CN1980664B - CRTH2 receptor ligands for therapeutic use - Google Patents
CRTH2 receptor ligands for therapeutic use Download PDFInfo
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- CN1980664B CN1980664B CN2005800226257A CN200580022625A CN1980664B CN 1980664 B CN1980664 B CN 1980664B CN 2005800226257 A CN2005800226257 A CN 2005800226257A CN 200580022625 A CN200580022625 A CN 200580022625A CN 1980664 B CN1980664 B CN 1980664B
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- phenoxy group
- carbonyl
- pyrazoles
- acetic acid
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- 0 CC(c1cnc(C)[n]1*)=O Chemical compound CC(c1cnc(C)[n]1*)=O 0.000 description 19
- PSOZJOZKEVZLKZ-UHFFFAOYSA-N Cc1c[o]c(C)n1 Chemical compound Cc1c[o]c(C)n1 PSOZJOZKEVZLKZ-UHFFFAOYSA-N 0.000 description 2
- OBSLLHNATPQFMJ-UHFFFAOYSA-N Cc1c[s]c(C)n1 Chemical compound Cc1c[s]c(C)n1 OBSLLHNATPQFMJ-UHFFFAOYSA-N 0.000 description 2
- FICAQKBMCKEFDI-UHFFFAOYSA-N Cc1n[o]c(C)c1 Chemical compound Cc1n[o]c(C)c1 FICAQKBMCKEFDI-UHFFFAOYSA-N 0.000 description 2
- HNJOAIYFUCQZAA-UHFFFAOYSA-N Cc1n[o]c(C)n1 Chemical compound Cc1n[o]c(C)n1 HNJOAIYFUCQZAA-UHFFFAOYSA-N 0.000 description 2
- KNQHSUACZOGVNT-AYPPTXKOSA-N CC(/C(/C=N)=C/NC)=O Chemical compound CC(/C(/C=N)=C/NC)=O KNQHSUACZOGVNT-AYPPTXKOSA-N 0.000 description 1
- GPKBITHTJCBAHO-DAXSKMNVSA-N CC(C)/C=C(/C(C)=O)\NN Chemical compound CC(C)/C=C(/C(C)=O)\NN GPKBITHTJCBAHO-DAXSKMNVSA-N 0.000 description 1
- UQKWNJQBFPROCJ-DAXSKMNVSA-N CC(C)/C=C(/C(C)=O)\ON Chemical compound CC(C)/C=C(/C(C)=O)\ON UQKWNJQBFPROCJ-DAXSKMNVSA-N 0.000 description 1
- FJQRCBASFPJECV-UHFFFAOYSA-N CC(C)c1cnc(C)[o]1 Chemical compound CC(C)c1cnc(C)[o]1 FJQRCBASFPJECV-UHFFFAOYSA-N 0.000 description 1
- RWAKMHCXYVOYAB-UHFFFAOYSA-N CC(C1C=NC(C)=NC1)=O Chemical compound CC(C1C=NC(C)=NC1)=O RWAKMHCXYVOYAB-UHFFFAOYSA-N 0.000 description 1
- SZYIVZGXCXFXDN-UHFFFAOYSA-N CC(c1c[n](C)cc1)=O Chemical compound CC(c1c[n](C)cc1)=O SZYIVZGXCXFXDN-UHFFFAOYSA-N 0.000 description 1
- QGZWNTJKBUPORC-UHFFFAOYSA-N CC(c1c[n](C)cn1)O Chemical compound CC(c1c[n](C)cn1)O QGZWNTJKBUPORC-UHFFFAOYSA-N 0.000 description 1
- LPQFLJXNMCVMCO-UHFFFAOYSA-N CC(c1cnc(C)cn1)=O Chemical compound CC(c1cnc(C)cn1)=O LPQFLJXNMCVMCO-UHFFFAOYSA-N 0.000 description 1
- ZKAIVKBIXUIQEU-UHFFFAOYSA-N CC1(CC2)[O]2CCC1CC(C=C)=C Chemical compound CC1(CC2)[O]2CCC1CC(C=C)=C ZKAIVKBIXUIQEU-UHFFFAOYSA-N 0.000 description 1
- SZAWGEKFHSJLCD-UHFFFAOYSA-N COc1ccc(CC2OC=C(c(cc(cc3)Br)c3OCC(O)=O)N2)cc1 Chemical compound COc1ccc(CC2OC=C(c(cc(cc3)Br)c3OCC(O)=O)N2)cc1 SZAWGEKFHSJLCD-UHFFFAOYSA-N 0.000 description 1
- LLPKQRMDOFYSGZ-UHFFFAOYSA-N Cc1c[nH]c(C)n1 Chemical compound Cc1c[nH]c(C)n1 LLPKQRMDOFYSGZ-UHFFFAOYSA-N 0.000 description 1
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Abstract
Compounds of formula (I) are useful for the treatment of disease responsive to modulation of CRTH2 receptor activity, such as asthma, rhinitis, allergic airway syndrome, and allergic rhinobronchitis; wherein X1 is -S-, -O-, -N=N-. -NR7-, -CR7=CR8-, -CR7=N-, wherein R7 and R8 are independently hydrogen or C1-C3 alkyl; A is a carboxyl group -COOH, or a carboxyl bioisostere; rings Ar<2> and Ar<3> each independently represent a phenyl or 5- or 6-membered monocyclic heteroaryl ring, or a bicyclic ring system consisting of a 5- or 6-membered carbocyclic or heterocyclic ring which is benz-fused or fused to a 5- or 6-membered monocyclic heteroaryl ring, said ring or ring system being optionally substituted; ring B is as defined for Ar<2> and Ar<3>, or an optionally substituted N-pyrrolidinyl, N-piperidinyl or N-azepinyl ring; s is 0 or 1; L1, L2 and L4 are linker radicals as defined in the description; Q1 and Q2 represent substituents as defined in the description.
Description
The present invention relates to has the disease of response in treatment to regulating the CRTH2 receptor active as a compounds of CRTH2 receptor (being expressed in the chemoattractant receptor-homology molecule on the 2 type t helper cells) part, mainly is the application that has in the disease of remarkable inflammatory component.The present invention also relates to the newcomer and the pharmaceutical composition that contains them of this class part.
Known multiclass anti-inflammatory drug comprises the nonsteroid anti-inflammatory drugs that is called NSAID and the inhibitor of cyclo-oxygenase (COX-1 and COX-2).Have in the ring therein the substituent benzoylphenylacetic acids of carboxyl methoxyl group and some benzophenone derivates be accredited as anti-inflammatory drug (referring to; Khanum etc. for example; Bioorganic Chemistry; the 32nd volume; No. 4; 2004, the 211-222 pages or leaves and the list of references of wherein being quoted).There is report to say that some adjacent phenyl amino formoxyl-phenoxyacetic acids and neighbour-benzamido-phenoxymethyl tetrazolium are possible anti-inflammatory drugs, referring to for example Drain etc., J.Pharm.Pharmac., 1971,23,857-864 and as above, 1970,22,684-693.WO 99/15520 discloses some and had carboxyl methoxyl group or the substituent benzophenone derivates of tetrazole radical methoxyl group in a ring, it is said that the synthetic member that this organizes derivant of institute has the activity as peroxisome proliferation-activated receptors (PPAR) inhibitor, and can be used for various diseases, comprise diabetes, heart disease and blood circulation disease.
The native ligand of g protein coupled receptor CRTH2 is a Prostaglandin D2.Hint that as its name CRTH2 is expressed on the 2 type t helper cells (Th2), but also known it can be expressed on eosinophilic granulocyte and the basophilic granulocyte.The active cell and then cause complicated biological answer-reply thereby PGD2 combines with the CRTH2 receptor comprises that inflammatory mediator discharges.Therefore, it is relevant with many diseases with strong inflammatory component that the PGD2 level raises, for example asthma, rhinitis and allergy.So blocking-up PGD2 can be the useful therapeutic scheme of this disease of treatment with combining of CRTH2 receptor.
Some are known as the micromolecule CRTH2 part of PGD2 antagonist obviously, for example, in following patent disclosure, proposed: WO 03/097042, WO 03/097598, WO03/066046, WO 03/066047, WO 03/101961, WO 03/101981, GB 2388540, WO 04/089885 and WO 05/018529.
The structure of mentioned PGD2 antagonist has bicyclo-relevant with the indole nucleus of indomethacin or tricyclic ring thimble system in more above-mentioned patent disclosures, and indomethacin is the present known and bonded antiinflammatory of CRTH2.Starting point of the present invention is to confirm a compounds, and this compounds has monocycle nuclear, and the substituent group of this monocycle nuclear partly is to examine by monocycle to select and locate, to interact with CRTH2 and to combine.Therefore, the type of compounds that the present invention relates to can be regulated the CRTH2 activity, can be used for treating the disease that can have benefited from this adjusting, for example asthma, allergy and rhinitis.
According to the present invention, compound or its salt, hydrate or the solvate that a kind of general formula (I) be provided is used for the treatment of the application in the compositions of disease of regulating the CRTH2 receptor active and have response in preparation:
In the formula:
A represents carboxyl-COOH or carboxyl bioisostere thing (bioisostere);
A
1Be hydrogen or methyl;
Ring Ar
1Be optional phenyl ring that replaces or 5-or 6-unit monocycle hetero-aromatic ring, wherein AA
1CHO-and L2 are connected on the adjacent annular atoms;
Ring Ar
2, Ar
3Represent phenyl ring independently of one another, or 5-or 6-unit monocycle hetero-aromatic ring, or by 5-or 6-unit carbocyclic ring or heterocycle with benzene condenses or condense two member ring systems of forming with 5-or 6-unit monocycle hetero-aromatic ring, described ring or member ring systems are chosen wantonly and are substituted;
T is 0 or 1;
L2 and L3 represent that independently of one another general formula is-(Alk
1)
m-(Z)
n-(Alk
2)
pBilvalent radical, wherein
M, n and p are 0 or 1 independently,
Alk
1And Alk
2Be the optional straight or branched C that replaces independently
1-C
3Alkylidene or C
2-C
3Alkenylene (alkenylene), can contain compatible-O-,-S-or-the NR-key, wherein R is hydrogen or C
1-C
3Alkyl, and
Z is-O-,-S-,-C (=O)-,-SO
2-,-SO-,-NR-,-NRSO
2-,-SO
2NR-,-C (=O) NR-,-NRC (=O)-,-NRCONH-,-NHCONR-,-NRC (=NR) NH-,-NHC (=NR) NR-,-C (R)=N-NR-or-NR-N=C (R)-, wherein R is hydrogen or C
1-C
3Alkyl; Or the 5-of bivalence or 6-unit's monocycle carbocyclic ring or heterocyclic radical,
Prerequisite is:
(A) total length of L2 and L3 is no more than the length of the not branching saturated chain of 10 carbon atoms;
(B) work as Ar
2, when being the optional phenyl that replaces, L2 is not-C (=O)-,-C (=O) NR-or-NRC (=O)-;
(C) (a) L2 is not a key, (b) when n be 1, when Z was aryl or heteroaryl, the p among the L2 was not 0,
(D) (a) L2 be not-O-,-SO
2-,-NR-,-CHR
XR
Y-or-CH (R
X) (OR
Y)-, be R wherein
XAnd R
YBe hydrogen, halogen, C independently
1-C
6Alkyl, C
2-C
6Thiazolinyl, C
2-C
6Alkynyl or C
3-C
7Cycloalkyl or be connected to form ring, (b) when p be 1, n is 1, when Z is aryl or heteroaryl, Alk
2Be not-CHR
XR
Y-or-CH (R
X) (OR
Y)-, be R wherein
XAnd R
YBe hydrogen, halogen, C independently
1-C
6Alkyl, C
2-C
6Thiazolinyl, C
2-C
6Alkynyl or C
3-C
7Cycloalkyl or be connected to form ring.
In one aspect of the invention, in chemical compound (I), the length of L2 and L3 all is no more than the length of the not branching saturated chain of 5 carbon atoms respectively, (ii) the total length of L2 and L3 be no more than 7 carbon atoms not branching saturated chain length and (iii) L2 and L3 do not contain the R substituent group that is different from hydrogen more than two.
Of the present invention more specifically aspect, can use chemical compound (I), wherein A as defined above
1Be hydrogen, Z is-O-,-S-,-C (=O)-,-SO
2-,-SO-,-NR-,-NRSO
2-,-C (=O) NR-,-NRCONH-,-NRC (=NR) NH-or-C (R)=N-NR-, wherein R is hydrogen or C
1-C
3Alkyl; Or the 5-of bivalence or 6-unit's monocycle carbocyclic ring or heterocyclic radical.
Of the present invention another more specifically aspect, can use chemical compound (I) as defined above, wherein L2 be-N=CR-,-OCR
2C (=O) NR-N=CR-,-C (=O) NR-,-N=CR-,-C (=O)-,-CH=CHC (=O)-(CH
2)
0-3NRC (=O)-,-NRC (=O) (CH
2)
0-3-,-O-N=CH-,-CH
2NRCH
2-,-NR (CH
2)
1-3-,-(CH
2)
1-3NR-,-S-,-CH
2OCH
2-,-O (CH
2)
1-3-,-(CH
2)
1-3O-,-CH
2SCH
2-,-S (CH
2)
0-3,-(CH
2)
0-3S-, bivalence (C
2-C
6) alkylidene, bivalence (C
2-C
6) alkenylene or bivalence (C
2-C
6) alkynylene (alkynylene), wherein R is hydrogen or C
1-C
3Alkyl.
Of the present invention another more specifically aspect, can use chemical compound (I) as defined above, wherein L2 be-NRN=CH-,-ON=CH-or-N=CH-; Perhaps L2 be-C (=O)-; Perhaps L2 be-NHC (=O)-or-C (=O) NH-.
Compound or its salt, hydrate or the solvate that an independent aspects of the present invention is above-mentioned general formula (I) is used for the treatment of the application in the compositions of disease of regulating the CRTH2 receptor active and have response, wherein chemical compound (I) in preparation:
A represents carboxyl-COOH or carboxyl bioisostere thing;
A
1Be hydrogen or methyl;
Ring Ar
1Be optional phenyl ring that replaces or 5-or 6-unit monocycle hetero-aromatic ring, wherein AA
1CHO-and L2 are connected on the adjacent annular atoms;
Ring Ar
2, Ar
3From representing phenyl ring independently, or 5-or 6-unit's monocycle hetero-aromatic ring or by 5-or 6-unit carbocyclic ring or heterocycle with benzene condenses or condense two member ring systems of forming with 5-or 6-unit monocycle hetero-aromatic ring, described ring or member ring systems are chosen wantonly and are substituted;
T is 0 or 1;
L3 represents that general formula is-(Alk
1)
m-(Z)
n-(Alk
2)
pBilvalent radical, wherein
M, n and p are 0 or 1 independently,
Alk
1And Alk
2Be the optional straight or branched C that replaces independently
1-C
3Alkylidene or C
2-C
3Alkenylene, can contain compatible-O-,-S-or-the NR-key, wherein R is hydrogen or C
1-C
3Alkyl, and
Z is-O-,-S-,-C (=O)-,-SO
2-,-SO-,-NR-,-NRSO
2-,-SO
2NR-,-C (=O) NR-,-NRC (=O)-,-NRCONH-,-NHCONR-, NRC (=NR) NH-,-NHC (=NR) NR-,-C (R)=N-NR-or-NR-N=C (R)-or the 5-of bivalence or 6-unit's monocycle carbocyclic ring or heterocyclic radical, wherein R is hydrogen or C
1-C
3Alkyl;
L2 represents to be selected from the bilvalent radical (being sometimes referred to as " L2 organizes A " in the literary composition) of following general formula, wherein key and the Ar of (i) labelling *
2Connect, and key and the Ar of labelling * *
1Connect, perhaps (ii) the key of labelling * and Ar
1Connect, and key and the Ar of labelling * *
2Connect:
Wherein R is hydrogen or C
1-C
3Alkyl;
The total length of L2 and L3 is no more than the length of the not branching saturated chain of 10 carbon atoms.
The present invention aspect this more specifically in the definition, in chemical compound (I), (i) length of L3 is no more than the length of the not branching saturated chain of 5 carbon atoms, (ii) the total length of L2 and L3 be no more than 7 carbon atoms not branching saturated chain length and (iii) L3 do not comprise the R substituent group that is different from hydrogen more than two.
Of the present invention above-mentioned aspect latter two in, in chemical compound (I), A1 can be a hydrogen, L2 can be a kind of (being sometimes referred to as " L2 organizes B " in the literary composition) in the following general formula, wherein the key of labelling * and Ar
2Connect, and key and the Ar of labelling * *
1Connect:
Wherein R is hydrogen or C
1-C
3Alkyl.
The chemical compound that the present invention relates to is by defining with reference to general formula (I), as the result of study to the part binding site of explanation CRTH2.This research obtains a comprehensive conclusion, promptly comprises a negative charge part that roughly becomes three angular orientations and (is expressed as AA
1CHO-) and two aromatics and/or hydrophobic part (be expressed as Ar
2L2, and H (Ar
3)
tL3-Ar
1Or be Ar
1) general pharmacophore, form with receptors bind and put interactional arrangement.Conclusion is substituent A A
1CHO-and Ar
2L2-should be positioned at Ar
1, the adjacent ring atom on.Connect base (linker) L2 and L3 and make molecule have certain motility, so that best combination.To the restriction that connects basic L2 and L3 and substituent length wherein is to meet total molecule size and the structural complexity that the present invention uses in order to limit.For fear of query, and purpose for description and claims, the total length of L2 and L3 is the n2+n3 sum, wherein n2 is the number that connects the connection atom in the shortest atomic link between the two ends atom of basic L2, and n3 is the number that connects the connection atom in the shortest atomic link between the two ends atom of basic L2.The molecular weight of the chemical compound that preferably the present invention relates to is not more than 600.Definition in optional substituent group in any part of chemical compound (I) such as the chemical compound (I).These substituent groups can be regulated pharmacokinetics and dissolution properties, and other combination of acquisition and receptor.
On the other hand, the invention provides a kind of treatment suffers from and comprises the chemical compound that as above defines and describe (I) that gives effectively to improve the amount of disease to described object to regulating the CRTH2 receptor active and have the method for object of the disease of response, this method.
Particularly, the chemical compound that the present invention relates to can be used for the level rising diseases associated of treatment and Prostaglandin D2 (PGD2) or one or more its active metabolites.
The example of this class disease comprises asthma, rhinitis, anaphylaxis air flue syndrome, allergia nose's bronchitis, bronchitis, chronic obstructive pulmonary disease (COPD), nasal polyp, sarcoidosis, farmer lung, fibroid lung, cystic fibrosis, chronic cough, conjunctivitis, atopic dermatitis, Alzheimer, amyotrophic lateral sclerosis, acquired immune deficiency syndrome and dementia and syndrome, Huntington Chorea, frontotemporal dementia FTD disease (frontotemporal dementia), dementia with Lewy body disease, vascular dementia, Ge-Ba syndrome, chronic demyelinating polyradiculoneuropathy, multifocal motor neuropathy, clump is sick, multiple sclerosis, encephalomyelitis, panencephalitis, cerebellar degeneration and encephalomyelitis, central nervous system injury, migraine, apoplexy, rheumatoid arthritis, ankylosing spondylitis, Behet disease, bursitis, carpal tunnel syndrome, inflammatory bowel, Crohn disease, ulcerative colitis, dermatomyositis, hlers-Danlos syndrome (EDS), fibromyalgia, MFP, osteoarthritis (OA), osteonecrosis, psoriatic arthritis, reiter syndrome (reactive arthritis), sarcoidosis, scleroderma, xerodermosteosis, soft tissue diseases, Still disease, tendinitis, polyarteritis nodosa (polyarteritis Nodossa), Wegner granulomatosis, myositis (polymyositis dermatomyositis), gout, atherosclerosis, lupus erythematosus, systemic lupus erythematosus (sle) (SLE), type i diabetes, the nephritic syndrome, glomerulonephritis, acute and chronic renal failure, eosinophilia fascitis (eosinophiliafascitis), Hyperimmunoglobulin E syndrome, sepsis, septic shock, intracardiac ischemia reperfusion damage (ischemic reperfusion injury in the heart), post-transplantation allograft rejection and graft versus host disease.
But the value of the chemical compound that the present invention relates to is mainly reflected in treatment asthma, rhinitis, anaphylaxis air flue syndrome and allergia nose's bronchitis.
The chemical compound of above-mentioned many general formulas (I) is novel with regard to their rights own, the present invention includes these novel chemical compounds itself.
Used term " (C in the literary composition
a-C
b) alkyl " refer to have the straight or branched alkyl of a to b carbon atom, wherein a and b are integers.Therefore, for example, when a is 1 and b when being 6, this term comprises methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, n-pentyl and n-hexyl.
Used term " bivalence (C in the literary composition
a-C
b) alkylidene " be meant saturated hydrocarbon chain with a to b carbon atom and two unsaturated valencys (unsatisfied valence), wherein a and b are integers.
Used term " (C in the literary composition
a-C
b) thiazolinyl " be meant straight or branched alkenyl part with a to b carbon atom and two keys of at least one E or Z spatial chemistry (if applicable), wherein a and b are integer.This term comprises, for example, and vinyl, pi-allyl, 1-and crotyl and 2-methyl-2-acrylic.
Used term " bivalence (C in the literary composition
a-C
b) alkenylene " be meant hydrocarbon chain with a to b carbon atom, at least one two key and two unsaturated valencys.
Used term " C in the literary composition
a-C
bAlkynyl " be meant to have two to six carbon atom and also have a triple-linked straight or branched alkyl, wherein a and b are integers.This term comprises, for example, and acetenyl, 1-and 2-propynyl, 1-, 2-and 3-butynyl, 1-, 2-, 3-and 4-pentynyl, 1-, 2-, 3-, 4-and 5-hexin base, 3-methyl isophthalic acid-butynyl, 1-methyl-valerylene base.
Used term " bivalence (C in the literary composition
a-C
b) alkynylene " be meant bivalent hydrocarbon chain with 2 to 6 carbon atoms, at least one triple bond and two unsaturated valencys, wherein a and b are integers.
Used term " carbocyclic ring " is meant that being up to 16 all is monocycle base, two cyclic groups or three cyclic groups of the annular atoms of carbon, comprises aryl and cycloalkyl in the literary composition.
Used term " cycloalkyl " is meant the monocycle saturated carbon cyclic group with 3-8 carbon atom in the literary composition, comprise, for example, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl and ring octyl group.
Nonrestrictive term " aryl " used in the literary composition is meant monocyclic, bicyclic or tricyclic isocyclic aryl, comprises having two bases by the direct-connected monocycle carbocyclic ring of covalent bond aromatic ring.The example of this class base is phenyl, xenyl and naphthyl.
Non-limiting term " heteroaryl " used in the literary composition is meant the heteroatomic monocyclic, bicyclic or tricyclic aryl that contains one or more S of being selected from, N and O, comprises having two these class monocycles that directly link to each other by covalent bond or passing through directly continuous this class monocycle of covalent bond and the base of a monocyclic aromatic rings.The example of this class base is thienyl, benzothienyl, furyl, benzofuranyl, pyrrole radicals, imidazole radicals, benzimidazolyl, thiazolyl, benzothiazolyl, isothiazolyl, benzisothiazole base, pyrazolyl, oxazolyl, benzoxazolyl, isoxazolyl, benzoisoxazole base, isothiazolyl, triazolyl, benzotriazole base, thiadiazolyl group, oxadiazole base, pyridine radicals, pyridazinyl, pyrimidine radicals, pyridazinyl, triazine radical, indyl and indazolyl.
Non-limiting term " heterocyclic radical " or " heterocycle " used in the literary composition comprise as defined above " heteroaryl ", also refer to contain the heteroatomic monocyclic, bicyclic or tricyclic non-aromatic group of one or more S of being selected from, N and O, and by contain one or more non-aromatic groups of this heteroatomic monocycle and another this base or with the covalently bound group of forming of monocycle carbocylic radical.The example of this class base is pyrrole radicals, furyl, thienyl, piperidyl, imidazole radicals, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl group, pyrazolyl, pyridine radicals, pyrrolidinyl, pyrimidine radicals, morpholinyl, piperazinyl, indyl, morpholinyl, benzofuranyl, pyranose, isoxazolyl, benzimidazolyl, methylenedioxyphenyl, ethylidene dioxy phenyl, dimaleoyl imino and succinimido.
Term " carboxyl bioisostere thing " be the term be familiar with of Pharmaceutical Chemist (referring to, for example " drug design and drug effect organic chemistry (The Organic Chemistry of DrugDesign and Drug Action) ", Richard B.Silverman, pub.Academic Press, 1992), be meant the group that has with the similar Acid-Base feature of carboxyl.Well-known carboxyl bioisostere thing comprises-SO
2NHR or-P (=O) (OH) (OR) (wherein R is, for example, hydrogen methyl or ethyl) ,-SO
2OH ,-P (=O) (OH) (NH
2) ,-C (=O) NHCN and meet the group of following general formula:
Unless the place of Chu Xianing has explanation in addition in the text, the term " replacement " that is applied to any part in the literary composition is meant at most and replaced by four compatible substituent groups, and each substituent group is independently, for example, and (C
1-C
6) alkyl, (C
1-C
6) alkoxyl, hydroxyl, hydroxyl (C
1-C
6) alkyl, sulfydryl, sulfydryl (C
1-C
6) alkyl, (C
1-C
6) alkylthio group, halogen (comprising fluorine, bromine and chlorine), perfluorinate or partially fluorinated (C
1-C
3) alkyl, (C
1-C
3) alkoxyl or (C
1-C
3) alkylthio group such as trifluoromethyl, trifluoromethoxy and trifluoromethylthio, nitro, itrile group (and CN), oxo, phenyl, phenoxy group ,-COOR
A,-COR
A,-OCOR
A,-SO
2R
A,-CONR
AR
B,-SO
2NR
AR
B,-NR
AR
B,-OCONR
AR
B,-NR
BCOR
A,-NR
BCOOR
A,-NR
BSO
2OR
AOr-NR
ACONR
AR
B, R wherein
AAnd R
BBe hydrogen or (C independently
1-C
6) alkyl, perhaps at R
AAnd R
BWhen linking to each other with same N atom, R
AAnd R
BForm the amino ring of ring with this nitrogen-atoms together.When substituent group was phenyl or phenoxy group, its phenyl ring itself can be replaced by above-mentioned any substituent group except that phenyl or phenoxy group." optional substituent group " can be a kind of in the above-mentioned substituent group.
Term " salt " used in the literary composition comprises base addition salts, acid-addition salts and quaternary ammonium salt.Acid compound of the present invention can form salt (comprising pharmaceutically acceptable salt) with following listed alkali: alkali metal hydroxide for example, such as sodium hydroxide and potassium hydroxide; Alkaline earth metal hydroxide is such as calcium hydroxide, barium hydroxide and magnesium hydroxide; Organic base is such as N-methyl D-glycosamine, choline three (hydroxymethyl) amino-methane, L-arginine, L-lysine, N-ethylpiperidine, dibenzylamine etc.Those chemical compounds (I) for alkalescence can form salt (comprising pharmaceutically acceptable salt) with following listed acid: mineral acid, for example, halogen acids example hydrochloric acid or hydrobromic acid, sulphuric acid, nitric acid or phosphoric acid etc.; Organic acid, for example acetic acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malic acid, salicylic acid, citric acid, methanesulfonic acid, p-methyl benzenesulfonic acid, benzoic acid, benzenesulfonic acid, glutamic acid, lactic acid and mandelic acid etc.
