 9.14a: preparation intermediate (±)-outer-6-vinyl-spiral shell [dicyclo [3.1.0] hexane-2,2 '-[1,3] dioxolane]
To prepare title compound to mode similar described in the example 9.14.
1H?NMR(400?MHz，CDCl
3)：δ?5.35(ddd，1H，J
1＝17.0Hz，J
2＝10.2Hz，J
3＝8.6Hz)，5.05(ddd，1H，J
1＝17.0Hz，J
2＝1.5Hz，J
3＝0.4Hz)，4.96(dd，1H，J
1＝10.3Hz，J
2＝1.6Hz)，4.06-4.00(m，1H)，3.99-3.88(m，3H)，1.98-1.88(m，1H)，1.84(dd，1H，J
1＝12.1Hz，J
2＝8.1Hz)，1.66(dd，1H，J
1＝14.2Hz，J
2＝8.8Hz)，1.56-1.43(m，4H)。
Example 9.14b: preparation intermediate (±)-Nei-6-(1-propenyl)-spiral shell [dicyclo [3.1.0] hexane-2,2 '-[1,3] dioxolane]
To prepare title compound to mode similar described in the example 9.14.
1H?NMR(400MHz，CDCl
3)：δ?5.75-5.68(m，1H)，5.52-5.47(m，1H)，3.99-3.88(m，4H)，2.06-1.96(m，1H)，1.89-1.70(m，5H)，1.68-1.52(m，4H)。
Example 9.14c: preparation intermediate (±)-Nei-6-cyclopropyl-spiral shell [dicyclo [3.1.0] hexane-2,2 '-[1,3] dioxolane]
To prepare title compound to mode similar described in the example 9.12a.
1H?NMR(400MHz，CDCl
3)：δ?4.02-3.88(m，4H)，2.09-1.99(m，1H)，1.91-1.50(m，3H)，1.48-1.39(m，2H)，1.22-1.17(m，1H)，0.78-0.71(m，1H)，0.65-0.52(m，2H)，0.33-0.26(m，2H)。
Example 9.15: preparation ketone intermediate
General reaction process:
At room temperature handle ketone through protection in acetone/H with the TsOH of catalytic amount
2Solution among the O (4/1).Solution stirring is spent the night.Remove acetone in a vacuum, and with hexane extraction product (3 times).With the organic layer that made up with 5%NaHCO
3Solution and salt water washing, dry (MgSO
4), and concentrate to obtain product ketone in a vacuum.
Example 9.15a:(±)-outer-6-methyl-dicyclo [3.1.0] hexane-2 ketone
1H?NMR(400MHz，CDCl
3)：δ?2.14-1.98(m，4H)，1.85(q，1H，J＝4.8Hz)，1.52(dd，1H，J
1＝5.0Hz，J
2＝2.5Hz)，1.36-1.30(m，1H)，1.12(d，3H，J＝6.0Hz)。
Example 9.15b:(±)-Nei-6-methyl-dicyclo [3.1.0] hexane-2 ketone
1H?NMR(400?MHz，CDCl
3)：δ?2.32-2.21(m，2H)，2.13-2.08(m，1H)，1.97-1.84(m，3H)，1.55-1.48(m，1H)，1.15(d，3H，J＝6.6Hz)。
Example 9.15c:(±)-Nei-6-ethyl-dicyclo [3.1.0] hexane-2 ketone
1H?NMR(400MHz，CDCl
3)：δ?2.34-2.20(m，2H)，2.15(q，1H，J＝6.0Hz)，2.00-1.87(m，3H)，1.48-1.36(m，3H)，1.04(t，3H，J＝6.5Hz)。
Example 9.15d:(±)-Nei-6-vinyl-dicyclo [3.1.0] hexane-2 ketone
1H?NMR(400MHz，CDCl
3)：δ?5.67(ddd，1H，J
1＝17.0Hz，J
2＝10.3Hz，J
3＝8.5Hz)，5.37(dt，1H，J
1＝17.0Hz，J
2＝1.4Hz)，5.27(dt，1H，J
1＝10.3Hz，J
2＝1.5Hz)，2.32-2.21(m，3H)，2.20-2.14(m，1H)，2.10-2.07(m，1H)，2.03-1.93(m，2H)。
Example 9.15e:(±)-6-Spirocyclopropyl-dicyclo [3.1.0] hexane-2 ketone
1H?NMR(400?MHz，CDCl
3)：δ?2.33(t，1H，J＝5.0Hz)，2.26-2.04(m，4H)，1.99-1.91(m，1H)，1.03(t，2H，J＝7.2Hz)，0.88-0.78(m，2H)。
Example 9.15f:(±)-outer-6-vinyl-dicyclo [3.1.0] hexane-2 ketone
1H?NMR(400MHz，CDCl
3)：δ5.35(ddd，1H，J
1＝17.0Hz，J
2＝10.2Hz，J
3＝8.5Hz)，5.15(ddd，1H，J
1＝17.0Hz，J
2＝1.2Hz，J
3＝0.4Hz)，4.99(dd，1H，J
1＝10.2Hz，J
2＝1.1Hz)，2.20-2.05(m，5H)，1.95-1.91(m，1H)，1.83(q，1H，J
1＝2.5Hz)。
Example 9.15g:(±)-Nei-6-(1-propenyl)-dicyclo [3.1.0] hexane-2 ketone
1HNMR(400MHz，CDCl
3)：δ?5.82-5.75(m，1H)，5.33-5.26(m，1H)，2.30-1.89(m，7H)，1.76-1.70(m，3H)。
Example 9.15h:(±)-Nei-6-cyclopropyl-dicyclo [3.1.0] hexane-2 ketone
1H?NMR(400MHz，CDCl
3)：δ?2.32-2.09(m，5H)，1.86-1.82(m，1H)，1.16-1.09(m，1H)，0.71-0.65(m，1H)，0.61-0.56(m，2H)，0.39-0.29(m，2H)。
Example 9.16: preparation (±)-outer-1-methyl isophthalic acid a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate
To prepare title compound to mode similar described in the example 9.2 step D.MS?m/z?(ES
+)：207.2[M+H]
+，
229.4[M+Na]
+；
1H?NMR(400MHz，CDCl
3)：δ?4.37-4.31(m，2H)，2.97(dd，1H，J
1＝17.1Hz，J
2＝5.7Hz)，2.86(d，1H，J＝17.1Hz)，2.01-1.97(m，2H)，1.36(t，3H，J＝7.1Hz)，1.13(d，3H，J＝6.1Hz)，0.78-0.72(m，1H)。
Example 9.17: preparation (±)-outer-1-methyl isophthalic acid a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid
To prepare title compound to mode similar described in the example 9.3.MS?m/z?(ES
+)：179.1[M+H]
+，201.5[M+Na]
+；
1H?NMR(400MHz，CDCl
3)：δ?3.02(dd，1H，J
1＝18.5Hz，J
2＝6.3Hz)，2.91(d，1H，J＝18.5Hz)，2.09(dd，1H，J
1＝5.6Hz，J
2＝2.2Hz)，1.78(dd，1H，J
1＝9.7Hz，J
2＝5.9Hz)，1.17(d，3H，J＝6.0Hz)，0.74(qdd，1H，J
1＝6.0Hz，J
2＝3.0Hz，J
3＝3.0Hz)。
Example 9.18: preparation (±)-outer-1-methyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene
Steps A: preparation (±)-outer-1-methyl isophthalic acid a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-benzoic acid amides
To prepare title compound to mode similar described in the example 9.1 step D.MS?m/z?(ES
+)：178.1[M+H]
+，200.1[M+Na]
+；
1H?NMR(400MHz，DMSO-d
6)：δ?2.84(dd，1H，J
1＝18.0Hz，J
2＝6.4Hz)，2.69(d，1H，J＝18.0Hz)，1.97(dd，1H，J
1＝5.8Hz，J
2＝2.3Hz)，1.68(dd，1H，J
1＝9.5Hz，J
2＝6.0Hz)，1.08(d，3H，J＝6.0Hz)，0.63(qdd，1H，J
1＝6.0Hz，J
2＝3.0Hz，J
3＝3.0Hz)。
Step B: preparation (±)-outer-1-methyl isophthalic acid a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-nitrile
To prepare title compound to mode similar described in example 9.2 step F.MS?m/z?(ES
+)：160.2[M+H]
+，319.1[2M+H]
+；
1H?NMR(400MHz，DMSO-d
6)：δ?2.80(dd，1H，J
1＝15.9Hz，J
2＝4.4Hz)，2.71(d，1H，J＝15.9Hz)，2.04-1.97(m，2H)，1.05(d，3H，J＝6.1Hz)，0.72-0.65(m，1H)。
Step C: preparation (±)-outer-1-methyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene
To prepare title compound to mode similar described in the example 9.2 step G.MS?m/z?(ES
+)：203.5[M+H]
+，225.4[M+Na]
+；
1H?NMR(400MHz，DMSO-d
6)：δ?2.89(ddd，1H，J
1＝16.2Hz，J
2＝4.7Hz，J
3＝1.6Hz)，2.81(d，1H，J＝16.2Hz)，2.02-1.98(m，2H)，1.08(d，3H，J＝6.1Hz)，0.70(qdd，1H，J
1＝6.1Hz，J
2＝3.0Hz，J
3＝3.0Hz)。
Example 9.19: preparation (±)-Nei-1-methyl isophthalic acid a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate
To prepare title compound to mode similar described in the example 9.2 step D.MS?m/z?(ES
+)：207.1[M+H]
+，229.2[M+Na]
+；
1H?NMR(400MHz，CDCl
3)：δ?4.37-4.30(m，2H)，2.92(dd，1H，J
1＝17.5Hz，J
2＝6.8Hz)，2.65(d，1H，J＝17.5Hz)，2.33(t，1H，J＝6.8Hz)，2.33(dd，1H，J
1＝15.0Hz，J
2＝6.8Hz)，1.38(t，3H，J＝7.1Hz)，1.39-1.30(m，1H)，0.71(d，3H，J＝6.5Hz)。
Example 9.20: preparation (±)-Nei-1-methyl isophthalic acid a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid
To prepare title compound to mode similar described in the example 9.3.MS?m/z?(ES
+)：179.1[M+H]
+，357.1[2M+H]
+；
1H?NMR(400MHz，CD
3OD)：δ?2.89(dd，1H，J
1＝17.3Hz，J
2＝6.7Hz)，2.64(d，1H，J＝17.2Hz)，2.30-2.18(m，2H))，1.34(qdd，1H，J
1＝6.4Hz，J
2＝7.0Hz，J
3＝7.0Hz).0.69(d，3H，J＝6.4Hz)。
Example 9.21: preparation (±)-Nei-1-methyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene
Steps A: preparation (±)-Nei-1-methyl isophthalic acid a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-benzoic acid amides
To prepare title compound to mode similar described in example 9.2 step e.MS?m/z?(ES
+)：178.1[M+H]
+，355.2[2M+H]
+；
1H?NMR(400MHz，CD
3OD)：δ?2.88(dd，1H，J
1＝16.5Hz，J
2＝4.8Hz)，2.66(d，1H，J＝16.8Hz)，2.30-2.22(m，2H))，1.32(qdd，1H，J
1＝6.4Hz，J
2＝7.0Hz，J
3＝7.0Hz).0.69(d，3H，J＝6.4Hz)。
Step B: preparation (±)-Nei-1-methyl isophthalic acid a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-nitrile
To prepare title compound to mode similar described in example 9.2 step F.MS?m/z?(ES
+)：160.1[M+H]
+，319.4[2M+H]
+；
1H?NMR(400MHz，CD
3OD)：δ?2.84(dd，1H，J
1＝16.6Hz，J
2＝6.7Hz)，2.59(d，1H，J＝16.6Hz)，2.36-2.27(m，2H))，1.39(qdd，1H，J
1＝6.4Hz，J
2＝7.0Hz，J
3＝7.0Hz).0.69(d，3H，J＝6.4Hz)。
Step C: preparation (±)-Nei-1-methyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene
To prepare title compound to mode similar described in the example 9.2 step G.MS?m/z?(ES
+)：203.4[M+H]
+，405.4[2M+H]
+；
1H?NMR(400MHz，CDCl
3)：δ3.18(dd，1H，J
1＝17.3Hz，J
2＝6.5Hz)，2.95(d，1H，J＝17.4Hz)，2.60-2.53(m，2H))，1.67(qdd，1H，J
1＝6.5Hz，J
2＝7.0Hz，J
3＝7.0Hz).0.82(d，3H，J＝6.5Hz)。
Example 9.22: preparation (±)-Nei-1-ethyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate
To prepare title compound to mode similar described in the example 9.2 step D.MS?m/z?(ES
+)：221.3[M+H]
+，243.3[M+Na]
+；
1HNMR(400MHz，CDCl
3)：δ?4.38-4.30(m，2H)，2.92(dd，1H，J
1＝17.5Hz，J
2＝6.9Hz)，2.65(d，1H，J＝17.5Hz)，2.35(ddd，1H，J
1＝7.6Hz，J
2＝6.2Hz，J
3＝1.3Hz)，2.21(dd，1H，J
1＝14.4?Hz，J
2＝6.7Hz)，1.37(t，3H，J＝7.1Hz)，1.23-1.17(m，1H)，1.11-1.01(m，1H)，0.91-0.83(m，4H)。
Example 9.23: preparation (±)-Nei-1-ethyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid
To prepare title compound to mode similar described in the example 9.3.MS?m/z?(ES
+)：193.0[M+H]
+，215.0[M+Na]
+；
1H?NMR(400MHz，DMSO-d
6)：δ?2.80(dd，1H，J
1＝17.2Hz，J
2＝6.8Hz)，2.49(d，1H，J＝17.2Hz)，2.24(ddd，1H，J
1＝7.6Hz，J
2＝6.2Hz，J
3＝1.0Hz)，2.15(dd，1H，J
1＝14.4Hz，J
2＝6.4Hz)，1.18-1.11(m，1H)，1.03-0.93(m，1H)，0.81(t，3H，J＝6.9Hz)，0.77-0.68(m，1H)。
Example 9.24: preparation (±)-Nei-1-ethyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene
Steps A: preparation (±)-Nei-1-ethyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-benzoic acid amides
To prepare title compound to mode similar described in the example 9.1 step D.MS?m/z?(ES
+)：192.0[M+H]
+，383.2[2M+H]
+。
Step B: preparation (±)-Nei-1-ethyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-nitrile
To prepare title compound to mode similar described in example 9.2 step F.MS?m/z?(ES
+)：174.1[M+H]
+，347.4[2M+H]
+。
Step C: preparation (±)-Nei-1-ethyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene
To prepare title compound to mode similar described in the example 9.2 step G.MS?m/z?(ES
+)：217.1[M+H]
+，433.1[2M+H]
+；
1H?NMR(400MHz，CD
3OD)：δ?2.91(dd，2H，J
1＝14.6Hz，J
2＝6.1Hz)，2.07-2.03(m，1H)，1.88-1.79(m，1H)，1.66-1.57(m，1H)，1.17(dd，1H，J
1＝7.7Hz，J
2＝4.7Hz)，1.09(t，3H，J＝7.4Hz)，0.56(dd，1H，J
1＝4.2Hz，J
2＝3.2Hz)。
Example 9.25: preparation (±)-Nei-1-vinyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate
To prepare title compound to mode similar described in the example 9.2 step D.MS?m/z?(ES
+)：219.2[M+H]
+，241.1[M+Na]
+；
1H?NMR(400MHz，CDCl
3)：δ?5.31-5.23(m，1H)，5.05-4.95(m，1H)，4.39-4.31(m，2H)，2.99(dd，1H，J
1＝17.5Hz，J
2＝6.7Hz)，2.76(d，1H，J＝17.5Hz)，2.60(ddd，1H，J
1＝7.6Hz，J
2＝6.0Hz，J
3＝1.2Hz)，2.42(dd，1H，J
1＝15.0Hz，J
2＝6.0Hz)，1.99(ddd，1H，J
1＝8.0Hz，J
2＝8.0Hz，J
3＝8.0Hz)，1.37(t，3H，J＝7.1Hz)。
Example 9.26: preparation (±)-Nei-1-vinyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid
To prepare title compound to mode similar described in the example 9.3.MS?m/z?(ES
+)：191.2[M+H]
+，381.3[2M+H]
+；
1H?NMR(400MHz，DMSO-d
6)：δ?5.25(dd，1H，J
1＝16.9Hz，J
2＝2.3Hz)，4.99(dd，1H，J
1＝10.4Hz，J
2＝2.4Hz)，4.85(ddd，1H，J
1＝16.9Hz，J
2＝10.4Hz，J
3＝9.2Hz)，2.88(dd，1H，J
1＝17.3Hz，J
2＝6.6Hz)，2.57-2.50(m，2H)，2.39(dd，1H，J
1＝14.5Hz，J
2＝6.2?Hz)，1.94(ddd，1H，J
1＝8.4Hz，J
2＝8.4Hz，J
3＝8.4Hz)。
Example 9.27: preparation (±)-Nei-4-(2H-tetrazolium-5-yl)-1-vinyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene
Steps A: preparation (±)-Nei-1-vinyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-benzoic acid amides
To prepare title compound to mode similar described in the example 9.1 step D.MS?m/z?(ES
+)：190.2[M+H]
+，379.2[2M+H]
+；
1H?NMR(400MHz，DMSO-d
6)：δ?5.25(dd，1H，J
1＝16.9Hz，J
2＝2.3Hz)，4.98(dd，1H，J
1＝10.4Hz，J
2＝2.4Hz)，4.90-4.81(m，1H)，2.88(bd，1H，J＝13.6Hz)，2.64-2.49(m，2H)，2.40(dd，1H，J
1＝13.7Hz，J
2＝6.9Hz)，1.92(ddd，1H，J
1＝8.4Hz，J
2＝8.4?Hz，J
3＝8.4Hz)。
Step B: preparation (±)-Nei-1-vinyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-nitrile
To prepare title compound to mode similar described in example 9.2 step F.MS?m/z?(ES
+)：172.3[M+H]
+，343.3[2M+H]
+；
1H?NMR(400MHz，CDCl
3)：δ?5.30(dd，1H，J
1＝16.9?Hz，J
2＝2.0Hz)，5.08(dd，1H，J
1＝10.4Hz，J
2＝2.0Hz)，4.93(ddd，1H，J
1＝16.9Hz，J
2＝10.4Hz，J
3＝8.5Hz)，2.96(dd，1H，J
1＝16.9?Hz，J
2＝6.7Hz)，2.73(d，1H，J＝16.9Hz)，2.60-2.49(m，2H)，2.03(ddd，1H，J
1＝8.3Hz，J
2＝8.3Hz，J
3＝8.3Hz)。
Step C: preparation (±)-Nei-4-(2H-tetrazolium-5-yl)-1-vinyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene
To prepare title compound to mode similar described in example 9.1 step F.MS?m/z?(ES
+)：215.2[M+H]
+，429.3[2M+H]
+；
1H?NMR(400MHz，CD
3OD)：δ?5.30-5.25(m，1H)，5.07-4.99(m，2H)，3.05(dd，1H，J
1＝16.6Hz，J
2＝6.6Hz)，2.82(d，1H，J＝16.6Hz)，2.62(dd，1H，J
1＝7.5Hz，J
2＝6.1Hz)，2.55(dd，1H，J
1＝13.5Hz，J
2＝7.0Hz)，2.06-2.00(m，1H)。
Example 9.28: preparation (±)-Nei-1-benzyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene
Described in example 9.4 step F, obtain title compound from the mixture of diastereomer through the HPLC purifying.MS：m/z(ES+)：301[M+Na]
+，279[M+H]
+，251[M-N2+H]
+；
1H?NMR(CD
3OD)：δ?7.2-7.05(m，2H)，7.03(t，1H，J＝6.8)，6.97(d，2H，J＝7.4)，3.0-2.8(m，1H)，2.77(d，1H，J＝16.7)，2.5-2.3(m，3H)，2.02(dd，1H，J
1＝14.5，J
2＝8.9)，1.55-1.45(m，1H)。
Example 9.29: preparation (±)-outer-1-propyl group-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate
Steps A: preparation (±)-outer-6-propyl group-dicyclo [3.1.0] oneself-2-alcohol
To prepare title compound to mode similar described in the example 9.2 step B.
1H NMR (CDCl
3): δ 4.21 (d, 1H, J=4.8), 1.95-1.80 (m, 1H), 1.67 (dd, 1H, J
1=12.5, J
2=8.2), 1.53 (dd, 1H, J
1=14.2, J
2=8.3), 1.48-1.28 (m, 4H), 1.20-1.05 (m, 3H), 0.88 (t, 3H, J=7.3), 0.37 (septet, 1H, J=3.3).Contain 30% (±) that have an appointment-Nei-6-n-propyl-dicyclo [3.1.0] oneself-2-alcohol.
Step B: preparation (±)-outer-6-propyl group-dicyclo [3.1.0] oneself-2-ketone
To prepare title compound to mode similar described in the example 9.2 step C.
1H?NMR(CDCl
3)：δ2.15-1.95(m，4H)，1.9-1.8(m，1H)，1.53(d，1H，J＝5.0)，1.50-1.35(m，2H)，1.35-1.25(m，3H)，0.91(t，3H，J＝7.3)。Contain 30% (±) that have an appointment-Nei-6-n-propyl-dicyclo [3.1.0] oneself-2-ketone.
Step C: preparation (±)-outer-1-propyl group-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate
To prepare title compound to mode similar described in the example 9.2 step D.MS:m/z (ES+): 257[M+Na]
+, 235[M+H]
+, 189[M-OEt]
+ 1H NMR (CDCl
3): δ 4.25 (q, 2H, J=7.1, OCH2), 2.86 (dd, 1H, J
1=17.1, J
2=6.2), 2.74 (d, 1H, J=17.1), 1.95-1.90 (m, 1H), 1.87-1.80 (m, 1H), 1.40-1.10 (m, 7H comprise 1.27 (t, 3H, J=7.2)), 0.85 (t, 3H, J=7.2), 0.60 (septet, 1H, J=3.4).Contain 30% (±) that have an appointment-Nei-1-n-propyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate.
