CN1863768A - 8-aza-11-deoxy prostaglandin analogues - Google Patents

8-aza-11-deoxy prostaglandin analogues Download PDF

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CN1863768A
CN1863768A CN 02814091 CN02814091A CN1863768A CN 1863768 A CN1863768 A CN 1863768A CN 02814091 CN02814091 CN 02814091 CN 02814091 A CN02814091 A CN 02814091A CN 1863768 A CN1863768 A CN 1863768A
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oxo
phenyl
group
tetramethyleneimine
hydroxyl
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托德·理查德·埃尔沃西
塔拉·米尔托德甘
米歇尔·格瑞特·勒皮尔
戴维·伯纳德·史密斯
肯斯·阿德里安·默里·沃克
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F Hoffmann La Roche AG
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Abstract

This invention relates to compounds according to Formula I or individual isomers, racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof, wherein A, B, R1 to R6 and Z are defined as in claim I. The invention further relates to pharmaceutical compositions comprising such compounds, the use of these compounds as therapeutic agents, and methods of preparation these compounds.

Description

Prostaglandin analogue as the EP4 receptor stimulant
The present invention relates to some 8-azepine-11-deoxy prostaglandin analogue and relevant pharmaceutical composition, as selective prostaglandins EP 4Using method of agonist and preparation method thereof.
Exist many contents to relate to prostaglandin(PG) or prostanoid (PGs) in the document, even this term generally refers to natural and synthetic prostaglandin(PG) and prostaglandin(PG)-sample compound and exists slight difference also can produce effect of depth to its biological activity as everyone knows in its chemical structure or three-dimensional chemical configuration.
Prostaglandin(PG) or prostanoid (PGs) are that a class derives from the bioactive compounds of membrane phospholipid and formed by the indispensable fatty acid and the pentamethylene ring of 20-carbon.They belong to by several main type of letter designation and difference and are replacement to the pentamethylene ring.Described main type further is divided into again the subscript 1,2 or 3 that reflects its lipid acid precursor.
An example of the particular types of PGE is the PGE with following array structure 2:
Figure A0281409100071
At present, known PGE 24 kinds of different receptor subtypes of acceptor and with they called after EP 1, EP 2, EP 3And EP 4
Has the PGE of being similar to 2In conjunction with active application of compound comprise prevent and/or treat amynologic disease (autoimmune disease, organ transplantation etc.), asthma, unusual bone forming, neuronal cell death, thrombosis and apoplexy, hepatopathy, miscarriage, masculinity and femininity sexual dysfunction, premature labor, such as the such inflammation of rheumatoid arthritis, or such as the such view membranous nephropathy of glaucoma.
For example, prostaglandin(PG) and associated receptor thereof: M.Abramovitz etc. " be used to measure the affinity of prostaglandin(PG) and related analogs and optionally recombinate the prostanoid acceptor application " (The Utilization of RecombinantProstanoid receptors to Determine the Affinities and Selectivities ofProstaglandins and Related Analogs)-" biological chemistry and biophysics journal " (Biochimica et Biophysica Acta) 2000 more completely described in following document, 1483,285-293.
" effect of prostaglandin E receptor hypotype in bone resorption: the analysis of using corresponding EPs specific agonist to carry out " (The Role of Prostaglandin E Receptor Subtypes in BoneResorption:An Analysis Using Specific Agonists for the Respective EPs)-" incretology " that the prostaglandin E receptor agonist that relates in the bone resorption for example is described in T.Suzawa etc. (Endocrinology) 2000,141,1554-1559; " prostaglandin(PG) (PG) E receptor subtype EP such as K.Ono 4By PGE 2The inductive bone marrow cells in mice forms the vital role in the osteoclast like cell " (Important Role of EP 4, a Subtype of Prostaglandin (PG) E Receptor, in Osteoclast-like Cell Formation from Mouse BoneMarrow Cells Induced by PGE 2)-" the incretology magazine " (J.of Endocrinology) 1998,158, R1-R5; M.Suda etc. " mouse bone-forming cell system in prostaglandin E receptor hypotype " (Prostaglandin E Receptor Subtypes in Mouse Osteoblastic CellLine)-" incretology " (Endocrinology) 1996,137,1698-1705.
These selective prostaglandins E receptor stimulant also is used for the treatment of gastric damage, for example, and referring to " PGEs such as H.Arak 2Hypotype is to the effect of cytoprotection in the rat stomach " (TheRoles of Prostaglandin E Receptor Subtypes in the Cytoprotective Action ofProstaglandin E 2In Rat Stomach)-" nutrition pharmacological treatments " (Aliment.Pharmacol.Ther.) 2000,14 (supplementary issues 1), 116-124; " E type prostaglandin(PG) passes through EP to T.Kunikata etc. 3And EP 4Acceptor suppresses the small intestine infringement that indomethacin brings out: use rat and reject the research that mouse carries out " (E Type Prostaglandin InhibitsIndomethacin-Induced Small Intestinal Lesions Through EP 3And EP 4Receptors:A Study Using Rats and Knockout Mice), " gastroenterology " (Gastroenterology) 118, summary #3787.
Other application of prostaglandin E receptor agonist is: improve renal function, for example be described in " prostaglandin E receptor and kidney " (Prostaglandin E Receptors andthe Kidney)-Am.J.Physiol.2000 of M.D.Breyer etc., 279, " the EP of F12-F23 and K.E.Purdy etc. 1With EP 4Receptor-mediated PGE 2Effect in the kidney of rats microcirculation " (EP 1And EP 4Receptors Mediate Prostaglandin E 2Actions in the Microcirculation of RatKidney)-" U.S.'s physiology magazine " (Am.J.Physio.) 2000,279, among the F755-F764; Other disease that is used for thrombosis and apoplexy and is used to have benefited from suppress platelet aggregation, for example B.Z.S.Paul etc. is at " distribution in thrombocyte and human umbilical artery smooth muscle cell of prostate gland IP and EP receptor subtype and isotype " (Distribution of Prostaglandin IP and EPReceptor Subtypes and Isoforms in Platelets and Human Umbilical ArterySmooth Muscle Cells)-" Britain's haematol magazine " (Br.J.Haematol.) 1998,102, described in the 1204-1211; By suppressing the anti-inflammatory action that TNF-α produces, for example be described in K.K.Meja etc. " the prostanoid acceptor is at PGE 2Characterization on the human blood monocyte when suppressing lipopolysaccharide-induced tumor necrosis factor-alpha and producing " (Characterization of prostanoid Receptor (s) on human blood monocytes atwhich Prostaglandin E 2Inhibits lipopolysaccharide-induced tumor necrosisfactor-alpha generation)-" Britain's pharmacology magazine " (Br.J.Pharmacol.) 1997,122,149-157 and A.Eigler etc. " anti-inflammatory action of cAMP elevating agents: " inhibition that the IL-10 synthetic is strengthened and simultaneously TNF produced " (Antiinflammatory activities ofcAMP-elevating agents:enhancement of IL-10 synthesis and concurrentsuppression of TNF production)-" white corpuscle biology magazine " (J.Leukoc.Biol.) 1998; 63, among the 101-107; Or be used for glaucoma, for example be described in " location of prostaglandin E receptor hypotype in mouse eye ciliary body " (Localization ofProstaglandin E Receptor Subtypes in The Ciliary Body of Mouse Eye)-" experimental eye research " (Exp.Eye Res.) 2000 of M.Takamatsu etc., 70, " the prostanoid EP of 623-628 and D.F.Woodward etc. 2The characterization of moleculesization of acceptor and ocular hypotension characteristic " (MolecularCharacterization and Ocular Hypotensive Properties of the Prostanoid EP 2Receptor)-" eye pharmacological treatments magazine " (J.Ocul.Pharmacol.Ther.) in 1995,11,447.
Transfer Pharmacia ﹠amp; Disclose by use among the International Publication No. WO 99/02164 of Upjohn AB and belonged to selectivity EP 2And/or EP 4The prostaglandin(PG) treatment impotence and/or the erective dysfunction of receptor stimulant.
The out of Memory that relates to prostaglandin(PG) and acceptor thereof is described in Goodman ﹠amp; " pharmacological basis of therapeutical agent " of Gillman ' s (The Pharmacological Basis of Therapeutics) the 9th edition, McGraw-Hill, New York, 1996, the 26 chapters are in the 601-616 page or leaf.
Corresponding to PGE 28-azepine-11-deoxidation-prostaglandin analogue can have following array structure:
Figure A0281409100101
8-azepine-11-deoxidation-prostaglandin(PG)
Carbon on the nitrogen replacement C-8 causes the change of the three-dimensional conformation of gained prostaglandin(PG), and because structure is relevant with biological activity, so this conformational change has important role to biological activity.Reported the 8-azepine-11-deoxy prostaglandin E analogue that has natural side chain in the document, for example, referring to transferring Syntex USA, the BE 841,165 of Inc..
Compound of the present invention is the 8-azepine prostaglandin(PG) (according to the prostaglandin(PG) nomenclature) that has the non-natural side chain on the C-12 position of pyrrolidone ring, and described chain contains heterocyclic radical, aryl or heteroaryl ring on the C-15 position of this chain.These compounds are at its EP 4The receptor agonist activity aspect has high selectivity.Optionally increase and to alleviate observed serious side effects after giving non-selective prostaglandin agonists usually.Therefore, compound of the present invention is an ideal.
The present invention relates to contain the compound of general formula I or the racemoid or the non-racemic mixture of its pharmaceutically acceptable salt or solvate, its individual isomer or isomer:
Wherein:
A is-CH 2-CH 2-or-CH=CH-;
B does not exist, is aryl or heteroaryl;
Z is-C (O) OR ' ,-C (O) NR ' R " ,-C (O) NSO 2R ' ,-PR ' (O) (OR ') ,-PO (OR ') 2Or tetrazolium-5-base; Wherein R ' and R " are hydrogen or (C independently of one another 1-C 6) alkyl;
M is 1,2,3,4,5 or 6;
R 1Be alkyl, alkenyl, alkynyl, cycloalkylalkyl, heterocyclic radical alkyl, aryl, arylalkyl or heteroaryl, when B is aryl or heteroaryl and R 3, R 4, R 5And R 6When being not hydrogen simultaneously, or R 1Be heterocyclic radical alkyl, aryl or heteroaryl, when B does not exist and R 3, R 4, R 5And R 6Be hydrogen simultaneously;
R 2Be hydrogen or (C 1-C 6) alkyl, (C 1-C 6) alkenyl or (C 1-C 6) alkynyl;
R 3, R 4, R 5And R 6Independently of one another is hydrogen or (C 1-C 6) alkyl; Or R 3And R 4, R 5And R 6Or R 3And R 5Can form (C with the atom that they connected 3-C 7) the alkyl ring.
In one aspect of the method, the present invention relates to pharmaceutical composition, it contains the compound of at least a general formula I for the treatment of significant quantity or the racemoid or the non-racemic mixture of its pharmaceutically acceptable salt or solvate, prodrug, individual isomer or isomer, itself and at least a suitable carriers, thinner or mixed with excipients.
In one aspect of the method, the invention provides can be by giving PGE P 4The methods of treatment of the mammalian diseases of receptor agonist treatment, particularly osteopathia, this method comprise the compound of Formula I for the treatment of significant quantity or the step of its pharmaceutically acceptable salt.
In one aspect of the method, the invention provides the preparation method of compound of Formula I.
Except as otherwise noted, used following term has following specified implication in this specification sheets and claims:
" alkoxyl group ", single or combination refers to group-OR, and wherein R is the alkyl that this paper defines, for example methoxyl group, oxyethyl group, propoxy-, butoxy etc.
" alkyl ", single or combination refers to the saturated monovalence alkyl of straight chain of 1-6 carbon atom or the saturated monovalence alkyl of side chain of 3-6 carbon atom, for example methyl, ethyl, propyl group, 2-propyl group, normal-butyl, isobutyl-, the tertiary butyl, amyl group etc.
" alkylidene group ", single or the combination, refer to the saturated bivalent hydrocarbon radical of straight chain of 1-6 carbon atom or the saturated bivalent hydrocarbon radical of side chain of 3-6 carbon atom, for example methylene radical, ethylidene, 2,2-dimethyl ethylidene, propylidene, 2-methyl propylidene, butylidene, pentylidene etc.
" alkylthio " or " alkyl alkylthio base ", single or combination refers to group-SR, and wherein R is an alkyl as defined above, for example methylthio group, ethylmercapto group, rosickyite base, butylthio etc.