Because have asymmetric atom or rotation restriction, chemical compound involved in the present invention can one or more stereoisomers form exist, can be used as and have the stereochemical a plurality of stereoisomers of R or S at each chiral centre and exist, or exist as have the stereochemical atropisomer of R or S at each chiral axis.The present invention includes all these class enantiomers and diastereomer and their mixture.
The prodrug of the chemical compound that the present invention relates to (I) such as the application of ester also are parts of the present invention.
For the application of the above-mentioned aspect of foundation the present invention, can there be following architectural feature in the chemical compound (I) with any compatible combining form:
L2 can be member's (certainly, L2 group A comprises L2 group B) of above-mentioned L2 group A;
L2 can be-N=CR-,-OCR
2C (=O) NR-N=CR-,-C (=O) NR-,-N=CR-,-C (=O)-,-CH=CHC (=O)--(CH
2)
0-3NRC (=O)-,-NRC (=O) (CH
2)
0-3-,-O-N=CH-,-CH
2NRCH
2-,-NR (CH
2)
1-3-,-(CH
2)
1-3NR-,-S-,-CH
2OCH
2-,-O (CH
2)
1-3-,-(CH
2)
1-3O-,-CH
2SCH
2-,-S (CH
2)
0-3-,-(CH
2)
0-3S-, bivalence (C
2-C
6) alkylidene, bivalence (C
2-C
6) alkenylene or bivalence (C
2-C
6) alkynylene, wherein R is hydrogen or C
1-C
3Alkyl; L2 can be-NRN=CH-,-ON=CH-,-N=CH-,-C (=O)-,-NHC (=O)-or-C (=O) NH-;
Ar
2Can be optional phenyl or 5-or the 6-membered nitrogen-containing heteroaryl ring that replaces, for example pyridine radicals, pyrimidine radicals, di azoly, thiazolyl, oxazolyl, triazine radical, quinolyl, pyrrole radicals, furyl, thiazolyl;
Ar
2In optional substituent group can be selected from fluorine, chlorine, bromine, (C
1-C
3) alkyl, trifluoromethyl, (C
1-C
3) alkoxyl, trifluoromethoxy, trifluoromethylthio, dimethylamino, cyano group, (C
1-C
3Alkyl) SO
2-, NH
2SO
2-, (C
1-C
3Alkyl) NHSO
2-, (C
1-C
3Alkyl)
2NSO
2-and nitro;
Ar
1Can be optional 5-or the 6-membered nitrogen-containing heteroaryl ring that replaces, for example pyridine radicals, pyrimidine radicals, di azoly, thiazolyl, oxazolyl, triazine radical, quinolyl, pyrrole radicals, furyl, thiazolyl, wherein L3 can go up with respect to ACHA with ring
1Ring carbon atom on 4 of the O-base links to each other on (for 6-unit ring), perhaps with ACHA
1The conduct of O-base is at 1, Ar
2The L2-base is as 4 ring carbon atom at 2 countings continuous (for 5-unit ring);
Ar
1Can be the optional phenyl ring that replaces, wherein on L3 and the phenyl ring with respect to ACHA
14 of the O-base link to each other;
When t is 1, Ar
3Can be the optional phenyl ring that replaces, or the optional 5-that replaces or 6-unit hetero-aromatic ring, for example pyridine radicals, pyrimidine radicals, di azoly, thiazolyl, oxazolyl, triazine radical, quinolyl, pyrrole radicals, furyl or thiazolyl;
Ring Ar
1Or Ar
3In optional substituent group can be selected from fluorine, chlorine, bromine, iodine, cyano group, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, (C
1-C
3Alkyl) SO
2-, NH
2SO
2-, (C
1-C
3Alkyl) NHSO
2-, (C
1-C
3Alkyl)
2NSO
2-, C
1-C
6Alkyl, C
1-C
6Alkoxyl, cycloalkyl, aryl, aryloxy group, aryl (C
1-C
6)-or aryl (C
1-C
6Alkoxyl)-;
When t was 0, L3 can be a key;
A can be-COOH or carboxyl bioisostere thing that described carboxyl bioisostere thing is selected from-SO
2NHR and-P (=O) (OH) (OR) (wherein R is hydrogen methyl or ethyl) ,-SO
2OH ,-P (=O) (OH) (NH
2) ,-C (=O) NHCN and meet the group of following general formula:
At present preferred A is a carboxyl;
A
1Can be hydrogen or methyl.
The chemical compound (I) that uses according to the present invention comprises chemical compound and salt, hydrate or the solvate of general formula (IV), it is believed that they itself are novel, forms another aspect of the present invention:
In the formula, A, A1, L3, Ar
3, Ar
2With t as in about general formula (I), defining and discuss, R13 represents hydrogen or one or more optional substituent groups, L2 is the member of L2 group A as defined above.Comprise A
1Be hydrogen, L2 is the member's of L2 group B a situation as defined above.
Can have following architectural feature in the chemical compound (IV), these architectural features can any compatible form make up:
A can be-COOH or carboxyl bioisostere thing that described carboxyl bioisostere thing is selected from-SO
2NHR and-P (=O) (OH) (OR) (wherein R is hydrogen methyl or ethyl) ,-SO
2OH ,-P (=O) (OH) (NH
2) ,-C (=O) NHCN and meet the group of following general formula:
At present preferred A is a carboxyl.
R
13Can represent that one or more are selected from following substituent group: fluorine, chlorine, bromine, iodine, cyano group, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, (C
1-C
3Alkyl) SO
2-, NH
2SO
2-, (C
1-C
3Alkyl) NHSO
2-, (C
1-C
3Alkyl)
2NSO
2-, C
1-C
6Alkyl, C
1-C
6Alkoxyl, cycloalkyl, aryl, aryloxy group, aryl (C
1-C
6)-or aryl (C
1-C
6Alkoxyl)-.
A
1Can be methyl, perhaps A
1Can be hydrogen.
A preferred subset of general formula (IV) has general formula (IVA)
In the formula, A, A
1, L3, t, Ar
3, R
13As above about general formula (I) and chemical compound (IV) in institute define and discuss, R
14Be optional phenyl that replaces or 5-or 6-unit heteroaryl.
Another preferred subset of chemical compound (IV) has general formula (IVB):
In the formula, A
1, L3, t and Ar
3Institute defines and discusses about general formula (I), (IV) with (IVA) as above, R
14Be optional phenyl that replaces or 5-or 6-unit heteroaryl.
Another preferred subset of general formula (IV) has general formula (IVC):
In the formula, R
13Expression is selected from following substituent group: fluorine, chlorine, bromine, iodine, (C
1-C
6) alkyl, trifluoromethyl, (C
1-C
6) alkoxyl, (C
1-C
6) alkyl thiol (alkylmercapto), trifluoromethoxy, trifluoromethylthio, dimethylamino, cyano group, (C
1-C
3Alkyl) SO
2-, NH
2SO
2-, (C
1-C
3Alkyl) NHSO
2-, (C
1-C
3Alkyl)
2NSO
2-and nitro, R
14Be optional phenyl that replaces or 5-or 6-unit heteroaryl.In this subclass, R
14Can be 2-replacement, 2,4-two replacements, 2,6-two replacements or 2,4, the trisubstituted phenyl ring of 6-, wherein substituent group is selected from fluorine, chlorine, bromine, iodine, (C
1-C
6) alkyl, trifluoromethyl, (C
1-C
6) alkoxyl, (C
1-C
6) alkyl thiol, trifluoromethoxy, trifluoromethylthio, dimethylamino, (C
1-C
3Alkyl) SO
2-, NH
2SO
2-, (C
1-C
3Alkyl) NHSO
2-, (C
1-C
3Alkyl)
2NSO
2-and cyano group.This subclass specifically comprises wherein A
1It is the chemical compound of hydrogen.
In office what as defined above with the wherein A1 that discusses be methyl chemical compound (I), (IV) (IVA), (IVB) or IVC) in, the carbon atom that A1 connected preferably has the S three-dimensional chemical configuration.
Concrete new compound of the present invention is as follows:
4-chloro-2-(1-phenyl-1H-pyrazoles-4-carbonyl) phenoxyacetic acid,
4-bromo-2-(1-phenyl-1H-pyrazoles-4-carbonyl) phenoxyacetic acid,
[4-bromo-2-(1-pyridine-2-base-1H-pyrazoles-4-carbonyl) phenoxy group] acetic acid,
4-bromo-2-[1-(2-chlorphenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
4-bromo-2-[1-(3-chlorphenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
4-bromo-2-[1-(4-bromophenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
4-bromo-2-[1-(4-chlorphenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
4-bromo-2-[1-(2-ethylphenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
4-bromo-2-[1-(2-bromophenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
4-bromo-2-[1-(2-fluorophenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
4-bromo-2-[1-(2-trifluoromethyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
4-bromo-2-[1-(3-bromophenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
4-bromo-2-[1-(2, the 4-Dichlorobenzene base)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
2-[1-(2-chlorphenyl)-1H-pyrazoles-4-carbonyl]-4-nitrophenoxy } acetic acid,
4-bromo-2-[1-(2, the 6-Dichlorobenzene base)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
2-[1-(2-bromophenyl)-1H-pyrazoles-4-carbonyl]-4-ethyl phenoxy group } acetic acid,
4-bromo-2-[1-(2, the 4-dibromo phenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
4-bromo-2-[1-(4-bromo-2-chlorphenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
4-bromo-2-[1-(2,4, the 6-trichlorophenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
2-[4-bromo-2-(1-phenyl-1H-pyrazoles-4-carbonyl) phenoxy group] propanoic acid,
(S)-and 2-[4-bromo-2-(1-phenyl-1H-pyrazoles-4-carbonyl) phenoxy group] propanoic acid,
2-{4-bromo-2-[1-(2-chlorphenyl)-1-H-pyrazoles-4-carbonyl] phenoxy group } propanoic acid,
(S)-and 2-{4-bromo-2-[1-(2-chlorphenyl)-1-H-pyrazoles-4-carbonyl] phenoxy group }-propanoic acid,
2-{4-bromo-2-[1-(2, the 6-Dichlorobenzene base)-1H-pyrazoles-4-carbonyl] phenoxy group } propanoic acid,
(S)-and 2-{4-bromo-2-[1-(2, the 6-Dichlorobenzene base)-1H-pyrazoles-4-carbonyl] phenoxy group } propanoic acid,
4-bromo-2-[1-(2-ethoxyl phenenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
4-bromo-2-[1-(4-bromo-2-ethylphenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
4-bromo-2-[1-(2-Phenoxyphenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
4-bromo-2-[1-(2-methyl mercapto phenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
4-bromo-2-[1-(2-bromo-4-aminomethyl phenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
2-{4-bromo-2-[1-(4-bromo-2-ethylphenyl)-1H-pyrazoles-4-carbonyl] phenoxy group } propanoic acid,
2-{4-bromo-2-[1-(2-Phenoxyphenyl)-1H-pyrazoles-4-carbonyl] phenoxy group } propanoic acid,
(S)-and 2-{4-bromo-2-[1-(2-Phenoxyphenyl)-1H-pyrazoles-4-carbonyl] phenoxy group } propanoic acid,
2-{4-bromo-2-[1-(2-methyl mercapto)-1H-pyrazoles-4-carbonyl] phenoxy group } propanoic acid,
(S)-and 2-{4-bromo-2-[1-(2-methyl mercapto)-1H-pyrazoles-4-carbonyl] phenoxy group } propanoic acid,
4-bromo-2-[1-(2, the 4-3,5-dimethylphenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
4-bromo-2-[1-(4-chloro-2-aminomethyl phenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
4-bromo-2-[1-(2, the 5-Dichlorobenzene base)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
2-{4-bromo-2-[1-(4-chloro-2-aminomethyl phenyl)-1H-pyrazoles-4-carbonyl] phenoxy group } propanoic acid,
2-{4-bromo-2-[1-(2,4, the 6-trichlorophenyl)-1H-pyrazoles-4-carbonyl] phenoxy group } propanoic acid,
4-bromo-2-[1-(2,6-diethyl-phenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
4-bromo-2-[1-(2, the 6-3,5-dimethylphenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
4-bromo-2-[1-(2-ethyl-6-aminomethyl phenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
4-bromo-2-[1-(2-chloro-6-aminomethyl phenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
4-bromo-2-[1-(3,5-dichloropyridine-4-yl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
[4-bromo-2-(1-naphthalene-1-base-1H-pyrazoles-4-carbonyl) phenoxy group] acetic acid,
4-bromo-2-[2-(4-benzyl chloride base) thiazole-4-yl] and phenoxy group } acetic acid,
{ 4-bromo-2-[3-(4-fluoro-phenyl)-[1,2,4] oxadiazole-5-yl] phenoxy group } acetic acid,
{ 4-bromo-2-[3-(4-methoxyl group-phenyl)-[1,2,4] oxadiazole-5-yl] phenoxy group } acetic acid,
{ 4-bromo-2-[3-(4-chlorphenyl)-[1,2,4] oxadiazole-5-yl] phenoxy group } acetic acid,
{ 4-bromo-2-[3-(4-fluoro-benzyl)-[1,2,4] oxadiazole-5-yl]-phenoxy group }-acetic acid,
4-bromo-2-[3-(2,6-two chloro-benzyls)-[1,2,4] oxadiazole-5-yl]-phenoxy group }-acetic acid,
{ 4-bromo-2-[3-(2-trifluoromethyl benzyl)-[1,2,4] oxadiazole-5-yl] phenoxy group }-acetic acid,
4-bromo-2-[3-(2,6-two chloro-phenyl) isoxazole-5-carbonyl] phenoxy group } acetic acid,
{ 4-bromo-2-[3-(1-phenycyclopropyl)-[1,2,4] oxadiazole-5-yl] phenoxy group } acetic acid,
{ 4-bromo-2-[3-(2, the 4-Dichlorobenzene base)-[1,2,4] oxadiazole-5-yl] phenoxy group } acetic acid,
And their salt, hydrate and solvate.
The present invention also comprises and comprises the chemical compound that belongs to above-mentioned general formula (IV), (IVA), (IVB) or chemical compound (IVC) and the pharmaceutical composition of pharmaceutically acceptable carrier.
Compositions
As mentioned above, the chemical compound that the present invention relates to can be regulated the CRTH2 activity, can be used for treating the disease that can have benefited from this adjusting.The example of this class disease comprises asthma, allergy and rhinitis as mentioned above.
Should understand, concrete dosage level to any concrete sufferer depends on many factors, comprises the activity, age, body weight of used particular compound, the seriousness of health status, sex, diet, administration time, route of administration, discharge rate, drug combination and the disease specific for the treatment of roughly.As needed in the pharmaceutical field, determine the best dosage level and the frequency of dosed administration according to clinical trial.
Can prepare the chemical compound that the present invention relates to, be used for by any administration compatible with their pharmacokinetic property.The form of the compositions of Orally-administrable can be tablet, capsule, powder, granule, lozenge, liquid preparation and gel preparation, such as oral, local or aseptic parenteral solution or suspension.The tablet and the capsule that are used for oral administration can be unit dosage forms, can contain conventional excipient, and binding agent for example is such as syrup, arabic gum, gelatin, Sorbitol, Tragacanth or polyvinylpyrrolidone; Filler is such as lactose, sugar, corn starch, calcium phosphate, Sorbitol or glycine; The tabletting lubricant is such as magnesium stearate, Talcum, Polyethylene Glycol or silicon dioxide; Disintegrating agent, such as potato starch, or acceptable wetting agent such as sodium lauryl sulphate.Can carry out coating to tablet according to the method for knowing in the common pharmaceutical industry.The form of oral liquid can be for example aqueous or oily suspensions, solution, emulsion, syrup or elixir, perhaps can show as dry products, and this product rebuilds with water or other suitable carriers before use.This class I liquid I preparation can contain conventional additive, and suspending agent for example is such as Sorbitol, syrup, methylcellulose, glucose syrup, the hydrogenant edible fat of gelatin; Emulsifying agent is such as lecithin, dehydrating sorbitol monooleate or arabic gum; Non-aqueous carrier (can comprise edible oil) is such as almond oil, fractionated Oleum Cocois, grease such as glycerol, propylene glycol or ethanol; Antiseptic, such as methyl parahydroxybenzoate or propyl p-hydroxybenzoate, or sorbic acid, and if necessary, conventional fumet or coloring agent.
For being locally applied to skin, medicine is made emulsifiable paste, lotion or ointment.The emulsifiable paste or the ointment formulation that can be used for described medicine are conventional formulations well-known in the art, and for example the standard drug handbook is as described in the British Pharmacopoeia (British Pharmacopoeia).
For being locally applied to eyes, medicine is formed in suitable sterile aqueous or solution in the non-aqueous carrier or suspension.Can also contain in this solution or the suspension: additive, buffer agent for example is such as sodium metabisulfite or disodiumedetate (disodium edeate); Antiseptic comprises bactericide and antifungal, such as phenylmercuric acetate or phenylmercuric nitrate, dichlorbenzalkonium chloride or chlorhexidine; And thickening agent, such as hypromellose.
Also this medicine can be mixed with and be used for sucking, for example spray into agent or dry powder or aerosol inhalant as nose.
Active component also can pass through parenteral in sterile media.According to carrier and the concentration used, medicine can suspend or be dissolved in the carrier.Advantageously, will be dissolved in the carrier as the adjuvant of local anesthetic, antiseptic and buffer agent and so on.
The chemical compound that the present invention relates to can be individually dosed, perhaps as being used for the treatment of the part of combined therapy of the medicine of the disease with main inflammatory component with other.In the situation of treatment asthma, rhinitis and anaphylaxis air flue syndrome, this class medicine comprises that corticosteroid, long-acting imbedibility beta-agonists, cromoglicic acid, nedocromil, theophylline, leukotriene receptor antagonist, hydryllin and anticholinergic (for example, ipratropium) and these medicines spray into agent, dry powder or the administration of aerosol inhalant as nose usually.
In treatment of arthritis and related inflammatory disease, other known drug comprises glucocorticoids, NSAID (prostaglandin synthesis inhibitors of nonsteroidal antiinflammatory drug-routine, cox 2 inhibitor, Salicylate) and DMARD (alleviating the moist medicine of wind resistance of disease, such as methotrexate, sulfasalazine, gold, ciclosporin).
Synthesis path
The synthetic of chemical compound involved in the present invention (I) has multiple synthetic schemes, but all schemes all depend on the known chemistry of synthesis of organic scholar.The chemical compound that therefore, can synthesize general formula I according to step that describe in the normative document and well-known to those skilled in the art.Common literature reference is; " Advanced Organic Chemistry (Advanced organic chemistry) ", the 4th edition (Wiley), J March; " comprehensive organic transformation (Comprehensive Organic Transformation) ", the 2nd edition (Wiley), R.C.Larock; " heterocyclic chemistry handbook (Handbook of HeterocyclicChemistry) ", the 2nd edition (Pergamon), A.R.Katritzky); The survey article that in " Synthesis ", " Acc.Chem.Res. ", " Chem.Rev ", finds for example; Perhaps can be by the main literature resource of online normative document search identification, or as the less important resource of " Chemical Abstracts " or " Beilstein " and so on.
In the following discussion, A represents carboxylic acid, carboxyl bioisostere thing or protected carboxylic acid or bioisostere thing or their precursor.In the later case, mean and to carry out deprotection steps.A
1Expression hydrogen or methyl.
Claimed chemical compound lot can pass through phenol precursor and LG-CH (A among the present invention
1)-A reaction comes synthetic, and wherein LG is a leaving group, and A is carboxylic acid or protected analog (analog) or precursor or bioisostere thing or its protected analog.
Shown in following equation, can form and be connected basic L2 by connecting two functionalized suitably and segments that contain active part La2 and Lb2 (if necessary) due care.La2 is defined as and can forms any part that given L2 as follows is connected base by for example nucleophilic displacement of fluorine, multiple bond addition or cyclization with Lb2.
For example, can pass through Ar
2-Alk
1-" leaving group " and nucleophile derivative H-Z-(Alk
2)
p-Ar
1(L1A) L3Ar
3H reacts to form and shows as-Alk
1-Z-(Alk
2)
p-connection base-L2-, wherein Z can be O, S or NR, Alk
1It can be alkyl.This reaction can also make Z and Alk by the functional group (functionalisation) of transposing La2 and Lb2
2Connect.Wherein Z is SO or SO
2The connection base can be by corresponding-(Alk
1)
m-S-(Alk
2)
pOxidation reaction takes place and obtains in-derivant under appropriate condition.
Other representational example-L2-is-Alk
1-Z-(Alk
2)
p-(wherein, Z is NH (CO) or NHSO
2), can pass through Ar
2-(Alk
1)-NH
2Respectively with acylated derivatives " leaving group "-CO-(Alk
2)
p-Ar
1(L1A) L3Ar
3H or " leaving group "-SO
2-(Alk
2)
p-Ar
1(L1A) L3Ar
3H reacts and forms.Perhaps, this conversion reaction can be by using suitable coupling agents such as dicyclohexylcarbodiimide (DCC) and promoter such as I-hydroxybenzotriazole, directly respectively with sour HO-CO-(Alk
2)
p-Ar
1(L1A) L3Ar
3H and HO-SO
2-(Alk
2)
p-Ar
1(L1A) L3Ar
3H reacts and carries out.Similarly ,-L2-is-Alk
1-Z-(Alk
2)
p-(wherein, Z is NH (CO) NH) can make Ar by using suitable acid or base catalysis
2-(Alk
1)-NH
2With isocyanate derivates OCN-(Alk
2)
p-Ar
1(L1A) L3Ar
3H reacts and forms.At NH (CO) or NHSO
2Situation in, this reaction can also be undertaken by the functional group of transposing La2 and Lb2, and " contrary-key (retro-bond) " is provided.Similarly, can make Z and Alk
2Between connect.
It is the example of divalent alkyl, bivalence alkenylene or bivalence alkynylene that the coupling reaction of metal catalytic such as Stille coupling reaction, Suzuki coupling reaction, Heck reaction and Sonogashira reaction can be used for synthetic L2.
Usually by corresponding hydrazine and aldehyde condensation reaction taking place in ethanol or under solvent-free condition forms the chemical compound that L2 is a hydrazone.
Equally, can be according to the cyclization step of standard, use suitable solvent, catalyst and temperature to prepare L2 to be-(Alk
1)
m-Z-(Alk
2)
p-chemical compound, wherein Z is a 5-unit heterocyclic system, for example,
For example, be that acyl group hydrazides, Lb2 are amide or thioamides by La2, perhaps the treating the secondary disease instead of preponderant disease by La2 and Lb2 forms 1,2, the 4-triazole to (reverse orientation).By La2 is that amidoxim (amidoxime), Lb2 are carboxylates, perhaps the treating the secondary disease instead of preponderant disease by La2 and Lb2 to, form 1,2, the 4-oxadiazole.By La2 is that acyl group hydrazides, Lb2 are carboxylates, perhaps the treating the secondary disease instead of preponderant disease by La2 and Lb2 to, form 1,3, the 4-oxadiazole.By La2 is that thioamides, Lb2 are halogenated ketones, perhaps the treating the secondary disease instead of preponderant disease by La2 and Lb2 to, form thiazole.By La2 is that alkynes, Lb2 are itrile oxides (nitriloxide), perhaps forms isoxazole in the cycloaddition reaction by contrary being oriented in.
In a comparable manner, as mentioned below, can be according to connecting the chemical compound that basic L3 prepares general formula I by forming for the step of describing among the L2.Therefore, La is defined as and can forms the given any part that is connected base as follows by for example nucleophilic displacement of fluorine, multiple bond addition or cyclization with Lb.
Ar
1Part also can be the center bearing bracket that is used in a step-wise fashion connecting L2 and L3 part.This can pass through Ar
1The aryl substituent of nuclear is connected with L2 and/or L3, and is then further functionalized again, forms final compound of Formula I and realizes.
And, Ar
1Part also can be assembled by the cyclization that contains L2 and the unitary reactant of L3, and wherein reactant can as followsly contain whole other parts:
Perhaps turn to the form of the structure of above-mentioned final general formula I with further sense.Such example is as follows:
For example, can be by acyl group hydrazides and amide or thioamides preparation 1,2,4-triazole; Can be by amidoxim and carboxylate preparation 1,2,4-oxadiazole; Can be by acyl group hydrazides and carboxylate preparation 1,3,4-oxadiazole; Can prepare thiazole by thioamides and α-Lu Daitong; Prepare pyridine by various cycloaddition reactions.
The construction unit that uses in the reaction can be purchased, or prepare according to standard scheme well known to those skilled in the art, these preparation schemes are at " Advanced Organic Chemistry (Advancedorganic chemistry) ", the 4th edition Edition (Wiley), J March, " comprehensive organic transformation (Comprehensive Organic Transformation) ", the 2nd edition (Wiley), R.C.Larock, " heterocyclic chemistry handbook (Handbook of Heterocyclic Chemistry) ", the 2nd edition (Pergamon) is described in A.R.Katritzky or other the suitable document resource.Example in the literary composition has been described synthetic Ar
1It is the concrete scheme of the chemical compound of phenyl.Can obtain similar compounds by changing the intermediate that uses among the embodiment.
Following examples have illustrated the preparation of chemical compound involved in the present invention.Some chemical compounds obtain by synthetic, and some then are to obtain by being purchased approach.In an embodiment:
General comment:
In Personal Chemistry Emrys Optimizer, carry out microwave chemical.On BrukerAvance AMX 300MHz instrument, obtain NMR spectrum.On the instrument of Agilent 1100 series, carry out LC/MS.The LC/MS method is as follows:
An10p8: post: XTerra MS C18; Flow: 1.0 ml/min; Gradient: 0-5 minute: 15-100%MeCN (in water), 5-71/2 minute: 100%MeCN; Modifier: 5mM ammonium formate; MS-ionization mode: API-ES (just).
An10n8: post: XTerra MS C18; Flow: 1.0 ml/min; Gradient: 0-5 minute: 15-100%MeCN (in water), 5-71/2 minute: 100%MeCN; Modifier: 5mM ammonium formate; MS-ionization mode: API-ES (bearing).
General route of synthesis I
General route of synthesis II
General step 1 (GP1):
The condensation reaction of 3-formacyl chromone and aryl hydrazine
KOH (1.0 milliliters, the 4.0 mMs) aqueous solution that in 3-formacyl chromone in ethanol (1.0 mM) in reaction tube and aryl hydrazine (1.0 mM), adds 4.0M.With this seal of tube,, and keep 7 minutes (420 seconds) by microwave heating to 120 ℃.The HCl of adding 3% up to pH＜1, leaves standstill so that precipitate in this reactant mixture.Filter out precipitate, wash with small amount of ethanol.Product directly uses, perhaps by carrying out purification with ethyl alcohol recrystallization or flash chromatography.