Example 9.30: preparation (±)-outer-1-propyl group-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid
To prepare title compound to mode similar described in the example 9.3.MS：m/z(ES+)：229[M+Na]
+，207[M+H]
+，189[M-OH]
+；
1H?NMR(CD
3OD)：δ?2.95-2.85(m，1H)，2.79(d，1H，J＝16.8)，2.00-1.90(m，2H)，1.47(m，2H，J＝7.1)，1.40-1.25(m，2H)，0.96(t，3H，J＝7.3)，0.63(m，1H，J＝3.4)。
Example 9.31: preparation (±)-outer-1-propyl group-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene
Steps A: preparation (±)-outer-1-propyl group-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-benzoic acid amides
To prepare title compound to mode similar described in example 9.2 step e.MS:m/z (ES+): 206[M+H]
+, 189[M-NH2]
+ 1H NMR (CD
3OD): δ 2.92 (dd, 1H, J
1=16.4, J
2=5.8), 2.82 (d, 1H, J=16.5), 2.05-1.90 (m, 2H), 1.47 (quintet, 2H, J=7.1), 1.38-1.28 (m, 2H), 0.96 (t, 3H, J=7.3), 0.66 (septet, 1H, J=3.3).
Step B: preparation (±)-outer-1-propyl group-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-nitrile
To prepare title compound to mode similar described in example 9.2 step F.MS:m/z (ES+): 188[M+H]
+ 1H NMR (CD
3OD): δ 2.88 (dd, 1H, J
1=16.3, J
2=6.0), 2.76 (d, 1H, J=16.2), 2.1-2.0 (m, 2H), 1.47 (quintet, 2H, J=7.3), 1.40-1.28 (m, 2H), 0.96 (t, 3H, J=7.3), 0.71 (septet, 1H, J=3.3).
Step C: preparation (±)-outer-1-propyl group-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene
To prepare title compound to mode similar described in the example 9.2 step G.MS:m/z (ES+): 231[M+H]
+, 203[M-N2+H]
+ 1H NMR (CD
3OD): δ 3.00 (dd, 1H, J
1=10.1, J
2=6.1), 2.91 (d, 1H, J=16.2), 2.07 (m, 2H), 1.50 (sextet, 2H, J=7.3), 1.35 (septet, 2H, J=7.0), 0.99 (t, 3H, J=6.1), 0.74 (septet, 1H, J=3.3).
Example 9.32: preparation (±)-Nei-1-propyl group-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid
Non-enantiomer mixture described in the use-case 9.29 step C is to prepare title compound to mode similar described in the example 9.3.MS：m/z(ES+)：229[M+Na]
+，207[M+H]
+，189[M-OH]
+。
Example 9.33: preparation (±)-Nei-1-propyl group-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene
Steps A: preparation (±)-Nei-1-propyl group-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-benzoic acid amides
To prepare title compound to mode similar described in example 9.2 step e.MS：m/z(ES+)：206[M+H]
+，189[M-NH2]
+；
1H?NMR(CDCl
3)：δ?6.45(br?s，1H)，5.95(br?s，1H)，2.93(dd，1H，J
1＝16.6，J
2＝6.6)，2.68(d，1H，J＝16.6)，2.4-2.3(m，2H)，1.4-1.2(m，3H)，1.15-1.00(m，1H)，0.88-0.78(m，4H)。
Step B: preparation (±)-Nei-1-propyl group-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-nitrile
To prepare title compound to mode similar described in example 9.2 step F.MS：m/z(ES+)：188[M+H]
+；
1H?NMR(CD
3OD)：δ?2.85(dd，1H，J
1＝16.6，J
2＝6.6)，2.60(d，1H，J＝16.6)，2.4-2.3(m，2H)，1.45-1.20(m，3H)，1.15-1.05(m，1H)，0.90-0.80(m，3H)，0.78-0.65(m，1H)。
Step C: preparation (±)-Nei-1-propyl group-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene
To prepare title compound to mode similar described in the example 9-2 step G.MS:m/z (ES+): 231[M+H]
+, 203[M-N2+H]
+ 1H NMR (CD
3OD): δ 2.97 (dd, 1H, J
1=10.2, J
2=6.4), 2.72 (J=18.3), (m, 2H), (m, 3H), (m, 1H), (m, 4H comprise 0.85 (t, 3H, J=7.4)) to 0.86-0.77 to 1.20-1.11 to 1.42-1.28 to 2.40-2.34 for d, 1H.
Example 9.34: preparation (±)-outer-1-butyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate
Steps A: preparation (±)-(E)-2-(suffering-3-thiazolinyl)-oxyethane
At room temperature, (1.000g, 10.2mmol) (9.12g, 102mmol) (0.057g 0.086mmol) stirred 24 hours in the sealing scintillation vial together with Zhan catalyzer-1 with own-1-alkene with 2-(fourth-3-thiazolinyl) oxyethane.Under reduced pressure remove solvent, and by (±)-(E)-2-(suffering-3-thiazolinyl) oxyethane of tubing string chromatography (0-10%EtOAc/ normal hexane/silicon-dioxide) purifying resistates to obtain being colorless oil.
1H?NMR(CDCl
3)：δ?5.5-5.4(m，2H)，3.0-2.9(m，1H)，2.8-2.7(m，1H)，2.5-2.45(m，1H)，2.2-2.1(m，2H)，1.99(q，2H，J＝5.7)，1.65-1.55(m，2H)，1.35-1.25(m，4H)，0.95-0.85(m，3H)。Contain 20% (the Z)-2-that has an appointment (suffering-3-thiazolinyl) oxyethane.
Step B: preparation (±)-outer-6-butyl-dicyclo [3.1.0] oneself-2-alcohol
To prepare title compound to mode similar described in the example 9.2 step B.
1H NMR (CDCl
3): δ 4.21 (d, 1H, J=4.8), 1.95-1.80 (m, 1H), 1.69 (dd, 1H, J
1=12.6, J
2=8.0), 1.54 (dd, 1H, J
1=11.6, J
2=5.7), 1.48-1.25 (m, 6H), 1.25-1.05 (m, 3H), 0.95-0.85 (m, 3H), 0.36 (septet, 1H, J=3.3).Contain 20% (±) that have an appointment-Nei-6-normal-butyl-dicyclo [3-1.0] oneself-2-alcohol.
Step C: preparation (±)-outer-6-butyl-dicyclo [3.1.0] oneself-2-ketone
To prepare title compound to mode similar described in the example 9.2 step C.
1H?NMR(CDCl
3)：δ2.15-1.95(m，4H)，1.9-1.8(m，1H)，1.54(t，1H，J＝2.4)，1.45-1.20(m，7H)，0.95-0.85(m，3H)。Contain 20% (±) that have an appointment-Nei-6-normal-butyl-dicyclo [3.1.0] oneself-2-ketone.
Step D: preparation (±)-outer-1-butyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate
To prepare title compound to mode similar described in the example 9.2 step D.MS:m/z (ES+): 249[M+H]
+, 203[M-OEt]
+ 1H NMR (CDCl
3): δ 4.30 (q, 2H, J=7.2, OCH2), 2.91 (dd, 1H, J
1=17.0, J
2=6.2), 2.79 (d, 1H, J=17.0), 1.98-1.93 (m, 1H), 1.89 (dd, 1H, J
1=9.8, J
2=6.0), 1.45-1.10 (m, 9H comprise 1.32 (t, 3H, J=7.1)), 0.87 (t, 3H, J=6.8), 0.70-0.60 (m, 1H).Contain 30% (±) that have an appointment-Nei-1-normal-butyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate.
Example 35: preparation (±)-outer-1-butyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid
To prepare title compound to mode similar described in the example 9.3.MS:m/z (ES+): 221[M+H]
+, 203[M-OH]
+ 1H NMR (CD
3OD): δ 2.95-2.85 (m, 1H), 2.78 (d, 1H, J=16.9), 2.00-1.90 (m, 2H), 1.5-1.25 (m, 6H), 0.93 (t, 3H, J=7.0), 0.62 (septet, 1H, J=3.3).
Example 36: preparation (±)-outer-1-butyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene
Steps A: preparation (±)-outer-1-butyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-benzoic acid amides
To prepare title compound to mode similar described in example 9.2 step e.MS:m/z (ES+): 220[M+H]
+, 203[M-NH2]
+ 1H NMR (CD
3OD): δ 2.92 (dd, 1H, J
1=16.4, J
2=5.9), 2.82 (d, 1H, J=16.0), 2.05-1.90 (m, 2H), 1.50-1.30 (m, 6H), 0.93 (t, 3H, J=7.0), 0.65 (septet, 1H, J=3.3).
Step B: preparation (±)-outer-1-butyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-nitrile
To prepare title compound to mode similar described in example 9.2 step F.MS:m/z (ES+): 202[M+H]
+ 1H NMR (CD
3OD): δ 2.89 (dd, 1H, J1=16.3, J
2=6.0), 2.76 (d, 1H, J=16.2), 2.1-2.0 (m, 2H), 1.50-1.30 (m, 6H), 0.93 (t, 3H, J=7.0), 0.70 (septet, 1H, J=3.3).
Step C: preparation (±)-outer-1-butyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene
To prepare title compound to mode similar described in the example 9.2 step G.MS:m/z (ES+): 245[M+H]+, 217[M-N2+H]
+ 1H NMR (CD
3OD): δ 2.99 (dd, 1H, J
1=10.2, J
2=6.0), 2.90 (d, 1H, J=16.2), 2.10-2.00 (m, 2H), 1.49-1.32 (m, 6H), 0.93 (t, 3H, J=7.0), 0.72 (septet, 1H, J=3.3).
Example 9.37: preparation (±)-Nei-1-butyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid
Non-enantiomer mixture described in the use-case 9.34 step D is to prepare title compound to mode similar described in the example 9.3.MS：m/z(ES+)：221[M+H]
+，203[M-OH]
+。
Example 9.38: preparation (±)-Nei-1-butyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene
Steps A: preparation (±)-Nei-1-normal-butyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-benzoic acid amides
Non-enantiomer mixture described in the use-case 9.36 step D is to prepare title compound to mode similar described in example 9.2 step e.MS：m/z(ES+)：220[M+H]
+，203[M-NH2]
+；
1H?NMR(CD
3OD)：δ?2.87(dd，1H，J
1＝16.7，J
2＝6.3)，2.66(d，1H，J＝16.7)，2.35-2.20(m，2H)，1.35-1.15(m，5H)，1.15-1.05(m，1H)，0.85-0.70(m，4H)。
Step B: preparation (±)-Nei-1-butyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-nitrile
To prepare title compound to mode similar described in example 9.2 step F.MS：m/z(ES+)：202[M+H]
+；
1H?NMR(CD
3OD)：δ?2.86(dd，1H，J
1＝16.5，J
2＝6.5)，2.60(d，1H，J＝16.4)，2.4-2.3(m，2H)，1.4-1.1(m，6H)，0.85-0.79(m，3H)，0.78-0.68(m，1H)。
Step C: preparation (±)-Nei-1-butyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene
To prepare title compound to mode similar described in the example 9.2 step G.MS:m/z (ES+): 245[M+H]
+, 217[M-N2+H]
+ 1H NMR (CD
3OD): δ 2.97 (dd, 1H, J
1=10.0, J
2=6.4), 2.78 (J=16.6), 2.38 (J=5.4), (m, 6H), (m, 3H), (m, 4H comprise 0.81 (t, 3H, J=7.2)) to 0.88-0.79 to 0.85-0.79 to 1.40-1.14 for quintet, 2H for d, 1H.
Example 9.39: preparation (±)-Nei-1-amyl group-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate
Steps A: the preparation (±)-Nei-6-n-pentyl-dicyclo [3.1.0] oneself-2-alcohol
To prepare title compound to mode similar described in the example 9.2 step B.
1H NMR (CDCl
3): δ 4.17 (dd, 1H, J
1=5.0, J
2=1.0), 2.15-2.00 (m, 1H), 1.80-1.45 (m, 3H), 1.40-1.25 (m, 8H), 1.22-1.15 (m, 3H), 0.95-0.85 (m, 3H), 0.75 (quintet, 1H, J=8.4).
Step B: the preparation (±)-Nei-6-amyl group-dicyclo [3.1.0] oneself-2-ketone
To prepare title compound to mode similar described in the example 9.2 step C.
1H?NMR(CDCl
3)：δ2.35-2.20(m，2H)，2.14(dd，1H，J
1＝11.8，J
2＝5.9)，2.05-1.85(m，3H)，1.50-1.20(m，9H)，0.95-0.85(m，3H)。
Step C: preparation (±)-Nei-1-amyl group-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate
To prepare title compound to mode similar described in the example 9.2 step D.MS：m/z(ES+)：263[M+H]
+，217[M-OEt]
+；
1H?NMR(CDCl
3)：δ?4.40-4.30(m，2H)，2.91(dd，1H，J
1＝17.5，J
2＝6.8)，2.66(d，1H，J＝17.5)，2.33(ddd，1H，J
1＝7.7，J
2＝6.2，J
3＝1.2)，2.20(dd，1H，J
1＝14.6，J
2＝6.5)，1.35-1.15(m，10H)，1.10-0.95(m，1H)，0.87(t，3H，J＝6.9)。
Example 9.40: preparation (±)-Nei-1-amyl group-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid
To prepare title compound to mode similar described in the example 9.3.MS：m/z(ES+)：235[M+H]
+，217[M-OH]
+；
1H?NMR(CD
3OD)：δ?2.86(dd，1H，J
1＝17.2，J
2＝6.7)，2.40(d，1H，J＝17.2)，2.33-2.28(m，1H)，2.28-2.20(m，1H)，1.40-1.15(m，7H)，1.13-1.05(m，1H)，0.88-0.82(m，3H)，0.82-0.73(m，1H)。
Example 9.41: preparation (±)-Nei-1-amyl group-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene
Steps A: preparation (±)-Nei-1-amyl group-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-benzoic acid amides
To prepare title compound to mode similar described in example 9.2 step e.MS：m/z(ES+)：234[M+H]
+，217[M-NH2]
+；
1H?NMR(CD
3OD)：δ?2.89(dd，1H，J
1＝16.8，J
2＝6.2)，2.67(d，1H，J＝16.8)，2.35-2.25(m，2H)，1.40-1.15(m，7H)，1.15-1.05(m，1H)，0.90-0.70(m，4H)。
Step B: preparation (±)-Nei-1-amyl group-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-nitrile
To prepare title compound to mode similar described in example 9.2 step F.MS：m/z(ES+)：216[M+H]
+。
Step C: preparation (±)-Nei-1-amyl group-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene
To prepare title compound to mode similar described in the example 9.2 step G.MS：m/z(ES+)：260[M+H]
+，232[M-N2+H]
+；
1H?NMR(CD
3OD)：δ?2.96(dd，1H，J
1＝16.5，J
2＝6.4)，2.75(d，1H，J＝16.5)，2.40-2.33(m，2H)，1.40-1.12(m，8H)，0.86-0.78(m，4H)。
Example 9.42: preparation (±)-outer-1-sec.-propyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate
Steps A: preparation (±)-outer-6-sec.-propyl-dicyclo [3.1.0] oneself-2-alcohol
To prepare title compound to mode similar described in the example 9.2 step B.
1H?NMR(CDCl
3)：δ?4.19(d，1H，J＝4.8)，1.94-1.85(m，2H)，1.65(dd，1H，J
1＝12.5，J
2＝8.2)，1.53(dd，1H，J
1＝14.2，J
2＝8.4)，1.36-1.26(m，1H)，1.22-1.20(m，1H)，1.14-1.12(m，1H)，0.95-0.87(m，7H)，0.37(m，1H)。
Step B: preparation (±)-outer-6-sec.-propyl-dicyclo [3.1.0] oneself-2-ketone
To prepare title compound to mode similar described in the example 9.2 step C.
1H?NMR(CDCl
3)：δ2.07-1.93(m，4H)，1.86-1.84(m，1H)，1.53(d，1H，J＝5.2)，1.05-1.02(m，2H)，0.98(d，3H，J＝5.1)，0.93(d，3H，J＝5.7)。
Step C: preparation (±)-outer-1-sec.-propyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate
To prepare title compound to mode similar described in the example 9.2 step D.MS：m/z(ES+)：235[M+H]
+，189[M-OEt]
+；
1H?NMR(CDCl
3)：δ?4.33(q，2H，J＝5.9)，2.90(dd，1H，J
1＝17.1，J
2＝5.3)，2.77(d，1H，J＝17.1)，1.91-1.89(m，1H)，1.30(t，3H，J＝10.1)，1.24-1.19(m，1H)，1.06-1.03(m，1H)，0.97(d，6H，J＝11.5)，0.45(m，1H)。
Example 9.43: preparation (±)-outer-1-sec.-propyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid
To prepare title compound to mode similar described in the example 9.3.MS:m/z (ES+): 207[M+H]
+, 189[M-OH]
+ 1H NMR (CD
3OD): δ 2.95-2.93 (m, 1H), 2.90 (d, 1H, J=16.7), 2.00 (m, 2H), 1.08-1.03 (m, 7H (comprise d, 6H, J=12.4)), 0.43 (septet, 1H, J=4.1).
Example 9.44: preparation (±)-outer-1-sec.-propyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene
With (±)-outer-6-sec.-propyl-dicyclo [3.1.0] oneself-(0.200g, 1.45mmol) (0.238mg 1.45mmol) is dissolved among the DMF (5mL) 2-ketone, and is cooled to 0 ℃ with 1H-tetrazolium-5-ethyl formate sodium salt.Slowly add uncle's fourth potassium oxide (1.0M in THF, 3.20mL, 3.20mmol), and at 0 ℃ with gained solution stirring 1 hour.Then slowly add hydrochloric acid (3.0N, 1.00mL, 2.90mmol), dropwise add subsequently single hydrazine hydrate (0.080mL, 1.67mmol).Reaction mixture temperature to room temperature and stirring spent the night.Under reduced pressure remove DMF, and reaction mixture is dissolved among the DMSO (5mL), by (±)-outer-1-sec.-propyl-4-(2H-tetrazolium-5-the yl)-1a of HPLC purifying to obtain being the pale solid shape, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene.MS:m/z (ES+): 231[M+H]
+, 203[M-N2+H]
+ 1H NMR (CD
3OD): δ 2.83 (dd, 1H, J
1=14.6, J
2=5.6), 2.65 (d, 1H, J=16.1), 1.95-1.86 (m, 2H), 0.81-0.88 (m, 7H (comprise d, 6H, J=12.9)), 0.31 (septet, 1H, J=3.3).
Example 9.45: preparation (±)-outer-1-isobutyl--1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate
Steps A: preparation (±)-outer-6-sec.-propyl-dicyclo [3.1.0] oneself-2-alcohol
To prepare title compound to mode similar described in the example 9.2 step B.
1H NMR (CDCl
3): δ 4.22 (m, 1H), 1.95-1.80 (m, 1H), 1.72-1.45 (m, 4H), 1.40-1.20 (m, 1H), 1.20-1.16 (m, 1H), 1.15-1.00 (m, 2H), 0.97-0.83 (m, and 6H) 0.37 (septet, 1H).Contain 30% (±) that have an appointment-Nei-6-isobutyl--dicyclo [3.1.0] oneself-2-alcohol.
Step B: preparation (±)-outer-6-isobutyl--dicyclo [3.1.0] oneself-2-ketone
To prepare title compound to mode similar described in the example 9.2 step C.
1H?NMR(CDCl
3)：δ2.13-1.97(m，4H)，1.88-1.82(m，1H)，1.74-1.66(m，1H)，1.55-1.51(d，1H，J＝5.1)，1.32-1.23(m，2H)，1.15-1.07(m，1H)0.95(d，3H，J＝2.5)，0.92(d，3H，J＝2.5)。Contain 30% (±) that have an appointment-Nei-6-isobutyl--dicyclo [3.1.0] oneself-2-ketone.
Step C: preparation (±)-outer-1-isobutyl--1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate
To prepare title compound to mode similar described in the example 9.2 step D.MS：m/z(ES+)：249[M+H]
+，203[M-OEt]
+；
1H?NMR(CDCl
3)：δ?4.30(q，2H，J＝7.1)，2.91(dd，1H，J
1＝17.0，J
2＝6.2)，2.77(d，1H，J＝17.0)，1.98-1.93(m，2H)，1.59-1.49(m，1H)，1.43-1.34(t，3H，J＝6.9)，1.24-1.15(m，1H)，0.85(m，7H)，0.64-0.57(m，1H)。Contain 30% (±) that have an appointment-Nei-1-isobutyl--1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate.
Example 9.46: preparation (±)-outer-1-isobutyl--1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid
To prepare title compound to mode similar described in the example 9.3.MS:m/z (ES+): 221[M+H]
+, 203[M-OH]
+ 1H NMR (CD
3OD): δ 2.95-2.90 (m, 1H), 2.80 (d, 1H, J=16.9), 1.96 (m, 2H), 1.78-1.72 (m, 1H), 1.26-1.23 (m, 2H), 0.98-0.94 (m, 6H), 0.62 (septet, 1H, J=3.3).
Example 9.47: preparation (±)-outer-1-isobutyl--4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene
To prepare title compound to mode similar described in the example 9.44.MS:m/z (ES+): 245[M+H]
+, 217[M-N2+H]
+ 1H NMR (CD
3OD): δ 2.99 (dd, 1H, J
1=16.2, J
2=5.6), 2.91 (d, 1H, J=16.0), 2.10-2.00 (m, 2H), 1.78-1.71 (m, 1H), 1.30-1.23 (m, 2H), 0.96 (m, 6H), 0.73 (septet, 1H, J=3.2).
Example 9.48: preparation (±)-Nei-1-isobutyl--1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid
Non-enantiomer mixture described in the use-case 9.45 step C is to prepare title compound to mode similar described in the example 9.3.MS:m/z (ES+): 221[M+H]
+, 203[M-OH]
+ 1H NMR (CD
3OD): δ 2.94-2.88 (dd, 1H, J=6.7), 2.65 (d, 1H, J=17.5), 2.35-2.24 (m, 2H), 1.63-1.54 (m, 1H), 1.34-1.27 (m, 1H), 1.07-0.98 (m, 1H), 0.90 (d, 3H, J=6.6), 0.84 (d, 3H, J=6.6), 0.66 (septet, 1H, J=3.1).