" aryl ", single or the combination, refer to monovalence monocycle or two aromatic hydrocarbon ring bases, it is optional to be replaced by one or more substituting groups, preferred one, two or three substituting groups independently of one another, these substituting groups be selected from alkyl, haloalkyl, halogen, nitro, cyano group, amino, methylene-dioxy, ethylenedioxy, Y-aryl, Y-heteroaryl, Y-cycloalkyl ,-the Y-heterocyclic radical ,-Y-OR ' ,-Y-NR ' R " ,-Y-C (O)-R ' ,-Y-S (O) 0-2-R ' ,-Y-N-SO 2-R ' ,-Y-SO 2The group that-NR ' R " ,-Y-N-C (O)-NR ' R " forms, wherein Y does not exist or C 1-C 3Alkylidene group and R ' and R " are hydrogen, alkyl, haloalkyl, hydroxyl, alkoxyl group, aryl, heteroaryl, cycloalkyl, heterocyclic radical separately independently of one another.In particular, term aryl is including, but not limited to phenyl, chloro-phenyl-, p-methoxy-phenyl, methoxymethyl phenyl, Phenoxyphenyl, 1-naphthyl, 2-naphthyl and derivative thereof.
" cycloalkyl ",, separately or with array mode,, refer to 3-7 the saturated monovalence cyclic hydrocarbon radical of encircling carbon, for example cyclopropyl, cyclobutyl, cyclohexyl, 4-methyl-cyclohexyl base etc.
" halo ",, separately or with array mode,, refer to fluoro, chloro, bromo or iodo, preferred fluoro and chloro.
" haloalkyl ",, separately or with array mode,, refer to the alkyl that replaced by one or more identical or different halogen atoms, for example-CH 2Cl ,-CF 3,-CH 2CF 3,-CH 2CCl 3Deng.
" heteroaryl ",, separately or with array mode, refer to the monovalence monocycle or the bicyclic groups that at least one contains one, two three ring hetero atoms that are selected from N, O or S, aromatic ring that the residue ring atom is C that have of 5-12 annular atoms, the tie point that wherein should understand heteroaryl is positioned on the aromatic ring.Described heteroaryl ring is optional independently of one another by one or more substituting groups, preferably one or two substituting group replaces, these substituting groups be selected from alkyl, haloalkyl, halogen, nitro, cyano group, amino, methylene-dioxy, Y-aryl, Y-heteroaryl, Y-cycloalkyl ,-the Y-heterocyclic radical ,-Y-OR ' ,-YNR ' R " ,-Y-C (O)-R ' ,-Y-O-C (O)-R ' ,-Y-S (O) 0-2-R ' ,-Y-N-SO 2-R ' ,-Y-SO 2-NR ' R " ,-Y-N-C (O)-N-R ' R ", wherein Y does not exist or C 1-C 3Alkylidene group and R ' and R " are hydrogen, alkyl, haloalkyl, hydroxyl, alkoxyl group, aryl, heteroaryl, cycloalkyl, heterocyclic radical separately independently of one another.In particular, the term heteroaryl comprises, but be not limited to pyridyl, furyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, different  azoles base, pyrryl, pyrazolyl, pyrimidyl, benzofuryl, the tetrahydrochysene benzfuran base, isobenzofuran-base, benzothiazolyl, the benzisothiazole base, the benzotriazole base, indyl, pseudoindoyl, the benzoxazol base, quinolyl, tetrahydric quinoline group, isoquinolyl, benzimidazolyl-, benzisoxa  azoles base or benzothienyl, imidazo [1,2-a]-pyridyl, imidazo [2,1-b] thiazolyl and derivative thereof.
" heterocyclic radical " separately or with array mode, refers to the saturated or unsaturated non-aromatic ring group of 3-8 annular atoms, and one of them or two annular atomses are to be selected from N, O or S (O) 0-2Heteroatoms, remaining annular atoms is C, one of them or two C atoms are optional by carbonyl substituted.Described heterocyclic ring can be chosen wantonly independently of one another by one, two or three substituting groups and replace, these substituting groups be selected from alkyl, haloalkyl, halogen, nitro, cyano group ,-Y-aryl, Y-heteroaryl, Y-cycloalkyl ,-the Y-heterocyclic radical ,-Y-OR ' ,-YNR ' R " ,-Y-C (O)-R ' ,-Y-S (O) 0-2-R ' ,-Y-N-SO 2-R ' ,-Y-SO 2-NR ' R " ,-Y-N-C (O)-N-R ' R ", wherein Y does not exist or is C 1-C 3Alkylidene group and R ' and R " are hydrogen, alkyl, haloalkyl, hydroxyl, alkoxyl group, aryl, heteroaryl, cycloalkyl, heterocyclic radical independently of one another.In particular; the term heterocyclic radical is including, but not limited to THP trtrahydropyranyl, piperidyl, N-methyl piperidine-3-base, piperazinyl, N-methylpyrrolidin-3-base, 3-pyrrolidyl, morpholinyl, thio-morpholinyl, thiomorpholine generation-1-oxide compound (thiomorpholinyl-1-oxide), thiomorpholine generation-1; the 1-dioxide (thiomorpholinyl-1,1-dioxide), pyrrolinyl, imidazolinyl, N-methylsulfonyl-piperidin-4-yl and derivative thereof.
" leaving group " has usually and its relevant implication in synthetic organic chemistry, i.e. atom that can be replaced by nucleophile or group and comprise halogen (such as chlorine, bromine and iodine), alkane sulfonyloxy, arylsulfonyloxy, alkyl-carbonyl oxygen base (for example acetoxyl group), aryl carbonyl oxygen base, mesyloxy, tosyloxy, trifluoro-methanesulfonyl oxy, aryloxy (for example 2,4-2,4-dinitrophenoxy base), methoxyl group, N, O-dimethyl hydroxyl amino etc.
" the optional phenyl that replaces "; separately or with array mode; refer to optionally independently of one another by one or more substituting groups, the phenyl ring that preferably replaced by one or two substituting group, these substituting groups are selected from the group that alkyl, hydroxyl, alkoxyl group, haloalkyl, halogen alkoxyl group, assorted alkyl, halogen, nitro, cyano group, amino, methylene-dioxy, ethylenedioxy and acyl group are formed.
" isomery " refers to has the same molecular formula but character or its atom binding sequence or the different compound of its atom spatial disposition mode.The isomer that atom spatial disposition mode is different is called " steric isomer ".The steric isomer of non-mirror images of each other is called " diastereomer "; And the steric isomer that belongs to non-superimposable mirror image is called " enantiomorph " or be called optically active isomer sometimes.Be called " chiral centre " with 4 kinds of different substituents bonded carbon atoms.
" chiral isomer " refers to the compound that has a chiral centre.It has the enantiomeric form of two kinds of reverse chiralitys and can be used as single enantiomorph or exist as the mixture of enantiomers form.The mixture that contains each reverse chirality enantiomeric form of equivalent is called " racemic mixture ".The compound that has an above chiral centre has 2 N+1Enantiomorph is right, and wherein n is the quantity of chiral centre.The compound that has an above chiral centre can be used as single diastereomer or has, is called " non-enantiomer mixture " as the non-enantiomer mixture form.When having a chiral centre, steric isomer is characterised in that the absolute configuration (R or S) of this chiral centre.The decision configuration refers to the substituent spatial disposition that is connected with chiral centre.The substituting group that is connected with chiral centre in considering is according to the Cahn-Ingold-Prelog sequence rule arrangement of Cahn, Ingold and Prelog (Angew.Chem.Inter.Edit.1966 such as Cahn, 5,385; Errata 511; Angew.Chem.1966 such as Cahn, 78,413; Cahn and Ingold, " chemical association magazine " be 1951 (London) (J.Chem.Soc.), and 612; Cahn etc. " experiment " (Experientia) 1956.12,81; Cahn, " chemical education magazine " (J., Chem.Educ.) 1964,41,116).
" geometrical isomer " refers to the diastereomer that exists owing to the rotation of being obstructed of relevant two keys.The difference of these configurations in name is prefix cis and trans or Z and E, and it represents that described group is positioned on this molecule on the identical or offside of two keys according to the Cahn-Ingold-Prelog rule.
" atropisomer (atropic isomers) " refers to the isomer that the restricted rotation that produces with the rotation steric hindrance because of the macoradical of relevant center key exists.
Compound of the present invention exists with stereoisomer form, can be used as single steric isomer thus or produces as mixture.
" pharmaceutically acceptable vehicle " refers to the Generally Recognized as safe that is used for pharmaceutical compositions, nontoxicity and neither biologically also be not unfavorable vehicle aspect other and comprising veterinary drug and people's medicine is used acceptable vehicle.Used " pharmaceutically acceptable vehicle " comprises a kind of and more than one these class vehicle in this specification sheets and the claim.
" the pharmaceutically acceptable salt " of compound refers to pharmaceutically acceptable and has the salt of the required pharmacologically active of parent compound.This class salt comprises: the salt of the sour addition that (1) and mineral acid form, and described mineral acid is all if any hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid etc.; Or the salt of the sour addition that forms with organic acid, described organic acid is all if any acetate, propionic acid, caproic acid, the pentamethylene propionic acid, oxyacetic acid, pyruvic acid, lactic acid, propanedioic acid, succsinic acid, oxysuccinic acid, toxilic acid, fumaric acid, tartrate, citric acid, phenylformic acid, 3-(4-hydroxy benzoyl) phenylformic acid, styracin, amygdalic acid, methylsulfonic acid, ethyl sulfonic acid, 1, the 2-ethionic acid, the 2-ethylenehydrinsulfonic acid, Phenylsulfonic acid, the 4-chlorobenzenesulfonic acid, the 2-naphthene sulfonic acid, the 4-toluenesulphonic acids, camphorsulfonic acid, 4-methyl bicyclic [2.2.2]-oct-2-ene-1-formic acid, glucoheptonic acid, the 3-phenylpropionic acid, trimethylacetic acid, tert.-butylacetic acid, lauryl sulfate, glyconic acid, L-glutamic acid, hydroxynaphthoic acid, Whitfield's ointment, stearic acid, muconic acid etc.; (2) when the acid proton that exists on the parent compound by alkalimetal ion for example, alkaline-earth metal from or the salt that forms when replacing of the such metal ion of aluminum ion; Or with the ligand that forms such as organic basess such as thanomin, diethanolamine, trolamine, tromethane, N-methylglucosamines.
Should understand solvent adduction form (solvate) or crystalline form (polymorph) that all pharmaceutically acceptable salt that relate to comprise the salt of the same acids addition that this paper defines.
" crystalline form " (or polymorph) refers to crystalline structure, and wherein compound can be according to the crystallization of different crystal packing arrangement form, and they all have identical elementary composition.Different crystalline forms has different X-ray diffraction patterns, infrared spectra, fusing point, density, hardness, crystalline form, optically-active and characteristic electron, stability and solvability usually.Recrystallization solvent, crystallization rate, storing temp and other factors can make a kind of crystalline form be dominant.
" solvate " refers to the solvent adduction form that contains stoichiometry or nonstoichiometry amount solvent.Some compound has the tendency of the crystalline solid state solvent molecule that obtains fixed molar ratio, forms solvate thus.If described solvent is a water, the solvate of Xing Chenging is a hydrate so, and when solvent was alcohol, the solvate of formation was an alcoholate when described.By one or more water moleculess and water are kept H 2One of material of the molecular state of O merges the formation hydrate, and this class combination can form one or more hydrates.
Term " prodrug " and " prodrug " can exchange in this article and use and refer to any compound that discharges the reactive precursor compound of general formula I when giving mammalian subject with this class prodrug in vivo.By modifying the prodrug that the one or more functional groups that exist on the compound of Formula I prepare compound of Formula I, according to this class mode make the gained modifier in vivo can cracking to discharge parent compound.Prodrug comprises the compound of general formula I, wherein the hydroxyl on the compound of Formula I, amino, sulfhedryl, carboxyl or carbonyl with cracking in vivo and any group that generates free hydroxyl group, amino or sulfhedryl again respectively be connected.The example of prodrug comprises; but be not limited to the ester class (acetic ester for example of compound of Formula I; the dialkylamino acetate esters; formate ester; phosphoric acid ester; sulfuric acid ester and benzoate derivatives) and the amino formate of hydroxyl-functional base (N for example; N-dimethylamino carbonyl); the ester moiety of carboxyl-functional base (ethyl ester class for example; morpholino second alkoxide); the N-acyl derivative of amino-functional base (for example N-ethanoyl) N-Mannich base; Schiff's base and enamine ketone; ketone and aldehyde functional group's oximes; acetal; ketals and enol ester class etc.; referring to Bundegaard; H. " prodrug design " (" Design of Prodrugs ") p1-92; Elesevier, New York-Oxford (1985).