General step 2 (GP2):
The alkylated reaction of phenol
In the phenol (0.5 mM) in acetone (1 milliliter), add bromoacetate (85 milligrams, 0.5 mM) or 2 bromopropionic acid ethyl ester (91 milligrams, 0.5 mM) and K
2CO
3(75 milligrams, 0.54 mM) at room temperature stirred this reactant mixture 12 hours.Then this reactant mixture is concentrated under vacuum, residue distributes between water and ethyl acetate.Organic facies salt water washing, dry (MgSO
4) and concentrate.Product directly uses, perhaps by carrying out purification with MeOH recrystallization or flash chromatography.
General step 3 (GP3):
The hydrolysis of ester
In the ester (0.10 mM) in THF (0.5 milliliter), be added in the LiOHH in the water (0.5 milliliter)
2O (6.3 milligrams, 0.15 mM).Reactant was at room temperature stirred more than 2 hours, add 3% HCl, CH is used in pH＜1 at least
2Cl
2Extract this mixture.Organic facies is carried out drying (MgSO
4) and concentrate, obtain product.
General step 4 (GP4):
Suzuki coupling/ester hydrolysis
To aryl bromide (0.20 mM), aryl boric acid (0.21 mM) and Pd (PPh
3)
2Cl
2Add MeCN (0.4 milliliter, the degassing) and 1.0M Na in (9 milligrams, 0.01 mM)
2CO
3(0.4 milliliter, the degassing).By feeding argon 1/2 minute and making the reactant mixture degassing with microwave heating (150 ℃, 300 seconds), add 3% HCl then, up to pH＜1, and use CH
2Cl
2Extraction.Extract passes through diatomite filtration, and concentrates, and comes the purification residue by solid phase extractions (pre-1 gram SAX post of filling) or flash chromatography.
Intermediate-1
4-bromo-2-(1-phenyl-1H-pyrazoles-4-carbonyl) ethyl phenoxyacetate.By (5-bromo-2-hydroxyl-phenyl)-(1-phenyl-1H-pyrazoles-4-yl) ketone and bromoacetate preparation, obtain 215 milligrams of (100%) white crystals according to GP2.This product need not purification, directly uses: LC/MS (an10p8): Rt6.15 minute, and m/z429[M+H]
+ 1H NMR (CDCl
3): δ 1.26 (t, J=7.1Hz, 3H), 4.24 (q, J=7.1Hz, 2H), 4.64 (s, 2H), 6.72 (d, J=8.9Hz, 1H), 7.34 (m, 1H), 7.46 (m, 2H), 7.53 (dd, J=8.9,2.5Hz, 1H), 7.59 (d, J=2.5Hz, 1H), 7.73-7.78 (m, 2H), 8.17 (s, 1H), 8.58 (s, 1H);
13C NMR (CDCl
3): δ 14.3,61.9, and 65.5,114.0,114.5,119.8,125.3,127.7,129.8,131.8,132.3,132.7,134.6,139.6,142.7,154.1,168.5,186.9.
4-bromo-2-(1-phenyl-1H-pyrazoles-4-carbonyl) phenoxyacetic acid.By 4-bromo-2-(1-phenyl-1H-pyrazoles-4-carbonyl) ethyl phenoxyacetate (31 milligrams, 0.072 mM) preparation, obtain 28.4 milligrams of (99%) white solid: LC/MS (an10p8): Rt 3.14 minutes, m/z401 according to GP3;
1H NMR (CDCl
3): δ 3.51 (s, 1H), 4.80 (s, 1H), 6.97 (d, J=8.7Hz, 1H), 7.38-7.44 (m, 1H), 7.49-7.55 (m, 2H), 7.64-7.69 (m, 1H), 7.72-7.77 (m, 3H), 8.19 (s, 1H), 8.52 (s, 1H);
13C NMR (CDCl
3): δ 67.2,115.1, and 116.6,120.1,124.5,128.4,130.0,131.9,133.3,136.2,139.2,143.3,155.2,169.9,187.6.
Intermediate-2
2-(1-phenyl-1H-pyrazoles-4-carbonyl) ethyl phenoxyacetate.By (2-hydroxy phenyl)-(1-phenyl-1H-pyrazoles-4-yl) ketone (264 milligrams, 1.0 mMs) and bromoacetate preparation, obtain the title compound of the white solid of 235 milligrams (67%): δ 1.26 (t according to GP2, J=7.1Hz, 3H), 4.24 (q, J=7.1Hz, 2H), 4.67 (s, 2H), 6.84 (d, J=8.3Hz, 1H), 7.10 (ts, J=7.4,0.8Hz, 1Hz), 7.29-7.36 (m, 1H), and 7.41-7.53 (m, 4H), 7.72-7.78 (m, 2H), 8.18 (s, 1H), 8.58 (s, 1H);
13C NMR (CDCl
3): δ 14.3,61.7, and 65.4,112.2,118.8,119.3,119.7,120.0,122.1,125.8,127.6,129.7,129.9,130.1,130.6,131.8,132.1,136.3,139.7,142.8,155.0,168.9,188.7.
2-(1-phenyl-1H-pyrazoles-4-carbonyl) phenoxyacetic acid.According to GP3 by 2-(1-phenyl-1H-pyrazoles-4-carbonyl) ethyl phenoxyacetate preparation, and with column chromatography purification (SiO
2, EtOAc: heptane, 1: 1), obtain the title compound of 15 milligrams of (56%) white solid: LC/MS (an10n8): Rt2.90 minute, m/z 321.0[M-H]
- 1H NMR (CDCl
3): δ 4.83 (s, 2H), 7.10 (d, J=8.3Hz, 1H), 7.20 (t, J=7.5Hz, 1H), 7.35-7.42 (m, 1H), 7.46-7.53 (m, 2H), 7.54-7.61 (m, 1H), 7.66 (dd, J=7.5,1.5Hz, 1H), 7.70-7.75 (m, 2H);
13CNMR (CDCl
3): δ 67.7,115.5, and 120.1,122.8,124.7,128.3,128.6,129.9,131.0,131.9,134.0,139.3,143.5,156.6,170.4,189.3.
Intermediate-3
4-fluoro-2-(1-phenyl-1H-pyrazoles-4-carbonyl) ethyl phenoxyacetate.By 4-fluoro-2-(1-phenyl-1H-pyrazoles-4-carbonyl) phenol (282 milligrams) and bromoacetate preparation, obtain 335 milligrams of (91%) yellow solid: LC/MS (an10n8): Rt 3.16, m/z 339.0[M-H according to GP2]
- 1HNMR (CDCl
3): δ 1.26 (t, J=7.0Hz, 3H), 4.23 (t, J=7.1Hz, 2H), 4.63 (s, 2H), 6.81 (dd, J=9.0,4.0Hz, 1H), 7.13 (ddd, J=8.9,4.5,3.0Hz, 1H), 7.21 (dd, J=8.1,3.2Hz, 1H), 7.31-7.37 (m, 1H), 7.24-7.50 (m, 2H), 7.72-7.78 (m, 2H), 8.18 (s, 1H), 8.58 (s, 1H);
13C NMR (CDCl
3): δ 14.3,61.8,66.1,114.0 (d, J
CF=7.6Hz), 116.8 (d, J
CF=24.5Hz), 118.3 (d, J
CF=23.5Hz), 119.7,125.2,127.7,129.7,131.8,139.6,142.8,151.1 (d, J
CF=2.2Hz), 157.6 (d, J
CF=241.1Hz), 168.7,187.1.
4-fluoro-2-(1-phenyl-1H-pyrazoles-4-carbonyl) phenoxyacetic acid. prepare by 4-fluoro-2-(1-phenyl-1H-pyrazoles-4-carbonyl) ethyl phenoxyacetate (31 milligrams) according to GP3, obtain 30 milligrams of (100%) light yellow solid: LC/MS (an10n8): Rt 3.16, m/z 339.0[M-H]
- 1HNMR (CDCl
3): δ 4.60 (s, 2H), 6.90 (dd, J=9.2Hz, 1H), 7.08-7.17 (m, 1H), 7.21 (dd, J=7.9,3.0Hz, 1H), 7.28-7.35 (m, 1H), 7.38-7.46 (m, 2H), 7.65 (d, J=7.5Hz, 2H), 8.06 (s, 1H), 8.44 (s, 1H).
Intermediate-4
4-bromo-2-(1-phenyl-1H-pyrazoles-4-carbonyl) phenoxy group acetonitrile.In (5-bromo-2-hydroxyl-phenyl)-(1-phenyl-1H-pyrazoles-4-yl) ketone (342 milligrams), add bromoacetonitrile (122 milligrams), acetone (2 milliliters) and K
2CO
3(140 milligrams) stir reactant 24 hours.Concentrated reaction mixture, residue distributes between water and EtOAc.Organic facies salt water washing, dry (MgSO4), and concentrate, obtain 383 milligrams of (100%) yellow solids, this solid directly uses in subsequent step: LC/MS (an10p8): Rt 4.39 minutes, m/z 381.5[M+1]
+ 1H NMR (CDCl
3): δ 4.80 (s, 2H), 7.07 (d, J=8.7Hz, 1H), 7.35-7.42 (m, 1H), 7.45-7.54 (m, 2H), 7.60-7.69 (m, 2H), 7.69-7.75 (m, 2H), 8.03 (s, 1H), 8.31 (s, 1H);
13CNMR (CDCl
3): δ 55.2,114.7, and 116.6,116.7,120.1,125.1,128.2,129.9,131.0,132.6,133.2,135.0,139.3,142.7,153.0,186.0.
[5-bromo-2-(2H-tetrazolium-5-ylmethoxy) phenyl] (1-phenyl-1H-pyrazoles-4-yl) ketone. in [4-bromo-2-(1-phenyl-1H-pyrazoles-4-carbonyl) phenoxy group]-acetonitrile (38 milligrams), add NaN3 (66 milligrams), ZnBr
2(59 milligrams), isopropyl alcohol (1.3 milliliters) and water (1.6 milliliters) are heated to backflow with this reactant mixture, and kept 1 hour.The HCl (1 milliliter) and the EtOAc (4 milliliters) of adding 3% in this mixture, and stir, biphase up to clearly occurring.HCl to aqueous phase adding 3% up to pH＜1, extracts with EtOAc.With the organic facies that the salt water washing merges, carry out drying (MgSO
4) and concentrate, obtain 47 milligrams of white foam: LC/MS (an10n8): Rt 2.93, m/z 243.0[M-H]
- 1H NMR (CDCl
3): δ 5.69 (s, 2H), 7.13 (d, J=8.6Hz, 1H), 7.39-7.45 (m, 1H), 7.49-7.56 (m, 2H), 7.62-7.71 (m, 2H), 7.71-7.79 (m, 1H), 8.13 (s, 1H), 8.45 (s, 1H);
13C NMR (CDCl
3): δ 63.3,115.6, and 117.7,120.3,124.5,128.6,130.0,131.2,132.0,132.9,136.3,139.1,143.5,154.7,188.4.
3-(1-phenyl-1H-pyrazoles-4-carbonyl) biphenyl-4-ethoxyacetic acid.Prepare by [4-bromo-2-(1-phenyl-1H-pyrazoles-4-carbonyl) phenoxy group] ethyl acetate and phenylboric acid according to GP4: LC/MS (an10p8): Rt 1.05 minutes, m/z 398.6[M-H]
- 1H NMR (CDCl
3): δ 4.86 (s, 2H), 7.17 (d, J=8.6Hz, 1H), 7.35-7.57 (m, 8H), 7.70-7.75 (m, 2H), 7.78 (dd, J=8.6,2.3Hz, 1H), 7.84 (d, J=2.3Hz, 1H), 8.20 (s, 1H), 8.54 (s, 1H);
13C NMR (CDCl
3): δ 67.7,115.8, and 120.1,124.8,127.1,128.0,128.3,129.1,129.3,129.4,129.9,132.3,136.2,139.3,139.3,143.5,155.8,170.4,189.3.
Intermediate-5
(5-bromo-2-hydroxy phenyl)-(1-pyridine-2-base-1H-pyrazoles-4-yl) ketone.To 6-bromo-3-formacyl chromone (253 milligrams) at isopropyl alcohol (3 milliliters) and CH
2Cl
2Add 2-hydrazino pyridine (109 milligrams) in the suspension in (2 milliliters), this mixture was stirred 15 minutes, form yellow slurry.In this slurry, add water (0.25 milliliter) solution of KOH (0.25 gram), this reactant mixture is heated to backflow, and kept 1 hour.This reactant mixture of dilute with water, the HCl of adding 3% up to pH＜1, and uses CH
2Cl
2(2x) extraction.Extract water and salt water washing, dry (MgSO
4) and concentrate, obtain 342 milligrams of orange foams, with this product of purification by flash chromatography (SiO
2, EA: heptane, 1: 1), obtain the yellow solid of 53 milligrams (15%): LC/MS (an10p8): Rt 5.0 minutes, m/z 343.5[M+H]
+ 1H NMR (CDCl
3): δ 6.98 (d, J=8.9Hz, 1H), 7.31 (ddd, J=7.3,4.9,0.9Hz, 1H), 7.60 (dd, J=8.9,2.5Hz, 1H), and 7.87-7.93 (m, 1H), 8.03 (d, J=2.4Hz, 1H), 8.04-8.09 (m, 1H), 8.02 (s, 1H), 8.47-8.51 (m, 1H), 9.13 (s, 1H), 11.94 (s, 1H);
13C NMR (CDCl
3): δ 110.9,113.3, and 120.8,121.6,122.8,123.1,130.5,133.5,138.9,139.3,143.3,148.7,161.9,191.4.
Intermediate-6
4-bromo-2-(1-pyridine-2-base-1H-pyrazoles-4-carbonyl) ethyl phenoxyacetate.Prepare by (5-bromo-2-hydroxy phenyl)-(1-pyridine-2-base-1H-pyrazoles-4-yl) ketone (43 milligrams) according to GP2, and by purification by flash chromatography (SiO
2, EtOAc: heptane, 1: 2), obtain 34 milligrams of (63%) light yellow solid: LC/MS (an10p8): Rt 4.9 minutes, m/z 429.5[M+H]
+ 1H NMR (CDCl
3): δ 1.23 (t, J=7.2Hz, 3H), 4.20 (q, J=7.2Hz, 2H), 4.62 (s, 2H), 6.76 (d, J=8.6Hz, 1H), 7.23-7.28 (m, 1H), 7.53 (ddd, J=8.9,2.6,1.0Hz, 1H), 7.58 (d, J=2.5Hz, 1H), 7.82-7.99 (m, 1H), 8.01 (d, J=8.1Hz, 1H), 8.19 (s, 1H), 8.40-8.44 (m, 1H), 8.99 (s, 1H);
13C NMR (CDCl
3): δ 14.3,61.8, and 66.1,114.5,114.7,131.6,132.3,132.4,134.6,139.1,148.5,154.4,168.3,187.1.
4-bromo-2-(1-pyridine-2-base-1H-pyrazoles-4-carbonyl) phenoxyacetic acid.By the preparation of [4-bromo-2-(1-pyridine-2-base-1H-pyrazoles-4-carbonyl) phenoxy group]-ethyl acetate (21 milligrams), obtain 20 milligrams of white foam: LC/MS (an10n8): Rt 2.8 minutes, m/z 401.9[M-H according to GP3]
- 1H NMR (CDCl
3): δ 4.79 (s, 2H), 6.98 (d, J=8.9Hz, 1H), 7.28-7.34 (m, 1H), 7.67 (dd, J=8.9,2.5Hz, 1H), 7.75 (d, J=2.5Hz, 1H), 7.86-7.94 (m, 1H), 8.02-8.08 (m, 1H), 8.22 (s, 1H), 8.43-8.48 (m, 1H), 9.04 (s, 1H).
Intermediate-7
(5-bromo-2-hydroxyl-phenyl)-[1-(4-methoxyphenyl)-1H-pyrazoles-4-yl] ketone.In the suspension of 6-bromo-3-formacyl chromone (cromone) (253 milligrams, 1.0 mMs) in ethanol (5 milliliters), add 4-methoxyl group phenylhydrazine (175 milligrams, 1.0 mMs), and this mixture was stirred 12 hours under argon, obtain orange slurry.In this slurry, add water (0.25 milliliter) solution of KOH (260 milligrams), this reactant mixture is heated to backflow, and kept 11/2 hour.The HCl of adding 3% up to pH＜1, and is placed on ice in this reactant mixture, so that precipitation.Filter out precipitate, with a small amount of cold washing with alcohol, obtain 256 milligrams of (69%) beige solids, this solid need not to be further purified direct use: LC/MS (an10p8): Rt 5.0 minutes, m/z 372.5[M+H]
+ 1H NMR (CDCl
3): δ 3.88 (s, 3H), 6.98 (d, J=8.9Hz, 1H), 7.03 (d, J=9.1Hz, 2H), 7.59 (dd, J=9.0,2.5Hz, 1H), 7.66 (d, J=9.1Hz, 2H), 8.02 (d, J=2.4Hz, 1H), 8.15s, 1H), 8.39 (s, 1H), 11.92 (s, 1H);
13C NMR (CDCl
3): δ 55.9,110.9, and 115.0,120.8,121.6,121.8,122.9,130.7,133.5,138.8,142.3,159.7,161.8.
Intermediate-8
4-bromo-2-[1-(4-methoxyphenyl)-1H-pyrazoles-4-carbonyl] ethyl phenoxyacetate.Prepare by (5-bromo-2-hydroxy phenyl)-[1-(4-methoxyphenyl)-1H-pyrazoles-4-yl] ketone and bromoacetate according to GP2: LC/MS (an10p8): Rt 4.59 minutes, m/z 458.4/460.4[M+H]
+ 1HNMR (CDCl
3): δ 1.26 (t, J=7.1Hz, 3H), 3.84 (s, 3H), 4.23 (q, J=7.1Hz, 2H), 4.62 (s, 2H), 6.72 (d, J=8.9Hz, 1H), 6.97 (d, J=8.7Hz, 2H), 7.52 (dd, J=8.9,2.6Hz, 1H), 7.58 (d, J=2.5Hz, 1H), 7.64 (d, J=8.9Hz, 2H), 8.13 (s, 1H), 8.46 (s, 1H);
13C NMR (CDCl
3): δ 14.3,55.8, and 61.9,65.6,114.1,114.4,114.8,121.4,125.0,131.6,132.4,132.6,133.2,134.5,142.5,154.1,159.2,168.5,186.9.
4-bromo-2-[1-(4-methoxyphenyl)-1H-pyrazoles-4-carbonyl] phenoxyacetic acid.According to GP3 by 4-bromo-2-[1-(4-methoxyl group-phenyl)-1H-pyrazoles-4-carbonyl] ethyl phenoxyacetate (23 milligrams) preparation, obtain 21 milligrams of (97%) white foam: LC/MS (an10n8): Rt 5.76 minutes, m/z428.9[M-H]
- 1H NMR (CDCl
3): δ 3.86 (s, 3H), 4.77 (s, 2H), 6.94 (d, J=8.9Hz, 1H), 6.99 (d, J=9.2Hz, 2H), 7.59-7.66 (m, 3H), 7.71 (d, J=2.4Hz, 1H), 8.14 (d, J=0.6Hz, 1H), 8.40 (d, J=0.6Hz, 1H)
13C NMR (CDCl
3): δ 55.9,67.2, and 115.0,115.1,116.6,121.8,124.2,130.7,131.8,132.7,133.2,136.1,143.2,155.2,159.7,169.9,187.6.
[3 ', 5 '-two fluoro-3-(1-phenyl-1H-pyrazoles-4-carbonyl) biphenyl-4-oxygen base] acetic acid.By [4-bromo-2-(1-phenyl-1H-pyrazoles-4-carbonyl) phenoxy group] ethyl acetate and 3,5-difluorophenyl boric acid prepares: LC/MS (an10n8): Rt 3.03 minutes, m/z 434.5[M+H according to GP4]
+ 1H NMR (CDCl
3): δ 4.85 (s, 2H), 6.81 (td, J=8.9,2.3Hz, 1H), 7.07 (d, J=8.3Hz, 2H), 7.14 (d, J=8.9Hz, 1H), 7.41 (d, J=6.6Hz, 1H), 7.48 (s, 1H), 7.52 (d, J=8.5Hz, 1H), 7.66-7.78 (m, 4H), 8.23 (s, 1H), 8.57 (s, 1H)
[4 '-chloro-3-(1-phenyl-1H-pyrazoles-4-carbonyl) biphenyl-4-oxygen base] acetic acid.Prepare by [4-bromo-2-(1-phenyl-1H-pyrazoles-4-carbonyl) phenoxy group] ethyl acetate and 4-chlorophenylboronic acid according to GP4: LC/MS (an10n8): Rt 3.08 minutes, m/z 432.5[M-H]
-
[4-chloro-2-(1-phenyl-1H-pyrazoles-4-carbonyl) phenoxy group] acetic acid.Prepare by (2-hydroxyl-5-chlorphenyl)-(1-phenyl-1H-pyrazoles-4-yl)-ketone and bromoacetate according to GP2 and GP3: LC/MS (an10p8): Rt 3.08 minutes, m/z 356.6[M+1]
+ 1H NMR (CDCl
3): δ 4.75 (s, 2H), 6.95 (d, J=8.9Hz, 1H), 7.33-7.41 (m, 1H), 7.44-7.52 (m, 3H), 7.55 (d, J=2.6Hz, 1H), 7.69-7.75 (m, 2H), 8.18 (s, 1H), 8.52 (s, 1H).
[4-methyl-2-(1-phenyl-1H-pyrazoles-4-carbonyl) phenoxy group] acetic acid.Prepare by (2-hydroxy-5-methyl base phenyl)-(1-phenyl-1H-pyrazoles-4-yl)-ketone and bromoacetate according to GP2 and GP3: LC/MS (an10p8): Rt 3.08 minutes, m/z 356.6[M+1]
+ 1H NMR (CDCl
3): δ 2.37 (s, 3H), 4.78 (s, 2H), 6.97 (d, J=9.0Hz, 1H), 7.33-7.51 (m, 5H), 7.73 (d, J=6Hz, 2H), 8.16 (s, 1H), 8.51 (s, 1H), 11.21 (br s, 1H).
[4-chloro-3-methyl-2-(1-phenyl-1H-pyrazoles-4-carbonyl) phenoxy group] acetic acid.Prepare by (3-chloro-6-hydroxy-2-methyl-phenyl)-(1-phenyl-1H-pyrazoles-4-yl) ketone and bromoacetate according to GP2 and GP3: LC/MS (an10p8): Rt 3.34 minutes, m/z 370.6[M+1]
+ 1H NMR (CDCl
3): δ 2.44 (s, 3H), 4.77 (s, 2H), 6.92 (s, 1H), 7.39 (d, J=9.0Hz, 1H), 7.46-7.51 (m, 2H), 7.59 (s, 1H), 7.72 (d, J=9.0Hz, 2H), 8.19 (s, 1H), 8.52 (s, 1H), 10.39 (br s, 1H).
[2,4-two chloro-6-(1-phenyl-1H-pyrazoles-4-carbonyl) phenoxy group] acetic acid.Prepare by (3,5-two chloro-2-hydroxy phenyls)-(1-phenyl-1H-pyrazoles-4-yl) ketone and bromoacetate according to GP2 and GP3: LC/MS (an10p8): Rt 3.27 minutes, m/z 390.5[M+1]
+ 1H NMR (CDCl
3): δ 4.72 (s, 2H), 7.38-7.51 (m, 4H), 7.57-7.58 (m, 1H), 7.70 (d, J=8.1Hz, 2H), 8.06 (s, 1H), 8.36 (s, 1H), 9.23 (br s, 1H).
4-bromo-2-[1-(2-chloro-phenyl)-1H-pyrazoles-4-carbonyl] phenoxyacetic acid.Prepare by 6-bromo-3-formacyl chromone, 2-chlorophenyl hydrazine and bromoacetate according to GP1, GP2 and GP3: LC/MS (an10p8) Rt 3.02 minutes, m/z 436.4[M+H]
+ 1H NMR (CDCl
3): δ 4.76 (s, 2H), 6.94 (d, J=8.9Hz, 1H), 7.39-7.47 (m, 2H), 7.53-7.67 (m, 3H), 7.74 (dd, J=2.4,0.9Hz, 1H), 8.21 (s, 1H), 8.40 (s, 1H);
13C NMR (CDCl
3): δ 67.2,115.0, and 116.7,123.9,127.9,128.2,128.7,130.55,130.59,131.1,133.3,136.2,136.6,137.1,143.1,155.2,170.0,187.5.
4-bromo-2-[1-(3-chloro-phenyl)-1H-pyrazoles-4-carbonyl] phenoxyacetic acid.According to preparing: LC/MS (an10p8) Rt 3.57 minutes, m/z436.4[M+H] by 6-bromo-3-formacyl chromone and 3-chlorophenyl hydrazine
+ 1H NMR (CDCl
3): δ 4.76 (s, 2H), 6.90 (d, J=8.9Hz, 1H), 7.34 (dm, J=6.8Hz, 1H), 7.41 (t, J=8.3Hz, 1H), 7.58-7.66 (m, 2H), 7.68 (d, J=2.0Hz, 1H), 7.78 (m, 1H), 8.17 (s, 1H), 8.51 (s, 1H);
13C NMR (CDCl
3): δ 66.8,115.1, and 116.2,117.9,120.4,124.9,128.3,130.7,131.0,132.0,133.2,135.8,136.1,140.2,143.4,155.0,170.1,187.4.
4-bromo-2-[1-(4-bromophenyl)-1H-pyrazoles-4-carbonyl] phenoxyacetic acid.Prepare by 6-bromo-3-formacyl chromone, 4-bromophenyl-hydrazine and bromoacetate according to GP1, GP2 and GP3: LC/MS (an10p8) Rt 3.75 minutes, m/z 480.3[M+H]
+ 1H NMR (CDCl
3): δ 4.75 (s, 2H), 6.89 (d, J=8.9Hz, 1H), 7.59-7.65 (m, 5H), 7.66-7.69 (m, 1H), 8.16 (s, 1H), 8.50 (s, 1H);
13C NMR (CDCl
3): δ 66.5,115.0, and 115.9,121.5,121.8,124.9,130.8,131.8,133.0,133.1,135.9,138.2,143.4,154.8,170.6,187.4.
4-bromo-2-[1-(4-chlorphenyl)-1H-pyrazoles-4-carbonyl] phenoxyacetic acid.Prepare by 6-bromo-3-formacyl chromone, 4-chlorophenyl hydrazine and bromoacetate according to GP1, GP2 and GP3: LC/MS (an10p8): Rt 3.53 minutes, m/z 436.4[M+H]
+ 1H NMR (CDCl
3): δ 4.74 (s, 2H), 6.88 (d, J=8.9Hz, 1H), 7.44 (d, J=8.5Hz, 2H), 7.61 (dd, J=8.9,2.4Hz, 1H), 7.63-7.70 (m, 3H), 8.17 (s, 1H), 8.49 (s, 1H);
13C NMR (CDCl
3): δ 66.4,114.9, and 115.7,121.2,124.9,130.0,130.9,131.9,133.1,133.9,135.9,137.7,143.3,154.7,170.8,187.4.