Example 9.49: preparation (±)-Nei-1-isobutyl--4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene
Non-enantiomer mixture described in the use-case 9.45 step B is to prepare title compound to mode similar described in the example 9.44.MS：m/z(ES+)：245[M+H]
+，217[M-N2+H]
+；
1H?NMR(CD
3OD)：δ2.84(dd，1H，J
1＝16.5，J
2＝6.6)，2.62(d，1H，J＝16.6)，2.38(m，2H)，1.50-1.43(m，1H)，1.22-1.18(m，1H)，1.00-0.94(m，1H)，0.76(d，3H，J＝6.6)，0.70(d，3H，J＝6.6)，0.59-0.52(m，1H)。
Example 9.50: preparation (±)-Nei-1-phenyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diazonium ring third [a] pentalene
Steps A: preparation (Z)-5-phenyl penta-obtusilic acid ethyl ester
At room temperature with bromination 3-ethoxycarbonyl propyl San Yi Ji Phosphonium (5.488g, 12.00mmol), phenyl aldehyde (3.820g, 36.00mmol) and uncle's fourth potassium oxide (4.040g 36.00mmol) is dissolved among the MTBE (300mL) and stirs and spend the night.With water (1 * 100mL) washing reaction mixture and with MTBE (3 * 100mL) aqueous phase extracted.Under reduced pressure from the organic phase that is made up, remove solvent, and by tubing string chromatography (0-10%EtOAc/ normal hexane, silicon-dioxide) purifying gained oily matter, to obtain being (Z)-5-phenyl penta-obtusilic acid ethyl ester of faint yellow oily thing.
1H?NMR(CDCl
3)：δ?7.36-7.31(m，2H)，7.28-7.21(m，3H)，6.47(d，1H，J＝11.6，Ph-CH)，5.63(dt，1H，J
1＝11.6，J
2＝7.2)，4.14(q，2H，J＝7.2)，2.66(dq，2H，J
1＝7.3，J
2＝1.7)，2.43(t，2H，J＝7.6)，1.24(t，3H，J＝7.1)。Contain 33% (E)-5-phenyl, penta-obtusilic acid ethyl ester of having an appointment.
Step B: preparation (Z)-5-phenyl penta-4-olefine aldehydr
At N
2It is following that (1.600g 7.833mmol) is dissolved in the methylene dichloride (100mL) and is cooled to-78 ℃ with (Z)-5-phenyl penta-obtusilic acid ethyl ester.(1M in hexane, 9mL 9.0mmol), and stir reaction mixture 3 hours down at-78 ℃ to add DIBAL.Slowly add methyl alcohol (25mL) and end excessive DIBAL.In the saturated solution (400mL) with gained solution impouring sodium tartrate/potassium.Add hexane (150mL) in addition and at room temperature mixture is stirred and spend the night.Collect organic phase, and under reduced pressure remove solvent.By tubing string chromatography (0-20%EtOAc/ normal hexane, silicon-dioxide) purifying gained oily matter to obtain being (Z)-5-phenyl penta-4-olefine aldehydr of faint yellow oily.
1H?NMR(CDCl
3)：δ9.77(s，1H)，7.36-7.29(m，2H)，7.25-7.21(m，3H)，6.49(d，1H，J＝11.5)，5.62(dt，1H，J
1＝11.6，J
2＝7.2，Ph-CHCH)，2.70-2.62(m，2H)，2.60-2.55(m，2H)。Contain 16% (the E)-5-phenyl penta-4-olefine aldehydr of having an appointment.
Step C: preparation (Z)-2-(4-phenyl fourth-3-thiazolinyl) oxyethane
With (Z)-5-phenyl penta-4-olefine aldehydr (0.475g, 2.97mmol) and methylene bromide (0.626g 3.60mmol) is dissolved among the THF (20mL), and be cooled to-78 ℃, under argon gas, dropwise added through 5 minutes n-Butyl Lithium (1.6M in hexane, 2.0mL, 3.20mmol).Make the gained mixture be slowly to warm to room temperature and stirring is spent the night.With the saturated NH of reaction mixture impouring
4In the Cl aqueous solution (20mL), (2 * 30mL) extract and under reduced pressure remove solvent with MTBE.By (Z)-2-(the 4-phenyl fourth-3-thiazolinyl) oxyethane of tubing string chromatography (0-20%EtOAc/ normal hexane, silicon-dioxide) purifying gained oily matter to obtain being faint yellow oily.
1H?NMR(CDCl
3)：δ?7.32-7.27(m，2H)，7.25-7.19(m，3H)，6.47(d，1H，J＝11.7)，5.68(J
1＝11.6，J
2＝7.3)，2.97-2.93(m，1H)，2.77-2.74(m，1H)，2.55-2.52(m，1H)，2.53-2.48(m，2H)，1.76-1.67(m，2H)。Contain 18% (the E)-2-that has an appointment (4-phenyl fourth-3-thiazolinyl) oxyethane.
Step D: the preparation (±)-Nei-6-phenyl-dicyclo [3.1.0] oneself-2-alcohol
To prepare title compound to mode similar described in the example 9.2 step B.
1H?NMR(CDCl
3)：δ7.31-7.17(m，5H)，4.20(d，1H，J＝5.2)，2.20(t，1H，J＝8.6)，2.13-2.03(m，2H)，1.92-1.79(m，2H)，1.78-1.63(m，2H)，0.51-0.40(m，1H，Ph-CH)。
Step e: the preparation (±)-Nei-6-phenyl-dicyclo [3.1.0] oneself-2-ketone
To prepare title compound to mode similar described in the example 9.2 step C.
1H?NMR(CDCl
3)：δ7.32-7.24(m，5H)，2.80(t，1H，J＝8.6)，2.45-2.36(m，1H)，2.32-2.15(m，2H)，2.08-1.82(m，2H)，0.98-0.86(m，1H，Ph-CH)。
Step F: preparation (±)-Nei-1-phenyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diazonium ring third [a] pentalene
To prepare title compound to mode similar described in the example 9.44.MS：m/z(ES+)：265[M+H]
+，237[M-N2+H]
+；
1H?NMR(CD
3OD)：δ?7.50-6.90(m，5H)，3.05-2.96(dd，1H，J
1＝16.4，J
2＝6.3)，2.84-2.76(m，1H)，2.76-2.67(m，1H)，2.64(t，1H，J＝8.1)，1.40-1.25(m，1H)。
Example 9.51: preparation (±)-outer-1-phenoxymethyl-4-(2H-tetrazolium-5-yl)-1a, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene
Steps A: the tertiary butyl-dimethyl-(5-Oxyranyle-penta-2-alkene oxygen base)-silane
To prepare title compound to mode similar described in example 9.2 steps A.
1H?NMR(400?MHz，CDCl
3)：δ?5.65(1H，dt，J＝15.3，6.2Hz)，5.57(1H，dt，J＝15.3，4.9Hz)，4.11(2H，m)，2.91(1H，m)，2.73(1H，m)，2.46(1H，dd，J＝5.0，2.7Hz)，2.19(2H，m)，1.61(2H，m)，0.89(9H，s)，0.05(6H，s)。
Step B: preparation (±)-outer-6-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-dicyclo [3.1.0] oneself-2-alcohol
Following at-78 ℃ by (17.5g, (2.5M in hexane, 51mL 124mmol) produce LiTMP 124mmol) to add n-Butyl Lithium in the stirred solution in t-BuOMe (400mL) to TMP.Faint yellow LiTMP solution is slowly to warm to 0 ℃.Under 0 ℃ by sleeve pipe to the tertiary butyl-dimethyl-(5-Oxyranyle-penta-2-alkene oxygen base)-(15.0g 62mmol) dropwise adds LiTMP solution in the stirred solution in t-BuOMe (200mL) to silane.At ambient temperature the gained mixture is stirred 18h, and then end with MeOH (20mL).It is 300mL that reaction is concentrated into cumulative volume, and with NH
4Cl (saturated aqueous solution, 3 * 150mL) and salt solution (150mL) washing soln.With organism through MgSO
4Drying is filtered, and concentrates and purifying (gradient: 5%EtOAc 30%EtOAc to the hexane in the hexane) to obtain being the title compound of faint yellow oily on the silica gel tubing string.
1H?NMR(400MHz，CDCl
3)：δ?4.25(1H，d，J＝4.8Hz)，3.49(1H，dd，J＝10.8，6.2Hz)，3.44(1H，dd，J＝10.8，6.4Hz)，1.93(1H，m)，1.72(1H，dd，J＝12.6，8.1Hz)，1.57(1H，dd，J＝14.5，8.4Hz)，1.38-1.24(4H，m)，0.89(9H，s)，0.71(1H，m)，0.04(6H，s)。
Step C: preparation (±)-outer-6-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-dicyclo [3.1.0] oneself-2-ketone
At ambient temperature with TPAP (0.181g, 0.52mmol) be added into (±)-outer-6-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-dicyclo [3.1.0] oneself-2-alcohol (2.5g, 10.3mmol), NMO (2.4g, 20.6mmol) and 4_ MS (3g) in CH
2Cl
2In the stirred solution (50mL).Mixture is stirred 3 h,, incline on the silica gel and with Et by diatomite filtration
2O/CH
2Cl
2(1: 1) elution.Evaporate organic solvent in a vacuum to obtain title compound.
1H?NMR(400?MHz，CDCl
3)：δ?3.69(1H，dd，J＝10.8，4.8Hz)，3.58(1H，dd，J＝10.8，5.3?Hz)，2.15(1H，m)，2.05(4H，m)，1.72(1H，m)，1.51(1H，m)，0.87(9H，s)，0.04(6H，s)。
Step D: preparation (±)-outer-1-methylol-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate
At room temperature, N
2Down, to ketone (2.2g, 9.2mmol) and oxalic acid diethyl ester (1.35g, 9.2mmol) solution of interpolation KOt-Bu in THF in the solution in EtOH (35mL) (10.1mL 1 M solution, 10.1mmol) in.To react and stir 4 h, make an addition to during stirring hydrazine hydrochloride in the water (4mL) (0.756g, 11mmol).At room temperature reaction mixture is stirred 20h, and be acidified to the pH value and be about 3 by adding HCl (the 6N aqueous solution).Remove volatile matter in a vacuum and with EtOAc (50mL) and H
2O (50mL) dilution gained solid.Separate each layer and with the EtOAc strip aqueous.Will through the combination organism with the salt water washing, through MgSO
4Drying is filtered and is concentrated to obtain title compound.Described compound need not to be further purified and is directly used in next reaction.
1H?NMR(400MHz，CDCl
3)：δ?4.23(2H，q，J＝7.1Hz)，3.41(1H，dd，J＝11.4，5.9Hz)，3.28(1H，dd，J＝11.4，6.8Hz)，2.84(1H，dd，J＝16.9，6.2Hz)，2.69(1H，d，J＝16.9Hz)，2.05(2H，m)，1.26(3H，t，J＝7.1Hz)，0.78(1H，m)。HPLC/MS:Alltech
_Prevail C18 tubing string (5 μ, 50 * 4.6mm), gradient: 5%v/v CH in the water (containing 1%v/v TFA)
3CN (containing 1%v/v TFA) 99%v/v CH to the water
3CN, 3.5 ml/min, t
r=1.54 minutes, ESI
+=223.2 (M+H).
Step e: preparation 1-methylol-1a, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-benzoic acid amides
(5.3g 23.9mmol) adds the ammonium hydroxide (28%NH in the water in the solution in the Yu diox (80mL) to ester
3, 400mL).Mixture is placed the heat-resisting bottle of 500mL, and at room temperature shake 22 h on the earthquake dish.In a vacuum mixture being condensed into cumulative volume is 100mL, obviously produces light yellow precipitate this moment.Filtering mixt and with H
2O washs solid.The further drying solid title compound of solid state that obtains being white in color.Described compound need not to be further purified and is directly used in next reaction.
1H?NMR(400?MHz，DMSO-d
6)：δ?7.29(1H，bs)，7.12(1H，s)，4.62(1H，bs)，3.39(1H，dd，J＝11.4，6.0Hz)，3.28(1H，dd，J＝16.4，5.3Hz)，2.82(1H，dd，J＝16.4，5.3Hz)，2.73(1H，d，J＝17.8)，2.03(2H，m)，1.75(1H，s)，0.76(1H，m)。HPLC/MS:Alltech
_Prevail C18 tubing string (5 μ, 50 * 4.6mm), gradient: 5%v/v CH in the water (containing 1%v/v TFA)
3CN (containing 1%v/v TFA) 99%v/v CH to the water
3CN, 3.5 ml/min, t
r=1.49 minutes, ESI
+=194.0 (M+H).
Step F: preparation (±)-outer-2-benzyl-1-methylol-1a, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-benzoic acid amides
Amide moieties is dissolved in the diox (60mL) and add NaOH (the 5 N aqueous solution, 10.0mL, 50.0mmol), then add bromotoluene (4.25 g, 24.9mmol).The mixture clarification that slowly becomes, and at room temperature will react and stir 20h.Make the mixture acidifying become the pH value to be about 2 by adding HCl (the 6 N aqueous solution), and be concentrated into drying in a vacuum.The gained resistates is dissolved among the EtOAc, and with NaHCO
3(saturated aqueous solution, 50mL) and H
2O (50mL) washing.(gradient: 40%EtOAc 75%EtOAc to the hexane in the hexane) resistates is to obtain the benzyl product for purifying on the silica gel tubing string.
1H?NMR(400MHz，CDCl
3)：δ?7.38(3H，m)，7.26(2H，m)，6.64(1H，bs)，5.30(1H，d，J＝15.0Hz)，5.23(1H，d，J＝15.0?Hz)，3.55(1H，m)，3.19(1H，m)，2.96(1H，dd，J＝16.6，6.2Hz)，2.88(1H，d，J＝16.6Hz)，2.07(1H，m)，1.76(1H，m)，1.05(1H，bs)，0.90(1H，m)。HPLC/MS:Alltech
_Prevail C18 tubing string (5 μ, 50 * 4.6 mm), gradient: 5%v/v CH in the water (containing 1%v/v TFA)
3CN (containing 1%v/v TFA) 99%v/v CH to the water
3CN, 3.5 ml/min, t
r=1.81 minutes, ESI
+=284.2 (M+H).
Step G: preparation (±)-outer-2-benzyl-1-chloromethyl-1a, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-eyeball
At N
2The flask that dry DMF (4mL) will be housed under the atmosphere is cooled to 0 ℃, dropwise add thionyl chloride (0.77mL, 10.6mmol).Stir after 5 minutes, dropwise add acid amides (1.0g, 3.5mmol) suspension in DMF (4mL).Mixture is slowly to warm to room temperature and stirs 20h, and add NaHCO
3(saturated aqueous solution 10mL), then adds H
2O (15mL).Mixture was stirred 10 minutes, and be concentrated in a vacuum near dry.With EtOAc (20mL) and H
2O (20mL) dilutes resistates.Separate each layer and with EtOAc (20mL) strip aqueous.Will through the combination organism with NaHCO
3(saturated aqueous solution, 30mL) and salt solution (30mL) washing, through MgSO
4Drying is filtered and is concentrated to obtain being brown buttery title compound.Described compound need not to be further purified and is directly used in next reaction.
1H?NMR(400MHz，CDCl
3)：δ?7.38(3H，m)，7.31(2H，m)，5.30(1H，d，J＝14.8)，5.26(1H，d，J＝14.8Hz)，3.47(1H，dd，J＝11.4，6.6Hz)，3.22(1H，dd，J＝11.4，8.1Hz)，2.89(1H，dd，J＝16.5，6.4Hz)，2.79(1H，d，J＝16.5Hz)，2.20(1H，m)，1.92(1H，m)，1.09(1H，m)。HPLC/MS:Alltech
_Prevail C18 tubing string (5 μ, 50 * 4.6 mm), gradient: 5%v/v CH in the water (containing 1%v/v TFA)
3CN (containing 1%v/v TFA) 99%v/v CH to the water
3CN, 3.5 ml/min, t
r=3.02 minutes, ESI
+=284.4 (M+H).
Step H: preparation (±)-outer-2-benzyl-1-phenoxymethyl-1a, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-eyeball
With nitrile (0.300g, 1.06mmol), phenol (0.141g, 1.5mmol) and K
2CO
3(0.277g 2.0mmol) is dissolved among the DMF (6mL).Sealed reaction vessel and in microwave reactor, be heated to 120 ℃ and last 40 minutes.After being cooled to surrounding temperature, respectively wash once with water, salt solution with the acetic acid ethyl dissolution reaction mixture and with it, through MgSO
4Dry and concentrated in a vacuum.By anti-phase HPLC purifying gained resistates: Phenomenex
_Luna C18 tubing string (10 μ, 250 * 21.2mm), gradient: 5% (v/v) CH in the water (containing 1%v/v TFA)
3CN (containing 1%v/v TFA) 95% (v/v) CH to the water
3CN, 20 ml/min, λ=214nm is with the title compound of the solid state that obtains being white in color after the freeze-drying.HPLC/MS:Alltech
_Prevail C18 tubing string (5 μ, 50 * 4.6mm), gradient: 5%v/v CH in the water (containing 1%v/v TFA)
3CN (containing 1%v/v TFA) 99%v/v CH to the water
3CN, 3.5 ml/min, t
r=3.50 minutes, ESI
+=342.3 (M+H).
Step I: preparation (±)-outer-2-benzyl-1-phenoxymethyl-4-(2H-tetrazolium-5-yl)-1a, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene
With nitrile (0.30g, 0.88mmol), ZnBr
2(0.400g, 1.76mmol) and NaN
3(0.345g 5.31mmol) is dissolved among the DMF (5mL).Sealed reaction vessel and in microwave reactor, be heated to 190 ℃ and last 15 minutes.After being cooled to surrounding temperature, by adding that HCl (the 1 N aqueous solution) makes the reaction mixture acidifying and through anti-phase HPLC purifying: Phenomenex
_Luna C18 tubing string (10 μ, 250 * 21.2mm), gradient: 5% (v/v) CH in the water (containing 1%v/v TFA)
3CN (containing 1%v/v TFA) 95% (v/v) CH to the water
3CN, 20 ml/min, λ=214nm is with the title compound of the solid state that obtains being white in color after the freeze-drying.HPLC/MS:Alltech
_Prevail C18 tubing string (5 μ, 50 * 4.6mm), gradient: 5%v/v CH in the water (containing 1%v/v TFA)
3CN (containing 1%v/v TFA) 99%v/v CH to the water
3CN, 3.5 ml/min, t
r=2.71 minutes, ESI
+=384.9 (M+H).
Step J: preparation (±)-outer-1-phenoxymethyl-4-(2H-tetrazolium-5-yl)-1a, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene
At room temperature, with the air bubbling by through the protection compound (0.150g, 0.39mmol) and KOt-Bu (the 1 M solution of 4.0mL in THF, 4.0mmol) stirred solution in DMSO (4mL) lasts 2h.Remove residue THF in a vacuum, and with EtOAc (20mL) and H
2O (20mL) diluted reaction mixture.Separating layer, and with organic layer with the salt water washing, through MgSO
4Drying concentrates and through anti-phase HPLC purifying: Phenomenex
_Luna C18 tubing string (10 μ, 250 * 21.2mm), gradient: 5% (v/v) CH in the water (containing 1%v/v TFA)
3CN (containing 1%v/v TFA) 95% (v/v) CH to the water
3CN, 20 ml/min, λ=214 nm is with the title compound of the solid state that obtains being white in color after the freeze-drying.
1H?NMR(400MHz，DMSO-d
6)：δ?7.28(2H，m)，6.94(3H，m)，4.06(1H，dd，J＝10.5，6.1Hz)，3.83(1H，dd，J＝10.4，7.9Hz)，2.98(1H，dd，J＝16.3，6.1Hz)，2.88(1H，d，J＝16.6Hz)，2.40(1H，m)，2.34(1H，m)，1.21(1H，m)。HPLC/MS:Alltech
_Prevail C18 tubing string (5 μ, 50 * 4.6mm), gradient: 5%v/v CH in the water (containing 1%v/v TFA)
3CN (containing 1%v/v TFA) 99%v/v CH to the water
3CN, 3.5 ml/min, t
r=2.08 minutes, ESI
+=295.4 (M+H).
Example 9.52: preparation (±)-outer-1-methoxymethyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid
Steps A: preparation (±)-outer-2-benzyl-1-methylol-1a, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate
(1.5g 6.75mmol) is dissolved among the DMF (20mL), and adds K with ester
2CO
3(1.84g, 13.5mmol) then add bromotoluene (1.73g, 10.1mmol).At room temperature will react and stir 20h.With EtOAc diluted mixture thing, and with its Yi Shui and salt water washing, through MgSO
4Dry and be concentrated into drying in a vacuum.(gradient: 40%EtOAc 75%EtOAc to the hexane in the hexane) resistates is with the benzyl product of the solid state that obtains being white in color for purifying on the silica gel tubing string.
1H?NMR(400MHz，CDCl
3)：δ?7.38(3H，m)，7.30(2H，m)，5.42(1H，d，J＝14.9Hz)，5.29(1H，d，J＝14.9Hz)，4.36(2H，q，J＝7.1Hz)，3.14(1H，m)，2.91(1H，dd，J＝16.7，6.3Hz)，2.82(1H，d，J＝16.7Hz)，2.03(1H，m)，1.67(1H，m)，1.37(3H，t，J＝7.1Hz)，0.85(1H，m)。HPLC/MS:Alltech
_Prevail C18 tubing string (5 μ, 50 * 4.6mm), gradient: 5%v/v CH in the water (containing 1%v/v TFA)
3CN (containing 1%v/v TFA) 99%v/v CH to the water
3CN, 3.5 ml/min, t
r=2.11 minutes, ESI
+=313.2 (M+H).
Step B: preparation (±)-outer-2-benzyl-1-methoxymethyl-1a, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate
Under 0 ℃, N2 to alcohol (0.350g, 1.1mmol) add in the solution in DMF (5mL) NaH (60% dispersion liquid, 0.088g, 2.2mmol).Mixture stirred 10 minutes and add MeI (0.239g, 1.7mmol).At ambient temperature reaction mixture is stirred 20h, and end with water.(2 * 10mL) extract mixtures, and the organic layer that is made up is washed with water (10mL), through MgSO with EtOAc
4Dry and concentrated in a vacuum.Purifying resistates on the silica gel tubing string, with hexane: EtOAc (6: 4) elution to obtain title compound.HPLC/MS:Alltech
_PrevailC18 tubing string (5 μ, 50 * 4.6mm), gradient: 5%v/v CH in the water (containing 1%v/v TFA)
3CN (containing 1%v/v TFA) 99%v/v CH to the water
3CN, 3.5 ml/min, t
r=2.65 minutes, ESI
+=327.4 (M+H).