" protecting group " refers to and shelters when reactive group in the molecule is connected, and reduces or prevents this reactive atomic group.The example of protecting group can be at " protecting group in the organic chemistry " (Protective Groups in Organic Chemistry) of T.W.Green and P.G.Futs; (Wiley; the 2nd edition .1991) and " comprehensive methodology of organic synthesis " (Compendium of Synthetic Organic Methods) of Harrison and Harrison etc.; (John Wiley and Sons find in 1971-1996) for 1-8 volume.Representational amino protecting group comprises trityl, allyloxy carbonyl, 9-fluorenyl methoxy carbonyl (FMOC), nitro-veratryl oxygen base carbonyl (NVOC) of formyl radical, ethanoyl, trifluoroacetyl group, benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (Boc), trimethylsilyl (TMS), 2-trimethylsilyl-ethylsulfonyl (SES), trityl and replacement etc.Representational hydroxyl protecting group comprises some protecting groups like this, and wherein hydroxyl is by acidylate or alkylation, such as benzyl and trityl ethers and alkyl ether, THP trtrahydropyranyl ethers, trialkylsilyl ethers class and allyl ether series.
Disease comprises " treatment ": (1) preventing disease, even the clinical symptom of contact or easily ill mammalian diseases does not develop and does not take place or show disease symptoms; (2) suppress disease, even disease or its clinical symptom stop or alleviating; Or (3) alleviation disease, even disease or its clinical symptom are degenerated.
" treatment significant quantity " refers to the consumption that is enough to make this class therapy for treating disease when to Mammals drug treatment disease." treatment significant quantity " is with described compound, disease and severity thereof different change the with contract mammiferous age of treatment, body weight etc.
" prostaglandin analogue " is the compound that occurs with the similar non-natural of prostaglandin(PG) on the structure.
" prostaglandin receptor " or " prostanoid acceptor " be when in conjunction with the time change the protein in conjunction with the natural appearance of prostaglandin(PG) of the function of cell.Prostaglandin receptor is characterised in that excitement or relaxes that this receptoroid is including, but not limited to EP 1, EP 2, EP 3, EP 4, DP, FP, IP, TP 1And TP 2On " pharmacology summary " (Pharmacological Reviews) 1994 the 6th volumes the 2nd phase 205-229 page or leaf these acceptors have been discussed further.
Following abbreviation used among the application has following meanings:
The DME glycol dimethyl ether
The DMF dimethyl formamide
The DMSO methyl-sulphoxide
The EtOAc ethyl acetate
The MS mass spectrum
The THF tetrahydrofuran (THF)
Rt chamber (environment) temperature
Nomenclature
Illustrate the naming ﹠ numbering of The compounds of this invention below:
In general, among the application used nomenclature based on the AUTONOM that is used to generate the IUPAC systematic nomenclature TMV.4.0 Beilstein Institute computer system.
For example, wherein Z is-C (O) OH; M is 5; R 2, R 3, R 4, R 5And R 6Be hydrogen; A is-CH 2=CH 2-; B does not exist, and R 1Be the compound called after 7-[(R of the general formula I of phenyl)-2-((E)-3-hydroxyl-3-phenyl-propenyl)-5-oxo-tetramethyleneimine-1-yl]-enanthic acid.
Although listed the most extensive definition of the present invention in the summary of the invention, some compound of preferred formula I.
In first embodiment, representational one group of compound is such compounds, and wherein B does not exist, R 1It is aryl; A, R 2, R 3, R 4, R 5, R 6With Z as above-mentioned definition.Preferred one group of compound in this embodiment is such compound, wherein R 1Be optional be selected from trifluoromethyl, halogen ,-Y-R a,-Y-OR aWith-Y-C (O) R aThe aryl that replaces of substituting group, wherein Y is key or (C 1-C 3) alkylidene group and R aBe hydrogen, (C 1-C 6) alkyl, aryl, heterocyclic radical, heteroaryl or heterocyclic radical.Preferred R 1Be optional being selected from-Y-R a,-Y-OR aWith-Y-C (O) R aThe aryl that replaces of substituting group, wherein Y is key or (C 1-C 3) alkylidene group and R aBe unsubstituted phenyl or be selected from (C by at least one 1-C 6) alkyl, (C 1-C 6) phenyl that replaces of the substituting group of alkoxyl group, trifluoromethyl or halogen.
In second embodiment of general formula I, B does not exist, A, R 2, R 3, R 4, R 5, R 6With Z as above-mentioned definition and R 1By-Y-R aThe phenyl that replaces, wherein Y is key or (C 1-C 3) alkylidene group and R aBe to choose wantonly to be selected from (C 1-C 6) alkyl, (C 1-C 6) phenyl that replaces of the substituting group of alkoxyl group, trifluoromethyl or halogen.Preferred R 1By at least one-Y-OR aThe phenyl that replaces, wherein Y is key or (C 1-C 3) alkylidene group and R aBe optional by (C 1-C 6) alkyl, (C 1-C 6) phenyl that replaces of alkoxyl group, trifluoromethyl or halogen.More preferably R 1By-Y-C (O) R aThe phenyl that replaces, wherein Y is key or (C 1-C 3) alkylidene group and R aBe to choose wantonly to be selected from (C 1-C 6) alkyl, (C 1-C 6) phenyl that replaces of the substituting group of alkoxyl group, trifluoromethyl or halogen.
In the 3rd embodiment of general formula I, wherein B does not exist, and A is-CH=CH-R 2, R 3, R 4, R 5, R 6With Z as above-mentioned definition and R 1It is heteroaryl.Representational compound is such some compounds, wherein said heteroaryl be selected from trifluoromethyl, halogen ,-Y-R a,-Y-OR aWith-Y-C (O) R aGroup replace, wherein Y is key or (C 1-C 3) alkylidene group and R aBe (C 1-C 6) alkyl, aryl, heterocyclic radical, heteroaryl or heterocyclic radical.
The 4th embodiment is the compound of general formula I, and wherein B does not exist, and A is-CH 2-CH 2-, R 2, R 3, R 4, R 5, R 6With Z as above-mentioned definition and R 1It is heteroaryl.Representational compound is such some compounds, wherein said heteroaryl be selected from trifluoromethyl, halogen ,-Y-R a,-Y-OR aWith-Y-C (O) R aGroup replace, wherein Y is key or (C 1-C 3) alkylidene group and R aBe (C 1-C 6) alkyl, aryl, heterocyclic radical, heteroaryl or heterocyclic radical.
The 5th embodiment is the compound of general formula I, and wherein B does not exist, R 3And R 4Be (C 1-C 6) alkyl; R 2, R 5, R 6With Z as above-mentioned definition; A is-CH 2-CH 2-, and R 1Be phenyl, heteroaryl, alkyl or cycloalkyl alkyl.Preferred R 1By at least one be selected from trifluoromethyl, halogen ,-Y-R a,-Y-OR aWith-Y-C (O) R aThe phenyl that replaces of group, wherein Y is key or (C 1-C 3) alkylidene group and R aBe (C 1-C 6) alkyl, aryl, heterocyclic radical, heteroaryl or heterocyclic radical.More preferably R 1By at least one be selected from trifluoromethyl, halogen ,-Y-R a,-Y-OR aWith-Y-C (O) R aThe heteroaryl that group replaces, wherein Y is key or (C 1-C 3) alkylidene group and R aBe (C 1-C 6) alkyl, aryl, heterocyclic radical, heteroaryl or heterocyclic radical.More preferably R 1It is the alkyl or cycloalkyl alkyl.
In the 6th embodiment, B does not exist, R 2, R 3, R 4, R 5, R 6With Z as above-mentioned definition, A is-CH=CH-R 1Be optional be selected from trifluoromethyl, halogen ,-Y-R a,-Y-OR aWith-Y-C (O) R aThe phenyl that replaces of substituting group, wherein Y is key or (C 1-C 3) alkylidene group and R aBe (C 1-C 6) alkyl, aryl, heterocyclic radical, heteroaryl or heterocyclic radical.
In the 7th embodiment, B does not exist, R 2, R 3, R 4, R 5, R 6With Z as above-mentioned definition, A is-CH 2-CH 2-, R 1Be optional be selected from trifluoromethyl, halogen ,-Y-R a,-Y-OR aWith-Y-C (O) R aThe phenyl that replaces of substituting group, wherein Y is key or (C 1-C 3) alkylidene group and R aBe (C 1-C 6) alkyl, aryl, heterocyclic radical, heteroaryl or heterocyclic radical.
In the 8th embodiment, B is an aryl, and m is 1 or 2, R 2, R 3, R 4, R 5, R 6, A and Z be as above-mentioned definition and R 1Be optional be selected from trifluoromethyl, halogen ,-Y-R a,-Y-OR aWith-Y-C (O) R aThe alkyl or aryl that replaces of substituting group, wherein Y is key or (C 1-C 3) alkylidene group and R aBe (C 1-C 6) alkyl, aryl, heterocyclic radical, heteroaryl or heterocyclic radical.Preferred R 1It is the optional phenyl that replaces.
In the 9th embodiment, B is a heteroaryl, and m is 1 or 2 and R 1Be alkyl, m is 1 or 2, R 2, R 3, R 4, R 5, R 6, A and Z be as above-mentioned definition.Preferred compound is that A is-those compounds of CH=CH-in this embodiment.
Other is the compound of general formula I preferably, wherein R 2Be hydrogen.
Also the compound of preferred general formula I is more such compounds, wherein R 3-R 6Be independently selected from hydrogen and alkyl.In addition, the preferably like this compound of some general formula Is, wherein R 3-R 6Be independently selected from hydrogen and methyl.
Another embodiment preferred of the present invention is the compound of general formula I, wherein R 3-R 6Be hydrogen.
The structure of compound of Formula I can comprise hydrolyzable amides, ester class or imide class on optically active isomer, diastereomer, enantiomorph or its pharmaceutically acceptable salt, the biology of said structure.Preferred stereochemistry is simulated the PGE of natural appearance 2Structure.
Compound of the present invention can exist with non-solvent form and solvation form, comprises hydrated form.In general, comprise that the solvation form of hydrated form and solvation form are equal to and are included in the scope of the present invention.
The compound of general formula I can further form the salt of pharmaceutically acceptable alkali addition.All these forms all belongs to scope of the present invention.
The present invention be more particularly directed to the compound of general formula I or the racemoid or the non-racemic mixture of its pharmaceutically acceptable salt or solvate, its individual isomer or isomer:
Figure A0281409100211
Wherein:
A is-CH 2-CH 2-or-CH=CH-;
B does not exist, is aryl or heteroaryl;
Z is-C (O) OR ' ,-C (O) NR ' R " ,-C (O) NSO 2R ' ,-PR ' (O) (OR ') ,-PO (OR ') 2Or tetrazolium-5-base; Wherein R ' and R " are hydrogen or (C independently of one another 1-C 6) alkyl;
M is 1,2,3,4,5 or 6;
R 1Be alkyl, alkenyl, alkynyl, cycloalkylalkyl, heterocyclic radical alkyl, aryl, arylalkyl or heteroaryl, when B is aryl or heteroaryl and R 3, R 4, R 5And R 6When being not hydrogen simultaneously; Or R 1Be heterocyclic radical alkyl, aryl or heteroaryl, when B does not exist and R 3, R 4, R 5And R 6When being hydrogen simultaneously;
R 2Be hydrogen or (C 1-C 6) alkyl, (C 1-C 6) alkenyl or (C 1-C 6) alkynyl;
R 3, R 4, R 5And R 6Independently of one another is hydrogen or (C 1-C 6) alkyl; Or R 3And R 4, R 5And R 6Or R 3And R 5Can form (C with the atom that they connected 3-C 7) the alkyl ring.
The compound of general formula I preferably, wherein B does not exist and R 1Be optional be selected from trifluoromethyl, halogen ,-Y-R a,-Y-OR aWith-Y-C (O) R aThe aryl that the substituting group of the group of forming replaces; Y is key or (C 1-C 3) alkylidene group and R aBe (C 1-C 6) alkyl, aryl, heterocyclic radical, heteroaryl or heterocyclic radical.
The further preferably compound of general formula I, wherein R 1It is unsubstituted phenyl.
The compound that another preferred aspect of the present invention is a general formula I, wherein R 1Be selected from trifluoromethyl, halogen ,-Y-R a,-Y-OR aWith-Y-C (O) R aThe aryl that the substituting group of the group of forming replaces; Y is key or (C 1-C 3) alkylidene group and R aBe (C 1-C 6) alkyl, aryl, heterocyclic radical, heteroaryl or heterocyclic radical.
The also preferably compound of general formula I, wherein R aBe to choose wantonly to be selected from (C 1-C 6) alkyl, (C 1-C 6) phenyl that replaces of the substituting group of the group formed of alkoxyl group, trifluoromethyl and halogen.
The further preferably compound of general formula I, wherein R 1By at least one-Y-R aThe phenyl that replaces, wherein Y is key or (C 1-C 3) alkylidene group; R aBe to choose wantonly to be selected from (C 1-C 6) alkyl, (C 1-C 6) phenyl that replaces of the substituting group of the group formed of alkoxyl group, trifluoromethyl and halogen.