4-bromo-2-[1-(2-ethylphenyl)-1H-pyrazoles-4-carbonyl] phenoxyacetic acid.Prepare by 6-bromo-3-formacyl chromone, 2 ethyl phenyl hydrazine and bromoacetate according to GP1, GP2 and GP3: LC/MS (an10n8): Rt 2.58 minutes, 427.0m/z[M-H]
+ 1H NMR (CDCl
3): δ 1.14 (t, J=7.5Hz, 3H), 2.58 (q, J=7.5,2H), 4.76 (s, 2H), 6.93 (d, J=8.9Hz, 1H), and 7.28-7.34 (m, 2H), 7.37-7.48 (m, 2H), 7.62 (dd, J=8.9,2.6Hz, 1H), 7.72 (d, J=2.5Hz, 1H), 8.15 (s, 1H), 8.18 (s, 1H).
4-nitro-2-[1-(4-chlorphenyl)-1H-pyrazoles-4-carbonyl] phenoxyacetic acid.Prepare by 6-nitro-3-formacyl chromone, 4-chlorophenyl hydrazine and bromoacetate according to GP1, GP2 and GP3: LC/MS (an10p8): Rt 2.44 minutes, m/z 401.7[M+H]
+ 1H NMR (CDCl
3): δ 4.84 (d, 2H), 7.1 (d, J=9.6Hz, 1H), 7.44 (d, J=8.1Hz, 2H), 7.67 (d, J=8.1Hz, 2H), 8.22 (s, 1H), 8.36 (d, J=9.2Hz, 1H), 8.41 (s, 1H), 8.53 (s, 1H);
13C NMR (CDCl
3): δ 65.6,112.9, and 121.3,124.9,126.2,128.2,130.0,130.1,131.9,134.1,137.6,142.4,143.3,159.7,169.9,186.2.
4-nitro-2-(1-phenyl-1H-pyrazoles-4-carbonyl) phenoxyacetic acid.Prepare by 6-nitro-3-formacyl chromone, 2 ethyl phenyl hydrazine and bromoacetate according to GP1, GP2 and GP3: LC/MS (an10p8) Rt 2.05 minutes, m/z 367.8[M+H]
+ 1H NMR (CDCl
3): δ 4.83 (s, 2H), 7.01 (d, J=9.0Hz, 1H), 7.34-7.42 (m, 1H), 7.44-7.53 (m, 1H), 7.65-7.72 (m, 1H), 8.26 (s, 1H), 8.34 (dd, J=9.0,2.6Hz, 1H), 8.41 (d, J=2.6Hz, 1H), 8.53 (s, 1H).
4-bromo-2-[1-(2-bromophenyl)-1H-pyrazoles-4-carbonyl] phenoxyacetic acid.Prepare by 6-bromo-3-formacyl chromone, 2 bromo phenyl hydrazine and bromoacetate according to GP1, GP2 and GP3: Rt 3.38 minutes, m/z 480.6[M+H]
+ 1H NMR (CDCl
3): δ 4.75 (s, 2H), 6.91 (d, J=9.0Hz, 1H), 7.34-7.64 (m, 6H), 7.73-7.74 (m, 2H), 8.22 (s, 1H), 8.36 (s, 1H).
4-bromo-2-[1-(2-fluorophenyl)-1H-pyrazoles-4-carbonyl] phenoxyacetic acid.Prepare by 6-bromo-3-formacyl chromone, 2-fluorobenzene hydrazine and bromoacetate according to GP1, GP2 and GP3: Rt 3.36 minutes, m/z 418.7[M+H]
+ 1H NMR (CDCl
3): δ 4.75 (s, 2H), 6.91 (d, J=8.9Hz, 1H), 7.21-7.42 (m, 3H), 7.62 (dd, J=8.9,2.4Hz, 1H), 7.70 (d, J=2.5Hz, 1H), 7.85-7.92 (m, 1H), 8.20 (s, 1H), 8.51 (d, J=2.3Hz, 1H);
13CNMR (CDCl
3): δ 66.9,115.0, and 116.3,117.1,117.4,124.62,124.63,125.0,125.39,125.44,127.4,127.5,129.6,129.7,130.8,133.2,135.8,136.8,143.0,152.3,155.0,155.6,170.5,187.4.
4-bromo-2-[1-(2-trifluoromethyl)-1H-pyrazoles-4-carbonyl] phenoxyacetic acid.Prepare by 6-bromo-3-formacyl chromone, 2-trifluoromethyl phenyl hydrazine and bromoacetate according to GP1, GP2 and GP3: LC/MS (an10p8): Rt 3.44 minutes, m/z 468.7[M+H]
+ 1H NMR (CDCl
3): δ 4.72 (s, 2H), 6.89 (d, J=8.9Hz, 1H), 7.53-7.75 (m, 5H), 7.84 (d, J=7.9Hz, 1H), 8.20 (s, 2H);
13C NMR (CDCl
3): δ 66.8,114.9,116.2,124.3,126.3,126.7,127.58,127.64,129.2,130.3.130.7,133.2,136.0,136.9,143.1,155.0,170.3,187.4.
4-bromo-2-[1-(3-bromophenyl)-1H-pyrazoles-4-carbonyl] phenoxyacetic acid.Prepare by 6-bromo-3-formacyl chromone, 3-bromophenyl-hydrazine and bromoacetate according to GP1, GP2 and GP3: LC/MS (an10p8): Rt 4.29 minutes, m/z 480.5[M+H]
+ 1H NMR (CDCl
3): δ 4.79 (s, 2H), 6.95 (d, J=9.0Hz, 1H), 7.28-7.40 (m, 1H), 7.53 (d, J=9Hz, 1H), 7.65-7.73 (m, 3H), 7.96 (s, 1H), 8.18 (s, 1H); 8.51 (s, 1H).
4-bromo-2-[1-(3-trifluoromethyl)-1H-pyrazoles-4-carbonyl] phenoxyacetic acid.Prepare by 6-bromo-3-formacyl chromone, 3-trifluoromethyl phenyl hydrazine and bromoacetate according to GP1, GP2 and GP3: LC/MS (an10p8): Rt 4.54 minutes, m/z 468.7[M+H]
+ 1H NMR (CDCl
3): δ 4.76 (s, 2H), 6.89 (d, J=8.9Hz, 1H), 7.57-7.66 (m, 3H), 7.68 (d, J=2.4Hz, 1H), 7.89-7.96 (m, 1H), 8.04 (s, 1H), 8.20 (s, 1H), 8.59 (s, 1H), 9.15 (br s, 1H).
4-bromo-2-[1-(2, the 4-Dichlorobenzene base)-1H-pyrazoles-4-carbonyl] phenoxyacetic acid.According to GP1, GP2 and GP3 by 6-bromo-3-formacyl chromone, 2,4-dichloro phenyl hydrazine and bromoacetate preparation: LC/MS (an10p8): Rt 4.35 minutes, m/z 468.6[M+H]
+ 1H NMR (DMSO-d
6): δ 4.76 (s, 2H), 7.03 (d, J=9.0Hz, 1H), 7.52 (m, 1H), 7.57-7.69 (m, 3H), 7.89 (m, 1H), 8.19 (s, 1H), 8.69 (s, 1H);
13C NMR (DMSO-d
6): δ 55.8,103.6, and 106.2,115.2,119.5,120.6,120.7,121.1,122.4,125.5,125.6,127.1,128.3,133.4,145.1,160.9,177.4.
4-nitro-2-[1-(2-chlorphenyl)-1H-pyrazoles-4-carbonyl] phenoxyacetic acid.Prepare by 6-nitro-3-formacyl chromone, 2-chlorophenyl hydrazine and bromoacetate according to GP1, GP2 and GP3: LC/MS (an10p8): Rt 2.42 minutes, m/z 401.8[M+H]
+ 1H NMR (CDCl
3): δ 4.83 (s, 2H), 7.01 (d, J=9.0Hz, 2H), 7.42-7.48 (m, 2H), 7.56-7.63 (m, 2H), 8.34-8.40 (m, 2H), 8.5 (s, 2H).
4-nitro-2-[1-(2-bromophenyl)-1H-pyrazoles-4-carbonyl] phenoxyacetic acid.Prepare by 6-nitro-3-formacyl chromone, 2 bromo phenyl hydrazine and bromoacetate according to GP1, GP2 and GP3: LC/MS (an10p8): Rt 2.33 minutes, m/z 445.9[M-H]
+ 1H NMR (CDCl
3): δ 4.85 (s, 2H), 7.04 (d, J=9Hz, 1H), 7.37-7.81 (m, 4H), 8.32-8.44 (m, 3H), 8.50 (s, 1H).
4-bromo-2-[1-(2, the 6-Dichlorobenzene base)-1H-pyrazoles-4-carbonyl] phenoxyacetic acid.According to GP1, GP2 and GP3 by 6-bromo-3-formacyl chromone, 2,6-dichloro phenyl hydrazine and bromoacetate preparation: LC/MS (an10p8): Rt 2.56 minutes, m/z 468.6[M+H]
+ 1H NMR (CDCl
3): δ 4.72,6.88 (d, J=8.9Hz, 1H), 7.37-7.44 (m, 1H), 7.45-7.52 (m, 2H), 7.59 (d, J=8.7Hz, 1H), 7.70 (m, 1H), 8.14 (s, 1H), 8.26 (s, 1H).
4-ethyl-2-[1-(2-bromophenyl)-1H-pyrazoles-4-carbonyl] phenoxyacetic acid.Prepare by 6-ethyl-3-formacyl chromone, 2 bromo phenyl hydrazine and bromoacetate according to GP1, GP2 and GP3: LC/MS (an10p8): Rt 2.88 minutes, m/z 428.8[M+H]
+
2-[1-(2-chlorphenyl)-1H-pyrazoles-4-carbonyl]-4-cumene ethoxyacetic acid.Prepare by 6-isopropyl-3-formacyl chromone, 2-chlorophenyl hydrazine and bromoacetate according to GP1, GP2 and GP3: LC/MS (an10p8): Rt 2.83 minutes, m/z 398.8[M+H]
+ 1H NMR (CDCl
3): δ 1.28 (d, J=7.0Hz, 6H), 2.93 (septet, J=6.9Hz, 1H), 4.82 (s, 2H), 7.04 (d, J=8.5Hz, 1H), 7.40-7.65 (m, 6H), 8.28 (s, 1H), 8.40 (s, 1H).
4-bromo-2-[1-(4-Trifluoromethoxyphen-l)-1H-pyrazoles-4-carbonyl] phenoxyacetic acid.Prepare by 6-bromo-3-formacyl chromone, 4-trifluoromethoxy phenylhydrazine and bromoacetate according to GP1, GP2 and GP3: LC/MS (an10p8): Rt 3.24 minutes, m/z 484.6[M+H]
+ 1H NMR (CDCl
3): δ 4.75 (s, 2H), 6.89 (d, J=8.9Hz, 1H), 7.34 (d, J=9.0Hz, 2H), 7.61 (dd, J=8.9,2.6Hz, 1H), 7.67 (m, 1H), 7.72-7.80 (m, 2H), 8.17 (s, 1H), 8.51 (s, 1H);
13C NMR (CDCl
3): δ 66.5,115.0, and 115.8,121.4,122.5,125.0,130.8,132.0,133.1,136.0,137.6,143.4,148.6,148.7,154.8,170.8,187.4.
4-bromo-2-[1-(2, the 4-dibromo phenyl)-1H-pyrazoles-4-carbonyl] phenoxyacetic acid.According to GP1, GP2 and GP3 by 6-bromo-3-formacyl chromone, 2,4-dibromo phenylhydrazine and bromoacetate preparation: LC/MS (an10p8): Rt 3.41 minutes, m/z 556.4[M+H]
+ 1H NMR (CDCl
3): δ 4.75 (s, 2H), 6.92 (d, J=9.0Hz, 1H), 7.45 (d, J=8.5Hz, 1H), 7.63 (m, 2H), 7.73 (d, J=2.5Hz, 1H), 7.92 (d, J=2.1Hz, 1H), 8.22 (s, 1H), 8.37 (s, 1H).
4-bromo-2-[1-(4-bromo-2-chlorphenyl)-1H-pyrazoles-4-carbonyl] phenoxyacetic acid.Prepare by 6-bromo-3-formacyl chromone, 4-bromo-2-chlorophenyl hydrazine and bromoacetate according to GP1, GP2 and GP3: LC/MS (an10p8): Rt 3.34 minutes, m/z 512.5[M+H]
+ 1H NMR (CDCl
3): δ 4.78 (s, 2H), 6.95 (d, J=8.6Hz, 1H), 7.51-7.76 (m, 5H), 8.21 (s, 1H), 8.42 (s, 1H).
4-bromo-2-[1-(2,4, the 6-trichlorophenyl)-1H-pyrazoles-4-carbonyl] phenoxyacetic acid.According to GP1, GP2 and GP3 by 6-bromo-3-formacyl chromone, 2,4,6-trichlorobenzene hydrazine and bromoacetate preparation: Rt 3.35 minutes, m/z 502.6[M+H]
+ 1H NMR (CDCl
3): δ 4.91 (s, 2H), 7.05 (d, J=8.9Hz, 1H), 7.68 (s, 2H), 7.78 (d, J=8.5Hz, 1H), 7.88 (s, 1H), 8.31 (s, 1H), 8.43 (s, 1H), 9.03 (br s, 1H).
4-methoxyl group-2-[1-phenyl-1H-pyrazoles-4-carbonyl] phenoxyacetic acid.According to GP1, GP2 and GP3 by 6-bromo-3-formacyl chromone, 2,4-dichloro phenyl hydrazine and bromoacetate preparation: LC/MS (an10n8): Rt 2.46 minutes, m/z 350.9[M-H]
+ 1H NMR (CDCl
3): δ 3.81 (s, 3H), 4.77 (s, 2H), 7.02-7.16 (m, 3H), 7.41 (d, J=7.5Hz, 1H), 7.50 (t, J=8.1Hz, 2H), 7.73 (d, J=8.5Hz, 2H), 8.17 (s, 1H), 8.52 (s, 1H).
2-[4-bromo-2-(1-phenyl-1H-pyrazoles-4-carbonyl) phenoxy group] propanoic acid.Prepare by (5-bromo-2-hydroxy phenyl)-(1-phenyl-1H-pyrazoles-4-yl) ketone and 2 bromopropionic acid ethyl ester according to GP2 and GP3: LC/MS (an10p8) Rt 2.51 minutes, m/z 415[M+H]
+ 1H NMR (CDCl
3): δ 1.65 (d, J=6.8Hz, 3H), 4.93 (q, J=6.8Hz, 1H), 6.96 (d, J=8.9Hz, 1H), and 7.35-7.43 (m, 1H), 7.46-7.53 (m, 2H), 7.62 (dd, J=8.9,2.5Hz, 1H), 7.70-7.76 (m, 3H), 8.17 (s, 1H), 8.52 (s, 1H);
13C NMR (CDCl
3): δ 18.8,75.2, and 114.8,116.7,120.1,124.4,128.3,130.0,133.3,136.2,139.2,143.3,155.0,173.1,187.8.
2 (S)-[4-bromo-2-(1-phenyl-1H-pyrazoles-4-carbonyl)-phenoxy group]-propanoic acid.With (5-bromo-2-hydroxy phenyl)-(1-phenyl-1H-pyrazoles-4-yl) ketone (100 milligrams, 0.29 mM), (R)-(+)-bromoacetic acid (44 milligrams, 0.29 mM), 2 bromopropionic acid ethyl ester and K
2CO
3(80 milligrams, 0.58 mM) stirred 16 hours under room temperature in acetone.Reactant mixture is concentrated, and residue distributes between EtOAc and rare HCl (pH～1).Organic facies is carried out drying (Na
2SO
4) and concentrate, by purification by flash chromatography residue (EtOAc: heptane, 1: 1), obtain 55 milligrams of (46%) title compound: chirality HPLC (post: Ciracel OD (24 centimetres of 0.46 cm x); Eluent: isocratic elution, 85% hexane+15%2-propanol+0.1%TFA; Flow 0.5 ml/min) Rt is 15.7 minutes, and＞90%e.e. (eluting raceme material, enantiomer baseline separation: Rt 15.7 and 16.7 minutes) MS and NMR spectrum are corresponding to the raceme material.
2-{4-bromo-2-[1-(2-chlorphenyl)-1-H-pyrazoles-4-carbonyl] phenoxy group } propanoic acid.Prepare by 6-bromo-3-formacyl chromone, 2-chlorophenyl hydrazine and 2 bromopropionic acid ethyl ester according to GP1, GP2 and GP3: LC/MS (an10n8): Rt 2.56 minutes, 448.9m/z[M-H]
+ 1H NMR (CDCl
3): δ 1.65 (d, J=7.0Hz, 3H), 4.93 (q, J=7.0Hz, 1H), 6.96 (d, J=8.9Hz, 1H), 7.41-7.47 (m, 2H), 7.55-7.64 (m, 3H), 7.74 (s, 1H), 8.23 (s, 1H), 8.42 (s, 1H);
13C NMR (CDCl
3): δ 18.9,75.4, and 115.0,117.0,124.1,128.1,128.4,128.9,130.7,131.3,133.6,136.4,136.8,137.3,143.3,155.2,173.5,188.0.
2-{4-bromo-2-[1-(2, the 6-Dichlorobenzene base)-1H-pyrazoles-4-carbonyl] phenoxy group } propanoic acid.According to GP1, GP2 and GP3 by 6-bromo-3-formacyl chromone, 2,6-dichloro phenyl hydrazine and the preparation of 2 bromopropionic acid ethyl ester: LC/MS (an10n8): Rt 2.55 minutes, 482.9 m/z[M-H]
+ 1H NMR (CDCl
3): δ 1.65 (d, J=6.8Hz, 3H), 4.91 (q, J=6.8Hz, 1H), 6.93 (d, J=8.9Hz, 1H), 7.41-7.53 (m, 3H), 7.62 (dd, J=8.9,2.5Hz, 1H), 7.74 (d, J=2.4,1H), 8.17 (s, 1H), 8.28 (s, 1H);
13C NMR (CDCl
3): δ 18.9,75.1, and 114.9,116.8,124.2,129.3,130.7,132.0,133.6,134.5,135.6,136.4,137.6,143.6,155.1,173.6,187.8.
4-bromo-2-[1-(2-cyano group-phenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid.Prepare by 6-bromo-3-formacyl chromone, 2-diazanyl benzonitrile (at J.Med.Chem.2003, the description among the 2008-2016 prepares according to people such as van der Mey) and bromoacetate according to GP1, GP2 and GP3:
1HNMR (DMSO-d
6): δ 4.72 (s, 2H), 7.17 (d, J=8.9Hz, 1H), 7.36 (t, J=15.1,7.3Hz, 1H), 7.8 (m, 4H), 8.29 (d, J=8.3Hz, 1H), 9.03 (s, 1H), 9.66 (s, 1H), 13.04 (br s, 1H).
4-bromo-2-[1-(2-ethoxyl phenenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid.Prepare by 6-bromo-3-formacyl chromone, 2-ethyoxyl phenylhydrazine and 2-bromoacetate according to GP1, GP2 and GP3: LC/MS (an10p8): Rt 2.33 minutes, m/z 446.7[M+H]
+ 1H NMR (CDCl
3): δ 1.47 (t, J=7.0Hz, 3H), 4.18 (q, J=7.0Hz, 2H), 4.78 (s, 2H), 6.97 (d, J=8.9Hz, 1H), 7.09 (d, J=8.7Hz, 2H), 7.36 (td, J=7.9,1.8Hz, 1H), 7.64 (dd, J=8.9,2.5Hz, 1H), 7.79 (d, J=2.5Hz, 1H), 7.80 (dd, J=7.9,1.6Hz, 1H), 8.22 (s, 1H), 8.65 (s, 1H).
4-bromo-2-[1-(4-bromo-2-ethylphenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid.Prepare by 6-bromo-3-formacyl chromone, 4-bromo-2 ethyl phenyl hydrazine and bromoacetate according to GP1, GP2 and GP3: LC/MS (an10n8): Rt 2.78 minutes, m/z 506.6[M-H]
- 1H NMR (CDCl
3): δ 1.16 (td, J=7.8,2.4Hz, 3H), 2.58 (qd, J=7.8,1.8Hz, 2H), 4.77 (s, 2H), 6.94 (d, J=9.0Hz, 1H), 7.22 (d, J=8.5Hz, 1H), 7.47 (d, J=8.5Hz, 1H), 7.56 (s, 1H), 7.65 (d, J=8.7Hz, 1H), 7.72 (s, 1H), 8.15 (s, 1H), 8.19 (s, 1H).
4-bromo-2-[1-(2-Phenoxyphenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid.Prepare by 6-bromo-3-formacyl chromone, 4-bromo-2 ethyl phenyl hydrazine and bromoacetate according to GP1, GP2 and GP3: LC/MS (an10n8): Rt 2.77 minutes, m/z 492.7[M-H]
- 1H NMR (CDCl
3): δ 4.75 (s, 2H), 6.95 (d, J=8.6Hz, 1H), 7.00-7.09 (m, 3H), 7.15 (t, J=7.5Hz, 1H), 7.29-7.40 (m, 4H), 7.62-7.68 (m, 2H), 7.90 (d, J=9.0Hz, 1H), 8.17 (s, 1H), 8.60 (s, 1H).
4-bromo-2-[1-(2-methyl mercapto phenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid.Prepare by 6-bromo-3-formyl primary colours, 2-methyl mercapto phenylhydrazine and bromoacetate according to GP1, GP2 and GP3: LC/MS (an10n8): Rt 2.26 minutes, m/z 446.7[M-H]
- 1H NMR (CDCl
3): δ 2.46 (s, 3H), 4.77 (s, 2H), 6.93 (d, J=8.9Hz, 1H), 7.28-7.32 (m, 1H), 7.39-7.49 (m, 3H), 7.62 (dd, J=9.0,2.5Hz, 1H), 7.76 (s, 1H), 8.23 (s, 1H), 8.31 (s, 1H).
4-bromo-2-[1-(2-bromo-4-aminomethyl phenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid.Prepare by 6-bromo-3-formacyl chromone, 2-bromo-4-procarbazine and bromoacetate according to GP1, GP2 and GP3: LC/MS (an10n8): Rt 2.47 minutes, m/z 492.6[M-H]
- 1H NMR (CDCl
3): δ 2.44 (s, 3H), 4.80 (s, 2H), 6.99 (d, J=8.9Hz, 1H), 7.27-7.30 (m, 1H), 7.46 (d, J=8.1Hz, 1H), 7.58 (s, 1H), 7.67 (d, J=9.0Hz, 1H), 7.80 (s, 1H), 8.20 (s, 1H), 8.33 (s, 1H).
2-{4-bromo-2-[1-(4-bromo-2-ethylphenyl)-1H-pyrazoles-4-carbonyl] phenoxy group } propanoic acid.Prepare by 6-bromo-3-formacyl chromone, 4-bromo-2 ethyl phenyl hydrazine and bromoacetate according to GP1, GP2 and GP3: LC/MS (an10p8): Rt 2.72 minutes, m/z 522.6[M+H]
+ 1H NMR (CDCl
3): δ 1.16 (t, J=7.7Hz, 3H), 1.67 (d, J=6.8Hz, 3H), 2.59 (q, J=7.5Hz, 2H), 4.95 (q, J=7.0Hz, 1H), 6.96 (d, J=9.0Hz, 1H), 7.21 (d, J=8.3Hz, 1H), 7.47 (d, J=8.7Hz, 1H), 7.55 (s, 1H), 7.63 (d, J=9.0Hz, 1H), 7.73 (s, 1H), 8.17 (s, 1H), 8.18 (s, 1H).
2-{4-bromo-2-[1-(2-Phenoxyphenyl)-1H-pyrazoles-4-carbonyl] phenoxy group } propanoic acid.Prepare by 6-bromo-3-formacyl chromone, 2-phenoxyphenylhydraziderivatives and 2 bromopropionic acid ethyl ester according to GP1, GP2 and GP3: LC/MS (an10p8): Rt 2.68 minutes, m/z508.7[M+H]
+ 1H NMR (CDCl
3): δ 1.65 (d, J=6.8Hz, 3H), 4.92 (q, J=7.3Hz, 1H), 6.96-7.18 (m, 5H), 7.26-7.39 (m, 4H), 7.62 (d, J=8.6Hz, 1H), 7.67 (s, 1H), 7.90 (d, J=7.5Hz, 1H), 8.17 (s, 1H), 8.61 (s, 1H).
2-{4-bromo-2-[1-(2-ethoxyl phenenyl)-1H-pyrazoles-4-carbonyl] phenoxy group } propanoic acid.Prepare by 6-bromo-3-formacyl chromone, 2-ethyoxyl phenylhydrazine and 2 bromopropionic acid ethyl ester according to GP1, GP2 and GP3:
LC/MS (an10p8): Rt 2.39 minutes, m/z 458.7[M+H]
+ 1H NMR (CDCl
3): δ 1.49 (t, J=7.1Hz, 3H), 1.86 (d, J=7.1Hz, 3H), 4.19 (m, 2H), 4.98 (q, J=6.9Hz, 1H), and 7.02-7.12 (m, 3H), 7.37 (t, J=8.2Hz, 1H), 7.66 (d, J=8.9Hz, 1H), 7.78 (s, 1H), 7.83 (d, J=7.9Hz, 1H), 8.20 (s, 1H), 8.67 (s, 1H).
2-{4-bromo-2-[1-(2-methyl mercapto)-1H-pyrazoles-4-carbonyl] phenoxy group } propanoic acid.Prepare by 6-bromo-3-formacyl chromone, 2-ethyoxyl phenylhydrazine and 2 bromopropionic acid ethyl ester according to GP1, GP2 and GP3: LC/MS (an10n8): Rt 2.56 minutes, 460.9 m/z[M-H]
+ 1HNMR (CDCl
3): δ 1.71 (d, J=6.8Hz, 3H), 2.46 (s, 3H), 4.96 (q, J=7.0Hz, 1H), 7.00 (d, J=8.9Hz, 1H), 7.29-7.34 (m, 1H), 7.40-7.50 (m, 3H), 7.64 (dd, J=8.9,2.5Hz, 1H), 7.80 (s, 1H), 8.22 (s, 1H), 8.32 (s, 1H).
2-{4-bromo-2-[1-(2-bromo-4-aminomethyl phenyl)-1H-pyrazoles-4-carbonyl] phenoxy group } propanoic acid.Prepare by 6-bromo-3-formacyl chromone, 2-bromo-4-procarbazine and 2 bromopropionic acid ethyl ester according to GP1, GP2 and GP3: LC/MS (an10n8): Rt 2.74 minutes, 506.8 m/z[M-H]
+ 1H NMR (CDCl
3): δ 1.72 (d, J=7.0Hz, 3H), 2.45 (s, 3H), 4.98 (q, J=7.0Hz, 1H), 7.03 (d, J=8.9Hz, 1H), and 7.28-7.30 (m, 1H), 7.46 (d, J=8.1Hz, 1H), 7.59 (s, 1H), 7.67 (dd, J=8.9,2.43Hz, 1H), 7.81 (d, J=2.6Hz, 1H), 8.19 (s, 1H), 8.34 (s, 1H).