Step C: preparation (±)-outer-1-methoxymethyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid
At room temperature, with the air bubbling by ester (0.075g, 0.23mmol) and KOt-Bu (the 1 M solution of 2.3mL in THF, 2.3mmol) stirred solution in DMSO (2.5mL) lasts 1h.Remove residue THF in a vacuum, and make the reaction acidifying, and make its purifying: Phenomenex by anti-phase HPLC by adding HCl (the 3 M aqueous solution)
_Luna C18 tubing string (10 μ, 250 * 21.2mm), gradient: 5% (v/v) CH in the water (containing 1%v/v TFA)
3CN (containing 1%v/v TFA) 95% (v/v) CH to the water
3CN, 20 ml/min, λ=214nm is with the title compound of the solid state that obtains being white in color after the freeze-drying.
1H?NMR(400MHz，DMSO-d
6)：δ13.0(1H，bs)，3.31(1H，dd，J＝16.7，6.4Hz)，3.24(3H，s)，3.22(1H，dd，J＝10.5，7.2?Hz)，2.84(1H，dd，J＝16.9，6.2?Hz)，2.69(1H，d，J＝14.8Hz)，2.09(1H，m)，2.04(1H，m)，0.84(1H，m)。HPLC/MS:Alltech
_Prevail C18 tubing string (5 μ, 50 * 4.6mm), gradient: 5%v/v CH in the water (containing 1%v/v TFA)
3CN (containing 1%v/v TFA) 99%v/v CH to the water
3CN, 3.5 ml/min, t
r=1.36 minutes, ESI
+=208.9 (M+H).
Example 9.53: preparation (1aR, 5aR)-(+)-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene
Program: ketone is dissolved among the DMF; Then in solution, add tetrazolium; Gained suspension is cooled to 0 ℃; In mixture, slowly make an addition to the uncle's fourth potassium oxide solution among the DMF, keep temperature to be lower than 10 ℃; Under 0 ℃, mixture was stirred 1 hour; Then slowly add 2N HCl solution, dropwise add hydrazine hydrate (64% hydrazine) subsequently; Make the reaction mixture temperature to ambient temperature overnight.
Handle: remove DMF, and with water resistates is divided molten, with EtOAc extraction (7 times); With organism through MgSO
4Drying is filtered, and concentrates in a vacuum; Purifying (25%CH on the anti-phase tubing string
3CN+0.1%TFA, 75% water+0.1%TFA, wavelength=265nm) (operation in 10 minutes) crude product; On SFC, separate (AS (21 * 250mm), 30%MeOH+0.1%TFA) isomer; Repurity (25%CH on the anti-phase tubing string
3CN+0.1%TFA, 75% water+0.1%TFA, wavelength=265nm) (operated in 10 minutes) to eliminate yellow; White solid is dissolved in the hot water, and makes its crystallization to obtain pure white/clear crystal.
Example 9.54: preparation (+)-Nei-1-methyl isophthalic acid a, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid and outer-1-methyl isophthalic acid a, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid
Steps A: preparation (R)-5-(chloromethyl) tetrahydrofuran (THF)-2-alcohol
At-78 ℃, N
2Down, through 15 fens clockwise (R)-5-(chloromethyl) dihydrofuran-2 (3H)-ketone (6.69g, 49.7mmol, for preparation referring to Movassaghi, M.; Jacobsen, E.N.J.Am.Chem.Soc.2002,124,245) add in the solution in DCM (150mL) diisobutylaluminium hydride (1M DCM, 62.1ml, 62.1mmol).Under-78 ℃ mixture was stirred 30 minutes, add MeOH (about 10mL) and remove mixture this moment under the state of cooling.Add Rochelle salt (Rochelle salt) (150mL saturated aqueous solution) and when mixture is stirred 1h with its temperature to room temperature.Remove organic phase and with EtOAc aqueous phase extracted (2 times).Will through the combination organism through MgSO
4Drying is filtered and is concentrated to obtain being clarification buttery (R)-5-(chloromethyl) tetrahydrofuran (THF)-2-alcohol (6.65g, 48.7mmol, 98% productive rate), and it is the mixture of epimer (1.25: 1).H NMR (400MHz, CDCl
3): main epimer: δ 5.62 (1H, m), 4.48 (1H, dq, J=7.6,5.6Hz), 3.67 (1H, dd, J=10.8,5.6Hz), 3.61 (1H, dd, J=11.2,6.0Hz), 2.65 (1H, m), 2.24 (1H, dq, J=12.4,8.0Hz), 2.10-1.72 (3H, m).Less important epimer: δ 5.30 (1H, m), 4.29 (1H, m), 3.53 (2H, m), 2.65 (1H, m), 2.10-1.72 (4H, m).
Step B: prepare suitable/anti--(R)-2-(penta-3-thiazolinyl)-oxyethane
Under 0 ℃, to bromination Yi base triphenyl phosphonium (5.57g, 15.0mmol) add in the suspension in THF (15mL) two (TMS) acid amides lithiums of 1 M among the THF (15.0ml, 15.0mmol).With solution stirring 0.5h, this moment is at 0 ℃ of interpolation (R)-5-(chloromethyl) tetrahydrofuran (THF)-2-alcohol (1.00g, 7.32mmol) solution in THF (15mL).Gained solution temperature to room temperature and stirring spent the night.With H
2O ends mixture, and with it with Et
2O extracts (2 times), through MgSO
4Drying is filtered and is concentrated.By silica gel chromatography (gradient: 1%Et in the pentane
2O 5%Et to the pentane
2O) purified mixture is to obtain being clarification buttery (R)-2-(penta-3-thiazolinyl)-oxyethane, and it is the inseparable mixture of olefin isomer (suitable: anti-=2.3: 1).
1H NMR (400MHz, CDCl
3): δ 5.55-5.26 (2H, m), 2.93 (1H, m), 2.76 (1H, m), 2.49 (from cis-isomeride, 0.7H, dd, J=6.0,2.8Hz), 2.48 (from trans-isomer(ide), 0.3H, dd, J=6.0,2.8Hz), 2.21 (from cis-isomeride, 1.4H, q, J=7.6Hz), 2.14 (from trans-isomer(ide), 0.6H, m), and 1.67-1.56 (5H, m).
Step C: the preparation (1S, 2S, 5R, 6S)-6-methyl bicycle [3.1.0] oneself-2-pure and mild (1S, 2S, 5R, 6R)-6-methyl bicycle [3.1.0] oneself-2-alcohol
Carry out (R)-2-(penta-3-thiazolinyl) oxyethane (980mg as mentioned described in example 9.1 steps A, 8.74mmol) intramolecular cyclopropane, to obtain the being (1S of inseparable mixture behind the silica gel column chromatography, 2S, 5R, 6S)-6-methyl bicycle [3.1.0] oneself-2-pure and mild (1S, 2S, 5R, 6R)-6-methyl bicycle [3.1.0] oneself-2-alcohol.
(1S, 2S, 5R, 6S)-6-methyl bicycle [3.1.0] oneself-2-alcohol:
1H?NMR(400MHz，CDCl
3)：δ?4.15(1H，d，J＝4.8Hz)，2.08(1H，m)，1.75-1.25(5H，m)，0.90(5H，m)。
(1S, 2S, 5R, 6S)-6-methyl bicycle [3.1.0] oneself-2-alcohol:
1H?NMR(400MHz，CDCl
3)：δ?4.21(1H，d，J＝4.8?Hz)，1.88(1H，m)，1.75-1.25(4H，m)，1.15(1H，m)，1.07(1H，m)，0.96(3H，d，J＝6.0?Hz)，0.41(1H，m)。
Step D: the preparation (1S, 5R)-6-methyl bicycle [3.1.0] oneself-2-ketone
Carry out described in the example 9.1 step B as mentioned (1S, 2S, 5R, 6S)-6-methyl bicycle [3.1.0] oneself-2-alcohol/(1S, 2S, 5R, 6R)-6-methyl bicycle [3.1.0] oneself-2-alcohol (658mg, 5.87mmol) oxidation, with obtain (1S, 5R)-6-methyl bicycle [3.1.0] oneself-2-ketone.Spectroscopic data and (±)-(1S, 5R)-6-methyl bicycle [3.1.0] oneself-spectroscopic data of 2-ketone (as mentioned) is identical.
Step e: preparation (1R, 1aR, 5aS)-and 1-methyl isophthalic acid a, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate and (1S, 1aR, 5aS)-1-methyl isophthalic acid a, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate
As mentioned among the example 9.1 step C (for racemic modification) described carry out mapping pure in-preparation of methylpyrazole derivatives and outer-methylpyrazole derivatives.Carry out the separation of isomer: Phenomenex by anti-phase HPLC
_LunaC18 tubing string (10 μ, 250 * 100mm), gradient: 5% (v/v) CH in the water (containing 1%v/v TFA)
3CN (containing 1%v/v TFA) 50% (v/v) CH to the water
3CN, 60 ml/min, λ=254nm to obtain interior-methylpyrazole, then obtains outer-methylpyrazole.
Step F: preparation (1R, 1aR, 5aS)-and 1-methyl isophthalic acid a, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid
Show in the example 9.3 as mentioned and carry out the ester hydrolysis, to obtain respective acids [α]
25 D+ 67.6 (c 0.524, MeOH).Spectroscopic data is identical with the racemize material.
Step G: preparation (1S, 1aR, 5aS)-and methyl isophthalic acid a, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid
Show in the example 9.3 as mentioned and carry out the ester hydrolysis, to obtain respective acids.Spectroscopic data is identical with the racemize material.
Example 9.55: preparation (-)-Nei-1-methyl isophthalic acid a, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid and outer-1-methyl isophthalic acid a, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid
Use (S)-5-(chloromethyl) dihydrofuran-2 (3H)-ketone as initial lactone (for preparation referring to Movassaghi, M.; Jacobsen, E.N.J.Am.Chem.Soc.2002,124,245) by the identical route of synthesis described in the example 9.3 above above compound is become pure enantiomer.The spin data of interior-methyl compound: [α]
25 D-93.0 (c0.552, MeOH).
Example 9.56: in the preparation-1-ethyl-1a, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid and outer-1-ethyl-1a, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid
Steps A: preparation (R)-4-(oneself-the 3-alkynyl)-2,2-dimethyl-1,3-dioxolane
At N
2Down in being cooled to-78 ℃ flask, add the 2-butyne gas 3mL condenses of in flask, having an appointment by injection needles.Then add THF (120mL), add subsequently DMPU (18.9ml, 156mmol).With N
2Purify flask and added n-Butyl Lithium (2.5 M hexanes through 5 minutes by syringe, 18.7ml, 46.9mmol) and restir 15 minutes, add (R)-4-(2-iodine ethyl)-2,2-dimethyl-1 this moment, 3-dioxolane (10.0g, 39.1mmol) solution in THF (30mL) is [by commercially available (R)-2-(2,2-dimethyl-1,3-dioxolane-4-yl) pure (R)-4-of ethanol preparation mapping (2-iodine ethyl)-2,2-dimethyl-1, the 3-dioxolane is to use Taber.D.F.; Xu, M.; Hartnett, J.C.J.Am.Chem.Soc.2002,124,13121 described programs are carried out].Sluggish temperature to room temperature and stirring amounted to 3 hours.With saturated NH
4Cl ends mixture, and with it with Et
2O extracts (2 times).With organism Yi Shui and salt water washing, through MgSO
4Drying is filtered and is concentrated.(gradient: 5%EtOAc 15%EtOAc to the hexane in the hexane) purifying substance is to obtain being clarification buttery (R)-4-(oneself-3-alkynyl)-2,2-dimethyl-1,3-dioxolane by silica gel chromatography.
1H?NMR(400MHz，CDCl
3)：δ?4.19(1H，m)，4.08(1H，dd，J＝8.0，6.0Hz)，3.58(1H，dd，J＝7.6，6.8Hz)，2.26(2H，m)，2.15(2H，qt，J＝5.2，2.4?Hz)，1.81(1H，m)，1.68(1H，m)，1.40(3H，s)，1.36(3H，s)，1.11(3H，t，J＝7.6Hz)。
Step B: preparation (R, Z)-4-(oneself-the 3-thiazolinyl)-2,2-dimethyl-1,3-dioxolane
To (R)-4-(own-the 3-alkynyl)-2,2-dimethyl-1, (6.49g 35.6mmol) adds 5% palladium/BaSO to the 3-dioxolane in the solution in hexane (100mL)
4(1.14g) and quinoline (newly distill by Zn dirt, 0.631ml, 5.34mmol).Then with H
2Purify flask, and at H
2Stir 2 h under the atmosphere.By the diatomite filtration reaction mixture, and in succession with 1 NHCl (2 times) and salt water washing.With organism through MgSO
4Drying, filter and concentrate with obtain (R, Z)-4-(oneself-3-thiazolinyl)-2,2-dimethyl-1, the 3-dioxolane, it uses under the situation that need not to be further purified.This material contains the 7% trans olefins isomer of having an appointment, and it enters route of synthesis as mixture (data not shown of less important isomer), after separating, finally obtain by anti-phase HPLC corresponding outside-ethyl pyrazoles acid derivative (seeing below).
1H?NMR(400MHz，CDCl
3)：δ?5.40(1H，m)，5.31(1H，m)，4.06(2H，m)，3.52(1H，t，J＝4.8Hz)，2.09(4H，m)，1.71(1H，m)，1.54(1H，m)，1.41(3H，s)，1.35(3H，s)，0.96(3H，t，J＝Hz)。
Step C: preparation (R, Z)-Xin-5-alkene-1, the 2-glycol
In the 80%AcOH aqueous solution (50 mL), incite somebody to action (R, Z)-4-(oneself-the 3-thiazolinyl)-2,2-dimethyl-1, (5.95g 32.3mmol) stirs 20h to the 3-dioxolane.In a vacuum enriched mixture and by silica gel chromatography (gradient: purifying 40%EtOAc 70%EtOAc to the hexane in the hexane), with obtain being the clarification buttery (R, Z)-Xin-5-alkene-1, the 2-glycol.
1H?NMR(400MHz，CDCl
3)：δ5.45(1H，m)，5.36(1H，m)，3.75(1H，m)，3.67(1H，dd，J＝10.8，2.8Hz)，3.45(1H，dd，J＝11.2，7.6Hz)，2.16(2H，m)，2.04(2H，m)，1.50(2H，m)，0.96(3H，t，J＝7.6Hz)。
Step D: preparation (R, Z)-2-(oneself-the 3-thiazolinyl) oxyethane
Under 0 ℃ to (R, Z)-Xin-5-alkene-1, (8.50g 58.9mmol) adds NaH (60% dispersion liquid in mineral oil, 7.06g, 177mmol) (7.06g dispersion liquid) to the 2-glycol in the solution in THF (230mL).With the mixture temperature to surrounding temperature and stirred 40 minutes.Reaction is cooled to 0 ℃, and the interpolation triisopropylphenylsulfonyl chloride (20.7g, 61.8mmol).Reaction temperature to room temperature, is stirred 1 h, with H
2O ends and with Et
2The O extraction.With organism with the salt water washing, through MgSO
4Drying is filtered and is concentrated.By silica gel chromatography (gradient: 2%Et in the pentane
2O 8%Et to the pentane
2O) purifying, obtain (R, Z)-2-(oneself-the 3-thiazolinyl) oxyethane.Slight racemize (98%ee to 84%ee) appears in this step after measured.For guaranteeing optical purity, use Jacobsen hydrolytic kinetic resolution (HKR, step e) further to split the product that is rich in enantiomer.
1H NMR (400MHz, CDCl
3): δ 5.41 (1H, m), 5.35 (1H, m), 2.93 (1H, m), 2.75 (1H, dd, J=5.2,4.4Hz), 2.49 (1H, dd, J=5.2,2.8Hz), 2.20 (2H, q, J=6.8Hz), 2.06 (2H, quintet, 7.6Hz), 1.59 (2H, m), 0.97 (3H, t, J=7.6Hz).
Step e: preparation (R, Z)-2-(oneself-the 3-thiazolinyl) oxyethane
Under 0 ℃ to containing (the R that is rich in enantiomer, Z)-2-(oneself-the 3-thiazolinyl) oxyethane (5.04g, 39.9mmol) and in the flask of THF (0.4mL) add in succession (R, R)-Co-Salen catalyzer (50mg, 0.248mmol), AcOH (60.0mg, 1.00mmol) and H
2O (130mg, 7.22mmol).With the mixture temperature to room temperature and stir 20h.By silica gel chromatography (gradient: 2%Et in the pentane
2O 10%Et to the pentane
2O) purifying, obtain mapping pure (R, Z)-2-(oneself-3-thiazolinyl) oxyethane.
Step F: the preparation (1S, 2S, 5R, 6S)-6-ethyl dicyclo [3.1.0] oneself-2-alcohol
Carry out described in example 9.1 steps A as mentioned (R, Z)-2-(oneself-3-thiazolinyl) oxyethane (3.00g, intramolecular cyclopropane 23.8mmol), with obtain being the clarification buttery (1S, 2S, 5R, 6S)-6-ethyl dicyclo [3.1.0] oneself-2-alcohol.
1HNMR(400?MHz，CDCl
3)：δ?4.18(1H，m)，2.08(1H，m)，1.79-1.51(4H，m)，1.40(2H，m)，1.20(2H，m)，0.96(3H，t，J＝7.6?Hz)，0.74(1H，m)。
Step G: the preparation (1S, 5R, 6S)-6-ethyl dicyclo [3.1.0] oneself-2-ketone
Carry out described in the example 9.1 step B as mentioned (1S, 2S, 5R, 6S)-6-ethyl dicyclo [3.1.0] oneself-oxidation of 2-alcohol (1.75g, 13.9 mmol), with obtain being the clarification buttery (1S, 5R, 6S)-6-ethyl dicyclo [3.1.0] oneself-2-ketone.Spectroscopic data and (±)-(1S, 5R, 6S)-6-ethyl dicyclo [3.1.0] oneself-spectroscopic data of 2-ketone is identical.
Step H: preparation (1R, 1aR, 5aS)-and 1-ethyl-1a, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid
With to the racemize of example 9.54 step e and F in-the similar mode of ethyl pyrazole compound from corresponding ketone carry out mapping pure in-preparation of ethyl pyrazole derivatives.Spectroscopic data is identical.
Step I: preparation (1S, 1aR, 5aS)-and 1-ethyl-1a, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid
By anti-phase HPLC separate as from the mapping of the minor impurity of above route of synthesis pure outer-the ethyl pyrazole derivatives.
Example 9.57: preparation (±)-Nei-1-methyl sulfenyl methyl isophthalic acid a, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid
Steps A: preparation (±)-Nei-spiral shell [dicyclo [3.1.0] hexane-2,2 '-[1,3] dioxolane]-6-ylmethyl methane sulfonate
At N
2Down, to (±)-Nei-spiral shell [dicyclo [3.1.0] hexane-2,2 '-[1,3] dioxolane]-(350 mg 2.06mmol) add Et in the solution in DCM (12 mL) to 6-base methyl alcohol
3N (561 μ l, 4.11mmol).Flask is cooled to 0 ℃, and dropwise add methane sulfonyl chloride (318 μ l, 4.11mmol).Stir after 5 minutes, with the flask temperature to room temperature and stir 1 h (through the TLC assaying reaction near finishing).Evaporation DCM, and with H
2O ends mixture.With mixture with EtOAc extraction (2 times), and with the extract that made up through MgSO
4Drying, filter and concentrate with obtain (±)-(1R, 5R, 6S)-spiral shell [dicyclo [3.1.0] hexane-2,2 '-[1,3] dioxolane]-6-ylmethyl methane sulfonate.
1H?NMR(400MHz，CDCl
3)：δ4.63(1H，dd，J＝11.2，6.3Hz)，4.34(1H，dd，J＝11.2，9.3Hz)，4.01-3.85(4H，m)，3.04(3H，s)，2.11(2H，m)，1.89(1H，m)，1.78(1H，m)，1.70(1H，m)，1.63(1H，m)，1.35(1H，m)。Described material need not to be further purified and is directly used in next reaction.
Step B: preparation (±)-Nei-6-(methyl sulfenyl methyl) spiral shell [dicyclo [3.1.0] hexane-2,2 '-[1,3] dioxolane]
To thick (±)-Nei-spiral shell [dicyclo [3.1.0] hexane-2,2 '-[1,3] dioxolane]-6-ylmethyl methane sulfonate (250mg, 1.01mmol) add in the solution in DMF (5.0mL) the sulfo-sodium methylate (176mg, 2.52mmol).Solution becomes gets very thickness when initial, at room temperature stirs and spends the night.Make mixture in EtOAc and H
2Divide molten between the O.Separate each layer and with the EtOAc strip aqueous.Will through the combination organism through MgSO
4Drying is filtered and is concentrated.(gradient: purifying 3%EtOAc 12%EtOAc to the hexane in the hexane) obtains being clarification buttery (±)-Nei-6-(methyl thiomethyl) spiral shell-[dicyclo [3.1.0] hexane-2,2 '-[1,3] dioxolane] by silica gel chromatography.
1H?NMR(400MHz，CDCl
3)：δ3.99-3.87(4H，m)，2.87(1H，dd，J＝13.5，5.4?Hz)，2.54(1H，dd，J＝13.4，8.8?Hz)，2.19(3H，s)，2.14-1.96(2H，m)，1.80(1H，m)，1.68-1.53(3H，m)，1.18(1H，qd，J＝8.6，5.4Hz)。
Step C:(±)-Nei-6-(methyl sulfenyl methyl)-dicyclo [3.1.0] oneself-2-ketone
To (±)-Nei-6-(methyl thiomethyl) spiral shell-[dicyclo [3.1.0] hexane-2,2 '-[1,3] dioxolane] (190mg, 0.949mmol) in acetone (4: 1,5mL) add tosic acid monohydrate (9.02mg, 47.4 μ mol) in the solution in.At room temperature stir 2h.Concentrate to remove acetone in a vacuum.With w/EtOAc extraction (2 times) and with salt water washing organism.Through MgSO
4Drying, filter and concentrate with obtain being clarification buttery (±)-Nei-6-methyl sulfenyl methyl-dicyclo [3.1.0] oneself-2-ketone.
1H?NMR(400MHz，CDCl
3)：δ?2.63(1H，dd，J＝13.6，6.5Hz)，2.53(1H，dd，J＝13.6?8.6Hz)，2.32(2H，m)，2.24(1H，m)，2.17(3H，s)，1.99(3H，m)，1.75(1H，m)。
Step D: preparation (±)-Nei-1-(methyl sulfenyl methyl)-1a, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate
As mentioned described in the example 9.1 step C with (±)-Nei-6-(methyl thiomethyl) dicyclo [3.1.0] oneself-2-ketone (52.0mg, 0.333mmol) change into corresponding in-1-methyl sulfenyl methyl isophthalic acid a, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate.