The compound that another preferred aspect of the present invention is a general formula I, wherein R 1By at least one-Y-R aThe phenyl that replaces; Wherein Y is key or (C 1-C 3) alkylidene group; R aIt is the optional heteroaryl that replaces.
The also preferably compound of general formula I, wherein R 1By at least one-Y-OR aThe phenyl that replaces, wherein Y is key or (C 1-C 3) alkylidene group and R aBe to choose wantonly to be selected from (C 1-C 6) alkyl, (C 1-C 6) phenyl that replaces of the substituting group of the group formed of alkoxyl group, trifluoromethyl and halogen.
The compound that another preferred aspect of the present invention is a general formula I, wherein R 1By at least one-Y-C (O) R aThe phenyl that replaces, wherein Y is key or (C 1-C 3) alkylidene group; And R aBe to choose wantonly to be selected from (C by at least one 1-C 6) alkyl, (C 1-C 6) phenyl that replaces of the substituting group of the group formed of alkoxyl group, trifluoromethyl and halogen.
The compound of general formula I further preferably, wherein B does not exist and R 1It is heteroaryl.
The compound that other preferred aspect of the present invention is a general formula, wherein R 1Be selected from trifluoromethyl, halogen ,-Y-R a,-Y-OR aWith-Y-C (O) R aThe heteroaryl that the substituting group of the group of forming replaces, wherein Y is key or (C 1-C 3) alkylidene group; And R aBe (C 1-C 6) alkyl, aryl, heterocyclic radical, heteroaryl or heterocyclic radical.
Other is the compound of general formula I preferably, and wherein B does not exist, R 3And R 4Be (C 1-C 6) alkyl.
The compound that another preferred aspect of the present invention is a general formula I, wherein R 1Be optional be selected from trifluoromethyl, halogen ,-Y-R a,-Y-OR aWith-Y-C (O) R aThe phenyl that the substituting group of the group of forming replaces; Y is key or (C 1-C 3) alkylidene group; And R aBe (C 1-C 6) alkyl, aryl, heterocyclic radical, heteroaryl or heterocyclic radical.
The compound that another preferred aspect of the present invention is a general formula I, wherein R 1Be optional be selected from trifluoromethyl, halogen ,-Y-R a,-Y-OR aWith-Y-C (O) R aThe heteroaryl that the substituting group of the group of forming replaces; Y is key or (C 1-C 3) alkylidene group; And R aBe (C 1-C 6) alkyl, aryl, heterocyclic radical, heteroaryl or heterocyclic radical.
The further preferably compound of general formula I, wherein R 1It is the alkyl or cycloalkyl alkyl.
The compound that another preferred aspect of the present invention is a general formula I, wherein A is-CH 2-CH 2
The compound of general formula I further preferably, wherein B does not exist and A is-CH 2-CH 2
The compound that another preferred aspect of the present invention is a general formula I, wherein B does not exist and R 1Be optional be selected from trifluoromethyl, halogen ,-Y-R a,-Y-OR aWith-Y-C (O) R aThe phenyl that the substituting group of the group of forming replaces; Wherein Y is key or (C 1-C 3) alkylidene group; And R aBe (C 1-C 6) alkyl, aryl, heterocyclic radical, heteroaryl or heterocyclic radical.
Other is the compound of general formula I preferably, and wherein B is an aryl, and m is 1 or 2 and R 1Be alkyl, aryl or heteroaryl.
In addition, the compound of preferred formula I, wherein R 1It is the optional phenyl that replaces.
The compound that another preferred aspect of the present invention is a general formula I, wherein R 1It is alkyl.
Other is the compound of general formula I preferably, and wherein B is a heteroaryl, and m is 1 or 2 and R 1It is alkyl.
The preferred compound of general formula I is selected from the group that following compounds is formed:
7-[2-((E)-3-hydroxyl-3-naphthalene-2-base-propenyl)-5-oxo-tetramethyleneimine-1-yl]-enanthic acid;
7-{ (R)-2-[(E)-3-hydroxyl-3-(3-phenoxy group-phenyl)-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid;
7-[(R)-2-((E)-3-hydroxyl-3-phenyl-propenyl)-5-oxo-tetramethyleneimine-1-yl]-enanthic acid;
7-((R)-2-{ (E)-3-hydroxyl-3-[3-(morpholine-4-alkylsulfonyl)-phenyl]-propenyl }-5-oxo-tetramethyleneimine-1-yl)-enanthic acid;
7-{ (R)-2-[(E)-3-hydroxyl-3-(3-methoxyl group-phenyl)-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid;
7-{ (R)-2-[(E)-3-hydroxyl-3-(4-phenoxy group-phenyl)-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid;
7-{ (R)-2-[(E)-3-(3-benzyl-phenyl)-3-hydroxyl-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid;
7-{ (R)-2-[(E)-3-(3-oxyethyl group-phenyl)-3-hydroxyl-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid;
7-{ (R)-2-[(E)-3-(3-ethyl-phenyl)-3-hydroxyl-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid;
7-{ (R)-2-[(E)-3-(3-benzoyl-phenyl)-3-hydroxyl-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid;
7-{ (R)-2-[(E)-3-(3-bromo-phenyl)-3-hydroxyl-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid;
7-[(R)-2-((E)-3-xenyl-3-base-3-hydroxyl-propenyl)-5-oxo-tetramethyleneimine-1-yl]-enanthic acid;
7-{ (R)-2-[(E)-3-hydroxyl-3-(2 '-methyl-xenyl-3-yl)-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid;
7-{ (S)-2-[3-hydroxyl-3-(5-o-tolyl-furans-2-yl)-propyl group]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid;
7-{ (S)-2-[3-(1-benzyl-1H-pyrazoles-4-yl)-3-hydroxyl-propyl group]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid;
7-{ (R)-5-[(E)-3-hydroxyl-3-(5-trifluoromethyl-furans-2-yl)-propenyl]-3,3-dimethyl-2-oxo-tetramethyleneimine-1-yl }-enanthic acid;
7-(R)-2-[(E)-3-hydroxyl-3-(3-hydroxyl-phenyl)-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid;
7-{ (R)-2-[(E)-3-hydroxyl-3-(3-pyrroles-1-ylmethyl-phenyl)-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid;
7-{ (R)-2-[(E)-3-hydroxyl-3-(3-pyrazol-1-yl methyl-phenyl)-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid;
7-{ (R)-2-[(E)-3-hydroxyl-3-(3-methoxymethyl-phenyl)-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid;
7-{ (R)-2-[(E)-3-(3-cyclopentyloxy-phenyl)-3-hydroxyl-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid;
7-{ (R)-2-[(E)-3-(2 '-oxyethyl group-xenyl-3-yl)-3-hydroxyl-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid;
7-{ (R)-2-[(E)-3-(2 '-chloro-xenyl-3-yl)-3-hydroxyl-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid;
7-((R)-2-{ (E)-3-hydroxyl-3-[3-(4-methoxyl group-phenoxy group)-phenyl]-propenyl }-5-oxo-tetramethyleneimine-1-yl)-enanthic acid;
7-{ (R)-2-[(E)-3-(4 '-chloro-xenyl-3-yl)-3-hydroxyl-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid; With
7-{ (R)-2-[(E)-3-(3 '-chloro-xenyl-3-yl)-3-hydroxyl-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid.
Other preferred compound is selected from the group of following compounds:
7-{ (R)-2-[(E)-3-(3-cyclopentyloxy-phenyl)-3-hydroxyl-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid;
7-{ (R)-2-[(E)-3-(2 '-oxyethyl group-xenyl-3-yl)-3-hydroxyl-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid;
7-{ (R)-2-[(E)-3-(2 '-chloro-xenyl-3-yl)-3-hydroxyl-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid;
7-((R)-2-{ (E)-3-hydroxyl-3-[3-(4-methoxyl group-phenoxy group)-phenyl]-propenyl }-5-oxo-tetramethyleneimine-1-yl)-enanthic acid;
7-{ (R)-2-[(E)-3-(4 '-chloro-xenyl-3-yl)-3-hydroxyl-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid;
7-{ (R)-2-[(E)-3-(3 '-chloro-xenyl-3-yl)-3-hydroxyl-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid;
7-{ (R)-2-[(E)-3-hydroxyl-3-(5-trifluoromethyl-furans-2-yl)-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid;
7-{ (R)-2-[(E)-3-hydroxyl-3-(3-trifluoromethyl-phenyl)-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid;
7-((S)-2-{3-[3-(4-fluoro-phenoxy group)-phenyl]-3-hydroxyl-propyl group }-5-oxo-tetramethyleneimine-1-yl)-enanthic acid;
7-{ (R)-2-[(E)-3-hydroxyl-3-(3-phenoxymethyl-phenyl)-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid;
7-{ (R)-2-[(E)-3-hydroxyl-3-(3-phenoxymethyl-phenyl)-propenyl]-5-oxo-tetramethyleneimine-1-yl }-Methylheptanoate;
7-(R)-2-{ (E)-3-hydroxyl-3-[3-(1-methyl isophthalic acid H-pyrroles-2-yl)-phenyl]-propenyl }-5-oxo-tetramethyleneimine-1-yl)-enanthic acid;
7-((R)-2-{ (E)-3-hydroxyl-3-[3-(1-methyl isophthalic acid H-pyrroles-2-yl)-phenyl]-propenyl }-5-oxo-tetramethyleneimine-1-yl)-Methylheptanoate;
7-{ (R)-2-[(E)-3-(3-butoxy-phenyl)-3-hydroxyl-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid;
7-{ (R)-2-[(E)-3-(3-benzyloxy-phenyl)-3-hydroxyl-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid;
7-((R)-2-{ (E)-3-[3-(2-chloro-benzyloxy)-phenyl]-3-hydroxyl-propenyl }-5-oxo-tetramethyleneimine-1-yl)-enanthic acid;
7-{ (R)-5-[(E)-3-hydroxyl-3-(5-trifluoromethyl-furans-2-yl)-propenyl]-3,3-dimethyl-2-oxo-tetramethyleneimine-1-yl }-enanthic acid;
7-[(R)-and 5-((E)-3-hydroxyl-Xin-1-thiazolinyl)-3,3-dimethyl-2-oxo-tetramethyleneimine-1-yl]-enanthic acid;
7-[2-((E)-3-hydroxyl-Xin-1-thiazolinyl)-3,3-dimethyl-5-oxo-tetramethyleneimine-1-yl]-enanthic acid;
7-[(R)-and 5-((S)-(E)-5-cyclobutyl-3-hydroxyl-penta-1-thiazolinyl)-3,3-dimethyl-2-oxo-tetramethyleneimine-1-yl]-enanthic acid;
7-{5-[(E)-and 3-hydroxyl-4-(3-methoxymethyl-phenyl)-but-1-ene base]-3,3-dimethyl-2-oxo-tetramethyleneimine-1-yl }-enanthic acid;
7-((R)-5-{ (E)-3-hydroxyl-3-[3-(4-methoxyl group-benzyl)-phenyl]-propenyl }-3,3-dimethyl-2-oxo-tetramethyleneimine-1-yl)-enanthic acid;
7-{ (R)-2-[(E)-3-hydroxyl-3-(between 3--tolyloxy-phenyl)-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid;
7-((R)-2-{ (E)-3-[3-(3-fluoro-phenoxy group)-phenyl]-3-hydroxyl-propenyl }-5-oxo-tetramethyleneimine-1-yl)-enanthic acid;
7-((R)-2-{ (E)-3-[3-(3-phenoxy group)-phenyl]-3-hydroxyl-propenyl }-5-oxo-tetramethyleneimine-1-yl)-enanthic acid;
7-((R)-2-{ (E)-3-hydroxyl-3-[3-(3-methoxyl group-phenoxy group)-phenyl]-propenyl }-5-oxo-tetramethyleneimine-1-yl)-enanthic acid;
7-((R)-2-{ (E)-3-hydroxyl-3-[3-(4-trifluoromethyl-phenoxy group)-phenyl]-propenyl }-5-oxo-tetramethyleneimine-1-yl)-enanthic acid;
7-{ (R)-2-[(E)-3-hydroxyl-3-(3-neighbour-tolyloxy-phenyl)-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid;
7-[(R)-2-((E)-3-xenyl-2-base-3-hydroxyl-propenyl)-5-oxo-tetramethyleneimine-1-yl]-enanthic acid;
7-((R)-2-{ (E)-3-hydroxyl-3-[3-(3-trifluoromethyl-phenoxy group)-phenyl]-propenyl }-5-oxo-tetramethyleneimine-1-yl)-enanthic acid;
7-((R)-2-{ (E)-3-hydroxyl-3-[3-(2-methoxyl group-phenoxy group)-phenyl]-propenyl }-5-oxo-tetramethyleneimine-1-yl)-enanthic acid;
7-((R)-2-{ (E)-3-hydroxyl-3-[3-(2-morpholine-4-base-oxyethyl group)-phenyl]-propenyl }-5-oxo-tetramethyleneimine-1-yl)-enanthic acid;
7-{ (R)-2-[(E)-3-(6,2 '-dimethyl-xenyl-3-yl)-3-hydroxyl-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid;
7-{ (S)-2-[(R)-3-hydroxyl-3-(3-trifluoromethyl-phenyl)-propyl group]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid;
7-{ (R)-2-[(E)-3-hydroxyl-3-(3-right-tolyloxy-phenyl)-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid;