2-{4-bromo-2-[1-(2, the 4-Dichlorobenzene base)-1H-pyrazoles-4-carbonyl] phenoxy group } propanoic acid.According to GP1, GP2 and GP3 by 6-bromo-3-formacyl chromone, 2,4-dichloro phenyl hydrazine and the preparation of 2 bromopropionic acid ethyl ester: LC/MS (an10n8): Rt 2.83 minutes, 482.8 m/z[M-H]
+ 1H NMR (CDCl
3): δ 1.50 (d, J=6.0Hz, 3H), 4.75 (q, J=4.5Hz, 1H), 6.88 (d, J=8.5Hz, 1H), 7.40 (dd, J=8.5,1.9Hz, 1H), 7.50 (d, J=7.5Hz, 1H), 7.54-7.57 (m, 2H), 7.61 (s, 1H), 8.16 (s, 1H), 8.32 (s, 1H).
4-bromo-2-[1-(2-Trifluoromethoxyphen-l)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid.Prepare by 6-bromo-3-formacyl chromone, 2-trifluoromethoxy phenylhydrazine and bromoacetate according to GP1, GP2 and GP3: LC/MS (an10n8): Rt 2.43 minutes, m/z 482.7[M-H]
- 1H NMR (CDCl
3): δ 4.77 (s, 2H), 6.95 (d, J=8.6Hz, 1H), 7.45-7.50 (m, 3H), 7.65 (dd, J=8.9,2.5Hz, 1H), 7.73 (d, J=2.4Hz, 1H), 7.82 (s, 1H), 8.23 (s, 1H), 8.40 (s, 1H).
2-[1-(2, the 6-Dichlorobenzene base)-1H-pyrazoles-4-carbonyl]-4-ethyl phenoxy group } acetic acid.According to GP1, GP2 and GP3 by 6-ethyl-3-formacyl chromone, 2,6-dichloro phenyl hydrazine and bromoacetate preparation: LC/MS (an10n8): Rt 2.25 minutes, m/z 416.8[M-H]
- 1H NMR (CDCl
3): δ 1.26 (t, J=7.5Hz, 3H), 2.69 (q, J=7.7Hz, 2H), 4.82 (s, 2H), 7.04 (d, J=8.7Hz, 1H), 7.39-7.44 (m, 1H), 7.46-7.54 (m, 4H), 8.14 (s, 1H), 8.25 (s, 1H).
4-bromo-2-[1-(2, the 4-3,5-dimethylphenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid.According to GP1, GP2 and GP3 by 6-bromo-3-formacyl chromone, 2,4-dimethyl hydrazinobenzene and bromoacetate preparation: LC/MS (an10n8): Rt 2.41 minutes, m/z 428.7[M-H]
- 1H NMR (CDCl
3): δ 2.26 (s, 3H), 2.40 (s, 3H), 4.75 (s, 2H), 6.91 (d, J=8.9Hz, 1H), 7.11 (d, J=8.1Hz, 1H), 7.17 (s, 1H), 7.23 (d, J=8.1Hz, 1H), 7.60 (dd, J=8.9,2.46Hz, 1H), 7.71 (s, 1H), 8.15 (s, 1H), 8.22 (s, 1H).
2-{4-bromo-2-[1-(2, the 4-3,5-dimethylphenyl)-1H-pyrazoles-4-carbonyl] phenoxy group } propanoic acid.According to GP1, GP2 and GP3 by 6-bromo-3-formacyl chromone, 2,4-dimethyl hydrazinobenzene and the preparation of 2 bromopropionic acid ethyl ester: LC/MS (an10n8): Rt 2.40 minutes, m/z 442.7[M-H]
- 1H NMR (CDCl
3): δ 1.67 (d, J=6.9Hz, 3H), 2.25 (s, 3H), 2.40 (s, 3H), 4.93 (q, J=6.8Hz, 1H), 6.97 (d, J=8.9Hz, 1H), 7.12 (d, J=8.1Hz, 1H), 7.17 (s, 1H), 7.25 (d, J=8.1Hz, 1H), 7.62 (dd, J=8.7,1.52Hz, 1H), 7.73 (s, 1H), 8.15-8.16 (m, 2H).
[2-(1-benzyl-1H-pyrazoles-4-carbonyl)-4-bromine phenoxy group] acetic acid.Prepare by 6-bromo-3-formacyl chromone, benzyl hydrazine and bromoacetate according to GP1, GP2 and GP3: LC/MS (an10n8): Rt 2.14 minutes, m/z 414.7[M-H]
- 1H NMR (CDCl
3): δ 4.70 (s, 2H), 5.36 (s, 2H), 6.88 (d, J=8.7Hz, 1H), 7.28-7.30 (m, 2H), 7.40-7.46 (m, 3H), 7.57 (d, J=8.9Hz, 1H), 7.63 (s, 1H), 8.01 (s, 1H), 8.04 (s, 1H).
2-[2-(1-benzyl-1H-pyrazoles-4-carbonyl)-4-bromine phenoxy group] propanoic acid.Prepare by 6-bromo-3-formacyl chromone, benzyl hydrazine and 2 bromopropionic acid ethyl ester according to GP1, GP2 and GP3: LC/MS (an10n8): Rt 2.16 minutes, m/z 428.8[M-H]
- 1H NMR (CDCl
3): δ 1.59 (d, J=6.8Hz, 3H), 4.88 (q, J=7.1Hz, 1H), 5.35 (s, 2H), 6.91 (d, J=8.9Hz, 1H), 7.30-7.42 (m, 5H), 7.53-7.71 (m, 2H), 8.01 (s, 2H).
4-bromo-2-[1-(4-chloro-2-aminomethyl phenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid.Prepare by 6-bromo-3-formacyl chromone, 4-chloro-2-procarbazine and bromoacetate according to GP1, GP2 and GP3: LC/MS (an10n8): Rt 2.49 minutes, m/z 448.7[M-H]
- 1H NMR (CDCl
3): δ 2.27 (s, 3H), 4.75 (s, 2H), 6.91 (d, J=8.9Hz, 1H), 7.31 (s, 2H), 7.36 (s, 1H), 7.63 (d, J=8.7Hz, 1H), 7.70 (s, 1H), 8.17 (s, 1H), 8.21 (s, 1H).
4-bromo-2-[1-(2, the 5-Dichlorobenzene base)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid.According to GP1, GP2 and GP3 by 6-bromo-3-formacyl chromone, 2,5-dichloro phenyl hydrazine and bromoacetate preparation: LC/MS (an10n8): Rt 2.46 minutes, m/z 468.6[M-H]
- 1H NMR (CDCl
3): δ 4.78 (s, 2H), 6.92 (d, J=8.9Hz, 1H), 7.39 (dd, J=8.7,2.44Hz, 1H), 7.50 (d, J=8.7Hz, 1H), 7.61 (dd, J=8.9,2.53Hz, 1H), 7.70 (dd, J=8.1,2.36Hz, 2H), 8.22 (s, 1H), 8.45 (s, 1H).
4-bromo-2-[1-(2-methoxyphenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid.Prepare by 6-bromo-3-formacyl chromone, 2-procarbazine and bromoacetate according to GP1, GP2 and GP3: LC/MS (an10n8): Rt 2.20 minutes, m/z 430.7[M-H]
- 1H NMR (CDCl
3): δ 3.96 (s, 3H), 4.79 (s, 2H), 6.96 (d, J=8.9Hz, 1H), 7.11 (t, J=8.2Hz, 2H), 7.40 (t.d, J=8.1,1.5Hz, 1H), 7.65 (dd, J=8.9,2.5Hz, 1H), 7.76 (d, J=2.5Hz, 2H), 8.18 (s, 1H), 8.60 (s, 1H).
4-bromo-2-[1-(3, the 4-Dichlorobenzene base)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid.According to GP1, GP2 and GP3 by 6-bromo-3-formacyl chromone, 3,4-chlorophenyl hydrazine and bromoacetate preparation: LC/MS (an10n8): Rt 2.77 minutes, m/z 468.6[M-H]
- 1H NMR (CDCl
3): δ 4.78 (s, 2H), 6.90 (d, J=8.7Hz, 1H), 7.59 (d, J=8.1Hz, 1H), 7.64 (d, J=8.9Hz, 1H), 7.69 (d, J=2.43Hz, 2H), 7.91 (d, J=2.46Hz, 1H), 8.18 (s, 1H), 8.53 (s, 1H).
2-{4-bromo-2-[1-(4-chloro-2-aminomethyl phenyl)-1H-pyrazoles-4-carbonyl] phenoxy group } propanoic acid.Prepare by 6-bromo-3-formacyl chromone, 4-chloro-2-procarbazine and 2 bromopropionic acid ethyl ester according to GP1, GP2 and GP3: LC/MS (an10n8): Rt 2.55 minutes, m/z 462.7[M-H]
- 1HNMR (CDCl
3): δ 1.65 (d, J=6.9Hz, 3H), 2.28 (s, 3H), 4.92 (d, J=6.8Hz, 1H), 6.95 (d, J=8.9Hz, 1H), 7.30 (s, 2H), 7.37 (s, 1H), 7.63 (d, J=8.9Hz, 1H), 7.72 (s, 1H), 8.19 (s, 2H).
2-{4-bromo-2-[1-(2, the 5-Dichlorobenzene base)-1H-pyrazoles-4-carbonyl] phenoxy group } propanoic acid.According to GP1, GP2 and GP3 by 6-bromo-3-formacyl chromone, 2,5-dichloro phenyl hydrazine and the preparation of 2 bromopropionic acid ethyl ester: LC/MS (an10n8): Rt 2.51 minutes, m/z 482.6[M-H]
- 1H NMR (CDCl
3): δ 1.70 (d, J=6.8Hz, 3H), 4.90 (q, J=6.9Hz, 1H), 6.93 (d, J=9.1Hz, 1H), 7.40 (dd, J=8.7,2.5Hz, 1H), 7.50 (d, J=8.6Hz, 1H), 7.62 (dd, J=8.9,2.5Hz, 1H), 7.68 (d, J=2.3Hz, 1H), 7.71 (d, J=2.4Hz, 1H), 8.22 (s, and 1H) 8.45 (s, 1H).
2-{4-bromo-2-[1-(3,4-two chloro-phenyl)-1H-pyrazoles-4-carbonyl] phenoxy group } propanoic acid.According to GP1, GP2 and GP3 by 6-bromo-3-formacyl chromone, 3,4-dichloro phenyl hydrazine and the preparation of 2 bromopropionic acid ethyl ester: LC/MS (an10n8): Rt 2.83 minutes, m/z 482.6[M-H]
- 1H NMR (CDCl
3): δ 1.63 (d, J=6.8Hz, 3H), 4.93 (q, J=6.9Hz, 1H), 6.92 (d, J=9.03Hz, 1H), 7.55-7.65 (m, 3H), 7.70 (s, 1H), 7.93 (d, J=2.25Hz, 1H), 8.20 (s, 1H), 8.57 (s, 1H).
2-{4-bromo-2-[1-(2-methoxyphenyl)-1H-pyrazoles-4-carbonyl] phenoxy group } propanoic acid.According to GP1, GP2 and GP3 by 6-ethyl-3-formacyl chromone, 2,6-dichloro phenyl hydrazine and the preparation of 2 bromopropionic acid ethyl ester: LC/MS (an10n8): Rt 2.23 minutes, m/z 444.7[M-H]
- 1H NMR (CDCl
3): δ 1.68 (d, J=7.0Hz, 3H), 3.95 (s, 3H), 4.95 (d, J=7.0Hz, 1H), 6.99 (d, J=8.7Hz, 1H), 7.10 (d, J=8.5Hz, 1H), 7.14 (s, 1H), and 7.37-7.43 (m, 1H), 7.63 (dd, J=8.9,2.6Hz, 1H), 7.77 (s, 1H), 7.79 (s, 1H), 8.19 (s, 1H), 8.62 (s, 1H).
[4-amino-2-(1-phenyl-1H-pyrazoles-4-carbonyl) phenoxy group] acetic acid. with (190 milligrams of 4-nitro-2-(phenyl-1H-pyrazoles-4-carbonyl) ethyl phenoxyacetates, 0.48 mM) and the mixture of 10%Pd/C (100 milligrams) in MeOH (50 milliliters) under nitrogen atmosphere, stirred 12 hours, filter by Celite pad then, and concentrate, make the product hydrolysis according to GP3, obtain title compound.
4-bromo-2-[1-(4-bromo-2-chlorphenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid.Prepare by 6-bromo-3-formacyl chromone, 4-bromo-2-chlorophenyl hydrazine and bromoacetate according to GP1, GP2 and GP3: LC/MS (an10n8): Rt 2.57 minutes, m/z 526.6[M-H]
- 1H NMR (DMSO): δ 1.31 (d, J=6.8Hz, 3H), 4.94 (q, J=6.6Hz, 1H), 6.92 (d, J=8.9Hz, 1H), 7.53 (d, J=2.5Hz, 1H), 7.59 (d, J=8.5Hz, 1H), 7.66 (dd, J=9.0,2.5Hz, 1H), 7.76 (dd, J=8.5,2.3Hz, 1H), 8.04 (d, J=2.1Hz, 1H), 8.22 (s, 1H), 8.77 (s, 1H).
2-{4-bromo-2-[1-(2,4, the 6-trichlorophenyl)-1H-pyrazoles-4-carbonyl] phenoxy group } propanoic acid.According to GP1, GP2 and GP3 by 6-bromo-3-formacyl chromone, 2,4,6-trichlorobenzene hydrazine and the preparation of 2 bromopropionic acid ethyl ester: LC/MS (an10n8): Rt 2.61 minutes, m/z 516.6[M-H]
+ 1H NMR (DMSO): δ 1.33 (d, J=6.8Hz, 3H), 4.94 (q, J=7.0Hz, 1H), 6.92 (d, J=9.2Hz, 1H), 7.54 (d, J=2.4Hz, 1H), 7.66 (dd, J=8.9,2.5Hz, 1H), 7.99 (s, 2H), 8.26 (s, 1H), 8.72 (s, 1H).
2-{4-bromo-2-[1-(2, the 4-dibromo phenyl)-1H-pyrazoles-4-carbonyl] phenoxy group } propanoic acid.According to GP1, GP2 and GP3 by 6-bromo-3-formacyl chromone, 2,4-dibromo phenylhydrazine and the preparation of 2 bromopropionic acid ethyl ester: LC/MS (an10p8): Rt 2.87 minutes, m/z 572.7[M+H]
+ 1H NMR (DMSO): δ 1.32 (d, J=6.8Hz, 3H), 4.93 (q, J=6.8Hz, 1H), 6.91 (d, J=8.9Hz, 1H), 7.54 (dd, J=8.3,2.3Hz, 2H), 7.66 (dd, J=8.9,2.5Hz, 1H), 7.78 (dd, J=8.6,2.2Hz, 1H), 8.15 (d, J=2.1Hz, 1H), 8.21 (s, 1H), 8.72 (s, 1H).
4-bromo-2-[1-(2,6-diethyl-phenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid.According to GP1, GP2 and GP3 by 6-bromo-3-formacyl chromone, 2,6-diethyl phenylhydrazine and bromoacetate preparation: LC/MS (an10n8): Rt 2.54 minutes, m/z 457.0[M-H]
+ 1H NMR (CDCl
3): δ 1.27 (t, J=7.3Hz, 6H), 2.35 (q, J=7.3Hz, 4H), 4.82 (s, 2H), 6.99 (d, J=8.9Hz, 1H), 7.29 (d, J=7.5Hz, 2H), 7.48 (m, 1H), 7.67 (m, 1H), 7.79 (s, 1H), 8.11 (s, 1H), 8.27 (s, 1H), 8.87 (br s, 1H).
4-bromo-2-[1-(2, the 6-3,5-dimethylphenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid.According to GP1, GP2 and GP3 by 6-bromo-3-formacyl chromone, 2,6-diethyl phenylhydrazine and bromoacetate preparation: LC/MS (an10n8): Rt 2.27 minutes, m/z428.9[M-H]
+ 1H NMR (CDCl
3): δ 2.07 (s, 6H), 4.74 (s, 2H), 6.91 (d, J=8.7Hz, 1H), 7.19 (d, J=7.3Hz, 2H), 7.25-7.35 (m, 1H), 7.55-7.66 (m, 1H), 7.71 (s, 1H), 8.06 (s, 1H), 8.23 (s, 1H), 8.91 (br s, 1H).
4-bromo-2-[1-(2-ethyl-6-aminomethyl phenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid.Prepare by 6-bromo-3-formacyl chromone, 2-ethyl-6-procarbazine and bromoacetate according to GP1, GP2 and GP3: Rt 2.43 minutes, m/z443.0[M-H]
+ 1H NMR (CDCl
3): δ 1.12 (t, J=7.8Hz, 3H), 2.05 (s, 3H), 2.33 (q, J=7.8Hz, 2H), 4.76 (s, 2H), 6.94 (d, J=8.7Hz, 1H), 7.14-7.25 (m, 2H), 7.31-7.41 (m, 1H), 7.56-66 (m, 1H), 7.72 (s, 1H), 8.06 (s, 1H), 8.22 (s, 1H), 8.93 (br s, 1H).
4-bromo-2-[1-(2-isopropyl phenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid.Prepare by 6-bromo-3-formacyl chromone, 2-ethyl-6-procarbazine and bromoacetate according to GP1, GP2 and GP3: LC/MS (an10p8): Rt 2.76 minutes, m/z 444.9[M+H]
+ 1H NMR (CDCl3-d): δ 1.22 (d, J=6.5Hz, 6H), 2.89 (septet, J=6.1Hz, 1H), 4.76 (s, 2H), 6.92 (d, J=8.7Hz, 1H), 7.30 (s, 2H), 7.49 (s, 2H), 7.62 (d, 1H), 7.72 (s, 1H), 8.15 (s, 1H), 8.20 (s, 1H), 8.92 (br s, 1H).
[4-ethyoxyl-2-(1-phenyl-1H-pyrazoles-4-carbonyl) phenoxy group] acetic acid.Prepare by 6-ethyoxyl-3-formacyl chromone, phenylhydrazine and bromoacetate according to GP1, GP2 and GP3: LC/MS (an10p8): Rt 1.97 minutes, m/z 367.1[M+H]
+ 1H NMR (CDCl
3): δ 1.43 (t, J=6.8Hz, 3H), 4.03 (q, J=6.9Hz, 2H), 4.78 (s, 2H), 7.01-7.13 (m, 2H), 7.15 (s, 1H), 7.36-7.43 (m, 1H), 7.46-7.57 (m, 2H), 7.71-7.75 (m, 2H), 8.16 (s, 1H), 8.50 (s, 1H).
[4-butyl-2-(1-phenyl-1H-pyrazoles-4-carbonyl) phenoxy group] acetic acid.With [4-bromo-2-(1-phenyl-1H-pyrazoles-4-carbonyl) phenoxy group] ethyl acetate (472 milligrams, 1.1 mMs), 1-butyl boron dihydroxide (102 milligrams, 1.0 mMs) and Pd (dppf) Cl
2(72 milligrams, 0.05 mM) solution in THF (10 milliliters) and water (1 milliliter) refluxed 24 hours under argon.Use CH
2Cl
2The extractive reaction mixture, organic facies is passed through diatomite filtration, and concentrates, by purification by flash chromatography residue (SiO2, EtOAc: heptane, 1: 10 to 1: 1).Concentrate the purest part (～10 milligrams), according to GP3 hydrolysed residue thing: LC/MS (an10p8): Rt 2.59 minutes, m/z 379.1[M+H]
+ 1HNMR (CDCl
3): δ 0.88 (t, J=7.5Hz, 3H), 1.29 (m, 2H), 1.49 (m, 2H), 2.48 (m, 2H), 4.51 (s, 2H), 6.84 (m, 1H), 7.14 (m, 1H), 7.30 (m, 2H), 7.42 (m, 2H), 7.65 (m, 2H), 7.97 (s, 1H), 8.46 (s, 1H).
4-bromo-2-[1-(2-chloro-6-aminomethyl phenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid.Prepare by 6-bromo-3-formacyl chromone, 2-chloro-6-procarbazine and bromoacetate according to GP1, GP2 and GP3: LC/MS (an10p8): Rt 2.49 minutes, m/z 450.9[M+H]
+ 1H NMR (CDCl
3): δ 2.16 (s, 3H), 4.80 (s, 2H), 6.98 (d, J=9.1Hz, 1H), 7.30 (m, 1H), 7.34-7.40 (m, 2H), 7.66 (d, 1H), 7.77 (m, 1H), 8.13 (s, 1H); 8.24 (s, 1H).
2-{4-bromo-2-[1-(2, the 6-3,5-dimethylphenyl)-1H-pyrazoles-4-carbonyl] phenoxy group } propanoic acid.According to GP1, GP2 and GP3 by 6-bromo-3-formacyl chromone, 2,6-dimethyl hydrazinobenzene and the preparation of 2 bromopropionic acid ethyl ester: LC/MS (an10n8): Rt 2.55 minutes, m/z 440.9[M-H]
+ 1H NMR (CDCl
3): δ 1.68 (d, J=6.8Hz, 3H), 2.11 (s, 6H), 4.94 (q, J=7.0Hz 1H), 6.97 (d, J=8.9Hz, 1H), 7.19 (d, J=7.5Hz 2H), 7.28-7.32 (m, 1H), 7.63 (d, J=8.1Hz, 1H), 7.75 (m, 1H), 8.05 (s, 1H), 8.22 (s, 1H).
2-{4-bromo-2-[1-(2,6-diethyl phenyl)-1H-pyrazoles-4-carbonyl] phenoxy group } propanoic acid.According to GP1, GP2 and GP3 by 6-bromo-3-formacyl chromone, 2,6-diethyl phenylhydrazine and the preparation of 2 bromopropionic acid ethyl ester: LC/MS (an10n8): Rt 2.85 minutes, m/z 469.0[M-H]
+ 1H NMR (CDCl
3): δ 1.08-1.21 (m, 6H), 1.69-1.76 (m, 3H), 2.18-2.48 (m, 4H), 2.67 (s, 1H), 4.97 (q, J=6.8Hz 1H), 6.84 (d, J=9.0Hz, 1H), 7.00 (d, J=9.0Hz, 1H), 7.24 (d, J=7.7Hz, 1H), 7.42 (d, J=8.1Hz, 1H), 7.65 (d, J=9.0Hz, 1H), 7.77 (s, 1H), 7.86 (s, 1H), 8.06 (s, 1H), 8.22 (s, 1H).
2-{4-bromo-2-[1-(2-isopropyl phenyl)-1H-pyrazoles-4-carbonyl] phenoxy group } propanoic acid.According to GP1, GP2 and GP3 by 6-bromo-3-formacyl chromone, 2,6-diethyl phenylhydrazine and the preparation of 2 bromopropionic acid ethyl ester: LC/MS (an10p8): Rt 2.54 minutes, m/z 459.0[M+H]
+ 1H NMR (CDCl
3): δ 1.19-1.27 (m, 7H), 1.67 (d, J=7.0Hz, 2H), 4.92 (q, J=6.8Hz, 1H), 6.96 (d, J=8.9Hz, 1H), 7.27-7.53 (m,, 4H), 7.58-7.67 (m, 1H), 7.73 (s, 1H), 8.17 (s, 1H), 8.20 (s, 1H).
4-bromo-2-[1-(3,5-dichloropyridine-4-yl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid.According to GP1, GP2 and GP3 by 6-bromo-3-formacyl chromone, 2,6-dichloropyridine-4 hydrazine and bromoacetate preparation: LC/MS (an10n8): Rt 2.08 minutes, m/z 469.8[M-H]
- 1H NMR (DMSO-d
6): δ 4.75 (s, 2H), 7.05 (d, J=9.1Hz, 1H), 7.56 (s, 1H), 7.64 (d, J=9.1Hz, 1H), 8.32 (s, 1H), 8.77 (s, 1H), 8.93 (s, 2H).
4-bromo-2-[1-(4-trifluoromethyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid.Prepare by 6-bromo-3-formacyl chromone, 4-trifluoromethyl phenyl hydrazine and bromoacetate according to GP1, GP2 and GP3: LC/MS (an10n8): Rt 2.88 minutes, m/z 468.9[M-H]
- 1H NMR (CDCl
3): δ 4.78 (s, 2H), 6.92 (d, J=8.9Hz, 1H), 7.65 (d, J=8.9Hz, 1H), 7.71 (s, 1H), 7.79 (d, J=8.9Hz, 2H), 7.91 (d, J=8.9Hz, 2H), 8.23 (s, 1H), 8.65 (s, 1H).
[4-bromo-2-(1-naphthalene-1-base-1H-pyrazoles-4-carbonyl) phenoxy group] acetic acid.Prepare by 6-bromo-3-formacyl chromone, 1-naphthylhydrazine and bromoacetate according to GP1, GP2 and GP3: LC/MS (an10p8): Rt 2.649 minutes, m/z 451.0[M+H]
+ 1H NMR (CDCl
3): δ 4.78 (s, 2H), 6.93 (d, J=8.85Hz, 1H), 7.52-7.68 (m, 6H), 7.73-7.82 (m, 2H), 7.93-8.05 (m, 2H), 8.33 (s, 1H), 8.38 (s, 1H).
General route of synthesis IV
General step 5 (GP5):
Mixture not diluted ground (neat) temperature in 140 ℃ in microwave oven of 2-(2-acetyl bromide) ethyl phenoxyacetate (0.1 mM) and amide (X=O) or thioamides (X=S) (2.5 mM) was heated 3 hours.After cooling, solid residue is at EtOAc and saturated NaHCO
3Distribute between the aqueous solution.Separate each phase, dry organic facies (MgSO
4), and under vacuum, concentrate.By the rough solid of purification by flash chromatography, obtain Xiang Ying De oxazole or thiazole.
Intermediate-9
(2-acetyl group-4-bromine phenoxy group) ethyl acetate.Prepare by 5 '-bromo-2 '-hydroxy acetophenone (2 grams, 9.3 mMs) and bromoacetate (1.03 milliliters, 9.3 mMs) according to GP2, obtain title compound (2.64 grams of white solid, 8.7 mM, 94%): LC/MS (an10p8) Rt3.3 minute, m/z 301[M+H]
+ 1H NMR (CDCl
3): δ 1.32 (t, 3H), 2.71 (s, 3H), 4.30 (q, 2H), 4.72 (s, 2H), 6.76 (d, 1H), 7.55 (dd, 1H), 7.88 (s, 1H).
Intermediate-10
[4-bromo-2-(2-acetyl bromide) phenoxy group] ethyl acetate.CHCl to (2-acetyl group-4-bromine phenoxy group) ethyl acetate of cooling off (0 ℃) (2.5 grams, 8.3 mMs)
3Slowly add bromine (425 microlitres, 8.3 mMs) in (25 milliliters) solution.After finishing, reactant mixture was at room temperature stirred 1 hour.Mixture is at CH
2C1
2And distribute between the saline.Organic facies is washed with saline, dry (MgSO
4), and under vacuum, concentrate, obtain the title compound (2.97 grams, 7.8 mMs, 94%) of white solid:
1H NMR (CDCl
3): δ 1.35 (t, 3H), 4.32 (q, 2H), 4.75 (s, 2H), 4.76 (s, 2H), 6.77 (d, 1H), 7.60 (dd, 1H), 7.97 (s, 1H).