1H?NMR(400?MHz，CDCl
3)：δ?11.2-9.4(1H，bs)，4.34(2H，m)，2.96(1H，dd，J＝17.7，6.8Hz)，2.75(1H，d，J＝17.7Hz)，2.50(1H，m)，2.32(1H，m)，2.15(2H，m)，2.08(3H，s)，1.57(1H，m)，1.37(3H，t，J＝7.1Hz)。HPLC/MS:Alltech
_Prevail C18 tubing string (5 μ, 50 * 4.6mm), gradient: 5%v/v CH in the water (containing 1%v/v TFA)
3CN (containing 1%v/v TFA) 99%v/v CH to the water
3CN, 3.5 ml/min, t
r=2.29 minutes, ESI
+=253.3 (M+H).
Step e: preparation (±)-Nei-1-(methyl thiomethyl)-1a, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid
In carrying out described in the example 9.3 as mentioned-1-(methyl thiomethyl)-1a, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate (34.0mg, 0.135mmol) the ester hydrolysis, with interior-1-(methyl the thiomethyl)-1a of the solid state that obtains being white in color after the freeze-drying, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid.
1H?NMR(400MHz，d
6-DMSO)：δ?13.6-12.1(1H，bs)，2.82(1H，dd，J＝17.4，6.8Hz)，2.57(1H，d，J＝17.4Hz)，2.40(1H，m)，2.23(1H，m)，2.08(1H，dd，J＝13.4，7.1Hz)，1.99(4H，m)，1.48(1H，m)。HPLC/MS:Alltech
_Prevail C18 tubing string (5 μ, 50 * 4.6mm), gradient: 5%v/v CH in the water (containing 1%v/vTFA)
3CN (containing 1%v/v TFA) 99%v/v CH to the water
3CN, 3.5 ml/min, t
r=1.59 minutes, ESI
+=225.3 (M+H).
Example 9.58: preparation (±)-outer-1-ethoxyl methyl-1a, 2,5,5a-tetrahydrochysene-1H-2, in 3-diaza-ring third [a] pentalene-4-formic acid and (±)-ethoxyl methyl-1a, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid
Steps A: prepare genial anti-(±)-2-(5-oxyethyl group-penta-3-thiazolinyl)-oxyethane
Carry out (±)-2-(fourth-3-thiazolinyl) oxyethane (3.80g as mentioned described in example 9.2 steps A, 38.7mmol) and ethyl allyl ether (10.0g, intersection metathesis 16mmol) is inseparable mixture (±)-2-(5-oxyethyl group-penta-3-thiazolinyl)-oxyethane of olefin isomer (anti-: suitable=10: 1) to obtain behind the silica gel column chromatography.
1H NMR (400 MHz, CDCl
3): trans-isomer(ide): δ 5.73 (1H, m), 5.63 (1H, m), 3.91 (2H, m), 3.48 (2H, q, J=7.0Hz), 2.93 (1H, m), 2.75 (1H, m), 2.48 (1H, dd, J=5.0,2.7Hz), 2.22 (2H, m), 1.63 (2H, m), 1.21 (3H, t, J=7.0Hz).Cis-isomeride: δ 5.62 (2H, m), 4.04 (2H, m), 3.48 (2H, q, J=7.0Hz), 2.93 (1H, m), 2.75 (1H, m), 2.49 (1H, m), 2.22 (2H, m), 1.63 (2H, m), 1.22 (3H, t, J=7.0Hz).
Step B: preparation (±)-outer-6-(ethoxyl methyl) dicyclo [3.1.0] oneself-2-pure and mild (±)-Nei-6-(ethoxyl methyl) dicyclo [3.1.0] oneself-2-alcohol
Carry out (±)-2-(5-oxyethyl group penta-3-thiazolinyl) oxyethane (3.34g as mentioned described in example 9.1 steps A, 23.6mmol) intramolecular cyclopropane, with obtain being clarification buttery (±)-outer-6-(ethoxyl methyl)-dicyclo [3.1.0] oneself-2-alcohol/(±)-Nei-6-(ethoxyl methyl) dicyclo [3.1.0] oneself-2-alcohol (relative ratios 10: 1).
1H?NMR(400MHz，CDCl
3)：δ4.29(1H，m)，3.47(2H，q，J＝7.1?Hz)，3.24(2H，m)，1.94(1H，m)，1.75(1H，dd，J＝12.6，8.1?Hz)，1.56(1H，m)，1.40-1.28(4H，m)，1.20(3H，t，J＝7.1?Hz)，0.78(1H，m)。
Step C: preparation (±)-outer-6-(ethoxyl methyl) dicyclo [3.1.0] oneself-2-ketone
Carry out described in the example 9.1 step B as mentioned (±)-Nei-6-(ethoxyl methyl) dicyclo [3.1.0] oneself-2-alcohol/(±)-outer-6-(ethoxyl methyl) dicyclo [3.1.0] oneself-2-alcohol (290mg, 1.86mmol) oxidation, with obtain being clarification buttery (±)-6-(ethoxyl methyl) dicyclo [3.1.0] oneself-2-ketone (exo isomer).
1H?NMR(400MHz，CDCl
3)：δ?3.46(3H，m)，(1H，dd，J＝10.4，6.7Hz)，2.19-2.01(5H，m)，1.70(1H，dd，J＝5.2，2.6Hz)，1.59(1H，m)，1.20(3H，t，J＝7.0Hz)。
Step D: preparation (±)-outer-1-ethoxyl methyl-1a, 2,5,5a-tetrahydrochysene-1H-2, in 3-diaza-ring third [a] pentalene-4-formic acid and (±)-ethoxyl methyl-1a, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid
Carry out described in the example 9.56 step H as mentioned (±)-outer-preparation of ethoxyl methyl pyrazoles/(±)-Nei-ethoxyl methyl pyrazoles acid derivative.Carry out the separation of isomer: Phenomenex by anti-phase HPLC
_Luna C18 tubing string (10 μ, 250 * 50mm), gradient: 5% (v/v) CH in the water (containing 1%v/v TFA)
3CN (containing 1%v/v TFA) 50% (v/v) CH to the water
3CN, 60 ml/min, λ=254nm, to obtain interior-methylpyrazole, then outer-methylpyrazole obtains white solid after the freeze-drying.
(±)-outer-1-ethoxyl methyl-1a, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid:
1H?NMR(400MHz，CDCl
3)：δ?13.50-12.03(1H，bs)，3.42(2H，q，J＝7.0?Hz)，3.35(1H，dd，J＝10.5，6.2)，3.23(1H，dd，J＝10.5，7.3Hz)，2.84(1H，dd，J＝16.9，6.2Hz)，2.69(1H，d，J＝17.0Hz)，2.09(1H，m)，2.03(1H，m)，1.11(3H，t，J＝7.0Hz)，0.83(1H，m)。HPLC/MS:Alltech_Prevail C18 tubing string (5 μ, 50 * 4.6mm), gradient: 5%v/v CH in the water (containing 1%v/v TFA)
3CN (containing 1%v/v TFA) 99%v/v CH to the water
3CN, 3.5 ml/min, t
r=1.56 minutes, ESI
+=223.2 (M+H).
(±)-Nei-1-ethoxyl methyl-1a, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid
1H?NMR(400MHz，CDCl
3)：δ?3.30-3.15(2H，m)，3.01(1H，dd，J＝10.7，6.8Hz)，2.91(1H，dd，J＝10.7，7.6Hz)，2.80(1H，dd，J＝17.3，6.8Hz)，2.57(1H，d，J＝17.3Hz)，2.35(1H，m)，2.24(1H，m)，1.451＝(1H，m)，1.10(1H，m)，1.00(3H，t，J＝7.0Hz)。HPLC/MS:Alltech_Prevail C18 tubing string (5 μ, 50 * 4.6mm), gradient: 5%v/v CH in the water (containing 1%v/v TFA)
3CN (containing 1%v/v TFA) 99%v/v CH to the water
3CN, 3.5 ml/min, t
r=1.42 minutes, ESI
+=223.2 (M+H).
Example 9.59: preparation (±)-Nei-1-cyclopropyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate
To prepare title compound to mode similar described in the example 9.2 step D.
MSm/z(ES
+)：233.4[M+H]
+，255.4[M+Na]
+；
1H?NMR(400MHz，CDCl
3)：δ4.37-4.31(m，2H)，2.98(dd，1H，J
1＝17.4Hz，J
2＝6.4Hz)，2.88(d，1H，J＝17.4Hz)，2.37-2.34(m，1H)，2.24-2.18(m，1H)，1.37(t，3H，J＝7.2Hz)，0.74(q，1H，J＝8.4Hz)，0.49-0.43(m，1H)，0.32-0.25(m，1H)，0.24-0.17(m，2H)，-0.02--0.12(m，1H)。
Example 9.60: preparation (±)-Nei-1-cyclopropyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid
To prepare title compound to mode similar described in the example 9.3.
MSm/z(ES
+)：205.3[M+H]
+；
1H?NMR(400MHz，CDCl
3)：δ3.06(dd，1H，J
1＝18.9Hz，J
2＝5.9Hz)，2.99(d，1H，J＝18.7Hz)，2.43(t，1H，J＝8.2Hz)，2.05(q，1H，J＝6.1Hz)，0.85(q，1H，J＝8.3Hz)，0.55-0.50(m，1H)，0.41-0.36(m，1H)，0.29-0.21(m，2H)，0.08-0.00(m，1H)。
Example 9.61: preparation (±)-Nei-1-cyclopropyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene
Steps A: preparation (±)-Nei-1-cyclopropyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-benzoic acid amides
To prepare title compound to mode similar described in the example 9.1 step D.MS?m/z?(ES
+)：204.5[M+H]
+，226.4[M+Na]
+；
1H?NMR(400MHz，CD
3OD)：δ2.99(dd，1H，J
1＝16.7Hz，J
2＝5.9Hz)，2.93(d，1H，J＝16.6Hz)，2.37-2.29(m，2H)，0.80(q，1H，J＝8.2?Hz)，0.54-0.48(m，1H)，0.33-0.25(m，2H)，0.22-0.18(m，1H)，0.01-0.05(m，1H)。
Step B: preparation (±)-Nei-1-cyclopropyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-nitrile
To prepare title compound to mode similar described in example 9.2 step F.MS?m/z(ES
+)：186.1[M+H]
+，371.2[2M+H]
+；
1H?NMR(400MHz，CD
3OD)：δ2.96(dd，1H，J
1＝16.5Hz，J
2＝6.2Hz)，2.86(d，1H，J＝16.4Hz)，2.41-2.35(m，2H)，0.87(q，1H，J＝8.2Hz)，0.57-0.52(m，1H)，0.34-0.27(m，2H)，0.22-0.18(m，1H)，-0.02--0.11(m，1H)。
Step C: preparation (±)-Nei-1-cyclopropyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene
To prepare title compound to mode similar described in the example 9.2 step G.MSm/z(ES
+)：229.3[M+H]
+，251.2[M+Na]
+；
1H?NMR(400MHz，CD
3OD)：δ2.99(dd，2H，J
1＝16.7Hz，J
2＝6.0Hz)，2.92(d，1H，J＝16.7Hz)，2.36-2.29(m，2H)，0.80(q，1H，J＝8.3Hz)，0.53-0.47(m，1H)，0.32-0.24(m，2H)，0.21-0.17(m，1H)，0.01-0.07(m，1H)。
Example 9.62: preparation (±)-outer-1-vinyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate
To prepare title compound to mode similar described in the example 9.2 step D.MSm/z(ES
+)：219.3[M+H]
+，241.1[M+Na]
+；
1H?NMR(400MHz，CDCl
3)：δ5.53-5.44(m，1H)，5.04(dd，1H，J
1＝17.1Hz，J
2＝1.0?Hz)，4.94(dd，1H，J
1＝10.34Hz，J
2＝1.4Hz)，4.33(q，2H，J＝7.2Hz)，3.02(dd，1H，J
1＝17.3?Hz，J
2＝6.1Hz)，2.90(d，1H，J＝17.3Hz)，2.34-2.30(m，1H)，2.21-2.17(m，1H)，1.35(t，3H，J＝7.2Hz)，1.33-1.29(m，1H)。
Example 9.63: preparation (±)-outer-1-vinyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid
To prepare title compound to mode similar described in the example 9.3.
MS?m/z(ES
+)：191.3[M+H]
+；
1H?NMR(400MHz，DMSO-d
6)：δ5.57-5.48(m，1H)，5.13(dd，1H，J
1＝17.1Hz，J
2＝1.6Hz)，4.97(dd，1H，J1＝10.3Hz，J2＝1.7?Hz)，2.98(dd，1H，J
1＝18.2Hz，J
2＝6.3Hz)，2.80(d，1H，J＝18.2Hz)，2.36(dd，1H，J
1＝6.1Hz，J
2＝2.6Hz)，2.07-2.03(m，1H)，1.37(dt，1H，J
1＝8.8Hz，J
2＝3.1Hz)。
Example 9.64: preparation (±)-outer-4-(2H-tetrazolium-5-yl)-1-vinyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene
Steps A: preparation (±)-outer-1-vinyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-benzoic acid amides
To prepare title compound to mode similar described in the example 9.1 step D.
MS?m/z?(ES
+)：190.3[M+H]
+，379.2[2M+H]
+；
1H?NMR(400MHz，DMSO-d
6)：δ5.58-5.49(m，1H)，5.09(dd，1H，J
1＝17.1Hz，J
2＝1.6?Hz)，4.94(dd，1H，J
1＝10.3?Hz，J
2＝1.6?Hz)，2.94(dd，1H，J
1＝17.1Hz，J
2＝6.1Hz)，2.78(d，1H，J＝17.1?Hz)，2.29(dd，1H，J
1＝5.8Hz，J
2＝2.1Hz)，2.25-2.21(m，1H)，1.26-1.23(m，1H)。
Step B: preparation (±)-outer-1-vinyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-nitrile
To prepare title compound to mode similar described in example 9.2 step F.MS?m/z?(ES
+)：172.3[M+H]
+，343.1[2M+H]
+；
1H?NMR(400MHz，CDC1
3)：δ5.52-5.43(m，1H)，5.09(dd，1H，J
1＝17.0Hz，J
2＝0.6Hz)，5.00(dd，1H，J
1＝10.3Hz，J
2＝1.2Hz)，2.99(dd，1H，J1＝16.7Hz，J2＝6.3Hz)，2.88(d，1H，J＝16.7Hz)，2.34-2.28(m，2H)，1.39-1.36(m，1H)。
Step C: preparation (±)-outer-4-(2H-tetrazolium-5-yl)-1-vinyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene
To prepare title compound to mode similar described in the example 9.2 step G.MS?m/z(ES
+)：215.3[M+H]
+，429.4[2M+H]
+；
1H?NMR(400MHz，CD
3OD)：δ5.62-5.53(m，1H)，5.12(d，1H，J＝17.1Hz)，4.99(d，1H，J＝10.4Hz)，3.14-3.08(m，1H)，3.02(d，1H，J＝16.5Hz)，2.38(s，1H)，2.07-2.04(m，1H)，1.42-1.39(m，1H)。
Example 9.65: preparation (±)-1-Spirocyclopropyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate
To prepare title compound to mode similar described in the example 9.2 step D.MS?m/z?(ES
+)：219.4[M+H]
+，241.2[M+Na]
+；
1H?NMR(400MHz，CDCl
3)：δ4.37-4.31(m，2H)，2.97(dd，1H，J
1＝17.0Hz，J
2＝6.1Hz)，2.70(d，1H，J＝17.0Hz)，2.58(d，1H，J＝5.5Hz)，2.52(t，1H，J＝5.8Hz)，1.37(t，3H，J＝7.1Hz)，1.07-1.02(m，1H)，0.98-0.93(m，1H)，0.53-0.46(m，2H)。
Example 9.66: preparation (±)-1-Spirocyclopropyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid
To prepare title compound to mode similar described in the example 9.3.MS?m/z(ES
+)：191.3[M+H]
+，213.2[M+Na]
+；
1H?NMR(400MHz，CD
3OD)：δ3.03(dd，1H，J
1＝18.1Hz，J
2＝6.1Hz)，2.78(d，1H，J＝17.8Hz)，2.63(d，1H，J＝5.7Hz)，2.34(t，1H，J＝5.7Hz)，1.12-1.03(m，2H)，0.68-0.63(m，1H)，0.54-0.49(m，1H)。
Example 9.67: preparation (±)-1-Spirocyclopropyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene
Steps A: preparation (±)-1-Spirocyclopropyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-benzoic acid amides
To prepare title compound to mode similar described in the example 9.1 step D.MS m/z (ES
+): 190.2[M+H]
+, 379.3[2M+H]
+ 1H NMR (400MHz, DMSO-d
6): δ 2.90 (dd, 1H, J
1=16.2Hz, J
2=5.4Hz), 2.66 (d, 1H, J=16.4Hz), 2.54 (2H, overlapping) with DMSO, 1.07-1.03 (m, 1H), 0.99-0.95 (m, 1H), 0.55-0.50 (m, 1H), 0.39-0.34 (m, 1H).
Step B: preparation (±)-1-Spirocyclopropyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-nitrile
To prepare title compound to mode similar described in example 9.2 step F.MS?m/z(ES
+)：172.3[M+H]
+，343.4[2M+H]
+；
1H?NMR(400MHz，CDCl
3)：δ2.93(dt，1H，J
1＝16.4Hz，J
2＝3.0Hz)，2.68(d，1H，J＝16.3Hz)，2.61(d，2H，J＝3.0Hz)，1.12-1.08(m，1H)，1.02-0.98(m，1H)，0.57-0.53(m，1H)，0.51-0.46(m，1H)。
Step C: preparation (±)-1-Spirocyclopropyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene
To prepare title compound to mode similar described in the example 9.2 step G.MS m/z (ES
+): 215.2[M+H]
+, 429.2[2M+H]
+ 1H NMR (400MHz, MeOD): δ 3.06 (dd, 1H, J
1=16.1Hz, J
2=6.1Hz), 2.85 (d, 1H, J=16.1Hz), 2.68 (t, 1H, J=5.8Hz), 2.64 (d, 1H, J=5.4Hz), 1.11 (quintet, 1H, J=4.4Hz), 1.03 (q, 1H, J=4.0Hz), 0.61 (q, 1H, J=4.6Hz), 0.49 (q, 1H, J=4.3Hz).
Example 9.68: preparation (±)-Nei-1-propenyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate
To prepare title compound to mode similar described in the example 9.2 step D.MS?m/z(ES
+)：233.4[M+H]
+，255.3[M+Na]
+。
Example 9.69: preparation (±)-Nei-1-propenyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid
To prepare title compound to mode similar described in the example 9.3.MS?m/z(ES
+)：205.2[M+H]
+。
Example 9.70: preparation (±)-Nei-1-propenyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene
Steps A: preparation (±)-Nei-1-propenyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-benzoic acid amides
To prepare title compound to mode similar described in example 9.2 step e.MS?m/z(ES
+)：204.1[M+H]
+。
Step B: preparation (±)-Nei-1-propenyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-nitrile
To prepare title compound to mode similar described in example 9.2 step F.MS?m/z?(ES
+)：186.1[M+H]
+，371.1[2M+H]
+。
Step C: preparation (±)-Nei-1-propenyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene
To prepare title compound to mode similar described in the example 9.2 step G, it is isomer mixture (1.7: 1).MS m/z (ES
+): 229.4[M+H]
+, 457.3[2M+H]
+Main isomer:
1H NMR (400MHz, MeOD): δ 5.59-5.51 (m, 1H), 4.69-4.62 (m, 1H), 3.02 (dd, 1H, J
1=6.5Hz, J
2=4.0Hz), 2.78 (d, 1H, J=16.5Hz), 2.64-2.55 (m, 2H), 2.15 (q, 1H, J=8.0Hz), 1.76 (dd, 3H, J
1=6.8Hz, J
2=1.6Hz).Less important isomer:
1H NMR (400MHz, MeOD): δ 5.79-5.71 (m, 1H), 4.75-4.69 (m, 1H), 3.06 (dd, 1H, J
1=6.5Hz, J
2=4.0 Hz), 2.83 (d, 1H, J=16.5 Hz), 2.58-2.49 (m, 2H), 2.00 (q, 1H, J=8.0Hz), 1.55 (dd, 3H, J
1=6.5Hz, J
2=1.5Hz).
Example 9.71: preparation 1-methoxymethyl-1a, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid
Steps A: the preparation spiral shell [dicyclo [3.1.0] hexane-2,2 '-[1,3] dioxolane]-6-base methyl alcohol
With NaBH
4(90mg 2.38mmol) is dissolved in MeOH (2mL) and dropwise be added into aldehyde (400mg 2.38mmol) is dissolved in the solution among the MeOH (8mL).To react at ambient temperature and stir 10 minutes, and the NaOH that follows with 10% ends.With the extracted with diethyl ether mixture, with it through MgSO
4Dry and concentrated in a vacuum.By tubing string chromatography (50%EtOAc/ normal hexane/silicon-dioxide) purifying resistates, to obtain 200 mg title compounds.
1H?NMR(400MHz，CDCl
3)：δ4.07-3.88(5H，m)，3.64(1H，ddd，J＝12.5，10.4，2.2Hz)，2.79(1H，dd，J＝11.0，2.2Hz)，2.18-2.05(2H，m)，1.82-1.60(4H，m)，1.40-1.30(1H，m)。
Step B: in the preparation 6--(methoxymethyl) spiral shell [dicyclo [3.1.0] hexane-2,2 '-[1,3] dioxolane]
To prepare title compound to mode similar described in the example 9.52 step B.
1H?NMR(400MHz，CDCl
3)：δ4.00-3.82(4H，m)，3.77(1H，dd，J＝10.5，5.4)，3.44(1H，dd，J＝10.5，8.5?Hz)，3.40(3H，s)，2.16-2.04(1H，m)，2.04-1.96(1H，m)1.87-1.79(1H，m)，1.72-1.65(1H，m)，1.64-1.54(2H，m)，1.28-1.15(1H，m)。
Step C: the preparation 6-in-methoxymethyl-dicyclo [3.1.0] oneself-2-ketone
To prepare title compound to mode similar described in the example 9.15.