7-((R)-2-{ (E)-3-[3-(4-fluoro-phenoxy group)-phenyl]-3-hydroxyl-propenyl }-5-oxo-tetramethyleneimine-1-yl)-enanthic acid;
7-((R)-2-{ (E)-3-[3-(4-chloro-phenoxy group)-phenyl]-3-hydroxyl-propenyl }-5-oxo-tetramethyleneimine-1-yl)-enanthic acid;
7-{ (R)-2-[(E)-3-(4 '-chloro-2 '-methyl-xenyl-3-yl)-3-hydroxyl-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid;
7-{ (R)-2-[3-(4 '-chloro-2 '-methyl-xenyl-3-yl)-3-hydroxyl-propyl group]-5-oxo-tetramethyleneimine-1-yl}-enanthic acid;
7-((R)-2-{ (E)-3-hydroxyl-3-[3-(methyl-o-tolyl-amino)-phenyl]-propenyl }-5-oxo-tetramethyleneimine-1-yl)-enanthic acid;
7-((R)-2-{ (E)-3-hydroxyl-3-[3-(methyl-phenyl-amino)-phenyl]-propenyl }-5-oxo-tetramethyleneimine-1-yl)-enanthic acid;
7-{ (R)-2-[(E)-3-hydroxyl-3-(3-styroyl oxygen base-phenyl)-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid;
7-[(R)-2-((E)-3-hydroxyl-3-{3-[2-(2-oxo-tetramethyleneimine-1-yl)-oxyethyl group]-phenyl }-propenyl)-5-oxo-tetramethyleneimine-1-yl]-enanthic acid;
7-{ (R)-2-[(E)-3-hydroxyl-3-(4 '-hydroxyl-2 '-methyl-xenyl-3-yl)-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid;
7-{ (R)-2-[(E)-3-hydroxyl-3-(3-indoles-1-base-phenyl)-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid;
7-{ (R)-2-[(E)-3-hydroxyl-3-((Z)-3-propenyl-phenyl)-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid;
7-{ (R)-2-[(E)-3-hydroxyl-3-(3-propyl group-phenyl)-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid;
7-{ (R)-2-[(E)-3-(3-formyl-dimethylamino-phenyl)-3-hydroxyl-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid;
7-((R)-2-{ (E)-3-[3-(2-tert.-butoxy-oxyethyl group)-phenyl]-3-hydroxyl-propenyl }-5-oxo-tetramethyleneimine-1-yl)-enanthic acid;
7-((R)-2-{ (E)-3-[3-(3-chloro-phenoxy group)-phenyl]-3-hydroxyl-propenyl }-5-oxo-tetramethyleneimine-1-yl)-enanthic acid;
7-{ (S)-2-[(R)-3-hydroxyl-3-(4 '-hydroxyl-2 '-methyl-xenyl-3-yl)-propyl group]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid;
7-((R)-2-{ (E)-3-hydroxyl-3-[3-(4-methoxyl group-benzyl)-phenyl]-propenyl }-5-oxo-tetramethyleneimine-1-yl)-enanthic acid;
7-((R)-2-{ (E)-3-hydroxyl-3-[3-(tetrahydropyrans-4-ylidenylmethyl)-phenyl]-propenyl }-5-oxo-tetramethyleneimine-1-yl)-enanthic acid;
7-((R)-2-{ (E)-3-hydroxyl-3-[3-(tetrahydropyran-4-base methyl)-phenyl]-propenyl }-5-oxo-tetramethyleneimine-1-yl)-enanthic acid;
7-[(R)-2-((E)-3-hydroxyl-3-{3-[1-(4-methoxyl group-phenyl)-formyl radical]-phenyl }-propenyl)-5-oxo-tetramethyleneimine-1-yl]-enanthic acid;
7-{ (R)-5-[(E)-3-(4 '-chloro-2 '-methyl-xenyl-3-yl)-3-hydroxyl-propenyl]-3,3-dimethyl-2-oxo-tetramethyleneimine-1-yl }-enanthic acid;
4-{3-[(R)-2-((S)-(E)-3-hydroxyl-Xin-1-thiazolinyl)-5-oxo-tetramethyleneimine-1-yl]-propyl group }-phenylformic acid;
3-{3-[(R)-2-((S)-(E)-3-hydroxyl-Xin-1-thiazolinyl)-5-oxo-tetramethyleneimine-1-yl]-propyl group }-phenylformic acid;
4-{2-[(R)-2-(S)-(E)-3-hydroxyl-Xin-1-thiazolinyl)-5-oxo-tetramethyleneimine-1-yl]-ethyl }-ethyl benzoate;
2-{3-[(R)-2-(S)-(E)-3-hydroxyl-Xin-1-thiazolinyl)-5-oxo-tetramethyleneimine-1-yl]-propyl group }-phenylformic acid;
4-{2-[(R)-2-((S)-(E)-3-hydroxyl-Xin-1-thiazolinyl)-5-oxo-tetramethyleneimine-1-yl]-ethyl }-phenylformic acid;
1-{2-[(R)-2-((E)-3-hydroxyl-Xin-1-thiazolinyl)-5-oxo-tetramethyleneimine-1-yl]-ethyl }-1H-pyrazoles-4-formic acid;
5-[(R)-2-((E)-3-hydroxyl-Xin-1-thiazolinyl)-5-oxo-tetramethyleneimine-1-yl]-ethyl)-thiophene-2-carboxylic acid;
4-(2-{ (S)-2-[(R)-3-(4 '-chloro-2 '-methyl-xenyl-3-yl)-3-hydroxyl-propyl group]-5-oxo-tetramethyleneimine-1-yl }-ethyl)-phenylformic acid;
The particularly preferred compound of general formula I is selected from the group that following compounds is formed:
7-{ (R)-2-[(E)-3-(4 '-chloro-2 '-methyl-xenyl-3-yl)-3-hydroxyl-propyl group]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid;
7-{ (R)-5-[(E)-3-hydroxyl-3-(5-trifluoromethyl-furans-2-yl)-propenyl]-3,3-dimethyl-2-oxo-tetramethyleneimine-1-yl }-enanthic acid;
7-{ (R)-5-[(E)-3-hydroxyl-4-(3-methoxymethyl-phenyl)-but-1-ene base]-3,3-dimethyl-2-oxo-tetramethyleneimine-1-yl }-enanthic acid;
7-((R)-2-{ (E)-3-[3-(4-chloro-phenoxy group)-phenyl]-3-hydroxyl-propenyl }-5-oxo-tetramethyleneimine-1-yl)-enanthic acid;
4-{2-[(R)-2-((E)-3-hydroxyl-Xin-1-thiazolinyl)-5-oxo-tetramethyleneimine-1-yl]-ethyl }-phenylformic acid;
4-(2-{ (S)-2-[(R)-3-(4 '-chloro-2 '-methyl-xenyl-3-yl)-3-hydroxyl-propyl group]-5-oxo-tetramethyleneimine-1-yl }-ethyl)-phenylformic acid; With
5-[(R)-2-((E)-3-hydroxyl-Xin-1-thiazolinyl)-5-oxo-tetramethyleneimine-1-yl]-ethyl)-thiophene-2-carboxylic acid.
Other preferably is used as the compound of the general formula I of therapeutic active substance.
Another preferred aspect of the present invention is the compound of general formula I that is used to produce the medicine of the prevention disease relevant with bone disorder (bonedisorder) with treatment.
Preferably the compound of general formula I is used for the treatment of application in the medicine of the disease relevant with bone disorder with prevention in production in addition.
Another embodiment preferred of the present invention is a pharmaceutical composition, comprises the compound with the general formula I of the treatment significant quantity of at least a suitable carriers, thinner or mixed with excipients.
Another preferred aspect of the present invention is can be by giving selectivity EP 4The methods of treatment of the mammalian diseases of prostaglandin agonists treatment, this method comprise the step of compound of described Mammals being treated the general formula I of significant quantity.Particularly preferably be above-mentioned methods of treatment, wherein said disease is relevant with bone disorder.
The preparation method of the compound of general formula I preferably in addition, this method comprises the following steps:
Make general formula aCompound and general formula mPhosphonate reaction,
Its formula of aThe structural formula of compound as follows:
Wherein m, R 3, R 4, R 5And R 6As hereinbefore defined and wherein R ' is methyl or ethyl;
Its formula of mStructural formula as follows:
R wherein 1As hereinbefore defined;
Reduce subsequently and optional being hydrolyzed and obtain the compound of general formula I:
Figure A0281409100312
R wherein 2Be hydrogen and m, R 1, R 3, R 4, R 5, R 6With Z as hereinbefore defined.
The preparation method of compound of Formula I preferably in addition, this method comprises the following steps:
Make the compound and the general formula of following general formula mPhosphonate reaction:
Wherein m, R 3, R 4, R 5And R 6As hereinbefore defined and wherein R ' is methyl or ethyl;
Its formula of mStructural formula as follows:
Figure A0281409100321
R wherein 1As hereinbefore defined;
Subsequently with general formula R 2The organometallic compound reaction of M, wherein M is metal or magnesium halide and R 2As hereinbefore defined; And optional being hydrolyzed and obtain the compound of general formula I:
Figure A0281409100322
A wherein, m, R 1, R 3, R 4, R 5, R 6With Z as hereinbefore defined.
Another embodiment preferred of the present invention is the preparation method of compound of Formula I, and this method comprises the following steps:
A) make the compound of following formula:
Figure A0281409100323
R wherein PBe protecting group, R 3, R 4, R 5And R 6As hereinbefore defined, the amine with following formula reacts:
Figure A0281409100331
Wherein m and Z are as hereinbefore defined;
Make the protected hydroxyl deprotection subsequently and obtain the compound of following formula:
Figure A0281409100332
B) make the hydroxyl activation on the above-mentioned compound that obtains and the gained compound is contacted with alkali, make the protected hydroxyl deprotection subsequently and obtain the compound of following formula:
Figure A0281409100333
C) compound oxidation that obtains among the step b is become the aldehyde of following formula:
Figure A0281409100334
D) make above-mentioned aldehyde and general formula mPhosphonate reaction:
Figure A0281409100341
R wherein 1As hereinbefore defined;
Thereby obtain the compound of following general formula:
Figure A0281409100342
E) make compound and the general formula R that obtains in the steps d 2The organometallic compound reaction of M, wherein M is metal or magnesium halide and R 2As hereinbefore defined; With
F) the optional compound that described ester is hydrolyzed into general formula I.
General synthetic reaction process
Can prepare compound of the present invention by the method described in the reaction process as follows.It will be understood by those skilled in the art that this reaction process necessarily revised to belong to scope of the present invention, for example, some step of being revised comprises using protecting group with the inconsistent functional group of special reaction condition.
Being used to prepare the raw material of these compounds and reagent is purchased from such as Aldrich ChemicalCo., (Milwaukee, WI), Bachem (Torrance, CA) or Sigma (St.Louis, MO) such supplier or by method preparation known in those skilled in the art.These reaction process only are used to explain some method that can synthesize The compounds of this invention and can carry out various modifications and those skilled in the art can obtain prompting with reference to this specification sheets disclosure to these reaction process.
Unless opposite specific descriptions are arranged, reaction as herein described all 125 ℃ in normal atmosphere peace treaty-78 ℃-Yue 150 ℃, more preferably from about 0 ℃-Yue and most preferably room temperature (envrionment temperature), for example carry out under about 20 ℃.
Following reaction process A has described the general preparation method of compound of Formula I and analogue thereof.In general, by making general formula mPhosphonic acid ester and general formula aAldehyde reaction obtain general formula bCompound and prepare these compounds.
Reaction process A
Figure A0281409100361
General formula aAldehydes (wherein R ' is a methyl, and B does not exist, and m is 5, R 3, R 4, R 5And R 6Be hydrogen, described group is corresponding in the general formula I those) on described group be as known in the art.For example, (R)-5-(hydroxymethyl)-2-Pyrrolidone is that commodity and its preparation and conversion are described in " chemicals bulletins " such as S.Saijo (Chem.Pharm.Bull.) 1980,28, among the 1449-1458; Can be according to Y.Nakagawa etc. at " tetrahedron " (Tetrahedron) 1998,54, (R)-3 of preparation described in the 10295-10307,3-dimethyl-5-(hydroxymethyl)-2-Pyrrolidone, wherein R 3And R 4Be methyl and R 5And R 6Be hydrogen; And can be according to R.L.Mackman etc. at J.Chem.Soc., Perkin Trans., 1997, prepare 4 described in the 2111-2122,4-dimethyl-5-(hydroxymethyl)-2-Pyrrolidone, wherein R 3And R 4Be hydrogen and R 5And R 6It is methyl.