[4-bromo-2-(2-Ben Ji oxazole-4-yl) phenoxy group] acetic acid.Prepare title compound according to GP5 and GP3 by [4-bromo-2-(2-acetyl bromide) phenoxy group] ethyl acetate and Benzoylamide: LC/MS (an10p8) Rt 2.6 minutes, m/z 374/376[M+H]
+
4-bromo-2-[2-(4-methoxyphenyl) oxazole-4-yl] phenoxy group } acetic acid.Prepare title compound according to GP5 and GP3 by [4-bromo-2-(2-acetyl bromide) phenoxy group] ethyl acetate and 4-methoxy benzamide: LC/MS (an10p8) Rt 2.61 minutes, m/z 404[M+H]
+
4-bromo-2-[2-(4-chlorphenyl) oxazole-4-yl] phenoxy group } acetic acid.Prepare title compound according to GP5 and GP3 by [4-bromo-2-(2-acetyl bromide) phenoxy group] ethyl acetate and 4-chlorobenzamide: LC/MS (an10p8) Rt 2.90 minutes, m/z 407.7[M+H]
+ 1H NMR (CDCl
3): δ 4.89 (s, 2H), 7.09 (d, 1H), 7.48 (d, 1H), 7.64 (d, 2H), 8.08 (d, 2H), 8.20 (s, 1H), 8.89 (s, 1H), 13.2 (br s, 1H).
4-bromo-2-[2-(3-methoxyphenyl) oxazole-4-yl] phenoxy group } acetic acid.Prepare title compound according to GP5 and GP3 by [4-bromo-2-(2-acetyl bromide) phenoxy group] ethyl acetate and 3-methoxy benzamide: LC/MS (an10p8) Rt 2.68 minutes, m/z 404[M+H]
+ 1H NMR (CDCl
3): δ 3.87 (s, 1H), 4.89 (s, 2H), 7.09 (m, 2H), 7.4-7.7 (m, 4H), 8.22 (s, 1H), 8.89 (s, 1H), 13.3 (br s, 1H).
4-bromo-2-[2-(4-ethoxyl phenenyl) oxazole-4-yl] phenoxy group } acetic acid.Prepare title compound according to GP5 and GP3 by [4-bromo-2-(2-acetyl bromide) phenoxy group] ethyl acetate and 4-ethyl benzamide: LC/MS (an10p8) Rt 2.80 minutes, m/z 418/420[M+H]
+ 1H NMR (CDCl
3): δ 1.36 (t, 3H), 4.10 (q, 2H), 4.88 (s, 2H), 7.07 (m, 3H), 7.47 (d, 1H), 8.00 (d, 2H), 8.20 (s, 1H), 8.82 (s, 1H), 13.4 (br s, 1H).
[2-(2-benzyl base oxazole-4-yl)-4-bromine phenoxy group] acetic acid.Prepare title compound according to GP5 and GP3 by [4-bromo-2-(2-acetyl bromide) phenoxy group] ethyl acetate and 2-phenyl-acetamides: LC/MS (an10p8) Rt 2.47 minutes, m/z 388[M+H]
+ 1H NMR (CDCl
3): δ 4.22 (s, 2H), 4.84 (s, 2H), 7.04 (d, 1H), 7.25 (m, 5H), 7.43 (d, 1H), 8.06 (s, 1H), 8.69 (s, 1H), 13 (br s, 1H).
4-bromo-2-[2-(3-methoxy-benzyl) oxazole-4-yl] phenoxy group } acetic acid.Prepare title compound according to GP5 and GP3 by [4-bromo-2-(2-acetyl bromide) phenoxy group] ethyl acetate and 2-(3-methoxyphenyl) acetamide: LC/MS (an10p8) Rt 2.45 minutes, m/z 418[M+H]
+
4-bromo-2-[2-(2-chloro-4-luorobenzyl) oxazole-4-yl] phenoxy group } acetic acid.Prepare title compound according to GP5 and GP3 by [4-bromo-2-(2-acetyl bromide) phenoxy group] ethyl acetate and 2-(2-chloro-4-fluorophenyl) acetamide: LC/MS (an10p8) Rt 2.75 minutes, m/z 440[M+H]
+
4-bromo-2-[2-(2,6-dichloro benzyl) oxazole-4-yl] phenoxy group } acetic acid.Prepare title compound according to GP5 and GP3 by [4-bromo-2-(2-acetyl bromide) phenoxy group] ethyl acetate and 2-(2, the 6-Dichlorobenzene base) acetamide: LC/MS (an10p8) Rt 2.75 minutes, m/z 456/458/460[M+H]
+
4-bromo-2-[2-(4-methoxy-benzyl) oxazole-4-yl] phenoxy group } acetic acid.Prepare title compound according to GP5 and GP3 by [4-bromo-2-(2-acetyl bromide) phenoxy group] ethyl acetate and 2-(4-methoxyphenyl) acetamide: LC/MS (an10p8) Rt 2.40 minutes, m/z 418[M+H]
+ 1H NMR (CDCl
3):
3.72 (s, 3H), 4.14 (s, 1H), 4.85 (s, 1H), 6.92 (m, 2H), 7.02 (d, 1H), 7.2 (d, 1H), 7.23 (d, 1H), 7.44 (d, 1H), 8.05 (s, 1H), 8.67 (s, 1H), 13.2 (br s, 1H).
[4-bromo-2-(2-phenyl thiazole-4-yl) phenoxy group] acetic acid.Prepare title compound according to GP5 and GP3 by [4-bromo-2-(2-acetyl bromide) phenoxy group] ethyl acetate and Aminothiocarbonylbenzene: LC/MS (an10p8) Rt 2.69 minutes, m/z 390[M+H]
+
4-bromo-2-[2-(4-benzyl chloride base) thiazole-4-yl] and phenoxy group } acetic acid.Prepare title compound according to GP5 and GP3 by [4-bromo-2-(2-acetyl bromide) phenoxy group] ethyl acetate and 2-(4-chlorphenyl) thioacetamide: LC/MS (an10p8) Rt 2.69 minutes, m/z 390[M+H]
+ 1H NMR (CDCl
3):
4.42 (s, 2H), 4.86 (s, 2H), 7.06 (d, 1H), 7.45 (m, 5H), 8.33 (s, 1H), 8.41 (s, 1H), 13.2 (br s, 1H).
General route of synthesis V
General step 6 (GP6)
Synthesizing of carbonyl thiazole
With thioamides (1.0 mM) and N, the mixture of dinethylformamide dimethylacetal (1.2 mM) under nitrogen in stirring at room 1 hour.Remove volatile material under the condition that does not heat in decompression, obtain corresponding N '-sulfo-aroyl carbonamidine, this product directly uses in subsequent step without being further purified.
In benzene (2.6 milliliters) solution of 2-(2-acetyl bromide) ethyl phenoxyacetate (1 mM) and N '-sulfo-aroyl carbonamidine (1 mM), add excessive triethylamine (5 mM).After at room temperature stirring is spent the night, under vacuum, remove and desolvate.Residue is at EtOAc and saturated NaHCO
3Distribute between the aqueous solution.Organic facies is carried out drying (MgSO
4), and under vacuum, concentrate.By the thick material of purification by flash chromatography, obtain thioamides.
[4-bromo-2-(2-phenyl thiazole-5-carbonyl) phenoxy group] acetic acid.Prepare title compound according to GP6 and GP3 by [4-bromo-2-(2-acetyl bromide) phenoxy group] ethyl acetate and Aminothiocarbonylbenzene: LC/MS (an10p8) Rt 2.44 minutes, m/z 418[M+H]
+
General route of synthesis VI
General step 7 (GP7)
Synthesizing of oxazole
Benzoylamide (1.0 mM) and 2-bromoacetyl benzene (0.5 mM) not diluted ground were heated 3 hours in 140 ℃ in Emrys Optimizer microwave oven.After cooling, add EtOAc and CH
2Cl
2, remove by filter formed precipitation.Filtrate concentrates under vacuum, by purification by flash chromatography, obtains Xiang Ying De oxazole.
Intermediate-11
(4-bromo-2-carbamyl phenoxyl) ethyl acetate.Prepare by bromine water poplar amide and bromoacetate according to GP2:
1H NMR (CDCl
3): δ 1.35 (t, 3H), 4.34 (q, 2H), 4.73 (s, 2H), 5.87 (br s, 1H), 6.76 (d, 1H), 7.56 (d, 1H), 8.33 (br s, 1H), 8.39 (s, 1H).
[4-bromo-2-(4-phenyl-oxazoles-2-yl)-phenoxy group] acetic acid.Prepare title compound according to GP7 by (4-bromo-2-carbamyl phenoxyl) ethyl acetate and 2-bromoacetyl benzene: LC/MS (an10p8) Rt 2.32 minutes, m/z 374/376[M+H]
+
General route of synthesis VII
General step 8 (GP8):
Synthesizing of hydroxyl oxime acyl chlorides (hydroximic acid chloride)
CH to aldoxime (1.0 mM)
2Cl
2Once add N-neoprene imidodicarbonic diamide (1.0 mM) in (1.7 milliliters) solution.With this reactant mixture under argon gas atmosphere in stirring at room 3 hours.Add entry.Separate each phase.Organic facies is carried out drying (MgSO
4), and under vacuum, concentrate, obtaining corresponding hydroxyl oxime chloride derivative, this product directly uses without being further purified.
General step 9 (GP9):
Synthesizing of isoxazole
In 4 hours, to the dry CH of hydroxyl oxime acyl chlorides (1.0 mM) and (4-bromo-2-propioloyl (propynoyl)-phenoxy group) ethyl acetate (1.0 mM)
2Cl
2Slowly add Et in (3.7 milliliters) solution
3The dry CH of N (1.0 mM)
2Cl
2(0.6 milliliter) solution (using spring pump (springe-pump)).After reinforced finishing, water, saline washing reaction mixture, and dry (MgSO
4), under vacuum, concentrate.Slightly oily by purification by flash chromatography, obtain corresponding isoxazole derivatives.
Synthesizing of intermediate-12
(4-bromo-2-formoxyl phenoxy group) ethyl acetate.Prepare by 5-bromo-2-hydroxy benzaldehyde according to GP2: LC/MS (an10p8) Rt 3.45 minutes, m/z 287[M+H]
+ 1H NMR (CDCl
3): δ 1.29 (t, 3H), 4.25 (q, 2H), 4.74 (s, 2H), 6.79 (d, 1H), 7.60 (d, 1H), 7.94 (s, 1H), 10.46 (s, 1H).
[4-bromo-2-(1-hydroxyl-3-TMS Propargyl) phenoxy group] ethyl acetate.Hexane (14.54 milliliters, the 36.36 mMs) solution that in cooling (78 ℃) solution of (trimethyl silyl) acetylene (3.93 grams, 40.0 mMs) in dry THF (40 milliliters), slowly adds the butyl lithium of 2.5M., this mixture is transferred in cooling (78 ℃) solution of (4-bromo-2-formoxyl phenoxy group) ethyl acetate (10.44 grams, 36.36 mMs) in dry THF (120 milliliters) after 30 minutes-78 ℃ of stirrings.After transfer is finished, this reactant mixture was stirred 45 minutes at-78 ℃.In this reactant mixture, slowly add saturated NH
4Cl (40 milliliters) aqueous solution adds Et then
2O (40 milliliters).Make the reactant mixture of quencher be warmed up to room temperature.Separate each phase, use Et
2O (2x) aqueous phase extracted.With the organic facies that the salt water washing merges, dry (MgSO
4), under vacuum, concentrate.By column chromatography (SiO
2) purification slightly oil, then with at CH
2Cl
2The trometamol of the loaded by polystyrene in (160 milliliters) (PS-Trisamine, 4.17 mM/grams, 8 grams) stirred 90 minutes together.Remove by filter resin, concentrated filtrate under vacuum obtains light yellow oily title compound (7.6 grams, 19.7 mMs, 54%).LC/MS (an10p8) Rt 4.30 minutes, m/z 408[M+Na]
+ 1HNMR (CDCl
3): δ 0.24 (s, 9H), 1.31 (t, 3H), 4.27 (q, 2H), 4.71 (s, 2H), 5.79 (s, 1H), 6.74 (d, 1H), 7.39 (dd, 1H), 7.79 (d, 1H).
[4-bromo-2-(3-TMS propioloyl) phenoxy group] ethyl acetate.CH to [4-bromo-2-(1-hydroxyl-3-TMS Propargyl) phenoxy group] ethyl acetate (0.95 gram, 2.46 mMs)
2Cl
2Add active MnO in two batches in (10 milliliters) solution
2(1.5 grams+1 gram) stirs reactant mixture 90 minutes.By the Celite pad solids removed by filtration, concentrated filtrate under vacuum obtains yellow oily title compound (0.83 gram, 2.16 mMs, 87%).LC/MS (an10p8) Rt 4.70 minutes, m/z 383[M+H]
+ 1H NMR (CDCl
3): δ 0.30 (s, 9H), 1.30 (t, 3H), 4.27 (q, 2H), 4.72 (s, 2H), 6.81 (d, 1H), 7.58 (dd, 1H), 8.10 (s, 1H).
(4-bromo-2-propioloyl phenoxy group) ethyl acetate.The Na that in methanol (20 milliliters) solution of [4-bromo-2-(3-TMS propioloyl) phenoxy group] ethyl acetate (0.83 gram, 2.16 mMs), adds 0.1M
2B
4O
7Aqueous solution (10 milliliters).After at room temperature stirring 2-3 minute, add Et
2O and 1N HCl aqueous solution.Separate each phase, with salt water washing organic facies, dry (MgSO
4), and under vacuum, concentrate, obtain leaving standstill the yellow oily title compound of post crystallization (0.65 gram, 2.09 mMs, 96%).LC/MS (an10p8) Rt 3.58 minutes, m/z 311[M+H]
+ 1HNMR (CDCl
3): δ 1.31 (t, 3H), 3.45 (s, 1H), 4.27 (q, 2H), 4.74 (s, 2H), 6.83 (d, 1H), 7.61 (dd, 1H), 8.14 (d, 1H).
[4-bromo-2-(3-phenyl-isoxazole azoles-5-carbonyl) phenoxy group] acetic acid prepares title compound according to GP8 and GP9 by benzaldoxime (benzalddoxime) and (4-bromo-2-propioloyl phenoxy group) ethyl acetate: LC/MS (an10n8) Rt 3.07 minutes, m/z 400[M-H]
- 1H NMR (DMSO): δ 4.77 (s, 2H), 7.13 (d, 1H), 7.53 (m, 3H), 7.73-7.92 (m, 5H).
4-bromo-2-[3-(2,6-two chloro-phenyl) isoxazole-5-carbonyl] and phenoxy group } acetic acid.By 2,6-dichloro benzaldoxime and (4-bromo-2-propioloyl phenoxy group) ethyl acetate prepare title compound: LC/MS (an10n8) Rt 2.74 minutes, m/z 471.9[M+H according to GP8 and GP9]
+
General route of synthesis VIII
General step 10 (GP10)
Synthesizing of amidoxim (amidoxime)
Sodium (1.25 mM) is joined in the dry methanol (1 milliliter), obtain solution A.Oxammonium hydrochloride. (1.2 mM) is dissolved in the dry methanol (1 milliliter), obtains solution B.Solution A and B are mixed, in ice bath, cool off, and filter.In this filtrate, add nitrile (1 mM) then, reactant mixture is at room temperature stirred spend the night.Under vacuum, remove and desolvate, obtain corresponding amidoxim.Chemical compound carries out purification (EtOAc/ heptane: 1/2), perhaps directly use without being further purified on silica gel chromatography.
General step 11 (GP11)
Synthesizing of oxadiazole
In dry ethanol (10 milliliters) solution of sodium (3.3 mM), add amidoxim (1.15 mM), molecular sieve (1 gram) and essence of Niobe (1 mM) successively.Under refluxing, stir after 12 hours, make the reactant mixture cooling, and filter by Celite pad.With methanol and CH
2Cl
2The washing Celite pad.Under vacuum, remove and desolvate, residue is stirred with water.Filter out precipitate, drying obtains Xiang Ying De oxadiazole.Chemical compound is purification (EtOAc: heptane, 1: 2) on silica gel chromatography, perhaps directly uses without being further purified.
[4-bromo-2-(the 3-phenyl-[and 1,2,4] oxadiazole-5-yls) phenoxy group] acetic acid.Prepare title compound according to GP10, GP11, GP2 and GP3 by 5-bromo-2 hydroxybenzoic acid methyl ester and benzonitrile: LC/MS (an10n8): Rt 2.41 minutes, m/z 373.4[M-H]
- 1H NMR (DMSO-d
6): δ 4.97 (s, 2H), 7.2 (d, 1H), 7.62 (s, 3H), 7.82 (d, 2H), 8.10 (d, 1H), 8.2 (s, 1H).
{ 4-bromo-2-[3-(4-fluoro-phenyl)-[1,2,4] oxadiazole-5-yl] phenoxy group } acetic acid.Prepare title compound according to GP10, GP11, GP2 and GP3 by 5-bromo-2 hydroxybenzoic acid methyl ester and 4-fluorine benzonitrile: LC/MS (an10n8) Rt 2.49, m/z 391.4[M-H]
-
{ 4-bromo-2-[3-(4-methoxyl group-phenyl)-[1,2,4] oxadiazole-5-yl] phenoxy group } acetic acid.Prepare title compound according to GP10, GP11, GP2 and GP3 by 5-bromo-2 hydroxybenzoic acid methyl ester and 4-HOMOVERATRONITRILE: LC/MS (an10n8) Rt 2.44 minutes, m/z 403.4[M-H]
-
{ 4-bromo-2-[3-(4-chlorphenyl)-[1,2,4] oxadiazole-5-yl] phenoxy group } acetic acid. prepare title compound according to GP10, GP11, GP2 and GP3 by 5-bromo-2 hydroxybenzoic acid methyl ester and 4-benzyl chloride nitrile: LC/MS (an10n8) Rt 2.68 minutes, m/z 407.4[M-H]
-
{ 4-bromo-2-[3-(4-Trifluoromethoxyphen-l)-[1,2,4] oxadiazole-5-yl] phenoxy group } acetic acid.Prepare title compound according to GP10, GP11, GP2 and GP3 by 5-bromo-2 hydroxybenzoic acid methyl ester and 4-trifluoromethoxy benzonitrile: LC/MS (an10n8) Rt 2.09 minutes, m/z 457.5[M-H]
- 1H NMR (DMSO-d
6): δ 4.96 (s, 2H), 7.21 (d, 1H), 7.59 (d, 2H), 7.82 (d, 1H), 8.22 (d, 3H).
{ 4-bromo-2-[3-(3-methoxyphenyl)-[1,2,4] oxadiazole-5-yl] phenoxy group } acetic acid.Prepare title compound according to GP10, GP11, GP2 and GP3 by 5-bromo-2 hydroxybenzoic acid methyl ester and 3-HOMOVERATRONITRILE: LC/MS (an10n8) Rt 2.47 minutes, m/z 403.4[M-H]
- 1HNMR (DMSO-d
6): δ 3.86 (s, 3H), 4.96 (s, 2H), 7.20 (d, 2H), 7.5 (t, 1H), 7.6 (s, 1H), 7.67 (d, 1H), 7.8 (d, 1H), 8.2 (s, 1H).
{ 4-bromo-2-[3-(3-chlorphenyl)-[1,2,4] oxadiazole-5-yl] phenoxy group } acetic acid.Prepare title compound according to GP10, GP11, GP2 and GP3 by 5-bromo-2 hydroxybenzoic acid methyl ester and 3-benzyl chloride nitrile: LC/MS (an10n8) Rt 2.69 minutes, m/z 407.4[M-H]
- 1H NMR (DMSO): δ 4.97 (s, 2H), 7.2 (d, 1H), 7.6 (m, 2H), 7.7 (d, 1H), 7.8 (d 2H), 8.2, (s, 1H).
{ 4-bromo-2-[3-(4-trifluoromethyl-phenyl)-[1,2,4] oxadiazole-5-yl] phenoxy group }-acetic acid.Prepare title compound according to GP10, GP11, GP2 and GP3 by 5-bromo-2 hydroxybenzoic acid methyl ester and 4-trifluoromethyl benzonitrile: LC/MS (an10n8) Rt 2.83 minutes, m/z 441.4[M-H]
- 1H NMR (DMSO-d
6): δ 4.97 (s, 2H), 7.2 (d, 1H), 7.8 (dd, 1H), 7.9 (d, 2H), 8.2 (d, 1H), 8.3 (d, 2H).
{ 4-bromo-2-[3-(2-methoxyphenyl)-[1,2,4] oxadiazole-5-yl] phenoxy group } acetic acid.Prepare title compound according to GP10, GP11, GP2 and GP3 by 5-bromo-2 hydroxybenzoic acid methyl ester and 2-HOMOVERATRONITRILE: LC/MS (an10n8) Rt 2.31 minutes, m/z 403.4[M-H]
- 1HNMR (DMSO-d
6): δ 2.5 (s, 3H), 4.94 (s, 2H), 7.2 (m, 3H), 7.5 (t, 1H), 7.7 (d, 1H), 7.9 (d, 1H), 8.1 (s, 1H).
{ 4-bromo-2-[3-(2-chlorphenyl)-[1,2,4] oxadiazole-5-yl] phenoxy group } acetic acid.Prepare title compound according to GP10, GP11, GP2 and GP3 by 5-bromo-2 hydroxybenzoic acid methyl ester and 2-benzyl chloride nitrile: LC/MS (an10n8) Rt 2.50 minutes, m/z 407.4[M-H]
- 1H NMR (DMSO-d
6): δ 4.94 (s, 2H), 7.2 (d, 1H), 7.5-7.7 (m, 3H), 7.8 (dd, 1H), 8.0 (d, 1H), 8.1 (s, 1H).
{ 2-[3-(3,5-couple-trifluoromethyl-phenyl)-[1,2,4] oxadiazole-5-yl]-4-bromo-phenoxy group }-acetic acid.By 5-bromo-2 hydroxybenzoic acid methyl ester and 3, the two trifluoromethoxy benzonitriles of 5-prepare title compound: LC/MS (an10n8) Rt 3,332 minutes, m/z509.5[M-H according to GP10, GP11, GP2 and GP3]
- 1H NMR (DMSO-d
6): δ 4.96 (s, 2H), 7.2 (d, 1H), 7.8 (d, 1H), 8.2 (s, 1H), 8.4 (s, 1H), 8.5 (s, 1H), 8.6 (s, 1H).
{ 4-bromo-2-[3-(2, the 6-Dichlorobenzene base)-[1,2,4] oxadiazole-5-yl] phenoxy group } acetic acid.By 5-bromo-2 hydroxybenzoic acid methyl ester and 2,6-two chloro-benzonitriles prepare title compound according to GP10, GP11, GP2 and GP3: LC/MS (an10n8) Rt 2.59 minutes, m/z 441.4[M-H]
-
{ 4-bromo-2-[3-(4-phenoxy group-phenyl)-[1,2,4] oxadiazole-5-yl]-phenoxy group }-acetic acid.Prepare title compound according to GP10, GP11, GP2 and GP3 by 5-bromo-2 hydroxybenzoic acid methyl ester and 4-phenoxy group benzonitrile: LC/MS (an10n8) Rt 3.29 minutes, m/z 465.5[M-H]
- 1HNMR (DMSO-d
6): δ 4.95 (s, 2H), 7.2 (m, 6H), 7.4 (t, 2H), 7.8 (d, 1H), 8.0 (d, 2H), 8.1 (s, 1H).
{ 4-bromo-2-[3-(3-trifluoromethyl)-[1,2,4] oxadiazole-5-yl] phenoxy group }-acetic acid.Prepare title compound according to GP10, GP11, GP2 and GP3 by 5-bromo-2 hydroxybenzoic acid methyl ester and 3-trifluoromethyl benzonitrile: LC/MS (an10n8) Rt 2.96 minutes, m/z 441.4[M-H]
- 1H NMR (DMSO-d
6): δ 4.97 (s, 2H), 7.2 (d, 1H), 7.8 (m, 2H), 8.0 (d, 1H), 8.2 (s, 1H), 8.3 (s, 1H), 8.4 (d, 1H).
{ 4-bromo-2-[3-(4-trifluoromethoxy-benzyl)-[1,2,4] oxadiazole-5-yl]-phenoxy group }-acetic acid.Prepare title compound according to GP10, GP11, GP2 and GP3 by 5-bromo-2 hydroxybenzoic acid methyl ester and (4-Trifluoromethoxyphen-l) acetonitrile: LC/MS (an10n8) Rt 2.76 minutes, m/z4715[M-H]
- 1H NMR (DMSO-d
6): δ 4.2 (s, 2H), 4.9 (s, 2H), 7.1 (d, 1H), 7.3 (d, 2H), 7.5 (d, 2H), 7.7 (d, 1H), 8.0 (s, 1H).
{ 4-bromo-2-[3-(4-chloro-benzyl)-[1,2,4] oxadiazole-5-yl]-phenoxy group }-acetic acid.Prepare title compound according to GP10, GP11, GP2 and GP3 by 5-bromo-2 hydroxybenzoic acid methyl ester and (4-chlorphenyl) acetonitrile: LC/MS (an10n8) Rt2.54 minute, m/z 421.4[M-H]
- 1HNMR (DMSO-d
6): δ 4.2 (s, 2H), 4.9 (s, 2H), 7.1 (d, 1H), 7.4 (s, 4H), 7.8 (d, 1H), 8.0 (s, 1H).
[2-(the 3-benzyl-[1,2,4] oxadiazole-5-yls)-4-bromo-phenoxy group]-acetic acid.Prepare title compound according to GP10, GP11, GP2 and GP3 by 5-bromo-2 hydroxybenzoic acid methyl ester and phenylacetonitrile: LC/MS (an10n8) Rt 2.26 minutes, m/z 387.4[M-H]
- 1H NMR (DMSO-d
6): δ 4.2 (s, 2H), 4.9 (s, 2H), 7.1 (d, 1H), 7.3 (m, 5H), 7.7 (d, 1H), 8.0 (s, 1H).
{ 4-bromo-2-[3-(4-fluoro-benzyl)-[1,2,4] oxadiazole-5-yl]-phenoxy group }-acetic acid.Prepare title compound according to GP10, GP11, GP2 and GP3 by 5-bromo-2 hydroxybenzoic acid methyl ester and (4-fluorophenyl) acetonitrile: LC/MS (an10n8) Rt 2.38 minutes, m/z 405.4[M-H]
-
4-bromo-2-[3-(3,5-two fluoro-benzyls)-[1,2,4] oxadiazole-5-yl]-phenoxy group }-acetic acid.Prepare title compound according to GP10, GP11, GP2 and GP3 by 5-bromo-2 hydroxybenzoic acid methyl ester and (3, the 5-difluorophenyl) acetonitrile: LC/MS (an10n8) Rt 2.44 minutes, m/z 423.4[M-H]
-
{ 4-bromo-2-[3-(4-methoxyl group-benzyl)-[1,2,4] oxadiazole-5-yl]-phenoxy group }-acetic acid.Prepare title compound according to GP10, GP11, GP2 and GP3 by 5-bromo-2 hydroxybenzoic acid methyl ester and (4-methoxyphenyl) acetonitrile: LC/MS (an10n8) Rt 2.25 minutes, m/z 417.4[M-H]
- 1H NMR (DMSO-d
6): δ 4.1 (s, 2H), 4.9 (s, 2H), 6.9 (d, 2H), 7.1 (d, 1H), 7.2 (d, 2H), 7.7 (d, 1H), 8.0 (s, 1H).