1H?NMR(400MHz，CDCl
3)：δ3.55(1H，dd，J＝10.8，6.4Hz)，3.45(1H，dd，J＝10.8，8.5Hz)，3.37(3H，s)，2.36-2.23(3H，m)，2.05-1.98(3H，m)，1.82-1.73(1H，m)。
Step D: in the preparation 1--methoxymethyl-1a, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate
To prepare title compound to mode similar described in the example 9.51 step D.HPLC/MS:Alltech
_PrevailC18 tubing string (5 μ, 50 * 4.6mm), 5%v/v CH in the gradient water (containing 1%v/v TFA)
3CN (containing 1%v/vTFA) 99%v/v CH to the water
3CN, 3.5 ml/min, t
r=1.84 minutes, ESI
+=236.9 (M+H).
Step e: in the preparation 1--methoxymethyl-1a, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid
To ester (0.090g, 0.38mmol) add in the solution in the Yu diox 1M lithium hydroxide aqueous solution (1.0ml, 1.0mmol).At ambient temperature solution stirring is spent the night, and make its acidifying by adding 1N HCl.Enriched mixture, and be purified by anti-phase HPLC: Phenomenex
_Luna C18 tubing string (10 μ, 250 * 21.2mm), gradient: 5% (v/v) CH in the water (containing 1%v/v TFA)
3CN (containing 1%v/v TFA) 95% (v/v) CH to the water
3CN, 20 ml/min, λ=214nm is with the title compound of the solid state that obtains being white in color after the freeze-drying.HPLC/MS:Alltech
_Prevail C18 tubing string (5 μ, 50 * 4.6mm), gradient: 5%v/v CH in the water (containing 1%v/v TFA)
3CN (containing 1%v/vTFA) 99%v/v CH to the water
3CN, 3.5 ml/min, t
r=1.17 minutes, ESI
+=209.1 (M+H).
Example 9.72: in the preparation 1--methoxymethyl-4-(1H-tetrazolium-5-yl)-1a, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene
To prepare title compound with mode similar described in the G to example 9.2 step e, F.HPLC/MS:Alltech
_Prevail C18 tubing string (5 μ, 50 * 4.6mm), gradient: 5%v/v CH in the water (containing 1%v/v TFA)
3CN (containing 1%v/v TFA) 99%v/v CH to the water
3CN, 3.5 ml/min, t
r=1.27 minutes, ESI
+=233.0 (M+H).
Example 9.73: in the preparation 1--phenoxymethyl-1a, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid
Steps A: in the preparation 6--(phenoxymethyl) spiral shell [dicyclo [3.1.0] hexane-2,2 '-[1,3] dioxolane]
With alcohol (170mg, 1.0mmol), phenol (141.2mg, 1.5mmol), PyPh
2P (395mg, 1.5mmol) and D
t(345mg 1.5mmol) is dissolved among the THF (5mL) BAD, and at ambient temperature its stirring is spent the night.Be added into 1N HCl in the reaction mixture and with extracted with diethyl ether (3 times).With the organic layer that is made up salt water washing, through MgSO
4Dry and concentrated.By tubing string chromatography (0-25%EtOAc/ normal hexane/silicon-dioxide) purifying resistates, to obtain title compound.
1H?NMR(400MHz，CDCl
3)：δ7.31-7.25(2H，m)，6.99-6.92(3H，m)，4.41(1H，dd，J＝10.6，5.2Hz)，4.03-3.89(5H，m)，2.18-2.08(1H，m)，2.08-1.99(1H，m)，1.92-1.84(1H，m)，1.81-1.75(1H，m)，1.70-1.63(1H，m)，1.63-1.56(1H，m)，1.44-1.35(1H，m)。
Step B: the preparation 6-in-phenoxymethyl-dicyclo [3.1.0] oneself-2-ketone
To prepare title compound to mode similar described in the example 9.15.
1H?NMR(400MHz，CDCl
3)：δ7.32-7.25(2H，m)，7.00-6.94(1H，m)，6.92-6.88(2H，m)，4.19(1H，dd，J＝10.6，6.1?Hz)，3.96(1H，dd，J＝10.6，8.9Hz)，2.38-2.32(3H，m)，2.13-1.94(4H，m)。
Step C: in the preparation 1--phenoxymethyl-1a, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate
To prepare title compound to mode similar described in the example 9.51 step D.
1H?NMR(400MHz，CDCl
3)：δ7.27-7.21(2H，m)，6.91(1H，t，J＝7.3Hz)，6.83-6.79(2H，m)，4.39-4.25(2H，m)，3.88-3.82(1H，m)，3.48(1H，dd，J＝10.4，8.3Hz)，3.02(1H，dd，J＝17.8，6.8Hz)，2.84(1H，d，17.8Hz)，2.61-2.56(1H，m)，2.50-2.43(1H，m)，1.85-1.76(1H，m)，1.35(3H，t，J＝7.1Hz)。HPLC/MS:Alltech
_Prevail C18 tubing string (5 μ, 50 * 4.6mm), gradient: 5%v/v CH in the water (containing 1%v/v TFA)
3CN (containing 1%v/v TFA) 99%v/v CH to the water
3CN, 3.5 ml/min, t
r=2.56 minutes, ESI
+=299.1 (M+H).
Step D: in the preparation 1--phenoxymethyl-1a, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid (compound)
To ester (0.025g, 0.084mmol) add in the solution in the Yu diox 1 M lithium hydroxide aqueous solution (0.23ml, 0.23mmol).Under 60 ℃,, and make its acidifying by adding 1 N HCl with solution stirring 3 hours.Enriched mixture, and be purified by anti-phase HPLC: Phenomenex
_Luna C18 tubing string (10 μ, 250 * 21.2mm), gradient: 5% (v/v) CH in the water (containing 1%v/v TFA)
3CN (containing 1%v/v TFA) 95% (v/v) CH to the water
3CN, 20 ml/min, λ=214nm is with the title compound of the solid state that obtains being white in color after the freeze-drying.HPLC/MS:Alltech
_Prevail C18 tubing string (5 μ, 50 * 4.6mm), gradient: 5%v/v CH in the water (containing 1%v/v TFA)
3CN (containing 1%v/v TFA) 99%v/v CH to the water
3CN, 3.5 ml/min, t
r=2.01 minutes, ESI
+=271.0 (M+H).
Example 9.74: in the preparation 1--phenoxymethyl-4-(1H-tetrazolium-5-yl)-1a, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene.Example 9-53 uses cyclopentyl ketone and tetrazyl ethyl ester
To prepare title compound with mode similar described in the G to example 9.2 step e, F.HPLC/MS:Alltech
_Prevail C18 tubing string (5 μ, 50 * 4.6mm), gradient: the 5%v/v CH that (contains 1%v/v TFA) in the water
3CN (containing 1%v/v TFA) 99%v/v CH to the water
3CN, 3.5 ml/min, t
r=1.96 minutes, ESI
+=295.3 (M+H).
Example 9.75: outside the preparation 1--methyl sulfenyl methyl isophthalic acid a, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid
Steps A: preparation 2-(5-methyl sulfenyl-penta-3-thiazolinyl)-oxyethane
(5.57g, 56.7mmol) (1.000g 11.3mmol) stirred 24 hours together with Zhan catalyzer 1 (MW=661.07,0.150g, 0.23mmol, ex ZannanPharma) with allyl methyl sulphur with epoxide under 20 ℃.Under reduced pressure remove solvent.By the remaining oily matter of tubing string chromatography (0-10%EtOAc/ normal hexane/silicon-dioxide) purifying, to obtain being the buttery title compound.
1H?NMR(400MHz，CDCl
3)：δ5.60-5.43(2H，m)，3.07(2H，d，J＝7.2Hz)，2.96-2.91(1H，m)，2.78-2.74(1H，m)，2.49(1H，dd，J＝5.0，2.7Hz)，2.28-2.19(2H，m)，2.02(3H，s)，1.70-1.57(2H，m)。
Step B: preparation (±)-outer-6-methyl sulfenyl methyl-dicyclo [3.1.0] oneself-2-alcohol
To prepare title compound to mode similar described in the example 9.51 step B.
1H?NMR(400MHz，CDCl
3)：δ4.28(1H，t，J＝5.0Hz)，2.41(2H，d，J＝7.0Hz)，2.14(3H，s)，2.00-1.89(1H，m)，1.75(1H，dd，12.7，8.1Hz)，1.58(1H，dd，J＝14.6，8.6Hz)，1.40-1.28(4H，m)，0.72-0.66(1H，m)。
Step C: preparation (±)-6-is outer-methyl sulfenyl methyl-dicyclo [3.1.0] oneself-2-ketone
To prepare title compound to mode similar described in the example 9.51 step C.
1H?NMR(400MHz，CDCl
3)：δ2.65(1H，dd，J＝13.5，5.8Hz)，2.38(1H，dd，J＝13.5，7.7Hz)，2.18(3H，s)，2.16-2.03(4H，m)，2.00(1H，dd，J＝9.1，5.1Hz)，1.78?1H，dd，J＝5.3，2.5Hz)，1.56-1.51(1H，m)。
Step D: outside preparation (±)-1--methyl sulfenyl methyl isophthalic acid a, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate
To prepare title compound to mode similar described in the example 9.51 step D.HPLC/MS:Alltech
_PrevailC18 tubing string (5 μ, 50 * 4.6mm), gradient: 5%v/v CH in the water (containing 1%v/v TFA)
3CN (containing 1%v/v TFA) 99%v/v CH to the water
3CN, 3.5 ml/min, t
r=2.35 minutes, ESI
+=253.1 (M+H).
Step e: preparation (±)-Nei-1-methyl sulfenyl methyl isophthalic acid a, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid
(40mg 159mmol) adds 1 M lithium hydroxide aqueous solution (428 μ l, 428 μ mol) in the solution in the Yu diox to ester.At ambient temperature solution stirring is spent the night, and make its acidifying by adding 1 N HCl.Enriched mixture, and be purified by anti-phase HPLC: Phenomenex
_Luna C18 tubing string (10 μ, 250 * 21.2 mm), gradient: 5% (v/v) CH in the water (containing 1%v/v TFA)
3CN (containing 1%v/v TFA) 95% (v/v) CH to the water
3CN, 20 ml/min, λ=214nm is with the title compound of the solid state that obtains being white in color after the freeze-drying.
1H?NMR(400MHz，CD
3OD)：δ2.94(1H，dd，J＝16.9，5.9Hz)，2.82(1H，d，16.8Hz)，2.53(2H，d，J＝7.0Hz)，2.14(3H，s)，2.16-2.08(2H，m)，0.92-0.86(1H，m)。HPLC/MS:Alltech
_Prevail C18 tubing string (5 μ, 50 * 4.6 mm), gradient: 5%v/v CH in the water (containing 1%v/v TFA)
3CN (containing 1%v/v TFA) 99%v/v CH to the water
3CN, 3.5 ml/min, t
r=1.64 minutes, ESI
+=225.2 (M+H).
Example 9.76: preparation (±)-spiral shell [1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-1,1 '-pentamethylene]-4-formic acid
Steps A: preparation (±)-spiral shell-[dicyclo [3.1.0] hexane-6-1 '-pentamethylene]-2-alcohol
To prepare title compound with mode similar described in the B to example 9.2 steps A.
1H?NMR(CDCl
3)：δ4.11(d，1H，J＝4.8)，2.05-1.98(m，1H)，1.69-1.46(m，8H)，1.40-1.26(m，5H)。
Step B: preparation (±)-spiral shell-[dicyclo [3.1.0] hexane-6-1 '-pentamethylene]-2-ketone
To prepare title compound to mode similar described in the example 9.2 step C.
1H?NMR(CDCl
3)：δ2.23-2.11(m，2H)，2.02-1.90(m，3H)，1.77-1.73(m，3H)，1.70-1.50(m，5H)，1.48-1.24(m，1H)。
Step C: preparation (±)-spiral shell [1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-1,1 '-pentamethylene]-the 4-ethyl formate
To prepare title compound to mode similar described in the example 9.2 step D.MS：m/z?(ES
+)：247[M+H]
+，201[M-OEt]
+。
Step D: preparation (±)-spiral shell [1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-1,1 '-pentamethylene]-4-formic acid
To prepare title compound to mode similar described in the example 9.3.MS：m/z?(ES
+)：219[M+H]
+，201[M-OH]
+。
1H?NMR(CD
3OD)：δ2.94(dd，1H，J
1＝17.1，J
2＝2.1)，2.72(d，1H，J＝17.1，2.17(s，2H)，1.78-1.53(m，6H)，1.34-1.24(m，1H)，0.94-0.84(m，1H)。
Example 9.77: preparation (±)-5-(spiral shell-[and 1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-1,1 '-pentamethylene]-the 4-yl)-the 1H-tetrazolium
To prepare title compound to mode similar described in the example 9.44.MS：m/z?(ES
+)：243[M+H]
+，215[M-N
2+H]
+。
1HNMR(CD
3OD)：δ2.88(dd，1H，J
1＝12.3，J
2＝6.1)，2.72(d，1H，J＝16.6)，2.18-2.07(m，2H)，1.63-1.40(m，6H)，1.28-1.13(m，1H)，0.83-0.71(m，1H)。
Example 9.78: preparation (±)-spiral shell [1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-1,1 '-hexanaphthene]-4-formic acid
Steps A: preparation (±)-spiral shell-[dicyclo [3.1.0] hexane-6-1 '-hexanaphthene]-2-alcohol
To prepare title compound with mode similar described in the B to example 9.2 steps A.
1HNMR(CDCl
3)：δ4.14(br?s，1H)，2.05-2.00(m，1H)，2.0-1.1(m，15H)。
Step B: preparation (±)-spiral shell-[dicyclo [3.1.0] hexane-6-1 '-hexanaphthene]-2-ketone
To prepare title compound to mode similar described in the example 9.2 step C.
1H?NMR(CDCl
3)：δ2.39-2.28(m，1H)，2.28-2.14(m，1H)，2.10-1.99(m，2H)，1.97-1.82(m，2H)，1.64(d，1H，J＝5.2)，1.60-1.44(m，7H)，1.33-1.25(m，2H)。
Step C: preparation (±)-spiral shell [1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-1,1 '-hexanaphthene]-the 4-ethyl formate
To prepare title compound to mode similar described in the example 9.2 step D.MS：m/z?(ES
+)：283[M+Na]
+，261[M+H]
+，215[M-OEt]
+。
1H NMR (CDCl
3): δ 5.30 (br s, 1H, N
H), 4.41-4.27 (m, 2H), 2.89 (dd, 1H, J
1=17.5, J
2=6.9), 2.64 (d, 1H, J=17.5), 2.08 (d, 1H, J=6.1), 1.98 (t, 1H, J=6.3), 1.62-1.42 (m, 4H), 1.40-1.25 (m, 7H comprise 1.36 (t, 3H, J=7.1), 1.10-0.90 (m, 2H).
Step D: preparation (±)-spiral shell [1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-1,1 '-hexanaphthene]-4-formic acid
To prepare title compound to mode similar described in the example 9.3.MS：m/z?(ES
+)：255[M+Na]
+，233[M+H]
+。
1H?NMR(CDCl
3)：δ?2.70(dd，1H，J
1＝18.5，J
2＝7.0)，2.46-2.40(m，2H)，1.90(d，1H，J＝6.2)，1.60(t，1H，J＝6.5)，1.40-1.15(m，7H)，1.10-0.88(m，2H)。
Example 9.79: preparation (±)-5-(spiral shell-[and 1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-1,1 '-hexanaphthene]-the 4-yl)-the 1H-tetrazolium
To prepare title compound to mode similar described in the example 9.44.MS：m/z?(ES
+)：279[M+Na]
+，257[M+H]
+，229[M-N
2+H]
+。
1H?NMR(CD
3OD)：δ?3.20-2.90(m，1H)，2.75(dd，1H，J
1＝16.5，J
2＝1.0)，2.15-2.08(m，2H)，1.67-1.40(m，6H)，1.40-1.24(m，2H)，1.21-1.12(m，1H)，1.07-0.98(m，1H)。
Example 9.80: preparation (±)-outer-1-allyl group-1a, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid
Steps A: preparation cyclobutyl phenylbenzene sulfonium trifluoro-methanyl sulfonate
(1.00g, 13.9mmol) solution in 25ml DCM is cooled to-20 ℃, and (1.35ml 16.6mmol), then adds Trifluoromethanesulfonic anhydride (2.33ml, 13.9mmol) (in 5ml DCM) to add anhydrous pyridine with cyclobutanol.Made the solution temperature to room temperature through 1 hour.Add pentane (40 mL), concussion and filtration gained mixture.Under reduced pressure bathe concentrated filtrate, until removing all volatile solvents with room temperature.Remaining oily matter is cooled to-20 ℃, and interpolation phenylbenzene sulfane (10.2ml, 61.0mmol).Under 25 ℃ mixture was stirred 20 hours, temperature is lasted 30 minutes to 45 ℃, and is cooled to room temperature.Add pentane, shake solution and collect the gained solid, to obtain cyclobutyl phenylbenzene sulfonium trifluoro-methanyl sulfonate (1.82g, 4.86mmol, 35.0%) through vacuum filtration.MS：m/z?(ES
+)：241[C
16H
17S]
+。
1H?NMR(D
6-DMSO)：δ?8.10(dt，4H，J
1＝7.8，J
2＝3.1)，7.84-7.72(m，6H)，5.90-5.78(m，1H)，5.15(ddd，2H，J
1＝14.9，J
2＝10.3，J
3＝1.4)，4.48(t，2H，J＝14.2)，2.45(dd，2H，J
1＝13.8，J
2＝7.1)。
Step B: preparation (±)-outer-6-allyl group-dicyclo [3.1.0] oneself-2-ketone
With cyclobutyl phenylbenzene sulfonium trifluoro-methanyl sulfonate (1.820g, 4.86mmol) solution in 30ml THF is cooled to-78 ℃, and dropwise make an addition to 1.7 M tert-butyl lithium in the pentane (2.700ml, 4.59mmol).After 30 minutes, make an addition to ring penta-2-ketenes among the THF (3ml) (0.190ml, 2.35mmol), and under-78 ℃ with solution stirring 2 hours.Add saturated NaHCO
3Come stopped reaction and with its temperature to room temperature.Product is extracted among the DCM, under reduced pressure remove solvent, and by tubing string chromatography (0-20%EtOAc/ normal hexane/silicon-dioxide) purifying with (±) that obtain being colorless oil-outer-6-allyl group-dicyclo [3.1.0] oneself-2-ketone (0.178g, 1.31mmol, 55.6%).Contain 50% (±) that have an appointment-Nei-6-allyl group-dicyclo [3.1.0] oneself-2-ketone.
1H?NMR(CDCl
3)：δ?5.95-5.75(m，1H)，5.20-5.00(m，2H)，2.38-2.20(m，1H)，2.20-1.90(m，5H)，1.65-1.50(m，2H)，1.40-1.32(m，2H)。
Step C: preparation (±)-outer-1-allyl group-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate
To prepare title compound to mode similar described in the example 9.2 step D.MS：m/z?(ES
+)：255[M+Na]
+，233[M+H]
+，187[M-OEt]
+。
1H NMR (CDCl
3): δ 5.91-5.81 (m, 1H), 5.02 (dd, 1H, J
1=17.2, J
2=1.6), 4.92 (dd, 1H, J
1=10.3, J
2=1.6), 4.34 (q, 2H, J=7.1), 2.97 (dd, 1H, J
1=17.1, J
2=6.3), 2.86 (d, 1H, J=17.1), 2.22-2.14 (m, 2H), 2.11-2.00 (m, 2H), 1.36 (t, 3H, J=7.1), 0.80 (septet, 1H, J=3.4).
Step D: preparation (±)-outer-1-allyl group-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid
To prepare title compound to mode similar described in the example 9.3.MS：m/z?(ES
+)：227[M+Na]
+，205[M+H]
+，187[M-OH]
+。
1H NMR (CD
3CN): δ 6.00-5.88 (m, 1H), 5.13 (dq, 1H, J
1=17.2, J
2=1.7), 5.03 (dq, 1H, J
1=10.3, J
2=2.1), 2.92 (dd, 1H, J
1=16.8, J
2=5.8), 2.78 (d, 1H, J=17.0), 2.3-2.0 (m, 4H), 0.71 (septet, 1H, J=3.4).
Example 9.81: preparation (±)-outer-1-allyl group-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene
To prepare title compound to mode similar described in the example 9.44.MS：m/z?(ES
+)：251[M+Na]
+，229[M+H]
+，201[M-N
2+H]
+。
1H NMR (CD
3CN): δ 5.98-5.84 (m, 1H, C
H=CH
2), 5.12 (ddd, 1H, J
1=17.2, J
2=3.6, J
3=1.7, CH=C
HH), 5.01 (d, 1H, ddd, 1H, J
1=10.2, J
2=3.3, J
3=1.4, CH=CH
H), 2.98 (ddd 1H, J
1=16.3, J
2=4.8, J
3=1.6), 2.88 (d, 1H, J=16.3), 2.14-2.04 (m, 2H), 0.80 (septet, 1H, J=3.4).
Example 9.82: preparation (±)-Nei-1-allyl group-1a, 2,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid
Steps A: preparation (±)-Nei-1-allyl group-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate
Non-enantiomer mixture described in the use-case 9.80 step B is to prepare title compound to mode similar described in the example 9.2 step D.MS：m/z(ES
+)：255[M+Na]
+，233[M+H]
+，187[M-OEt]
+。
1HNMR (CDCl
3): δ 5.84-5.74 (m, 1H), 5.00 (dd, 1H, J
1=17.2, J
2=1.7), 4.95 (dd, 1H, J
1=10.2, J
2=1.5), and 4.39-4.31 (m, 2H), 2.95 (dd, 1H, J
1=17.5, J
2=6.9), 2.70 (d, 1H, J=17.5), 2.44 (t, 1H, J=7.6), 2.31 (dd, 1H, J
1=14.5, J
2=6.5.), (m, 2H), (m, 4H comprise 1.37 (t, 3H, J=7.1)) to 1.42-1.33 to 1.79-1.66.
Step B: preparation (±)-Nei-1-allyl group-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid
To prepare title compound to mode similar described in the example 9.3.MS：m/z?(ES
+)：227[M+Na]
+，205[M+H]
+，187[M-OH]
+。
1H NMR (CD
3CN): δ 5.68-5.56 (m, 1H), 4.81 (dq, 1H, J
1=15.5, J
2=1.7), 5.03 (dq, 1H, J
1=10.2, J
2=1.4), 2.68 (dd, 1H, J
1=17.4, J
2=6.8), 2.43 (d, 1H, J=17.3), 2.17-2.12 (m, 1H), 2.10-2.03 (m, 1H), 1.61-1.50 (m, 1H), 1.45-1.36 (m, 1H), 1.13 (quintet, 1H, J=7.8).