In the such solvent that has that the alkali such such as sodium hydride, potassium tert.-butoxide, hexamethyl two silicon nitrides or lithium chloride and tertiary amine exists, make aldehyde such as acetonitrile, tetrahydrofuran (THF), methyl ethyl ether or t-butyl methyl ether aWith general formula mThe beta-keto phosphonate reaction and obtain general formula bCompound, wherein-CH=CH-is equivalent to the A on the general formula I.
Such as methylene dichloride, toluene, ethanol or tetrahydrofuran (THF) or be dissolved in the such solvent of the combination of sodium borohydride-Cerium II Chloride (III) of the protonic solvent such and use such as the simple reductone of the such hydride of zinc borohydride such as methyl alcohol bAnd obtain general formula eThe non-enantiomer mixture of alcohols.
In order to obtain the compound of general formula I, wherein A is-CH 2-CH 2-and R 1Be aryl or heteroaryl, beginning is reducing compound in the hydrogen environment that has the catalyzer such such as platinum oxide or palladium/carbon to exist bOn two keys.Operable other hydride reagent for example has: R.Noyori etc. are in " Journal of the American Chemical Society " (J.Am.Chem.Soc.) 1984,106, the combination of the lithium aluminum hydride-ethanol of the stoichiometry described in the 6717-6725-(-)-dinaphthol; E.J.Corey etc. are in " Journal of the American Chemical Society " (J.Am.Chem.Soc.) 1987,109, the combination of (S)-2-methyl-" the CBS "-oxazaborolidine of the catalytic amount described in the 7925-7926 and the borine-methyl-sulfide of stoichiometry; Or M.M.Midland etc. is at " Journal of the American Chemical Society " (J.Am.Chem.Soc.) 1980,102, (S)-3-pinane base of the stoichiometry described in the 867-869-9-boron two ring [3.3.1] nonanes, thus obtain compound c
Alternatively, can be by contact sodium borohydride in the protonic solvent as ethanol or 2-methyl cellosolve by general formula bCompound directly obtain general formula I (if radicals R 1Aryl or heteroaryl) saturated alcohol (the general structure that promptly relates to reaction process A eCompound).
By making general formula bWith cCompound with contain the as above defined R of mutual-through type I 2Organomagnesium halide reaction, more preferably with general formula R 2The Grignard reagent prepared in reaction general formula of MgBr dCompound
Use the well-known step of those skilled in the art, such as in proton that contains water or ether bonding solvent, carrying out such alkali addition of for example lithium hydroxide, sodium hydroxide or potassium hydroxide or for example such sour addition of sulfuric acid or hydrochloric acid or by using C.Luth etc. at " Journal of the American Chemical Society " (J.Am.Chem.Soc.) 1978,100, the VII type lipase of the phosphate buffered aqueous solution that is dissolved in 0.05M pH6.8 described in the 6211-6217 is with described ester class cWith eBe hydrolyzed into corresponding acid dWith f
Can prepare general formula according to the method described in the following reaction process B mPhosphonic acid ester.
Reaction process B
Benzoic acid derivative, for example general formula gWith jCompound (wherein L is a leaving group as defined herein) be easy to be purchased or be easy to synthetic and change into general formula respectively by those skilled in the art hWith kCompound.General formula hThe preparation condition of compound be described among " tetrahedron communication " (Tetrahedron Lett.) 1998,39,2937 of D.A.Evans etc.General formula kThe preparation method of compound " Journal of the American Chemical Society " (J.Am.Chem.Soc.) 1987 that be described in A.M.Echavarren and J.K.Stille, 109, " chemistry summary " of 5478-5486, N.Miyaura and A.Suzuki (Chem.Rev.) 1995,95,2457-2483 and A.F.Littke etc. at " Journal of the American Chemical Society " (J.Am.Chem.Soc.) 2000,122, among the 4020-4028.By contacting the dialkyl methyl phosphonic acid ester with compound hWith kChange into compound m, begin described dialkyl methyl phosphonic acid ester used such as general butyllithium or the such alkali of LDA in the inertia ether solvents such such as tetrahydrofuran (THF) or t-butyl methyl ether and handle.
Reaction process C has described the general synthetic method of compound of Formula I, and wherein B is aryl or heteroaryl.
Reaction process C
Figure A0281409100391
General formula qCompound be known.General formula for example qThe compound furanone be commodity, R wherein 3, R 4, R 5And R 6Be hydrogen.General formula rCompound also be known.For example phenylethylamine is commodity and can changes into corresponding ester by those skilled in the art, wherein rOn Z be that p-C (O) OH and m are 1.
In the step 1 of reaction process C, at first use the protecting group described in this specification sheets, for example benzyl protection compound qOn hydroxyl.Make protected lactone qWith pure amine rOr condensation and obtain compound in the polar solvent such such as acetonitrile, N-N-methyl-2-2-pyrrolidone N-, Virahol or tetrahydrofuran (THF) sBy handling the activation structure with benzene sulfonyl chloride or methylsulfonyl chloride sOn primary hydroxyl (one-tenth leaving group) prepare general formula tCompound.The alkali such by contact such as potassium tert.-butoxide, sodium methylate etc. forms lactan.By with hydrogen for example with such as in Ruan-the such catalyzer of Ni, platinum oxide or palladium/carbon makes the primary hydroxyl deprotection obtain general structure tCompound.By method as known in the art with compound tChange into aldehyde AaBy among the above-mentioned reaction process A to transforming aldehyde aDescribed method is with aldehyde AaChange into compound of the present invention.
Use
Compound of the present invention is selectivity EP 4Prostaglandin agonists and can being used for the treatment of and PGE P 4Several disease situations of receptor-mediated disease-related, especially for the disease situation relevant with bone disorder, it is characterized in that the degeneration of low bone mass and osseous tissue, the result causes bone fragility to increase and is easy to fracture, and especially those need the situation that bone mass, bone volume or bone strength significantly increase.The disease relevant with low bone mass refers to the disease that the bone mass level is lower than specific normal value of age.Also comprise children's idiopathic osteoporosis and primary osteoporosis.The treatment osteoporosis comprises prevention or alleviates such as rachiocamposis, height loss, prosthese operation, such long-term complications and the prevention prostate gland dysfunction of union of fracture.Also comprise treatment and periodontitis or the inwardly relevant bone loss of growth of prosthese.Those skilled in the art think that in fact the term bone mass refers to the bone mass on the per unit area that is called bone mineral matter density sometimes.Have been found that 8-azepine of the present invention-11-deoxy prostaglandin analogue is useful on the treatment osteopathia.
Other application of these compounds comprises and prevents and/or treats transformation reactions, alveolar abscess, presenile dementia, amyotrophic lateral sclerosis (ALS), sacroiliitis, asthma, atopy, bronchitis, burn, cancer, cardiovascular disorder, regional ileitis, the chronic obstructive respiratory disease, congestive heart failure, gingivitis, glomerulonephritis, hepatitis, liver injury, acute hepatitis, hypertension, hypercytokinemia, immunological disease, inflammatory bowel, mucocutaneous lymphnode syndrome, liver failure, hepatopathy, lung failure, Macrophage Activation Syndrome, multiple organ failure, multiple sclerosis, myocardial ischemia, ephritis, neurodegeneration, neuronal death, the organ-graft refection, periodontitis, platelet aggregation, injury of lung, pulmonary fibrosis, pulmonary emphysema, renal failure, renal insufficiency, ephrosis, respiratory disease, septicemia, Sepsis, shock, sleep and platelet aggregation obstacle, Still disease (Still disease), the systematicness glaucoma, thrombosis, ulcerative colitis and uremia or as skeletonization promotor.
Test
Compound of Formula I of the present invention with belong to PGE 2The EP of receptor subtype 4Receptors bind also works to it.Can be as embodiment 10In the use more specifically the described effect of using the cell activity test determination The compounds of this invention of expressing the prostanoid receptor subtype.Can be as embodiment 11Described in measure these compounds and combine activity with competitiveness between the target thing.Can be as embodiment 12In more specifically describe, at " metabolic osteopathy " (Metab.Bone Dis.) 5, the step described in the 177-181 (1984) estimates the effect of The compounds of this invention to bone density according to Gunness-Hey and Hock.
Administration and pharmaceutical composition
In general, the active agent delivery mode that is used for similar application by any acceptable application is treated the The compounds of this invention of significant quantity.The compounds of this invention, be that the actual amount of active ingredient depends on many factors, such as effect, route of administration and administering mode and other factor of the severity of the disease of being treated, curee's age and relative health condition, used compound.
Compound of Formula I is sent out the treatment significant quantity can be in the scope of about 0.00005-10mg/ kilogram recipient body weight/day; Preferred about 0.0001-1mg/kg/ days.Therefore, with regard to regard to people's administration of 70kg, preferably about 0.01mg-1.0mg/ days of dosage range.
In general, by following by way of in any one with compound of the present invention as the pharmaceutical composition administration: oral, whole body (for example in skin, nose or use suppository) or non-enteron aisle (for example intramuscular, intravenously or subcutaneous) administration.Preferred administering mode is to use and can carries out oral administration according to dosage every day of infringement degree adjustment.Composition can adopt tablet, pill, capsule, semisolid, pulvis, sustained release preparation, solution, suspensoid, elixir, aerosol or the form of other suitable composition arbitrarily.
Various factors is depended in the selection of preparation, such as the administering mode (for example preparation of oral administration preferred tablet, pill or capsule form) of medicine and the bioavailability of drug substance.Recently especially based on can by increase surface-area, promptly reduce theory that granular size improves bioavailability to the medicament research and development that shows extremely low bioavailability pharmaceutical preparation.For example, U.S. Pat 4,107 has been described in 288 and has been had size at 10-1, and the particulate pharmaceutical preparation of 000nm scope wherein is supported in described active substance on the cross-linked macromolecular matrix.U.S. Pat 5,145, described the production method of pharmaceutical preparation in 684, wherein under the situation that has coating materials to exist, described drug substance has been ground into nanoparticle (mean particle size is 400nm) and then they is dispensed into the pharmaceutical preparation that liquid medium obtains showing significantly high bioavailability.
Described composition generally is made up of the compound and at least a pharmaceutically acceptable vehicle of general formula I.Acceptable vehicle is that avirulent, auxiliary administration and treatment beneficial effect that can mutual-through type I compound produce detrimentally affect.This class vehicle can be solid, liquid, semisolid or be the general available gas vehicle of those skilled in the art with regard to aerosol composition arbitrarily.
The solid pharmaceutical vehicle comprises starch, Mierocrystalline cellulose, talcum, glucose, lactose, sucrose, gelatin, Fructus Hordei Germinatus, rice, flour, chalk, silica gel, Magnesium Stearate, sodium stearate, Zerol, sodium-chlor, skim-milk etc.Liquid and semisolid excipient can be selected from glycerine, propylene glycol, water, ethanol and various oil, comprise those oil that derive from oil, animal, plant or synthetic source, for example peanut oil, soybean oil, mineral oil, sesame wet goods.The preferred liquid vehicle that is used in particular for injection liquid comprises water, salt solution, D/W and glycols.
Coercible gas can be used for the The compounds of this invention of dispersed gas solation.Be suitable for this purpose inertia other be nitrogen, carbonic acid gas etc.
Drug excipient that other is suitable and preparation thereof are described among " RemingtonShi pharmaceutical science " (Remington ' s Pharmaceutical Sciences) (MackPublishing Company, the 18th edition, 1990) that E.W.Martin edits.
Compound concentrations can change in the gamut that those skilled in the art use in the preparation.In general, said preparation contains by weight percentage the compound that (wt%) accounts for the general formula I of total formulation weight 0.01-99.99wt%, wherein uses one or more suitable drug excipient balances.The contained concentration of preferred described compound is about 1-80wt%.The representational pharmaceutical preparation that contains compound of Formula I is described among the embodiment 9.
Embodiment
Following series preparation and embodiment are used to make those skilled in the art more to be expressly understood and to implement the present invention.They should not regarded as and limit scope of the present invention and only be as illustrating and be representative of the present invention to of the present invention.
Embodiment 1
7-{ (R)-2-[(E)-3-(3-benzyl-phenyl)-3-hydroxyl-propenyl]-5-oxo-tetramethyleneimine-1-yl } enanthic acid (1)
Figure A0281409100431
Step 1:
3-benzyl-methyl benzoate
(5.12g is 22.6mmol) at methyl alcohol (45mL) and dense H with 3-benzoyl-phenylformic acid under 60 ℃ 2SO 4Stirred 18 hours (2.0mL).With this reaction mixture with ethyl acetate dilution and use NaHCO 3Solution washing.Use MgSO 4Dry organic layer, (5.4g 22.6mmol), is yellow oil to filter and be concentrated into the 3-benzoyl-methyl benzoate that obtains quantitative yield.