{ 4-bromo-2-[3-(2-methoxyl group-benzyl)-[1,2,4] oxadiazole-5-yl]-phenoxy group }-acetic acid.Prepare title compound according to GP10, GP11, GP2 and GP3 by 5-bromo-2 hydroxybenzoic acid methyl ester and (2-methoxyl group-phenyl)-acetonitrile: LC/MS (an10n8) Rt 2.25 minutes, m/z 417.4[M-H]
- 1H NMR (DMSO-d
6): δ 3.7 (s, 3H), 4.1 (s, 2H), 4.9 (s, 2H), 6.9 (t, 1H), 7.0 (d, 1H), 7.1 (d, 1H), 7.2 (m, 2H), 7.7 (d, 1H), 8.0 (s, 1H).
{ 4-bromo-2-[3-(2-chloro-benzyl)-[1,2,4] oxadiazole-5-yl]-phenoxy group }-acetic acid.Prepare title compound according to GP10, GP11, GP2 and GP3 by 5-bromo-2 hydroxybenzoic acid methyl ester and (2-chlorphenyl) acetonitrile: LC/MS (an10n8) Rt 2.48 minutes, m/z 421.4[M-H]
- 1HNMR (DMSO-d
6): δ 4.2 (s, 2H), 4.9 (s, 2H), 7.1 (d, 1H), 7.3 (m, 2H), 7.4 (m, 2H), 7.7 (dd, 1H), 8.0 (d, 1H).
4-bromo-2-[3-(2,6-two chloro-benzyls)-[1,2,4] oxadiazole-5-yl]-phenoxy group }-acetic acid.Prepare title compound according to GP10, GP11, GP2 and GP3 by 5-bromo-2 hydroxybenzoic acid methyl ester and (2, the 6-Dichlorobenzene base) acetonitrile: LC/MS (an10n8) Rt 2.58 minutes, m/z 455/457/459[M-H]
- 1H NMR (DMSO-d
6): δ 4.4 (s, 2H), 4.9 (s, 2H), 7.1 (d, 1H), 7.4 (t, 1H), 7.5 (d, 2H), 8.7-7.8 (dd, 1H), 8.0 (d, 1H).
4-bromo-2-[3-(2,4-two chloro-benzyls)-[1,2,4] oxadiazole-5-yl]-phenoxy group }-acetic acid.Prepare title compound according to GP10, GP11, GP2 and GP3 by 5-bromo-2 hydroxybenzoic acid methyl ester and (2, the 4-Dichlorobenzene base) acetonitrile: LC/MS (an10n8) Rt 2,78 minutes, m/z 455/457/459[M-H]
-
{ 4-bromo-2-[3-(3, the 4-dichloro benzyl)-[1,2,4] oxadiazole-5-yl]-phenoxy group } acetic acid.Prepare title compound according to GP10, GP11, GP2 and GP3 by 5-bromo-2 hydroxybenzoic acid methyl ester and (3, the 4-Dichlorobenzene base) acetonitrile: LC/MS (an10n8) Rt 2.81 minutes, m/z 455/457/459[M-H]
- 1H NMR (DMSO-d
6): δ 4.3 (s, 2H), 4.8 (s, 2H), 7.1 (d, 1H), 7.3 (dd, 1H), 7.6 (d, 1H), 7.6 (d, 1H), 7.7 (dd, 1H), 8.0 (d, 1H).
{ 4-bromo-2-[3-(3, the 4-dimethoxy-benzyl)-[1,2,4] oxadiazole-5-yl] phenoxy group }-acetic acid.Prepare title compound according to GP10, GP11, GP2 and GP3 by 5-bromo-2 hydroxybenzoic acid methyl ester and (3, the 4-Dimethoxyphenyl) acetonitrile: LC/MS (an10n8) Rt 2.20 minutes, m/z 447,4[M-H]
- 1H NMR (DMSO-d
6): δ 3.72 (s, 3H), 3.74 (s, 3H), 4.1 (s, 2H), 4.9 (s, 2H), 6.8 (m, 2H), 6.9 (s, 1H), 7.1 (d, 1H), 7.7 (dd, 1H), 8.0 (d, 1H).
{ 4-bromo-2-[3-(3-methoxy-benzyl)-[1,2,4] oxadiazole-5-yl] phenoxy group } acetic acid.Prepare title compound according to GP10, GP11, GP2 and GP3 by 5-bromo-2 hydroxybenzoic acid methyl ester and (3-methoxyphenyl) acetonitrile: LC/MS (an10n8) Rt 2.38 minutes, m/z 417.4[M-H]
- 1H NMR (DMSO-d
6): δ 4.1 (s, 2H), 4.9 (s, 2H), 6.8 (d, 1H), 6.9 (m, 2H), 7.1 (d, 1H), 7.2 (t, 1H), 7:8 (m, 1H), 8.0 (d, 1H).
{ 4-bromo-2-[3-(4-methyl-benzyl)-[1,2,4] oxadiazole-5-yl] phenoxy group } acetic acid.Prepare title compound according to GP10, GP11, GP2 and GP3 by 5-bromo-2 hydroxybenzoic acid methyl ester and (4-aminomethyl phenyl) acetonitrile: LC/MS (an10n8) Rt 2.72 minutes, m/z 401.4[M-H]
- 1HNMR (DMSO-d
6): δ 3.3 (s, 3H), 4.1 (s, 2H), 4.9 (s, 2H), 7.1 (m, 3H), 7.2 (d, 2H), 7.7 (dd, 1H), 8.0 (d, 1H).
{ 4-bromo-2-[3-(2-trifluoromethyl benzyl)-[1,2,4] oxadiazole-5-yl] phenoxy group }-acetic acid.Prepare title compound according to GP10, GP11, GP2 and GP3 by 5-bromo-2 hydroxybenzoic acid methyl ester and (2-trifluoromethyl) acetonitrile: LC/MS (an10n8) Rt 2.77 minutes, m/z 455.5[M-H]
- 1H NMR (DMSO-d
6): δ 4.3 (s, 2H), 4.9 (s, 2H), 7.1 (d, 1H), 7.5-7.6 (m, 2H), 7:6-7.7 (t, 1H), 7.7-7.8 (m, 2H), 8.0 (d, 1H).
{ 4-bromo-2-[3-(3, the 5-dimethoxy-benzyl)-[1,2,4] oxadiazole-5-yl] phenoxy group } acetic acid.Prepare title compound according to GP10, GP11, GP2 and GP3 by 5-bromo-2 hydroxybenzoic acid methyl ester and (3, the 5-Dimethoxyphenyl) acetonitrile: LC/MS (an10n8) Rt 2.61 minutes, m/z 447.4[M-H]
- 1H NMR (DMSO-d
6): δ 3.7 (s, 6H), 4.1 (s, 2H), 4.9 (s, 2H), 6.4 (d, 1H), 6.5 (d, 2H), 7.1 (d, 1H), 7.8 (dd, 1H), 8.0 (d, 1H).
{ 4-bromo-2-[3-(2, the 4-Dichlorobenzene base)-[1,2,4] oxadiazole-5-yl] phenoxy group } acetic acid.By 5-bromo-2-hydroxy-benzoic acid methyl ester and 2, the 4-dichloro-benzonitrile prepares title compound according to GP10, GP11, GP2 and GP3: LC/MS (an10n8) Rt 2.93m/z 441/443/445[M-H]
- 1HNMR (DMSO): δ 4.7 (s, 1H), 6.95-6.98 (d, 1H), 7.42-7.44 (d, 1H), 7.58-7.60 (d, 1H), 7.67 (s, 1H), 7.82-7.85 (d, 1H), 7.94-7.95 (s, 1H).
{ 4-bromo-2-[3-(3-benzyl chloride base)-[1,2,4] oxadiazole-5-yl] phenoxy group } acetic acid.Prepare title compound according to GP10, GP11, GP2 and GP3 by 5-bromo-2-hydroxy-benzoic acid methyl ester and 3-chlorphenyl acetonitrile: LC/MS (an10n8) Rt 2.79m/z 421.4[M-H]
- 1H NMR (DMSO): δ 4.21 (s, 2H), 4.92 (s, 2H), 7.15-7.18 (d, 1H), 7.32-7.39 (m, 3H), 7.45 (s, 1H), 7.76-7.80 (dd, 1H), 8.03-8.04 (d, 1H).
2-[3-(4-acetyl-amino benzyl)-[1,2,4] oxadiazole-5-yl]-4-bromine phenoxy group } acetic acid.Prepare title compound according to GP10, GP11, GP2 and GP3 by 5-bromo-2 hydroxybenzoic acid methyl ester and 4-acetamido phenylacetonitrile: LC/MS (an10n8) Rt 2.15m/z 444.4[M-H]
- 1H NMR (DMSO): δ 2.02 (s, 3H), 4.10 (s, 2H), 4.92 (s, 2H), 7.14-7.17 (d, 1H), 7.25-7.27 (d, 2H), 7.52-7.54 (d, 2H), 7.76-7.78 (d, 1H), 8.03 (s, 1H).
{ 4-bromo-2-[3-(1-phenycyclopropyl)-[1,2,4] oxadiazole-5-yl] phenoxy group } acetic acid.Prepare title compound according to GP10, GP11, GP2 and GP3 by 5-bromo-2-hydroxy-benzoic acid methyl ester and 1-phenyl-1-cyclopropane nitrile: LC/MS (an10n8) Rt.2.756m/z 413.4[M-H]
- 1HNMR (DMSO-d
6): δ 0.92 (m, 2H), 1.11 (m, 2H), 4.38 (s, 2H), 6.63-6.66 (d, 1H), 6.79-6.88 (m, 3H), 6.93-6.95 (m, 2H), 7.25-7.29 (dd, 1H), 7.50-7.51 (d, 1H).
[4-bromo-2-(3-pyridine-2-base-[and 1,2,4] oxadiazole-5-yls) phenoxy group] acetic acid.Prepare title compound according to GP10, GP11, GP2 and GP3 by 5-bromo-2 hydroxybenzoic acid methyl ester and pyridine-2-nitrile: LC/MS (an10n8) Rt 1.89 minutes, m/z 374.4[M-H]
- 1H NMR (DMSO-d
6): δ 4.9 (s, 2H), 7.2 (d, 1H), 7.6 (m, 1H), 7.8 (d, 1H), 8.0 (t, 1H), 8.2 (m, 2H), 8.8 (d, 1H).
General route of synthesis IX
4-bromo-2-[5-(4 '-methoxyl biphenyl-4-yl)-[1,2,4] oxadiazole-3-yl] phenoxy group } acetic acid.According to GP10, GP11, GP2 and GP3 by 2-hydroxyl-5-bromo-benzonitrile and 4 '-methoxyl group-biphenyl-4-carboxylic acid methyl ester prepares title compound: LC/MS (an10n8) Rt 2.96 minutes, m/z 479.5[M-H]
-
{ 4-bromo-2-[5-(4-chlorphenyl)-[1,2,4] oxadiazole-3-yl] phenoxy group } acetic acid.Prepare title compound according to GP10, GP11, GP2 and GP3 by 2-hydroxyl-5-bromo-benzonitrile and 4-chloro benzoic ether: LC/MS (an10n8) Rt 2.61 minutes, m/z 407.4[M-H]
- 1H NMR (DMSO-d
6): δ 4.3 (s, 2H), 6.9 (d, 1H), 7.6 (dd, 1H), 7.7 (d, 2H), 8.0 (d, 1H), 8.2 (d, 2H).
{ 4-bromo-2-[5-(3-chlorphenyl)-[1,2,4] oxadiazole-3-yl] phenoxy group } acetic acid.Prepare title compound according to GP10, GP11, GP2 and GP3 by 2-hydroxyl-5-bromobenzyl nitrile and 3-chloro benzoic ether: LC/MS (an10n8) Rt 2.61 minutes, m/z 407.4[M-H]
- 1H NMR (DMSO-d
6): δ 4.4 (s, 2H), 6.9 (d, 1H), 7.6 (m, 2H), 7.8 (d, 1H), 8.0 (s, 1H), 8.2 (m, 2H).
{ 4-bromo-2-[5-(2-chlorphenyl)-[1,2,4] oxadiazole-3-yl] phenoxy group } acetic acid.Prepare title compound according to GP10, GP11, GP2 and GP3 by 2-hydroxyl-5-bromobenzyl nitrile and 2-chloro benzoic ether: LC/MS (an10n8) Rt 2.45 minutes, m/z 407.4[M-H]
- 1H NMR (DMSO-d
6): δ 4.3 (s, 2H), 6.9 (d, 1H) 7.6-7.7 (m, 4H), 8.0 (s, 1H), 8.2 (d, 1H).
[4-bromo-2-(the 5-phenyl-[and 1,2,4] oxadiazole-3-yls) phenoxy group] acetic acid.Prepare title compound according to GP10, GP11, GP2 and GP3 by 2-hydroxyl-5-bromobenzyl nitrile and essence of Niobe: LC/MS (an10n8) Rt 2.33 minutes, m/z 373.4[M-H]
- 1H NMR (DMSO-d
6): δ 4.8 (s, 2H), 7.1 (d, 1H), 7.6-7.7 (m, 4H), 8.0 (d, 1H), 8.2 (d, 2H).
General route of synthesis X
Intermediate-13
4-bromo-2-[(ethoxy carbonyl methylamino) methyl] ethyl phenoxyacetate.4-bromo-2-formoxyl ethyl phenoxyacetate (1.44 grams, 5 mMs) is dissolved in the dichloromethane (50 milliliters), adds glycine ethyl ester hydrochloride (1.39 grams, 10 mMs) and Et
3N (1.4 milliliters, 10 mMs).Mixture is at room temperature stirred 4 hours (h).Add entry and dichloromethane, make organic facies by the filter that is separated, evaporation then, obtain 4-bromo-2-[(E)-ethoxy carbonyl methyl-imino methyl] phenoxy group } ethyl acetate, this product is dissolved in the dichloromethane (50 milliliters) again, with NaBH (OAc)
3(2.11 grams, 10 mMs) and AcOH (1 milliliter) handle, and stir 5 hours down in room temperature (rt) then.Add saturated Na
2CO
3, water and dichloromethane, make organic facies by the filter that is separated, evaporation obtains title compound (1.56 grams, gross production rate 84%).
General step 12 (GP12)
With isocyanate reaction, encircle then and/hydrolysis
Aldehyde (0.6 mM) is dissolved in the dichloromethane (6 milliliters), adds isocyanates (1.2 mM) and Et
3N (176 microlitres, 1.26 mMs).This mixture at room temperature stirred spend the night.Add glycine (150 milligrams, 2 mMs) (as the scavenger of excess isocyanate) then, with this mixture restir 2 hours.Add entry and dichloromethane at last, make organic facies by the filter that is separated, evaporation obtains urea then, the urea that obtains is dissolved in the acetic acid (3.5 milliliters), and puts in the sealed glass bottle.Add 4M HCl (3.5 milliliters) then, with this mixture heated to 100 ℃, and keep 900 seconds (s) by microwave.Behind cool to room temperature, form white precipitate, after filtering and washing with water, obtain hydantoin.If this product does not precipitate after the hydrolysis, then in mixture, add dichloromethane and water, make organic facies by the filter that is separated.The evaporation organic facies obtains product, and this product is further purified (use the 100%MeOH balance, use the MeOH eluant solution of 10% AcOH then) in some cases on 1 gram SAX Acetate SPE post.
4-bromo-2-[3-(4-benzyl chloride base)-2,4-dioxo alkyl imidazole-1-ylmethyl] phenoxyacetic acid.According to GP12 by 4-bromo-2-[(ethoxy carbonyl methylamino) methyl] (235 milligrams of ethyl phenoxyacetates, 0.63 mM) and 4-benzyl chloride based isocyanate (166 microlitres, 1.26 preparation (productive rate: 183.4 milligrams mM), 62%): LC/MS (an10p8): Rt 2.3 minutes, m/z 465[M-H]
- 1HNMR (DMSO-d
6): δ 4.05 (s, 2H), 4.48 (s, 2H), 4.55 (s, 2H), 4.73 (s, 2H), 6.92 (d, J=8.3Hz, 1H), 7.25-7.45 (m, 6H), 13.11 (br.s, 1H).
4-bromo-2-(2,4-dioxo-3-phenethyl imidazolidine-1-ylmethyl) phenoxyacetic acid.According to GP12 by 4-bromo-2-[(ethoxy carbonyl methylamino) methyl] and the preparation of ethyl phenoxyacetate and phenethyl isocyanates: LC/MS (an10p8): Rt 2.2 minutes, m/z 445[M-H]
- 1H NMR (DMSO-d
6): δ 2.84 (t, J=7.2Hz, 2H), 3.59 (t, J=7.2Hz, 2H), 3.94 (s, 2H), 4.45 (s, 2H), 4.76 (s, 2H), 6.93 (d, J=8.6Hz, 1H), 7.17-7.46 (m, 7H), 12.45 (br.s, 1H).
General route of synthesis XI
General step 13 (GP13)
The N-alkylation
With 2-[2, and 4-dioxo Thiazolidine-(5Z)-ylidenylmethyl (dioxothiazolidin-(5Z)-ylidenemethyl)] ethyl phenoxyacetate (0.85 mM), Cs
2CO
3(326 milligrams, 1.0 mMs) and acetonitrile (10 milliliters) stir in the sealed glass bottle.Add alkylating agent (1.0 mM) then, with this mixture heated to 120 ℃, and kept 600 seconds by microwave.Add entry, with this mixture of dichloromethane extraction.Make organic facies by the filter that is separated, then evaporation.Product directly uses in subsequent step, perhaps by column chromatography (SiO
2) carry out purification.
General step 14 (GP14)
Hydrogenation
With 5-benzal thiazolidine-2,4-diketone (～0.8 mM), ammonium formate (1.0 grams, 16 mMs), Pt/C (5 weight %, 500 milligrams, 0.13 mM) and acetic acid (12 milliliters) in the sealed glass bottle, mix, by microwave heating to 135 ℃, and kept 1800 seconds.Add methanol (15 milliliters) then, this mixture is passed through 20 microns PE filters earlier, filters by 1 gram SAXAcetate SPE post, wash with another part methanol (10 milliliters).After methanol evaporation, add dichloromethane and water, make organic facies by the filter that is separated, concentrate, obtain product, this product directly uses, perhaps by column chromatography at SiO
2Last purification.
General step 15 (GP15)
Thiazolidine-2, the alkylation of the 5-position of 4-diketone
With 3-alkyl-5-aryl methyl thiazolidine-2,4-diketone (0.15 mM), methyl iodide (28 microlitres, 0.45 mM), Cs
2CO
3(147 milligrams, 0.45 mM) and acetonitrile (10 milliliters) mix in the seal glass bottle, by microwave heating to 120 ℃, and keep 3600 seconds.Add entry and dichloromethane, make organic facies by the filter that is separated, evaporation obtains product then, and this product is directly used in hydrolysis.
General step 16 (GP16)
The hydrolysis of acid esters
Ethyl phenoxyacetate (0.02-0.2 mM) is dissolved in the acetic acid (5 milliliters), adds 4MHCl (5 milliliters), with this mixture heated to 100 ℃, and kept 900 seconds by microwave.Behind cool to room temperature, form white precipitate, filter out this precipitation, wash with water, dry then, obtain product.If, then add dichloromethane in hydrolysis afterproduct precipitation not, wash organic facies with water, and concentrate, residue is purification (use the 100%MeOH balance, use the MeOH eluant solution of 10% AcOH then) on 1 gram SAX Acetate SPE post, obtains product.
Intermediate-14
4-bromo-2-[2,4-dioxo Thiazolidine ylidenylmethyl] ethyl phenoxyacetate.With 4-bromo-2-formoxyl ethyl phenoxyacetate (2.47 grams; 8.7 mM), 2; 4-thiazolidinedione (1.13 grams (90%); 8.7 mM) and (671 milligrams of ammonium acetates; 8.7 mM) in the bottle of sealing, mix with toluene (9 milliliters); by microwave heating to 120 ℃, and kept 600 seconds.Behind cool to room temperature, scrape the inside that cleans the windows, be settled out product.Filter this precipitate, use toluene wash, obtain the title compound (2.38 grams, 71%) of yellow solid shape.
4-bromo-2-[3-(4-benzyl chloride base)-2,4-dioxo Thiazolidine-5-ylmethyl] phenoxyacetic acid. according to GP13, GP14 and GP16 by 4-chlorine benzyl bromide a-bromotoluene and 4-bromo-2-[2,4-dioxo Thiazolidine-(5Z)-ylidenylmethyl] the ethyl phenoxyacetate preparation, obtain 50.4 milligrams of (gross production rate 21%) title compound: LC/MS (an10p8): Rt 2.6 minutes, m/z 482[M-H]
-.
1H NMR (DMSO-d
6): δ 3.05 (dd, J=13.8,9.7Hz, 1H), 3.57 (dd, J=13.8,4.9Hz, 1H), 5.11 (dd, J=9.7,4.9Hz, 1H), 4.67 (s, 2H), 4.75 (s, 2H), 6.91 (d, J=8.7,1H), 7.25-7.28 (m, 2H), 7.37-7.42 (m, 4H), 13.15 (br.s, 1H).
4-bromo-2-[3-(4-methyl-benzyl)-2,4-dioxo Thiazolidine-5-ylmethyl] phenoxyacetic acid.According to GP13, GP14 and GP16 by 4-methyl-benzyl bromine and 4-bromo-2-[2,4-dioxo Thiazolidine-(5Z)-ylidenylmethyl] ethyl phenoxyacetate preparation (productive rate: 14 milligrams, 21%): LC/MS (an10p8): Rt 2.5 minutes, m/z 462[M-H]
-.
1H NMR (DMSO-d
6): δ 2.98-3.07 (m, 1H), 3.53-3.59 (m, 1H), 4.63 (s, 2H), 4.74 (s, 2H), 5.07-5.13 (m, 1H), 6.89-6.91 (m, 1H), 7.11-7.16 (m, 4H), 7.38-7.43 (m, 2H), 13.11 (br s, 1H).
4-bromo-2-{3-[2-(4-chlorphenyl)-2-oxoethyl]-2,4-dioxo Thiazolidine-5-ylmethyl } phenoxyacetic acid.According to GP13, GP14 and GP16 by 2-bromo-1-(4-chlorphenyl) ethyl ketone and 4-bromo-2-[2,4-dioxo Thiazolidine-(5Z)-ylidenylmethyl] ethyl phenoxyacetate preparation (productive rate: 8.2 milligrams, 34%): LC/MS (an10p8): Rt 2.8 minutes, m/z 510[M-H]
-.
1H NMR (DMSO-d
6): δ 3.01-3.09 (m, 1H), 3.57-3.63 (m, 1H), 4.79 (s, 2H), 5.17 (s, 2H), 5.21-5.24 (m, 1H), 6.91-6.95 (m, 1H), 7.44 (m, 2H), 7.66-7.69 (m, 2H), 8.07-8.09 (m, 2H).
4-bromo-2-[3-(3-benzyl chloride base)-2,4-dioxo Thiazolidine-5-ylmethyl] phenoxyacetic acid (7d).According to GP13, GP14 and GP16 by 3-chlorine benzyl bromide a-bromotoluene and 4-bromo-2-[2,4-dioxo Thiazolidine-(5Z)-ylidenylmethyl] the ethyl phenoxyacetate preparation: LC/MS (an10p8): Rt 2.6 minutes, m/z 484[M+H]
+.
1H NMR (DMSO-d6): δ 3.02-3.10 (m, 1H), 3.54-3.60 (m, 1H), 4.69 (s, 2H), 4.75 (s, 2H), 5.09-5.14 (m, 1H), 6.89-6.92 (m, 1H), 7.18 (m, 1H), 7.33-7.43 (m, 5H), 13.01 (br s, 1H).
4-bromo-2-(2,4-dioxo-3-pyridin-4-yl methylthiazol alkane-5-ylmethyl) phenoxyacetic acid.According to GP13, GP14 and GP16 by 4-bromo methyl cycloheptapyridine and 4-bromo-2-[2,4-dioxo Thiazolidine-(5Z)-ylidenylmethyl] the ethyl phenoxyacetate preparation: LC/MS (an10p8): Rt 2.1 minutes, m/z 451[M+H]
+
4-bromo-2-[3-(4-benzyl chloride base)-5-methyl-2,4-dioxo Thiazolidine-5-ylmethyl] phenoxyacetic acid.According to GP13, GP14, GP15 and GP16 by 4-bromo methyl cycloheptapyridine preparation (productive rate: 29 milligrams, 15%): LC/MS (an10p8): Rt 3.0 minutes, m/z496[M-H]
- 1H NMR (DMSO-d6): 1.71 (s, 3H), 3.24 (d, J=13.8Hz, 1H), 3.39 (d, J=13.8Hz, 1H), 4.63-4.68 (m, 4H), 6.86 (d, J=8.6Hz, 1H), 7.13-7.43 (m, 6H), 13.08 (br s, 1H).
4-bromo-2-[3-(2, the 6-dichloro benzyl)-5-methyl-2,4-dioxo Thiazolidine-5-ylmethyl] phenoxyacetic acid.By 2, the preparation of 6-dichloro benzyl bromine obtains 21.1 milligrams of title compound: LC/MS (an10n8): Rt 2.9 minutes, m/z 532[M-H according to GP13, GP14, GP15 and GP16]
- 1H NMR (DMSO-d
6): δ 1.63 (s, 3H), 3.16 (d, J=13.6Hz, 1H), 3.40 (d, J=13.6Hz, 1H), 4.65 (s, 2H), 4.92 (s, 2H), 6.86 (d, J=8.9Hz, 1H), 7.21 (d, J=2.5Hz, 1H), 7.35-7.48 (m, 4H), 12.38 (br s, 1H).
4-bromo-2-[3-(2-benzyl chloride base)-5-methyl-2,4-dioxo Thiazolidine-5-ylmethyl] phenoxyacetic acid.By the preparation of 2-chlorine benzyl bromide a-bromotoluene, obtain 22.0 milligrams of title compound: LC/MS (an10n8): Rt 2.8 minutes, m/z 498[M-H according to GP13, GP14, GP15 and GP16]
- 1HNMR (DMSO-d
6): δ 1.76 (s, 3H), 3.28 (d, J=13.7Hz, 1H), 3.43 (d, J=13.7Hz, 1H), 4.67 (d, J=3.2Hz, 2H), 4.73 (s, 2H), 6.81 (d, J=8.9Hz, 1H), 6.90 (d, J=8.7Hz, 1H), 7.24-7.36 (m, 3H), 7.43-7.50 (m, 2H), 12.18 (br s, 1H).
Biological test
Materials and methods
Generation/the source of cDNA construction. the coded sequence (genbank accession number NM_004778) of the people CRTH2 receptor by pcr amplification people Hippocampus cDNA library, utilize 5 ' HindIII and 3 ' EcoRI to be inserted into pcDNA3.1 (+) expression vector (invitrogen).For producing CRTH2-Renilla luciferase (CRTH2-Rluc) fusion rotein, the CRTH2 coded sequence and the Rluc that do not have termination codon by pcr amplification merge in reading frame and sub-clone is gone into pcDNA3.1 (+) Zeo expression vector (invitrogen).The N-end has GFP
2People's β-arrestin 2 of label ((β arr2-GFP of β-arr2)
2) and the Renilla luciferase available from BioSignal Packard Inc, (Montreal, Canada).By digestion with restriction enzyme and on the both direction of ABI Prism (Applied Biosystems, Foster City, California) order-checking confirmed the sequence homogeny of construction.