Example 9.83: preparation (±)-Nei-1-allyl group-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene
Non-enantiomer mixture described in the use-case 9.80 step B is to prepare title compound to mode similar described in the example 9.44.MS：m/z?(ES
+)：251[M+Na]
+，229[M+H]
+，201[M-N
2+H]
+。
1H NMR (CD
3CN): δ 5.77-5.68 (m, 1H), 4.92-4.80 (m, 2H), 2.88 (dd, 1H, J
1=16.7, J
2=6.8), 2.64 (d, 1H, J=16.7), 2.37-2.30 (m, 1H), 2.30-2.23 (m, 1H), 1.75-1.67 (m, 1H), 1.55-1.476 (m, 1H), 1.29 (quintet, 1H, J=7.9).
Example 9.84: preparation (±)-stranger-4-methyl-3b, 4,4a, 5-tetrahydrochysene-1H-ring third [3,4] ring penta [1,2-c] pyrazoles-3-formic acid
Steps A: preparation (±)-outer-4-methyl-3b, 4,4a, 5-tetrahydrochysene-1H-ring third [3,4] ring penta [1,2-c] pyrazoles-3-ethyl formate
With to the described similar mode of example 9.2 step D, by 6-outer-methyl bicycle [3.1.0] oneself-3-ketone and 6-in-methyl bicycle [3.1.0] is own-1: 1 mixture of 3-ketone prepares title compound (referring to P.S.Mariano, E.Bay, D.G.Watson, T.Rose and C.Bracken, J.Org.Chem.1980,45,1753; J.Nishimura, N.Kawabata, J.Furukawa, Tetrahedron.1969,25,2647).MS：m/z(ES
+)：229[M+Na]
+，207[M+H]
+，161[M-OEt]
+。
1H?NMR(CDCl
3)：δ4.39(t，2H，J＝7.2)，2.96(dd，1H，J
1＝16.9，J
2＝6.6)，2.82(d，1H，J＝16.8)，2.03-2.01(m，1H)，1.89-1.85(m，1H)，1.40(t，3H，J＝7.2)，1.14(d，3H，J＝6.1)，0.69-0.64(m，1H)。
Step B: preparation (±)-outer-4-methyl-3b, 4,4a, 5-tetrahydrochysene-1H-ring third [3,4] ring penta [1,2-c] pyrazoles-3-formic acid
Between the reaction period described in example 9.84 steps A, separate title compound.MS：m/z(ES
+)：179[M+H]
+，161[M-OH]
+。
1H?NMR(CD
3CN)：δ?2.90(dd，1H，J
1＝16.5，J
2＝6.6)，2.74(d，1H，J＝16.0)，2.02-1.99(m，1H)，1.88-1.78(m，1H)，1.13(d，3H，J＝6.1)，0.62-0.55(m，1H)。
Example 9.85: preparation (±)-Nei-4-methyl-3b, 4,4a, 5-tetrahydrochysene-1H-ring third [3,4] ring penta [1,2-c] pyrazoles-3-formic acid
Steps A: preparation (±)-Nei-4-methyl-3b, 4,4a, 5-tetrahydrochysene-1H-ring third [3,4] ring penta [1,2-c] pyrazoles-3-ethyl formate
Non-enantiomer mixture described in use-case 9.84 steps A, with the preparation title compound of similar manner described in the example 9.2 step D.MS：m/z(ES
+)：229[M+Na]
+，207[M+H]
+，161[M-OEt]
+。
Step B: preparation (±)-Nei-4-methyl-3b, 4,4a, 5-tetrahydrochysene-1H-ring third [3,4] ring penta [1,2-c] pyrazoles-3-formic acid
Between the reaction period described in example 9.85 steps A, separate title compound.MS：m/z(ES
+)：179[M+H]
+，161[M-OH]
+。
1H?NMR(CD
3CN)：δ2.83(dd，1H，J
1＝16.8，J
2＝6.9)，2.55(d，1H，J＝16.9)，2.29(t，1H，J＝6.9)，2.10(dd，1H，J
1＝14.4，J
2＝6.6)，1.37-1.31(m，1H)，0.61(d，3H，J＝6.4)。
Example 9.86: preparation (±)-Nei-1-cyclopropyl methyl isophthalic acid a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid
Steps A: preparation 4-(2-iodo-ethyl)-2,2-dimethyl-[1,3] dioxolane
With triphenylphosphine (172mmol, 45g) and imidazoles (172mmol, 12g) be dissolved in the THF/ acetonitrile (3: 1,300ml) in.Cooling mixture under ice bath, (172mmol 44g) divided four parts of interpolations with iodine through 20 minutes under vigorous stirring.With gained slurry temperature to 20 ℃, and then be cooled to 0 ℃.In reaction mixture, dropwise added (±)-2-(2,2-dimethyl-[1,3] dioxolane-4-yl)-ethanol (156 mmol, 25 g) through 15 minutes.At room temperature mixture is stirred and spend the night.Enriched mixture dilutes it with 5% sodium hydrogen carbonate solution, and with hexane extraction.With the organic layer that made up with MgSO
4Dry and concentrated.Silica gel column chromatography obtains being clarification buttery 4-(2-iodo-ethyl)-2,2-dimethyl-[1,3] dioxolane.
1H?NMR(400MHz，CDCl
3)：δ?4.18-4.12(m，1H)，4.06(dd，1H，J
1＝8.0Hz，J
2＝6.1Hz)，3.55(dd，1H，J
1＝8.0Hz，J
2＝6.5Hz)，3.28-3.17(m，2H)，2.11-1.98(m，2H)，1.38(s，3H)，1.33(s，3H)。
Step B: preparation [4-(2,2-dimethyl-[1,3] dioxolane-4-yl)-Ding-1-alkynyl]-trimethylammonium-silane
Under-78 ℃, to TMS-acetylene (72mmol, 7.1g) at anhydrous THF of 150ml and DMPU (27ml, slowly add 2.5 M (78mmol in the solution 222mmol), 31ml) the BuLi in hexane, and then in described mixture, add 4-(2-iodo-ethyl)-2,2-dimethyl-[1,3] dioxolane.Under-78 ℃, it was stirred 15 minutes, and be slowly to warm to room temperature.With saturated NH
4Cl stopped reaction mixture and extract with EtOAc.With the organic layer that made up with H
2O and salt water washing are through MgSO
4Dry and concentrated.Silica gel column chromatography (2% to 10%EtOAc/ hexane) obtains being clarification buttery 4-(2,2-dimethyl-[1,3] dioxolane-4-yl)-Ding-1-alkynyl]-trimethylammonium-silane.
1H?NMR(400MHz，CDCl
3)：δ4.19-4.12(m，1H)，4.07(dd，1H，J
1＝8.0Hz，J
2＝6.0Hz)，3.57(dd，1H，J
1＝8.0Hz，J
2＝6.9Hz)，2.39-2.26(m，2H)，1.86-1.79(m，1H)，1.76-1.68(m，1H)，1.39(s，3H)，1.34(s，3H)，0.13(s，9H)。
Step C: preparation 4-fourth-3-alkynyl-2,2-dimethyl-[1,3] dioxolane
To 4-(2,2-dimethyl-[1,3] dioxolane-4-yl)-Ding-1-alkynyl]-(44mmol 10.0g) adds K in the solution in 40ml methyl alcohol to trimethylammonium-silane
2CO
3(49mmol, 6.7g).At room temperature mixture is stirred 4 h.Concentrated reaction mixture is with NH
4Cl solution dilution and extract with EtOAc.With the organic layer that made up through MgSO
4Drying, and concentrate.Silica gel column chromatography (4% to 12%EtOAc/ hexane) obtains being clarification buttery 4-fourth-3-alkynyl-2,2-dimethyl-[1,3] dioxolane.
1H?NMR(400MHz，CDCl
3)：δ?4.21-4.15(m，1H)，4.05(dd，1H，J
1＝8.0Hz，J
2＝6.0Hz)，3.55(dd，1H，J
1＝8.0Hz，J
2＝6.9Hz)，2.31-2.26(m，2H)，1.94(t，1H，J＝2.6Hz)，1.84-1.75(m，1H)，1.73-1.68(m，1H)，1.38(s，3H)，1.33(s，3H)。
Step D: preparation 4-(5-cyclopropyl-penta-3-alkynyl)-2,2-dimethyl-[1,3] dioxolane
To 4-fourth-3-alkynyl-2, (6mmol, 1.0g) (26mmol 3g) adds 2.5 M BuLi in hexane (9.01mmol, 3.6mL) solution in to 2-dimethyl-[1,3] dioxolane in the solution in the anhydrous THF of 40ml and anhydrous DMPU under-78 ℃.Under-78 ℃, it was stirred 15 minutes, and be slowly to warm to room temperature.With saturated NH
4Cl stopped reaction mixture and extract with EtOAc.With the organic layer that made up with H
2O and salt water washing are through MgSO
4Dry and concentrated.Silica gel column chromatography (2% to 10%EtOAc/ hexane) obtains being clarification buttery 4-(5-cyclopropyl-penta-3-alkynyl)-2,2-dimethyl-[1,3] dioxolane.
1H?NMR(400MHz，CDCl
3)：δ?4.22-5.15(m，1H)，4.07(dd，1H，J
1＝8.0Hz，J
2＝6.0Hz)，3.57(dd，1H，J
1＝7.9Hz，J
2＝7.1Hz)，2.29-2.23(m，2H)，2.20-2.16(m，2H)，1.83-1.77(m，1H)，1.72-1.65(m，1H)，1.40(s，3H)，1.35(s，3H)，0.91-0.86(m，1H)，0.46-0.41(m，2H)，0.21-0.17(m，2H)。
Step e: preparation 4-(5-cyclopropyl-penta-3-thiazolinyl)-2,2-dimethyl-[1,3] dioxolane
To 4-(5-cyclopropyl-penta-3-alkynyl)-2, (1.92mmol, (0.192mmol 24.8mg), then adds 5%Pd/BaSO to 2-dimethyl-[1,3] dioxolane 0.40g) to add quinoline in the solution in hexane (5mL)
4(0.384 mmol).At room temperature H
2Stirred 4 hours under the atmosphere.TLC displaying reaction is finished.By diatomite filtration, and it is concentrated.With the hexane dilution, with NH
4Cl, salt water washing are through MgSO
4Dry.Silica gel column chromatography (2% to 7%EtOAc/ hexane) obtains being clarification buttery 4-(5-cyclopropyl-penta-3-thiazolinyl)-2,2-dimethyl-[1,3] dioxolane.
1H?NMR(400MHz，CDCl
3)：δ5.52-5.45(m，1H)，5.40-5.34(m，1H)，4.11-4.04(m，1H)，4.02(dd，1H，J
1＝8.0Hz，J
2＝6.0Hz)，3.51(t，1H，J＝7.5Hz)，2.17-2.04(m，2H)，1.97(t，2H，J＝7.0Hz)，1.74-1.66(m，1H)，1.58-1.49(m，1H)，1.41(s，3H)，1.35(s，3H)，0.73-0.68(m，1H)，0.43-0.39(m，2H)，0.08-0.04(m，2H)。
Step F: preparation 7-cyclopropyl-heptan-5-alkene-1,2-glycol
At room temperature will be in the 4-among the 80%AcOH (5 mL) (5-cyclopropyl-penta-3-thiazolinyl)-2,2-dimethyl-[1,3] dioxolane (0.30g, 1.4mmol) spend the night by stirring.Concentrate and clarify buttery 7-cyclopropyl-heptan-5-alkene-1,2-glycol by being with collection through silica gel column chromatography (EtOAc of 70-90% in hexane) purifying.
1H?NMR(400?MHz，CDCl
3)：δ5.52-5.47(m，1H)，5.41-5.35(m，1H)，3.77-3.71(m，1H)，3.66(d，1H，J＝11.2?Hz)，3.46(dd，1H，J
1＝11.2Hz，J
2＝7.7Hz)，2.19-2.10(m，2H)，1.97(t，2H，J＝7.1?Hz)，1.53-1.46(m，2H)，0.74-0.68(m，1H)，0.44-0.39(m，2H)，0.08-0.04(m，2H)。
Step G: preparation 2-(4-cyclopropyl-but-2-ene base)-oxyethane
Under 0 ℃ to 7-cyclopropyl-heptan-5-alkene-1, the 2-glycol (1.45g, 9.28mmol) add in the solution in THF (30mL) 60% sodium hydride (1.1g, 27.84mmol).Mixture is slowly to warm to room temperature and stirs 1h.(3.41g 10.2mmol), then at room temperature stirs 1.5h to add TrisIm at 0 ℃ with portion.With water termination mixture and with Et
2The O extraction.With organism with the salt water washing, through MgSO
4Dry, filtration and concentrated.(gradient: 7%EtOAc 14%EtOAc to the hexane in the hexane) purifying obtains being clarification buttery 2-(4-cyclopropyl-but-2-ene base)-oxyethane by silica gel column chromatography.
1H?NMR(400MHz，CDCl
3)：δ?5.54-5.48(m，1H)，5.44-5.37(m，1H)，2.94-2.91(m，1H)，2.75(dd，1H，J
1＝4.9Hz，J
2＝4.1Hz)，2.48(dd，1H，J
1＝5.0Hz，J
2＝2.7Hz)，2.19(q，2H，J＝7.3Hz)，1.98(t，2H，J＝7.0Hz)，1.62-1.56(m，2H)，0.75-0.66(m，1H)，0.44-0.39(m，2H)，0.09-0.05(m，2H)。
Step H: the preparation 6-cyclopropyl methyl-dicyclo [3.1.0] oneself-2-alcohol
Under-78 ℃, to tetramethyl piperidine (0.624ml, 3.7mmol) add in the solution in MTBE (5ml) n-Butyl Lithium 2.5M hexane (1.5ml, 3.7mmol).Solution is slowly to warm near 0 ℃, and under 0 ℃ through 10 minutes, (0.288g is 1.898mmol) in the solution in MTBE (2mL) by sleeve pipe it to be added into 2-(4-cyclopropyl-but-2-ene base)-oxyethane.Make the mixture temperature to room temperature, stirring is spent the night, with 1 N HCl washing (2 times) and with the salt water washing.Organism is passed through MgSO
4Dry, filter and concentrate with obtain being clarification buttery 6-cyclopropyl methyl-dicyclo [3.1.0] oneself-2-alcohol;
1H NMR (400MHz, CDCl
3): δ 4.19 (d, 1H, J=5.5Hz), 2.15-2.06 (m, 1H), 1.75 (dd, 1H, J
1=11.0Hz, J
2=9.7Hz), and 1.69-1.52 (m, 4H), 1.42 (dd, 1H, J
1=8.1Hz, J
2=6.2Hz), and 0.98-0.87 (m, 2H), 0.75-0.68 (m, 1H), 0.46-0.41 (m, 2H), 0.03 (dd, 2H, J
1=9.1Hz, J
2=4.7Hz).
Step I: the preparation 6-cyclopropyl methyl-dicyclo [3.1.0] oneself-2-ketone
To 6-cyclopropyl methyl-dicyclo [3.1.0] oneself-2-alcohol (220mg, 1.45mmol) add 4A molecular sieve (200mg), NMO (N-methylmorpholine N-oxide compound) (339mg in succession in the solution in 10mL DCM, 2.90mmol), the TPAP marker (25.448mg, 0.0725mmol).At room temperature mixture is stirred spend the night and by silica gel plug (3: 1, DCM: Et
2O) with obtain being clarification buttery 6-cyclopropyl methyl-dicyclo [3.1.0] oneself-2-ketone.
1H?NMR(400MHz，CDCl
3)：δ?2.32-2.21(m，2H)，2.16(dd，1H，J
1＝13.4Hz，J
2＝5.4Hz)，1.97-1.86(m，3H)，1.61-1.53(m，1H)，1.38-1.28(m，2H)，0.82-0.73(m，1H)，0.49-0.44(m，2H)，0.09-0.05(m，2H)。
Step J: preparation (±)-Nei-1-cyclopropyl methyl isophthalic acid a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate
With with example 9.2, mode similar described in the step D prepares title compound.MS?m/z?(ES
+)：247.3[M+H]
+，269.1[M+Na]
+；
1H?NMR(400MHz，CDCl
3)：δ?4.38-4.29(m，2H)，2.93(dd，1H，J
1＝17.4Hz，J
2＝6.8Hz)，2.65(d，1H，J＝17.4Hz)，2.40(t，1H，J＝6.9Hz)，2.23(dd，1H，J
1＝14.0Hz，J
2＝6.7Hz)，1.40-1.35(m，1H)，1.37(t，3H，J＝7.1Hz)，1.03-0.96(m，1H)，0.78-0.64(m，2H)，0.39-0.32(m，2H)，-0.02--0.12(m，2H)。
Step K: preparation (±)-Nei-1-cyclopropyl methyl isophthalic acid a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid
To prepare title compound to mode similar described in the example 9.3.MS?m/z?(ES
+)：219.3[M+H]
+；
1HNMR(400MHz，CD
3OD)：δ?2.95(dd，1H，J
1＝18.5Hz，J
2＝6.9Hz)，2.69(d，1H，J＝18.5Hz)，2.40(t，1H，J＝6.9Hz)，2.17(dd，1H，J
1＝14.0Hz，J
2＝6.7Hz)，1.47-1.42(m，1H)，1.15-1.08(m，1H)，0.86-0.79(m，1H)，0.76-0.68(m，1H)，0.44-0.36(m，2H)，0.02--0.11(m，2H)。
In whole the application's case, quote various open case, patent and disclosed patent application cases.These open cases of institute's reference in the application's case, patent and the disclosure of publication application case all incorporate in this disclosure by reference.Being in disclosed modification of the present invention in those of skill in the art's scope and expansion all is covered by in above the disclosure and claims hereinafter.
Although the those skilled in the art can utilize multiple expression vector,, most preferably utilize the pCMV carrier for the purpose of Dary with endogenous and exogenous human GPCR.This carrier is in Nikkei American type culture collection (American Type Culture Collection October 13 in 1998, ATCC) (0801 University Blvd., Manassas, VA 20110-2209 USA) deposits in the internationally recognized microorganism that is used for patented procedure under the regulation of budapest treaty (BudapestTreaty for the International Recognition of the Deposit of Microorganisms for the Purpose ofPatent Procedure) and deposit.DNA is tested by ATCC, and determines available.ATCC deposits numbering: ATCC#203351 below pCMV having been specified.
Claims (67)
1. the compound of a formula (Ia):
Or its pharmaceutically acceptable salt, hydrate or solvate,
Wherein:
X is that N and Z are CR
7, or X is CR
7And Z is N;
R
1And R
4Be selected from the group that forms by following each group independently of one another: H, C
1-6Acyl group, C
1-6Acyloxy, C
2-6Thiazolinyl, C
1-6Alkoxyl group, C
1-6Alkyl, C
1-6Alkylamino, C
1-6Alkyl formamides, C
1-6Alkylthio methane amide, C
2-6Alkynyl, C
1-6Alkyl sulfonamide, C
1-6Alkyl sulphinyl, C
1-6Alkyl sulphonyl, C
1-6Alkylthio, C
1-6Alkyl sulfide urea groups, C
1-6Alkyl urea groups, amino, C
1-6-alkylamidoalkyl, amino-C
1-6-alkyl sulphonyl, C
1-6-alkylthioamide base, C
1-6-alkoxy carbonyl, methane amide, carboxyl, cyano group, C
3-7Cycloalkyl, C
2-6Dialkylamino, C
1-6Dialkylformamide, C
1-6Dialkyl group thioformamide, halogen, C
1-6Halogen alkoxyl group, C
1-6Alkylhalide group, C
1-6Alkylhalide group sulfinyl, C
1-6Alkylhalide group alkylsulfonyl, C
1-6Alkylhalide group sulfenyl, heterocyclic radical, hydroxyl, nitro, sulphonamide and mercaptan;
R
2And R
3Be selected from the group that forms by following each group independently of one another: H, C
1-6Acyl group, C
1-6Acyloxy, C
2-6Thiazolinyl, C
1-6Alkoxyl group, C
1-6Alkyl, C
1-6Alkylamino, C
1-6Alkyl formamides, C
1-6Alkylthio methane amide, C
2-6Alkynyl, C
1-6Alkyl sulfonamide, C
1-6Alkyl sulphinyl, C
1-6Alkyl sulphonyl, C
1-6Alkylthio, C
1-6Alkyl sulfide urea groups, C
1-6Alkyl urea groups, amino, C
1-6-alkylamidoalkyl, amino-C
1-6-alkyl sulphonyl, C
1-6-alkylthioamide base, aryl sulfonyl kia, aryl sulfonyl, arylthio, amidino, C
1-6-alkoxy carbonyl, methane amide, carboxyl, cyano group, C
3-7Cycloalkyl, C
3-7Cycloalkyloxy, C
2-6Dialkylamino, C
1-6Dialkylformamide, C
1-6Dialkyl group thioformamide, C
1-6-dialkyl amide base, C
1-6-dialkyl group thioamides base, halogen, C
1-6Halogen alkoxyl group, C
1-6Alkylhalide group, C
1-6Alkylhalide group sulfinyl, C
1-6Alkylhalide group alkylsulfonyl, C
1-6Alkylhalide group sulfenyl, heterocyclic radical, heterocyclyloxy base, heterocyclic radical alkylsulfonyl, heterocyclic radical carbonyl, heteroaryl, heteroaryl carbonyl, hydroxyl, nitro, C
4-7Oxo-cycloalkyl, phenoxy group, phenyl, sulphonamide, sulfonic acid and mercaptan; Wherein said C
1-6The alkyl substituting group through being selected from the group that is made up of following each group according to circumstances replaces: C
1-6Acyl group, C
1-6Acyloxy, C
1-6Alkoxyl group, C
1-6Alkylamino, C
1-6Alkyl sulphinyl, C
1-6Alkyl sulphonyl, C
1-6Alkylthio, amino, C
1-6-alkoxy carbonyl, methane amide, carboxyl, cyano group, C
3-7Cycloalkyl, C
3-7Cycloalkyloxy, C
2-6Dialkylamino, C
1-6Halogen alkoxyl group, C
1-6Alkylhalide group sulfinyl, C
1-6Alkylhalide group alkylsulfonyl, C
1-6Alkylhalide group sulfenyl, hydroxyl, nitro, phenoxy group and phenyl; Or
R
2And R
3Form C jointly together with both carbon of institute's bond
3-6Cycloalkyl;
R
5And R
6Be selected from the group that forms by following each group independently of one another: H, C
1-6Acyl group, C
1-6Acyloxy, C
2-6Thiazolinyl, C
1-6Alkoxyl group, C
1-6Alkyl, C
1-6Alkylamino, C
1-6Alkyl formamides, C
1-6Alkylthio methane amide, C
2-6Alkynyl, C
1-6Alkyl sulfonamide, C
1-6Alkyl sulphinyl, C
1-6Alkyl sulphonyl, C
1-6Alkylthio, C
1-6Alkyl sulfide urea groups, C
1-6Alkyl urea groups, amino, C
1-6-alkoxy carbonyl, methane amide, carboxyl, cyano group, C
3-7Cycloalkyl, C
2-6Dialkylamino, C
1-6Dialkylformamide, C
1-6Dialkyl group thioformamide, halogen, C
1-6Halogen alkoxyl group, C
1-6Alkylhalide group, C
1-6Alkylhalide group sulfinyl, C
1-6Alkylhalide group alkylsulfonyl, C
1-6Alkylhalide group sulfenyl, heterocyclic radical, hydroxyl, nitro, sulphonamide and mercaptan; And
R
7Be C
1-6-alkoxy carbonyl, carboxyl or tetrazolium-5-base.