At room temperature (653mg is 2.72mmol) trifluoroacetic acid (3mL) and triethyl silicane (1.3mL, 8.15mmol) the middle stirring 22 hours with 3-benzoyl-methyl benzoate.With this reaction mixture with ethyl acetate dilution and use NaHCO 3Solution washing.Use MgSO 4Dry organic layer, filtration also concentrate.1 ethyl acetate) and (589mg 2.6mmol), is oily matter to obtain 3-benzyl-methyl benzoate make gained oily matter carry out column chromatography (25 hexanes:.
Step 2:
[2-(3-benzoyl-phenyl)-2-oxo-ethyl]-dimethyl phosphonate
To-78 ℃ of following dimethyl methyl phosphonate acid esters (hexane (2.44mL, 3.9mmol) solution that add 1.6M BuLi among the 0.423mL, THF solution (10mL) 3.9mmol).Add 3-benzyl-methyl benzoate (589mg, THF solution (5mL) 2.6mmol) after 1 hour.After 15 minutes with this reaction mixture temperature to room temperature and restir 3 hours.Use NaHCO 3The aqueous solution makes this reaction mixture quenching and uses ethyl acetate extraction.Use MgSO 4Dry organic layer, filtration also concentrate.1 hexane) and (677mg 2.12mmol), is oily matter to obtain [2-(3-benzyl-phenyl)-2-oxo-ethyl]-dimethyl phosphonate make resistates carry out column chromatography (18 ethyl acetate:.
Step 3:
7-{ (R)-2-[(E)-3-(3-benzyl-phenyl)-3-oxo-propenyl]-5-oxo-tetramethyleneimine-1-yl }-oil of cognac
Figure A0281409100451
Sodium hydride mineral oil solution to 60% (20mg, 0.51mmol) middle [2-(3-benzyl-phenyl)-2-oxo-ethyl]-dimethyl phosphonate (164mg, the DME solution (5mL) 0.51mmol) of adding.1.5 add 7-((R)-2-formyl radical-5-oxo-tetramethyleneimine-1-yl)-oil of cognac (126mg, DME solution (5mL) 0.47mmol) after hour.This reaction mixture was at room temperature stirred 45 minutes, then with ethyl acetate dilution and use NaHCO 3Solution washing.Use MgSO 4Dry organic layer, filtration also concentrate.Make resistates carry out column chromatography (2.5 ethyl acetate: 1 hexane) obtain 7-{ (R)-2-[(E)-3-(3-benzyl-phenyl)-3-hydroxyl-propenyl]-5-oxo-tetramethyleneimine-1-yl-(112mg 0.24mmol), is oily matter to oil of cognac.
Step 4:
7-{ (R)-2-[(E)-3-(3-benzyl-phenyl)-3-hydroxyl-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid (1)
Figure A0281409100452
To 7-{ (R)-2-[(E)-3-(3-benzyl-phenyl)-3-hydroxyl-propenyl]-5-oxo-tetramethyleneimine-1-yl }-oil of cognac (adding NaBH among the 112mg, ethanolic soln 0.24mmol) (5mL) 4(37mg, 0.97mmol).This reaction mixture was at room temperature stirred 2 hours and concentrated then near doing.Resistates is dissolved in ethyl acetate and washs with salt brine solution.Use MgSO 4Dry organic layer, filtration also concentrate and obtain 7-{ (R)-2-[(E)-3-(3-benzyl-phenyl)-3-hydroxyl-propenyl of quantitative yield]-5-oxo-tetramethyleneimine-1-yl }-(122mg 0.24mmol), is oily matter to oil of cognac.Subsequently it is dissolved in alcohol (5mL) and adds lithium hydroxide monohydrate (44mg, aqueous solution 1.05mmol) (2.5mL).After at room temperature stirring 4 hours, this reaction mixture is concentrated near doing.With the gained strong solution with salt solution dilution and use washed with dichloromethane.Be extracted into methylene dichloride with 1N HCl acidifying water layer and with product.Use MgSO 4Dry organic layer, filtration also concentrate and obtain 7-{ (R)-2-[(E)-3-(3-benzyl-phenyl)-3-hydroxyl-propenyl]-5-oxo-tetramethyleneimine-1-yl }-(77mg 0.18mmol), is oily matter to enanthic acid (1).MS：436[(M+H) +]。
According to embodiment 1 described method and use by [2-(3-benzyl-phenyl)-2-oxo-ethyl]-dimethyl phosphonate in the suitable phosphonic acid ester step of replacing 3 of the methyl esters class described in corresponding known acid or step 1 and/or 2 preparation and prepare the compound of following general formula I:
(2-naphthalene-2-base-2-oxo-ethyl)-dimethyl phosphonate obtains 7-[(R)-2-((E)-3-hydroxyl-3-naphthalene-2-base-propenyl)-5-oxo-tetramethyleneimine-1-yl]-enanthic acid (2) MS:396[(M+H) +];
[2-oxo-2-(3-phenoxy group-phenyl)-ethyl]-dimethyl phosphonate obtains 7-{ (R)-2-[(E)-3-hydroxyl-3-(3-phenoxy group-phenyl)-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid (3) MS:438[(M+H) +];
(2-oxo-2-phenyl-ethyl)-dimethyl phosphonate obtains 7-[(R)-2-((E)-3-hydroxyl-3-phenyl-propenyl)-5-oxo-tetramethyleneimine-1-yl]-enanthic acid (4) MS:346[(M+H)+];
[2-(3-methoxyl group-phenyl)-2-oxo-ethyl]-dimethyl phosphonate obtains 7-{ (R)-2-[(E)-3-hydroxyl-3-(3-methoxyl group-phenyl)-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid (5) MS:376[(M+H) +];
[2-oxo-2-(4-phenoxy group-phenyl)-ethyl]-dimethyl phosphonate obtains 7-{ (R)-2-[(E)-3-hydroxyl-3-(4-phenoxy group-phenyl)-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid (6) MS:438[(M+H) +];
[2-(3-oxyethyl group-phenyl)-2-oxo-ethyl]-dimethyl phosphonate obtains 7-{ (R)-2-[(E)-3-(3-oxyethyl group-phenyl)-3-hydroxyl-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid (7) MS:390[(M+H) +];
[2-(3-ethyl-phenyl)-2-oxo-ethyl]-dimethyl phosphonate obtains 7-{ (R)-2-[(E)-3-(3-ethyl-phenyl)-3-hydroxyl-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid (8) MS:374[(M+H) +];
[2-(3-morpholine-4-alkylsulfonyl)-phenyl-2-oxo-ethyl] dimethyl phosphonate obtain 7-((R)-2-{ (E)-3-hydroxyl-3-[3-(morpholine-4-alkylsulfonyl)-phenyl]-propenyl-5-oxo-tetramethyleneimine-1-yl)-enanthic acid (9) MS:495[(M+H) +];
[2-(3-bromo-phenyl)-2-oxo-ethyl] dimethyl phosphonate obtains 7-{ (R)-2-[(E)-3-(3-bromo-phenyl)-3-hydroxyl-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid (10) MS:425[(M+H) +];
[2-(3-hydroxyl-phenyl)-2-oxo-ethyl] dimethyl phosphonate obtain 7-(R)-2-[(E)-3-hydroxyl-3-(3-hydroxyl-phenyl)-propenyl]-5-oxo-tetramethyleneimine-1-yl-enanthic acid (11) MS:362[(M+H) +];
[2-(3-pyrroles-1-ylmethyl-phenyl)-2-oxo-ethyl] dimethyl phosphonate obtains 7-{ (R)-2-[(E)-3-hydroxyl-3-(3-pyrroles-1-ylmethyl-phenyl)-propenyl]-5-oxo-tetramethyleneimine-1-yl } enanthic acid (12) MS:425[(M+H) +];
[2-(3-pyrazol-1-yl methyl-phenyl)-2-oxo-ethyl] dimethyl phosphonate obtains 7-{ (R)-2-[(E)-3-hydroxyl-3-(3-pyrazol-1-yl methyl-phenyl)-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid (13) MS:426[(M+H) +];
[2-(3-methoxymethyl-phenyl)-2-oxo-ethyl] dimethyl phosphonate 7-{ (R)-2-[(E)-3-hydroxyl-3-(3-methoxymethyl-phenyl)-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid (14) MS:390[(M+H) +];
[2-(3-cyclopentyloxy-phenyl)-2-oxo-ethyl] dimethyl phosphonate obtains 7-{ (R)-2-[(E)-3-(3-cyclopentyloxy-phenyl)-3-hydroxyl-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid (15), MS:m/z430 (M + 1);
[2-(3-trifluoromethyl-phenyl)-2-oxo-ethyl] dimethyl phosphonate obtains 7-{ (R)-2-[(E)-3-hydroxyl-3-(3-trifluoromethyl-phenyl)-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid (16), MS:m/z414 (M + 1);
[2-(3-trifluoromethyl-phenyl)-2-oxo-ethyl] dimethyl phosphonate obtains 7-{ (S)-2-[(R)-3-hydroxyl-3-(3-trifluoromethyl-phenyl)-propyl group]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid [(17), (1atm hydrogen behind the product of step of hydrogenation 3, catalyzer is the 10% palladium/carbon among the EtOAc, 1.5 after hour contact by E.J.Corey etc. at " Journal of the American Chemical Society " (J.Am.Chem.Soc.) 1987,109, reaction conditions described in the 7925-7926, use is from (S)-2 methyl-CBS catalyzer of Aldrich, the toluene solution of 1M) replace sodium borohydride to handle], MS:m/z 416 (M + 1);
[2-(3-phenoxymethyl-phenyl)-2-oxo-ethyl] dimethyl phosphonate obtains 7-{ (R)-2[(E)-3-hydroxyl-3-(3-phenoxymethyl-phenyl)-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid (18), MS:m/z 452 (M + 1);
7-{ (R)-2-[(E)-3-hydroxyl-3-(3-phenoxymethyl-phenyl)-propenyl]-5-oxo-tetramethyleneimine-1-yl }-Methylheptanoate (19), MS:m/z 466 (M + 1);
2-[3-(1-methyl isophthalic acid H-pyrroles-2-yl)-phenyl)-2-oxo-ethyl] dimethyl phosphonate obtain 7-((R)-2-{ (E)-3-hydroxyl-3-[3-(1-methyl isophthalic acid H-pyrroles-2-yl)-phenyl]-propenyl-5-oxo-tetramethyleneimine-1-yl)-enanthic acid (20), MS:m/z 425 (M + 1);
7-((R)-2-{ (E)-3-hydroxyl-3-[3-(1-methyl isophthalic acid H-pyrroles-2-yl)-phenyl]-propenyl }-5-oxo-tetramethyleneimine-1-yl)-Methylheptanoate (21), MS:m/z 440 (M + 1);
[2-(3-butoxy-phenyl)-2-oxo-ethyl] dimethyl phosphonate obtains 7-{ (R)-2-[(E)-3-(3-butoxy-phenyl)-3-hydroxyl-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid (22), MS:m/z 418 (M + 1);
[2-(3-benzyloxy-phenyl)-2-oxo-ethyl] dimethyl phosphonate obtains 7-{ (R)-2-[(E) 3-(3-benzyloxy-phenyl)-3-hydroxyl-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid (23), MS:m/z 452 (M + 1);
{ 2-[3-(2-chlorine benzyloxy)-phenyl]-2-oxo-ethyl } dimethyl phosphonate obtains 7-{ (R)-2-[(E)-3-(2-chlorine benzyloxy)-phenyl)-3-hydroxyl-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid (24), MS:m/z 487 (M + 1);
The 2-[2-xenyl)-2-oxo-ethyl] dimethyl phosphonate obtains 7-[(R)-2-((E)-3-xenyl-2-base-3-hydroxyl-propenyl)-5-oxo-tetramethyleneimine-1-yl]-enanthic acid (25), MS:m/z 422 (M + 1);
[2-(3-(2-morpholino-4-base-oxyethyl group)-phenyl)-2-oxo-ethyl] dimethyl phosphonate obtain 7-((R)-2-{ (E)-3-hydroxyl-3-[3-(2-morpholine-4-base-oxyethyl group)-phenyl]-propenyl-5-oxo-tetramethyleneimine-1-yl)-enanthic acid (26), MS:m/z 475 (M + 1);
[3-(methyl-phenyl-amino)-phenyl-2-oxo-ethyl] dimethyl phosphonate obtain 7-((R)-2-{ (E)-3-hydroxyl-3-[3-(methyl-phenyl-amino)-phenyl]-propenyl-5-oxo-tetramethyleneimine-1-yl)-enanthic acid (27), MS:m/z 451 (M + 1);