Serial ID CRTH2 (protein sequence):
MSANATLKPLCPILEQMSRLQSHSNTSIRYIDHAAVLLHGLASLLGLVE
NGVILFVVGCRMRQTVVTTWVLHLALS
DLLASASLPFFTYFLAVGHSWELGTTF
CKLHSSIFFLNMFASGFLLSAISLDRCLQVVRPVWAQNHRTVAAAHKVCLVL
WALAVLNTVPYFVFRDTISRLDGRIMCYYNVLLLNPGPDRDATCNSRQAALAVSKFLLAFLV
PLAIIAS?SHAAVSLRLQHRGRRRPGRFVRLVAAVVAAFALCWG
PYHVFSLLEARAHANPGLRPLVWRGLPFVTSLAFFNSVAN
PVLYVLTCPDMLRKLRRSLRTVLESVLVDDSELGGAGSSRRRRTSSTARSASPLALCSRPEEPRGPARLLGWLLGSCAASPQTGPLNRALSSTSS
Serial ID CRTH2 (nucleotide sequence):
atgtcggc
caacgccaca?ctgaagccac?tctgccccat?cctggagcag?atgagccgtc
tccagagcca
cagcaacacc?agcatccgct?acatcgacca?cgcggccgtg?ctgctgcacg
ggctggcctc
gctgctgggc?ctggtggaga?atggagtcat?cctcttcgtg?gtgggctgcc
gcatgcgcca
gaccgtggtc?accacctggg?tgctgcacct?ggcgctgtcc?gacctgttgg
cctctgcttc
cctgcccttc?ttcacctact?tcttggccgt?gggccactcg?tgggagctgg
gcaccacctt
ctgcaaactg?cactcctcca?tcttctttct?caacatgttc?gccagcggct
tcctgctcag
cgccatcagc?ctggaccgct?gcctgcaggt?ggtgcggccg?gtgtgggcgc
agaaccaccg
caccgtggcc?gcggcgcaca?aagtctgcct?ggtgctttgg?gcactagcgg
tgctcaacac
ggtgccctat?ttcgtgttcc?gggacaccat?ctcgcggctg?gacgggcgca
ttatgtgcta
ctacaatgtg?ctgctcctga?acccggggcc?tgaccgcgat?gccacgtgca
actcgcgcca
ggcggccctg?gccgtcagca?agttcctgct?ggccttcctg?gtgccgctgg
cgatcatcgc
ctcgagccac?gcggccgtga?gcctgcggtt?gcagcaccgc?ggccgccggc
ggccaggccg
cttcgtgcgc?ctggtggcag?ccgtcgtggc?cgccttcgcg?ctctgctggg
ggccctacca
cgtgttcagc?ctgctggagg?cgcgggcgca?cgcaaacccg?gggctgcggc
cgctcgtgtg
gcgcgggctg?cccttcgtca?ccagcctggc?cttcttcaac?agcgtggcca
acccggtgct
ctacgtgctc?acctgccccg?acatgctgcg?caagctgcgg?cgctcgctgc
gcacggtgct
ggagagcgtg?ctggtggacg?acagcgagct?gggtggcgcg?ggaagcagcc
gccgccgccg
cacctcctcc?accgcccgct?cggcctcccc?tttagctctc?tgcagccgcc
cggaggaacc
gcggggcccc?gcgcgtctcc?tcggctggct?gctgggcagc?tgcgcagcgt
ccccgcagac
gggccccctg?aaccgggcgc?tgagcagcac?ctcgagttag
The growth and remain on 37 ℃, 10%CO in the improved Eagle culture medium of Dulbecco (DMEM) 1885 of having added 10% hyclone, 100 units/ml penicillin, 1000 μ g/ml streptomycins of cell culture and transfection .COS-7 cell
2In the atmosphere.The HEK293 cell maintains has added 10% (v/v) heat-inactivated fetal bovine serum (HIFCS), 2mM Glutamax
TMThe minimum essential medium (MEM) of-I, 1% non essential amino acid (NEAA), 1% Sodium Pyruvate and 10 μ g/ml gentamycins.For in conjunction with experiment, adopt the calcium phosphate-DNA coprecipitation method with the CRTH2 receptor and add chloroquine and come transient transfection COS7 cell (as Holst etc., 2001+ is described).Shift (BRET) test for carrying out the luminous resonance energy of functional living being, prepared stably expressing beta arr2-GFP
2HEK293 cell clone (CRTH2-HEK293 cell) with CRTH2-Rluc.
In conjunction with test. transfection was inoculated the COS-7 cell into 96 orifice plates with the density of 30.000 cells/well after 24 hours.After 18-24 hour, utilize 0.1nM[then
3H] (NEN 172Ci/mmol) carries out competitive binding experiment on to full cell to PGD2 in the binding buffer liquid that is made of HBSS (GIBCO) and 10mM HEPES.Dilute competitive part with DMSO, constant 1% (v/v) that is maintained at final incubation volume of described DMSO.When not having and have 10 μ M PGD2 to exist, measure total and non-specific binding situation.Carried out association reaction routinely 3 hours at 4 ℃, with ice-cooled binding buffer liquid washed twice (each 100 μ l) with cessation reaction.After in Microscint 20, being incubated overnight, carrying out liquid scintillation counting with TOPCOUNTER (Packard) and measure radioactivity.The stable HEK293 cell of density inoculation with 30.000 cells/well carries out the combination test after 18-24 hour substantially as described in above COS7 cell.Mensuration is by carrying out in duplicate.
The BRET test.
To stably express people CRTH2-Rluc and GFP
2The HEK293 cell of-β-arr2 carries out functional BRET test.Make cell separation and with 2 * 10
6The density of individual cells/well is resuspended among the D-PBS that contains 1000mg/L L-glucose, is used for the BRET test then.With the D-PBS that contains 1000mg/L L-glucose with DeepBlueC
TMBe diluted to 50 μ M (photaesthesia).100 μ L cell suspending liquids are transferred in the hole of 96-hole microplate (white OptiPlate) and place in MithrasLB 940 instruments (BERTHOLD TECHNOLOGIES, Bad Wildbad, Germany).Use the agonist in syringe 1 injection 12 μ L/ holes then, utilize the DeepBlueC in syringe 2 injections 10 μ L/ holes simultaneously
TMInject after 5 seconds, the light output valve in METHOD FOR CONTINUOUS DETERMINATION 400nm and each hole, 515nm place is passed through GFP
2The ratio of the fluorescence that-β-arr2 (515nm) is sent and receptor-Rluc (400nm) light that sends is calculated BRET signal (mBRET ratio).Add antagonist, then microplate is placed Mithras LB 940, incubation 15 minutes adds agonist and DeepBlueC then
TMIn DMSO, make the constant concentration of DMSO in the final test be maintained at 1% compound dissolution.
People eosinophilic granulocyte alteration of form test. according to the scheme of Ethics Committee of Graz university approval and as mentioned previously (Bohm etc., 2004) from healthy volunteer's blood sample collection.Glucosan precipitation and Histopaque gradient by citrate whole blood (citrated whole blood) prepare polymorphonuclear leukocyte (containing eosinophilic granulocyte and neutrophilic granulocyte) prepared product.(comprise and contain Ca with the test buffer
2+/ Mg
2+, having added the PBS of 0.1%BSA, 10mM HEPES and 10mM glucose, the pH7.4) cell that obtains of washing is with 5 * 10
6Individual cell/mL suspends.Cell 37 ℃ with antagonist or carrier (PBS or DMSO) incubation 10 minutes, use the agonist (PGD2 or eosinophil chemotactic protein) of various concentration to stimulate 4 minutes then at 37 ℃.Sample transfer is extremely mixed with cessation reaction on ice and with 250 μ L fixative solutions.Use FACSCalibu flow cytometer (Becton Dickinson) analytic sample immediately and identify the eosinophilic granulocyte according to their autofluorescence in FL-1 and FL-2 channel.Alteration of form is replied and is quantified as the percentage ratio of when not having antagonist the PGD2 maximum being replied.
Material
Culture medium for tissue culture and reagent are available from Gibco invitrogen corporation (Breda, Holland).PGD2 derives from Cayman, and [3H] PGD2 derives from NEN.
Data analysis
Utilize GraphPadPrism software 3.0 (Graphpad Prism Inc., San Diego, the U.S.) march line analysis, IC
50Value is calculated as measuring of antagonism effectiveness.
List of references
Holst B, Hastrup H, Raffetseder U, Martini L, Schwartz TW, " G albumen merges two kinds of bioactive molecule phenotypes of tachykinin NK-1 1 receptor that is disclosed with mutation " (Twoactive molecular phenotypes of the tachykinin NK1 receptor revealed byG-protein fusions and mutagenesis), J Biol Chem., June 8 calendar year 2001; 276 (23): 19793-9.Epub, February 22 calendar year 2001.
Biological data
In following receptor binding assays and the test of functional antagonist, test chemical compound, assessed their IC
50Value.These chemical compounds are divided three classes:
A:IC
50Be lower than 0.5 μ M.
B:IC
50Value is between 0.5 μ M and 5 μ M.
C:IC
50Value is higher than 5 μ M.
Table 1-7 has provided above-mentioned synthetic chemical compound and some derive from test result biology of the chemical compound of commercial source.The example of Fig. 1 has shown that above-claimed cpd suppresses the ability of the inductive eosinophilic granulocyte's alteration of form of Prostaglandin D2.
Table 1
Table 2
| n | X | R1 | R2 | R3 | R4 | R5 | In conjunction with IC 50 | Antagonism IC 50 | |
| D83 | O | O | H | H | H | H | H | A | C |
| D84 | O | O | H | H | ?OMe | ?H | ?H | A | B |
| D85 | 0 | O | H | H | Cl | H | H | A | C |
| D86 | O | O | H | OMe | H | H | H | A | A |
| D87 | O | O | H | H | OEt | H | H | A | C |
| D88 | 1 | O | H | H | H | H | H | A | A |
| D89 | 1 | O | H | OMe | H | H | H | A | A |
| D90 | 1 | O | Cl | H | F | H | H | A | A |
| D91 | 1 | O | Cl | H | H | H | Cl | A | A |
| D92 | 1 | O | H | H | OMe | H | H | A | A |
| D93 | 0 | S | H | H | H | H | H | A | A |
| D94 | 1 | S | H | H | Cl | H | H | A | A |
Table 3
| n | R1 | R2 | R3 | R4 | R5 | In conjunction with IC 50 | Antagonism IC 50 | |
| D99 | 0 | H | H | H | H | H | A | A |
| D100 | 0 | H | H | F | H | H | A | A |
| D101 | 0 | H | H | OMe | H | H | A | A |
| D102 | 0 | H | H | Cl | H | H | A | A |
| D103 | 0 | H | H | OCF 3 | H | H | A | A |
| D104 | 0 | H | OMe | H | H | H | A | A |
| D105 | 0 | H | Cl | H | H | H | A | A |
| D106 | 0 | H | H | CF 3 | H | H | A | A |
| D107 | 0 | OMe | H | H | H | H | A | A |
| D108 | 0 | Cl | H | H | H | H | A | A |
| D109 | 0 | H | CF 3 | H | CF 3 | H | A | C |
| D110 | 0 | Cl | H | H | H | Cl | A | A |
| D111 | 0 | H | H | OPh | H | H | A | A |
| D112 | 0 | H | CF 3 | H | H | H | A | A |
| D113 | 1 | H | H | OCF 3 | H | H | A | A |
| D114 | 1 | H | H | Cl | H | H | A | A |
| D115 | 1 | H | H | H | H | H | A | A |
| D116 | 1 | H | H | F | H | H | A | A |
| D117 | 1 | H | F | H | F | H | A | A |
| D118 | 1 | H | H | OMe | H | H | A | A |
| D119 | 1 | H | OMe | H | H | H | A | A |
| D120 | 1 | Cl | H | H | H | H | A | A |
| D121 | 1 | Cl | H | H | H | Cl | A | A |
| D122 | 1 | Cl | H | Cl | H | H | A | A |
| D123 | 1 | H | Cl | Cl | H | H | A | A |
| D124 | 1 | H | OMe | OMe | H | H | A | A |
| D125 | 1 | H | OMe | H | H | H | A | C |
| D126 | 1 | H | H | Me | H | H | A | A |
| D127 | 1 | CF 3 | H | H | H | H | A | A |
| D128 | 1 | H | OMe | H | OMe | H | A | B |
| D129 | 0 | Cl | H | Cl | H | H | A | A |
| D130 | 1 | H | Cl | H | H | H | A | A |
| D131 | 1 | H | H | NHAc | H | H | A | A |
Table 4
| n | R1 | R2 | R3 | R4 | R5 | Active | In conjunction with IC 50 | Antagonism IC 50 | |
| D134 | 0 | H | H | 4-PhOMe | H | H | A | A | A |
| D135 | 0 | H | H | Cl | H | H | A | A | A |
| D136 | 0 | H | Cl | H | H | H | A | A | A |
| D137 | 0 | Cl | H | H | H | H | A | A | A |
| D138 | 0 | H | H | H | H | H | A | A | C |
Table 5
Table 6
Table 7
Claims (18)
1. the compound or its salt of a general formula (I) is used for the treatment of application in asthma, rhinitis, anaphylaxis air flue syndrome or the bronchitic compositions of allergia nose in preparation:
In the formula:
A represents carboxyl or is selected from-SO
2NHR ,-P (=O) (OH) (OR) ,-SO
2OH ,-P (=O) (OH) (NH
2) ,-C (=O) the carboxyl bioisostere thing of the following group of NHCN and general formula, wherein R is a hydrogen, methyl or ethyl:
A
1Be hydrogen or methyl;
Ring Ar
1Be the optional phenyl ring that replaces, wherein AA
1CHO-and L2 are connected on the adjacent annular atoms, and wherein Ren Xuan substituent group is selected from halogen, nitro, C
1-C
6Alkyl, C
1-C
6Alkoxyl, by optional phenyl, the NR that replaces of halogen
AR
B, R wherein
AAnd R
BBe hydrogen or C independently
1-6Alkyl;
Ring Ar
2Optional phenyl or the pyridine radicals that replaces of expression, wherein, described substituent group is selected from C
1-C
6Alkyl, C
1-C
6Alkoxyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, halogen, cyano group or phenoxy group;
L2 is the bilvalent radical that is selected from one of following general formula, wherein key and the Ar of (i) labelling *
2Link to each other, and key and the Ar of labelling * *
1Link to each other, perhaps (ii) the key of labelling * and Ar
1Link to each other, and key and the Ar of labelling * *
2Link to each other:
Wherein, R is hydrogen or C
1-C
3Alkyl.
2. application as claimed in claim 1 is characterized in that, in chemical compound (I), A1 is a hydrogen, and L2 has a kind of in the following general formula, the wherein key of labelling * and Ar
2Link to each other, and key and the Ar of labelling * *
1Link to each other:
Wherein, R is hydrogen or C
1-C
3Alkyl.
3. application as claimed in claim 1 or 2 is characterized in that, in chemical compound (I), and Ar
1In optional substituent group be selected from fluorine, chlorine, bromine, the phenyl that is randomly replaced, C by fluorine or chlorine
1-C
6Alkyl, C
1-C
6Alkoxyl and nitro.
4. the application described in claim 1 or 2 is characterized in that, in chemical compound (I), and Ar
2In optional substituent group be selected from fluorine, chlorine, bromine, C
1-C
3Alkyl, trifluoromethyl, C
1-C
3Alkoxyl, trifluoromethoxy and cyano group.
5. application as claimed in claim 1 or 2 is characterized in that, in chemical compound (I), A is a carboxyl.
6. application as claimed in claim 1 or 2 is characterized in that, in chemical compound (I), and A
1Be hydrogen.
7. the compound or its salt of a general formula (IV):
In the formula, A, A
1, Ar
2With L2 as defined in claim 1,
R
13Expression hydrogen or one or more optional substituent groups, described substituent group is selected from halogen, nitro, C
1-C
6Alkyl, C
1-C
6Alkoxyl, by the optional phenyl that replaces of halogen ,-NR
AR
B, R wherein
AAnd R
BBe hydrogen or C independently
1-6Alkyl.
8. chemical compound as claimed in claim 7 is characterized in that A
1Be hydrogen, L2 is selected from following, wherein the key of labelling * and Ar
2Link to each other, and the key of labelling * * links to each other with phenyl ring:
Wherein R is hydrogen or C
1-C
3Alkyl.
9. as claim 7 or 8 described chemical compounds, it is characterized in that A is a carboxyl.
10. the compound or its salt of a general formula (IVA):
In the formula, A, A
1And R
13Define R as in the claim 7 to 9 each
14By C
1-C
6Alkyl, C
1-C
6Optional phenyl or the pyridine radicals that replaces of alkoxyl, trifluoromethyl, trifluoromethoxy, halogen, cyano group or phenoxy group.
11. the compound or its salt of a general formula (IVC):
In the formula, A
1Definition and claim 1 in identical, R
13Represent hydrogen or represent the substituent group that one or more are optional, described substituent group is selected from halogen, nitro, C
1-C
6Alkyl, C
1-C
6Alkoxyl, by the optional phenyl that replaces of halogen ,-NR
AR
B, R wherein
AAnd R
BBe hydrogen or C independently
1-6Alkyl; R
14By C
1-C
6Alkyl, C
1-C
6Optional phenyl or the pyridine radicals that replaces of alkoxyl, trifluoromethyl, trifluoromethoxy, halogen, cyano group or phenoxy group.
12. chemical compound as claimed in claim 11 is characterized in that, R
14Be 2-replacement, 2,4-two replacements, 2,6-two replacements or 2,4, the trisubstituted phenyl ring of 6-, wherein said substituent group is selected from fluorine, chlorine, bromine, iodine, C
1-C
6Alkyl, trifluoromethyl, C
1-C
6Alkoxyl, trifluoromethoxy and cyano group.
13. chemical compound as claimed in claim 11 is characterized in that, R
14Be 2-replacement or 2,6-Disubstituted pyridine ring, wherein said substituent group is selected from fluorine, chlorine, C
1-C
6Alkyl, trifluoromethyl, C
1-C
6Alkoxyl, trifluoromethoxy and cyano group.
14., it is characterized in that A as each described chemical compound in the claim 11 to 13
1Be hydrogen.
15. the enantiomer as each described chemical compound in the claim 7 to 14, wherein A
1Be methyl, with A
1The carbon atom that links to each other has the S three-dimensional chemical configuration.
16. a compound or its salt, described chemical compound is selected from down group:
4-chloro-2-(1-phenyl-1H-pyrazoles-4-carbonyl) phenoxyacetic acid,
4-bromo-2-(1-phenyl-1H-pyrazoles-4-carbonyl) phenoxyacetic acid,
[4-bromo-2-(1-pyridine-2-base-1H-pyrazoles-4-carbonyl) phenoxy group] acetic acid,
4-bromo-2-[1-(2-chlorphenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
4-bromo-2-[1-(3-chlorphenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
4-bromo-2-[1-(4-bromophenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
4-bromo-2-[1-(4-chlorphenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
4-bromo-2-[1-(2-ethylphenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
4-bromo-2-[1-(2-bromophenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
4-bromo-2-[1-(2-fluorophenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
4-bromo-2-[1-(2-trifluoromethyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
4-bromo-2-[1-(3-bromophenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
4-bromo-2-[1-(2, the 4-Dichlorobenzene base)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
2-[1-(2-chlorphenyl)-1H-pyrazoles-4-carbonyl]-4-nitrophenoxy } acetic acid,
2-[1-(2-bromophenyl)-1H-pyrazoles-4-carbonyl]-4-ethyl phenoxy group } acetic acid,
4-bromo-2-[1-(2, the 4-dibromo phenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
4-bromo-2-[1-(4-bromo-2-chlorphenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
4-bromo-2-[1-(2,4, the 6-trichlorophenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
2-[4-bromo-2-(1-phenyl-1H-pyrazoles-4-carbonyl) phenoxy group] propanoic acid,
(S)-and 2-[4-bromo-2-(1-phenyl-1H-pyrazoles-4-carbonyl) phenoxy group] propanoic acid,
2-{4-bromo-2-[1-(2-chlorphenyl)-1-H-pyrazoles-4-carbonyl] phenoxy group } propanoic acid,
(S)-and 2-{4-bromo-2-[1-(2-chlorphenyl)-1-H-pyrazoles-4-carbonyl] phenoxy group }
Propanoic acid,
2-{4-bromo-2-[1-(2, the 6-Dichlorobenzene base)-1H-pyrazoles-4-carbonyl] phenoxy group } propanoic acid,
4-bromo-2-[1-(2-ethoxyl phenenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
4-bromo-2-[1-(4-bromo-2-ethylphenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
4-bromo-2-[1-(2-Phenoxyphenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
4-bromo-2-[1-(2-methyl mercapto phenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
4-bromo-2-[1-(2-bromo-4-aminomethyl phenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
2-{4-bromo-2-[1-(4-bromo-2-ethylphenyl)-1H-pyrazoles-4-carbonyl] phenoxy group } propanoic acid,
2-{4-bromo-2-[1-(2-Phenoxyphenyl)-1H-pyrazoles-4-carbonyl] phenoxy group } propanoic acid,
2-{4-bromo-2-[1-(2-methyl mercapto)-1H-pyrazoles-4-carbonyl] phenoxy group } propanoic acid,
4-bromo-2-[1-(2, the 4-3,5-dimethylphenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
4-bromo-2-[1-(4-chloro-2-aminomethyl phenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
4-bromo-2-[1-(2, the 5-Dichlorobenzene base)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
2-{4-bromo-2-[1-(4-chloro-2-aminomethyl phenyl)-1H-pyrazoles-4-carbonyl] phenoxy group } propanoic acid,
2-{4-bromo-2-[1-(2,4, the 6-trichlorophenyl)-1H-pyrazoles-4-carbonyl] phenoxy group } propanoic acid,
4-bromo-2-[1-(2,6-diethyl-phenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
4-bromo-2-[1-(2, the 6-3,5-dimethylphenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid
4-bromo-2-[1-(2-ethyl-6-aminomethyl phenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
4-bromo-2-[1-(2-chloro-6-aminomethyl phenyl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
4-bromo-2-[1-(3,5-dichloropyridine-4-yl)-1H-pyrazoles-4-carbonyl] and phenoxy group } acetic acid,
[4-bromo-2-(1-naphthalene-1-base-1H-pyrazoles-4-carbonyl) phenoxy group] acetic acid,
4-bromo-2-[2-(4-benzyl chloride base) thiazole-4-yl] and phenoxy group } acetic acid,
{ 4-bromo-2-[3-(4-fluoro-phenyl)-[1,2,4]
Diazole-5-yl] phenoxy group } acetic acid,
{ 4-bromo-2-[3-(4-methoxyl group-phenyl)-[1,2,4]
Diazole-5-yl] phenoxy group } acetic acid,
{ 4-bromo-2-[3-(4-chlorphenyl)-[1,2,4]
Diazole-5-yl] phenoxy group } acetic acid,
{ 4-bromo-2-[3-(4-fluoro-benzyl)-[1,2,4]
Diazole-5-yl]-phenoxy group }-acetic acid,
{ 4-bromo-2-[3-(2,6-two chloro-benzyls)-[1,2,4]
Diazole-5-yl]-phenoxy group }-acetic acid,
{ 4-bromo-2-[3-(2-trifluoromethyl benzyl)-[1,2,4]
Diazole-5-yl] phenoxy group }-acetic acid,
4-bromo-2-[3-(2,6-two chloro-phenyl) is different
Azoles-5-carbonyl] phenoxy group } acetic acid,
{ 4-bromo-2-[3-(1-phenycyclopropyl)-[1,2,4]
Diazole-5-yl] phenoxy group } acetic acid,
{ 4-bromo-2-[3-(2, the 4-Dichlorobenzene base)-[1,2,4]
Diazole-5-yl] phenoxy group } acetic acid.
17. a compound or its salt, wherein said chemical compound are { 4-bromo-2-[1-(2, the 6-Dichlorobenzene base)-1H-pyrazoles-4-carbonyl] phenoxy group } acetic acid.
18. a pharmaceutical composition, it comprises as claim 7 to 14, the enantiomer of each described chemical compound or the described chemical compound of claim 15 and pharmaceutically acceptable carrier among the 16-17.
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0412198.4 | 2004-05-29 | ||
| GB0412198A GB0412198D0 (en) | 2004-05-29 | 2004-05-29 | Medicinal use of receptor ligands |
| GB0414196.6 | 2004-06-24 | ||
| GB0414196A GB0414196D0 (en) | 2004-06-24 | 2004-06-24 | Medicinal use of receptor ligands |
| GB0424018A GB0424018D0 (en) | 2004-10-29 | 2004-10-29 | Medicinal use of receptor ligands |
| GB0424018.0 | 2004-10-29 | ||
| PCT/EP2005/005884 WO2005115382A1 (en) | 2004-05-29 | 2005-05-30 | Crth2 receptor ligands for medicinal uses |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1980664A CN1980664A (en) | 2007-06-13 |
| CN1980664B true CN1980664B (en) | 2011-02-23 |
Family
ID=38131507
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2005800226257A Expired - Fee Related CN1980664B (en) | 2004-05-29 | 2005-05-30 | CRTH2 receptor ligands for therapeutic use |
| CN 200580022519 Pending CN1980908A (en) | 2004-05-29 | 2005-05-30 | Substituted thiazoleacetic as CRTH2 ligands |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200580022519 Pending CN1980908A (en) | 2004-05-29 | 2005-05-30 | Substituted thiazoleacetic as CRTH2 ligands |
Country Status (4)
| Country | Link |
|---|---|
| CN (2) | CN1980664B (en) |
| EC (2) | ECSP067104A (en) |
| UA (1) | UA85512C2 (en) |
| ZA (2) | ZA200610598B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2280278A4 (en) | 2008-05-09 | 2015-04-08 | Sysmex Corp | Blood analyzer, blood analysis method and hemolytic agent |
| SG181900A1 (en) | 2009-12-23 | 2012-08-30 | Ironwood Pharmaceuticals Inc | Crth2 modulators |
-
2005
- 2005-05-30 CN CN2005800226257A patent/CN1980664B/en not_active Expired - Fee Related
- 2005-05-30 UA UAA200614018A patent/UA85512C2/en unknown
- 2005-05-30 CN CN 200580022519 patent/CN1980908A/en active Pending
-
2006
- 2006-12-15 ZA ZA200610598A patent/ZA200610598B/en unknown
- 2006-12-15 ZA ZA200610597A patent/ZA200610597B/en unknown
- 2006-12-20 EC ECSP067104 patent/ECSP067104A/en unknown
- 2006-12-26 EC ECSP067115 patent/ECSP067115A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200610598B (en) | 2008-01-30 |
| ECSP067104A (en) | 2007-04-26 |
| CN1980664A (en) | 2007-06-13 |
| CN1980908A (en) | 2007-06-13 |
| UA85512C2 (en) | 2009-01-26 |
| ZA200610597B (en) | 2008-01-30 |
| ECSP067115A (en) | 2007-03-29 |
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