2. compound according to claim 1, wherein:
R
2And R
3Be selected from the group that forms by following each group independently of one another: H, C
1-6Acyl group, C
1-6Acyloxy, C
2-6Thiazolinyl, C
1-6Alkoxyl group, C
1-6Alkyl, C
1-6Alkylamino, C
1-6Alkyl formamides, C
1-6Alkylthio methane amide, C
2-6Alkynyl, C
1-6Alkyl sulfonamide, C
1-6Alkyl sulphinyl, C
1-6Alkyl sulphonyl, C
1-6Alkylthio, C
1-6Alkyl sulfide urea groups, C
1-6Alkyl urea groups, amino, C
1-6-alkylamidoalkyl, amino-C
1-6-alkyl sulphonyl, C
1-6-alkylthioamide base, aryl sulfonyl kia, aryl sulfonyl, arylthio, amidino, C
1-6-alkoxy carbonyl, methane amide, carboxyl, cyano group, C
3-7Cycloalkyl, C
3-7Cycloalkyloxy, C
2-6Dialkylamino, C
1-6Dialkylformamide, C
1-6Dialkyl group thioformamide, C
1-6Dialkyl amide base, C
1-6Dialkyl group thioamides base, halogen, C
1-6Halogen alkoxyl group, C
1-6Alkylhalide group, C
1-6Alkylhalide group sulfinyl, C
1-6Alkylhalide group alkylsulfonyl, C
1-6Alkylhalide group sulfenyl, heterocyclic radical, heterocyclyloxy base, heterocyclic radical alkylsulfonyl, heterocyclic radical carbonyl, heteroaryl, heteroaryl carbonyl, hydroxyl, nitro, C
4-7Oxo-cycloalkyl, phenoxy group, phenyl, sulphonamide, sulfonic acid and mercaptan; Wherein said C
1-6The alkyl substituting group through being selected from the group that is made up of following each group according to circumstances replaces: C
1-6Acyl group, C
1-6Acyloxy, C
1-6Alkoxyl group, C
1-6Alkylamino, C
1-6Alkyl sulphinyl, C
1-6Alkyl sulphonyl, C
1-6Alkylthio, amino, C
1-6-alkoxy carbonyl, methane amide, carboxyl, cyano group, C
3-7Cycloalkyl, C
3-7Cycloalkyloxy, C
2-6Dialkylamino, C
1-6Halogen alkoxyl group, C
1-6Alkylhalide group sulfinyl, C
1-6Alkylhalide group alkylsulfonyl, C
1-6Alkylhalide group sulfenyl, hydroxyl, nitro, phenoxy group and phenyl.
3. compound according to claim 1 and 2, its restricted condition are R
1With R
4Be cis each other.
4. according to the described compound of arbitrary claim in the claim 1 to 3, wherein X is N; Z is CR
7And R
7Be C
1-6-alkoxy carbonyl or carboxyl.
5. according to the described compound of arbitrary claim in the claim 1 to 3, wherein X is N; Z is CR
7And R
7Be carboxyl.
6. according to the described compound of arbitrary claim in the claim 1 to 3, wherein X is N; Z is CR
7And R
7Be tetrazolium-5-base.
7. according to the described compound of arbitrary claim in the claim 1 to 3, wherein X is CR
7R
7Be C
1-6-alkoxy carbonyl or carboxyl; And Z is N.
8. according to the described compound of arbitrary claim in the claim 1 to 3, wherein X is CR
7R
7Be carboxyl; And Z is N.
9. according to the described compound of arbitrary claim in the claim 1 to 3, wherein X is CR
7R
7Be tetrazolium-5-base; And Z is N.
10. according to the described compound of arbitrary claim, wherein R in the claim 1 to 9
1Be H or halogen.
11. according to the described compound of arbitrary claim, wherein R in the claim 1 to 9
1Be H.
12. according to the described compound of arbitrary claim, wherein R in the claim 1 to 11
4Be H or halogen.
13. according to the described compound of arbitrary claim, wherein R in the claim 1 to 11
4Be H.
14. according to the described compound of arbitrary claim, wherein R in the claim 1 to 9
1With R
4Be H.
15. according to the described compound of arbitrary claim, wherein R in the claim 1 to 14
5Be H or halogen.
16. according to the described compound of arbitrary claim, wherein R in the claim 1 to 14
5Be H.
17. according to the described compound of arbitrary claim, wherein R in the claim 1 to 16
6Be H or halogen.
18. according to the described compound of arbitrary claim, wherein R in the claim 1 to 16
6Be H.
19. according to the described compound of arbitrary claim, wherein R in the claim 1 to 14
5With R
6Be H.
20. according to the described compound of arbitrary claim, wherein R in the claim 1 to 9
1, R
4, R
5And R
6H respectively does for oneself.
21. according to the described compound of arbitrary claim, wherein R in the claim 1 to 20
2And R
3Be selected from independently of one another by H, C
1-6The group that alkyl and halogen are formed; Wherein said C
1-6The alkyl substituting group through being selected from the group that is made up of following each group according to circumstances replaces: C
1-6Acyloxy, C
1-6Alkoxyl group, C
1-6Alkylamino, C
1-6Alkyl sulphinyl, C
1-6Alkyl sulphonyl, C
1-6Alkylthio, amino, C
3-7Cycloalkyloxy, C
2-6Dialkylamino, C
1-6Halogen alkoxyl group, C
1-6Alkylhalide group sulfinyl, C
1-6Alkylhalide group alkylsulfonyl, C
1-6Alkylhalide group sulfenyl, hydroxyl, phenoxy group and phenyl.
22. according to the described compound of arbitrary claim, wherein R in the claim 1 to 20
2Be H or C
1-6Alkyl; And R
3Be H, C
1-6Alkyl or halogen; Wherein said C
1-6The alkyl substituting group through being selected from the group that is made up of following each group according to circumstances replaces: C
1-6Acyloxy, C
1-6Alkoxyl group, C
1-6Alkylamino, C
1-6Alkyl sulphinyl, C
1-6Alkyl sulphonyl, C
1-6Alkylthio, amino, C
3-7Cycloalkyloxy, C
2-6Dialkylamino, C
1-6Halogen alkoxyl group, C
1-6Alkylhalide group sulfinyl, C
1-6Alkylhalide group alkylsulfonyl, C
1-6Alkylhalide group sulfenyl, hydroxyl, phenoxy group and phenyl.
23. according to the described compound of arbitrary claim, wherein R in the claim 1 to 20
2Be H or C
1-6Alkyl; And R
3Be H, C
2-6Thiazolinyl, C
1-6Alkyl, C
3-7Cycloalkyl, halogen or phenyl; Wherein said C
1-6The alkyl substituting group through being selected from the group that is made up of following each group according to circumstances replaces: C
1-6Alkoxyl group, C
1-6Alkylthio, hydroxyl, phenoxy group and phenyl; Or
R
2And R
3Form cyclopropyl, cyclopentyl or cyclohexyl jointly together with both carbon of institute's bond.
24. according to the described compound of arbitrary claim, wherein R in the claim 1 to 20
2Be H or C
1-6Alkyl; And R
3Be H, C
2-6Thiazolinyl, C
1-6Alkyl, halogen or phenyl; Wherein said C
1-6The alkyl substituting group through being selected from the group that is made up of following each group according to circumstances replaces: C
1-6Alkoxyl group, hydroxyl, phenoxy group and phenyl.
25. according to the described compound of arbitrary claim, wherein R in the claim 1 to 20
2Be H or CH
3And R
3Be H, CH
3Or benzyl.
26. according to the described compound of arbitrary claim, wherein R in the claim 1 to 20
2Be H or CH
3And R
3Be H, methyl, ethyl, n-propyl, sec.-propyl, isobutyl-, normal-butyl, n-pentyl, vinyl, methylol, methoxymethyl, benzyl, phenyl or phenoxymethyl.
27. according to the described compound of arbitrary claim, wherein R in the claim 1 to 20
2Be H or CH
3And R
3Be H, methyl, ethyl, n-propyl, sec.-propyl, isobutyl-, normal-butyl, n-pentyl, vinyl, methylol, methoxymethyl, benzyl, phenyl, phenoxymethyl, methyl sulfenyl methyl, ethoxyl methyl, cyclopropyl, 1-fourth-2 thiazolinyl or allyl group; Or
R
2And R
3Form cyclopropyl, cyclopentyl or cyclohexyl jointly together with both carbon of institute's bond.
28. according to the described compound of arbitrary claim in the claim 1 to 3, wherein:
X is N, and Z is CR
7, R wherein
7For carboxyl ,-CO
2Et or tetrazolium-5-base; Or
X is CR
7, R wherein
7For carboxyl ,-CO
2Et or tetrazyl, and Z is N;
R
1, R
4, R
5And R
6H respectively does for oneself;
R
2Be H or CH
3And
R
3Be H, methyl, ethyl, n-propyl, sec.-propyl, isobutyl-, normal-butyl, n-pentyl, vinyl, methylol, methoxymethyl, benzyl, phenyl or phenoxymethyl; Or
Its pharmaceutically acceptable salt, hydrate or solvate.
29. according to the described compound of arbitrary claim in the claim 1 to 3, wherein:
X is N, and Z is CR
7, and R
7For carboxyl ,-CO
2Et or tetrazolium-5-base;
R
1, R
4, R
5And R
6H respectively does for oneself;
R
2Be H or CH
3And
R
3Be H, methyl, ethyl, n-propyl, sec.-propyl, isobutyl-, normal-butyl, n-pentyl, vinyl, methylol, methoxymethyl, benzyl, phenyl or phenoxymethyl; Or
Its pharmaceutically acceptable salt, hydrate or solvate.
30. according to the described compound of arbitrary claim in the claim 1 to 3, wherein:
X is N, and Z is CR
7, and R
7Be carboxyl; Or
X is CR
7, R
7Be carboxyl or tetrazolium-5-base, and Z is N;
R
1, R
4, R
5And R
6H respectively does for oneself;
R
2Be H or CH
3And
R
3Be H, CH
3Or benzyl; Or
Its pharmaceutically acceptable salt, hydrate or solvate.
31. according to the described compound of arbitrary claim in the claim 1 to 3, it has following array structure:
Or its pharmaceutically acceptable salt, solvate or hydrate.
32. according to the described compound of arbitrary claim in the claim 1 to 3, it has following array structure:
Or its pharmaceutically acceptable salt, solvate or hydrate.
33. according to the described compound of arbitrary claim in the claim 1 to 3, it is to be selected from the group that is made up of following each thing:
3b, 4,4a, 5-tetrahydrochysene-2H-ring third [3,4] ring penta [1,2-c] pyrazoles-3-formic acid;
1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid; With
4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene; Or its pharmaceutically acceptable salt, hydrate or solvate.
34. compound according to claim 33, the stereochemistry of wherein being appointed as two carbon of 3b and 4a or 1a and 5a is R.
35. according to the described compound of arbitrary claim in the claim 1 to 3, it is to be selected from the group that is made up of following each thing:
1-benzyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid;
1,1-dimethyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid;
1,1-dimethyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene; With
1-benzyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene; Or its pharmaceutically acceptable salt, hydrate or solvate.
36. according to the described compound of arbitrary claim in the claim 1 to 3, it is to be selected from the group that is made up of following each thing:
1-methyl isophthalic acid a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid;
1-isobutyl--1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid;
1-butyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid;
1-amyl group-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid;
1-propyl group-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid;
1-methoxymethyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid;
1-ethyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid;
1-benzyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid;
1-benzyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate;
1,1-dimethyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate;
1-phenyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate;
1-phenyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid;
1-ethyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate;
1-methyl isophthalic acid a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate;
1-amyl group-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate;
1-sec.-propyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid;
1-vinyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate;
1-vinyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid;
1-ethyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate;
1-methoxymethyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate;
1-methylol-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-ethyl formate; With
1-methylol-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid; Or
Its pharmaceutically acceptable salt, hydrate or solvate.
37. according to the described compound of arbitrary claim in the claim 1 to 3, it is to be selected from the group that is made up of following each thing:
1-methyl sulfenyl methyl isophthalic acid a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid;
1-ethoxyl methyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid;
1-cyclopropyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid;
1-Spirocyclopropyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid;
(E)-and 1-propenyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid;
(Z)-and 1-propenyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid;
1-phenoxymethyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid;
Spiral shell [1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-1,1 '-pentamethylene]-4-formic acid;
Spiral shell [1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-1,1 '-hexanaphthene]-4-formic acid;
1-allyl group-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid; With
4-methyl-3b, 4,4a, 5-tetrahydrochysene-2H-ring third [3,4] ring penta [1,2-c] pyrazoles-3-formic acid;
1-cyclopropyl methyl isophthalic acid a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-4-formic acid; Or
Its pharmaceutically acceptable salt, hydrate or solvate.
38. according to the described compound of arbitrary claim in the claim 1 to 3, it is to be selected from the group that is made up of following each thing:
1-methyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene;
1-ethyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene;
1-propyl group-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene;
1-isobutyl--4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene;
1-phenyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene;
1-benzyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene;
1-amyl group-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene;
1-butyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene;
1-sec.-propyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene;
1-phenoxymethyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene;
4-(2H-tetrazolium-5-yl)-1-vinyl-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene;
1-methoxymethyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene; With
4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-1-yl]-methyl alcohol; Or its pharmaceutically acceptable salt, hydrate or solvate.
39. according to the described compound of arbitrary claim in the claim 1 to 3, it is to be selected from the group that is made up of following each thing:
1-cyclopropyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene;
1-Spirocyclopropyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene;
(E)-and 1-propenyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene;
(Z)-and 1-propenyl-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene;
5-(spiral shell-[and 1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-1,1 '-pentamethylene]-the 4-yl)-the 1H-tetrazolium;
5-(spiral shell-[and 1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene-1,1 '-hexanaphthene]-the 4-yl)-the 1H-tetrazolium; With
1-allyl group-4-(2H-tetrazolium-5-yl)-1a, 3,5,5a-tetrahydrochysene-1H-2,3-diaza-ring third [a] pentalene; Or its pharmaceutically acceptable salt, hydrate or solvate.
40. according to the described compound of arbitrary claim in the claim 35 to 39, the stereochemistry of the carbon of the wherein said 1a of being appointed as is that the stereochemistry of the carbon of R and the described 5a of being appointed as is S.
41., be interior type wherein with the described stereochemistry of being appointed as the preferred group of 1 carbon bond knot according to the described compound of arbitrary claim in the claim 31 to 40.
42., be external form wherein with the described stereochemistry of being appointed as the preferred group of 1 carbon bond knot according to the described compound of arbitrary claim in the claim 31 to 40.
43. a medical composition, it comprises the described compound of arbitrary claim in the claim 1 to 42 that makes up with pharmaceutically acceptable supporting agent.
44. according to the described medical composition of claim 43, it further comprises the medicament that is selected from the group that is made up of following each thing: alpha-glucosidase inhibitor, aldose reductase inhibitor, biguanides, HMG-CoA reductase inhibitor, squalene synthetic inhibitor, Bei Te (fibrate), LDL katabolism toughener, angiotonin converting enzyme inhibitor, insulin secretion enhancers, thiazolidinedione and DP receptor antagonist.
45. a method for the treatment of metabolic-related disorders, it comprises described compound of arbitrary claim or the described medical composition of claim 43 in the claim 1 to 42 of the individuality throwing of this treatment of needs and treatment significant quantity.
46. a method for the treatment of metabolic-related disorders, it comprises described compound of arbitrary claim and DP receptor antagonist in the claim 1 to 42 of the individuality throwing of this treatment of needs and treatment significant quantity.
47. according to the described method of claim 46, wherein said DP receptor antagonist is to be selected from the group that is made up of following each thing:
Or its pharmaceutically acceptable salt, solvate or hydrate.
48. a method of regulating the RUP25 acceptor, it comprises makes described acceptor contact with the described compound of arbitrary claim in the claim 1 to 42.
49. the method for metabolic-related disorders in the individuality of regulating the RUP25 acceptor and need with treatment this adjusting, it comprises, and the described compound of arbitrary claim contacts in the claim 1 to 42 that makes described acceptor and treatment significant quantity.
50. according to claim 48 or 49 described methods, wherein said compound is an agonist.
51. according to the described method of claim 50, wherein said agonist is the part agonist.
52. treat and need the atherosis method of the atherosclerotic human patients medium sized artery of treatment for one kind, it comprises the described compound of arbitrary claim in the claim 1 to 42 of described patient's throwing and the atherosclerotic amount of effective treatment.
53. a method for the treatment of hyperlipemia in the human patients that needs the treatment hyperlipemia, it comprises the described compound of arbitrary claim in the claim 1 to 42 of the amount of described patient's throwing and effective treatment hyperlipemia.
54. the method for HDL in the individuality that raises, it comprises the described compound of arbitrary claim in described individual claim 1 to 42 of throwing with the treatment significant quantity.
55. according to the described method of arbitrary claim in claim 45 to 47 and 49 to 54, wherein said individuality is a Mammals.
56. according to the described method of claim 55, wherein said Mammals is human.
57. according to the described compound of arbitrary claim in the claim 1 to 42, it is the methods of treatment that is used for the mankind or animal body by treatment.
58. according to the described compound of arbitrary claim in the claim 1 to 42, it is the methods of treatment that is used for the metabolic-related disorders of the mankind or animal body by treatment.
59. according to the described compound of arbitrary claim in the claim 1 to 42, it is the methods of treatment that is used for the metabolic-related disorders of the mankind or animal body by treatment, and wherein said metabolic-related disorders is to be selected from the group that is made up of following each illness: hyperlipemia, atherosclerosis, coronary heart disease, insulin resistant, obesity, glucose dosis tolerata go down, atheromatous disease, hypertension, apoplexy, X syndromes, heart trouble and diabetes B.
60. according to the described compound of arbitrary claim in the claim 1 to 42, it is the methods of treatment that is used for the metabolic-related disorders of the mankind or animal body by treatment, and wherein said metabolic-related disorders is to be selected from the group that is made up of following each illness: hyperlipemia, atherosclerosis, coronary heart disease, insulin resistant and diabetes B.
61. according to the described compound of arbitrary claim in the claim 1 to 42, it is the atherosclerosis therapy method that is used for the mankind or animal body by treatment.
62. according to the described compound of arbitrary claim in the claim 1 to 42, it is the rising method that is used for the mankind or animal body HDL by treatment.
63. the purposes of the described compound of arbitrary claim in the claim 1 to 42, it is to be used to make the medicine of using for the treatment metabolic-related disorders.
64. the purposes of the described compound of arbitrary claim in the claim 1 to 42, it is to be used to make the medicine of using for the treatment metabolic-related disorders, and described metabolic-related disorders is to be selected from the group that is made up of following each illness: hyperlipemia, atherosclerosis, coronary heart disease, insulin resistant, obesity, glucose dosis tolerata go down, atheromatous disease, hypertension, apoplexy, X syndromes, heart trouble and diabetes B.
65. the purposes of the described compound of arbitrary claim in the claim 1 to 42, it is to be used to make the medicine of using for the treatment atherosclerosis.
66. the purposes of the described compound of arbitrary claim in the claim 1 to 42, it is to be used for making the medicine of using for rising individuality HDL.
67. a method for preparing medical composition, it comprises the described compound of arbitrary claim in the claim 1 to 42 is mixed mutually with pharmaceutically acceptable supporting agent.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US63866804P | 2004-12-23 | 2004-12-23 | |
| US60/638,668 | 2004-12-23 | ||
| US60/676,521 | 2005-04-29 |
Related Child Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011102214069A Division CN102321024A (en) | 2004-12-23 | 2005-12-22 | Fused pyrazole derivatives and methods of treatment of metabolic-related disorders thereof |
| CN2011102214054A Division CN102311378A (en) | 2004-12-23 | 2005-12-22 | Fused pyrazole derivatives and uses thereof in methods of treatment of metabolic-related disorders |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101087765A true CN101087765A (en) | 2007-12-12 |
Family
ID=38938221
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200580044454 Pending CN101087765A (en) | 2004-12-23 | 2005-12-22 | Fused pyrazole derivatives and uses of methods of treatment of metabolic-related disorders thereof |
Country Status (4)
| Country | Link |
|---|---|
| CN (1) | CN101087765A (en) |
| CR (1) | CR9178A (en) |
| UA (1) | UA90878C2 (en) |
| ZA (1) | ZA200705147B (en) |
-
2005
- 2005-12-22 CN CN 200580044454 patent/CN101087765A/en active Pending
- 2005-12-22 UA UAA200708375A patent/UA90878C2/en unknown
-
2007
- 2007-06-12 CR CR9178A patent/CR9178A/en not_active Application Discontinuation
- 2007-06-21 ZA ZA200705147A patent/ZA200705147B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CR9178A (en) | 2007-10-23 |
| UA90878C2 (en) | 2010-06-10 |
| ZA200705147B (en) | 2008-10-29 |
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