[3-(methyl-o-tolyl-amino)-phenyl-2-oxo-ethyl] dimethyl phosphonate obtain 7-((R)-2-{ (E)-3-hydroxyl-3-[3-(methyl-o-tolyl-amino)-phenyl]-propenyl-5-oxo-tetramethyleneimine-1-yl)-enanthic acid (28), MS:m/z 465 (M + 1);
[2-(3-styroyl oxygen base-phenyl)-2-oxo-ethyl] dimethyl phosphonate obtains 7-{ (R)-2-[(E)-3-hydroxyl-3-(3-styroyl oxygen base-phenyl)-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid (29), MS:m/z 466 (M + 1);
[2-{3-[2-(2-oxo-tetramethyleneimine-1-yl)-oxyethyl group]-phenyl } 2-oxo-ethyl] dimethyl phosphonate obtains 7-[(R)-2-((E)-3-hydroxyl-3-{3-[2-(2-oxo-tetramethyleneimine-1-yl)-oxyethyl group]-phenyl } propenyl)-5-oxo-tetramethyleneimine-1-yl]-enanthic acid (30), MS:m/z 473 (M + 1);
[2-[3-(2-tert.-butoxy-oxyethyl group)-phenyl]-2-oxo-ethyl] dimethyl phosphonate obtain 7-((R)-2-{ (E)-3-[3-(2-tert.-butoxy-oxyethyl group)-phenyl]-3-hydroxyl-propenyl-5-oxo-tetramethyleneimine-1-yl)-enanthic acid (31), MS:m/z 462 (M + 1);
[2-[3-indoles-1-base-phenyl]-2-oxo-ethyl] dimethyl phosphonate obtains 7-{ (R)-2-[(E)-3-hydroxyl-3-(3-indoles-1-base-phenyl)-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid (32), MS:m/z 461 (M + 1);
2-[(Z)-3-propenyl-phenyl]-2-oxo-ethyl } dimethyl phosphonate obtains 7-{ (R)-2-[(E)-3-hydroxyl-3-((Z)-3-propenyl-phenyl)-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid (33), MS:m/z 386 (M + 1);
[2-(3-propyl group-phenyl)-2-oxo-ethyl] dimethyl phosphonate obtains 7-{ (R)-2-[(E)-3-hydroxyl-3-(3-propyl group-phenyl)-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid (34), MS:m/z 388 (M + 1);
[2-(3-formyl-dimethylamino-phenyl)-2-oxo-ethyl] dimethyl phosphonate obtains 7-{ (R)-2-[(E)-3-(3-formyl-dimethylamino-phenyl)-3-hydroxyl-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid (35), MS:m/z 417 (M + 1);
{ 2-[3-(tetrahydropyrans-4-ylidenylmethyl)-phenyl]-2-oxo-ethyl } dimethyl phosphonate obtain 7-((R)-2-{ (E)-3-hydroxyl-3-[3-(tetrahydropyran-4-base ylidenylmethyl)-phenyl]-propenyl-5-oxo-tetramethyleneimine-1-yl)-enanthic acid (36), MS:m/z 442 (M + 1);
{ 2-[3-(tetrahydropyran-4-base methyl)-phenyl]-2-oxo-ethyl } dimethyl phosphonate obtain 7-((R)-2-{ (E)-3-hydroxyl-3-[3-(tetrahydropyrans-4-methyl)-phenyl]-propenyl-5-oxo-tetramethyleneimine-1-yl)-enanthic acid (37), MS:m/z 444 (M + 1);
{ 2-[3-(4-methoxyl group-benzyl)-phenyl]-2-oxo-ethyl } dimethyl phosphonate obtain 7-((R)-2-{ (E)-3-hydroxyl-3-[3-(4-methoxyl group-benzyl)-phenyl]-propenyl-5-oxo-tetramethyleneimine-1-yl)-enanthic acid (38), MS:m/z 466 (M + 1); With
[2-oxo-2-(5-trifluoromethyl-furans-2-yl)-ethyl]-dimethyl phosphonate obtains 7-{ (R)-2-[(E)-3-hydroxyl-3-(5-trifluoromethyl-furans-2-yl)-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid (39), MS:m/z 404 (M + 1).
Embodiment 2
7-{ (R)-2-[(E)-3-(3-benzoyl-phenyl)-3-hydroxyl-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid (40)
Figure A0281409100501
Step 1:
3-(dimethoxy-phenyl-methyl)-methyl benzoate
Figure A0281409100502
Under 65 ℃ with 3-benzoyl-phenylformic acid (2g, 8.84mmol) and methylsulfonic acid (0.115mL, methanol solution 1.77mmol) (15mL) heating 20 hours and be cooled to room temperature then.(1.45mL 13.26mmol) also continues to stir 24 hours to add trimethyl orthoformate in this solution.Dilute this reaction soln and use NaHCO with ethyl acetate then 3Washing.Use MgSO 4Dry organic layer, filtration also concentrate.Carry out flash chromatography (20 hexanes: 1 ethyl acetate+0.25% triethylamine) obtain 3-(dimethoxy-phenyl-methyl)-methyl benzoate (951mg), be oily matter.
Step 2:
2-[3-(dimethoxy-phenyl-methyl)-phenyl]-2-oxo-ethyl }-dimethyl phosphonate
To-78 ℃ dimethyl methyl phosphonate acid esters (0.54mL, add in the THF solution (5mL) 4.98mmol) 1.6M BuLi (3.11mL, 4.98mmol).After stirring 40 minutes, add 3-(dimethoxy-phenyl-methyl)-methyl benzoate (951mg, THF solution (5mL) 3.32mmol).After 15 minutes, with this reaction mixture temperature to room temperature.With this reaction mixture restir 1 hour and at room temperature then by adding NaHCO 3Solution makes this system quenching.With the ethyl acetate dilution, use NaHCO subsequently 3Washing.Use MgSO 4Dry organic layer, filtration also concentrate.Carry out flash chromatography (15 ethyl acetate: 1 hexane+0.25% triethylamine) obtain { 2-[3-(dimethoxy-phenyl-methyl)-phenyl]-2-oxo-ethyl }-(784mg 2.07mmol), is oily matter to dimethyl phosphonate.
Step 3:
7-((R)-2-{ (E)-3-[3-(dimethoxy-phenyl-methyl)-phenyl]-3-oxo-propenyl }-5-oxo-tetramethyleneimine-1-yl)-oil of cognac
Figure A0281409100521
(20mg adds in 0.51mmol) { 2-[3-(dimethoxy-phenyl-methyl)-phenyl]-2-oxo-ethyl }-dimethyl phosphonate (193mg, glycol dimethyl ether solution (5mL) 0.51mmol) to 60% sodium hydride.1.5 after hour, add 7-((R)-2-f formyl radical-5-oxo-tetramethyleneimine-1-yl)-oil of cognac (126mg, glycol dimethyl ether solution (5mL) 0.47mmol).With this reaction mixture stir 1 hour, with the ethyl acetate dilution and use NaHCO 3Washing.Use MgSO 4Dry organic layer, filtration also concentrate.Carry out flash chromatography (3 ethyl acetate: 1 hexane+0.25%TEA) obtain 7-((R)-2-{ (E)-3-[3-(dimethoxy-phenyl-methyl)-phenyl]-3-oxo-propenyl-5-oxo-tetramethyleneimine-1-yl)-oil of cognac (124mg, 0.24mmol), be oily matter.
Step 4:
7-((R)-2-{ (E)-3-[3-(dimethoxy-phenyl-methyl)-phenyl]-3-hydroxyl-propenyl }-5-oxo-tetramethyleneimine-1-yl)-enanthic acid
Figure A0281409100522
To 7-((R)-2-{ (E)-3-[3-(dimethoxy-phenyl-methyl)-phenyl]-3-oxo-propenyl-5-oxo-tetramethyleneimine-1-yl)-(124mg adds NaBH in ethanolic soln 0.24mmol) (5mL) to oil of cognac 4(36mg, 0.96mmol).This reaction mixture was stirred 2.25 hours and be concentrated into dried then.Resistates is dissolved in ethyl acetate and uses NaHCO 3Washing.Use MgSO 4Dry organic layer, filtration and concentrate and obtain 7-((R)-2-{ (E)-3-[3-(dimethoxy-phenyl-methyl)-phenyl]-3-hydroxyl-propenyl-5-oxo-tetramethyleneimine-1-yl)-oil of cognac.To 7-((R)-2-{ (E)-3-[3-(dimethoxy-phenyl-methyl)-phenyl]-3-hydroxyl-propenyl-5-oxo-tetramethyleneimine-1-yl)-add LiOH monohydrate (46mg, aqueous solution 1.09mmol) (2.5mL) in the methanol solution (5mL) of oil of cognac.This reaction mixture was stirred 6 hours and concentrated to remove methyl alcohol then.Use CH 2Cl 2Dilute this aqueous concentrates and add 1N HCl, use CH 2Cl 2Extract and use MgSO 4Dry.This mixture filtered and is concentrated into obtain 7-((R)-2-{ (E)-3-[3-(dimethoxy-phenyl-methyl)-phenyl]-3-hydroxyl-propenyl-5-oxo-tetramethyleneimine-1-yl)-(116mg 0.23mmol), is oily matter to enanthic acid.
Step 5:
7-{ (R)-2-[(E)-3-(3-benzoyl-phenyl)-3-hydroxyl-propenyl]-5-oxo-tetramethyleneimine-1-base-enanthic acid
With acid/ketone acetal 7-((R)-2-{ (E)-3-[3-(dimethoxy-phenyl-methyl)-phenyl]-3-hydroxyl-propenyl-5-oxo-tetramethyleneimine-1-yl)-enanthic acid (116mg, 0.23mmol) (1mL 1.0mmol) stirs 18 hours together with 1N HCl to two  alkane solution (5mL).With this reaction soln with ethyl acetate dilution and use NaHCO 3Washing.Use MgSO 4Dry organic layer, filtration also concentrate and obtain 7-{ (R)-2-[(E)-3-(3-benzoyl-phenyl)-3-hydroxyl-propenyl]-5-oxo-tetramethyleneimine-1-yl }-(83mg 0.18mmol), is oily matter to enanthic acid (40); MS:450[(M+H) +].
Prepare the compound of following general formula I with following by { 2-[3-(dimethoxy-phenyl-methyl)-phenyl]-2-oxo-ethyl } dimethyl phosphonate in the suitable phosphonic acid ester step of replacing 3 of the respective acids described in step 1 and/or 2 or ester class preparation similarly;
(2-{3-[dimethoxy-(4-p-methoxy-phenyl)-methyl]-phenyl }-2-oxo-ethyl)-dimethyl phosphonate
7-[(R)-2-((E)-3-hydroxyl-3-{3-[1-(4-methoxyl group-phenyl)-formyl radical]-phenyl }-propenyl)-5-oxo-tetramethyleneimine-1-yl]-enanthic acid (41), MS:m/z 480 (M + 1).
Embodiment 3
7-{ (R)-2-((E)-3-hydroxyl-3-(2 '-methyl-xenyl-3-yl)-propenyl]-5-oxo-tetramethyleneimine-1-yl }-Methylheptanoate (42)
Step 1:
7-{ (R)-2-[(E)-3-(3-bromo-phenyl)-3-oxo-propenyl]-5-oxo-tetramethyleneimine-1-yl }-Methylheptanoate
Figure A0281409100542
Be dissolved in adding [2-(3-bromo-phenyl)-2-oxo-ethyl]-dimethyl phosphonate (1.82g, 1.05 equivalents) in the resulting solution of 30mL glycol dimethyl ether to NaH (0.14g, 1 equivalent) down and in the nitrogen environment at 0 ℃.At 0 ℃ after following 1 hour, slowly add 7-((R)-2-formyl radical-5-oxo-tetramethyleneimine-1-yl)-Methylheptanoate of being dissolved in 2mL DME (1.44g, 5.64mmol).Remove ice bath and then with this mixture restir 3 hours at room temperature.Add saturated ammonium chloride solution and with this solution of ethyl acetate extraction.Concentrate with the anhydrous magnesium sulfate drying organic layer, under reduced pressure and pass through purification by chromatography.EtOAc (1): hexane (1), follow by EtOAc (5): hexane (1), thereby obtain 7-{ (R)-2-[(E)-3-(3-bromo-phenyl)-3-oxo-propenyl of 1.6g]-5-oxo-tetramethyleneimine-1-yl }-Methylheptanoate.
Step 2:
7-{ (R)-2-[(E)-3-(3-bromo-phenyl)-3-hydroxyl-propenyl]-5-oxo-tetramethyleneimine-1-yl } Methylheptanoate
Figure A0281409100551
At 0 ℃ of 7-{ (R)-2-[(E)-3-(3-bromo-phenyl)-3-oxo-propenyl to stirring down and in the nitrogen environment]-5-oxo-tetramethyleneimine-1-yl }-(0.78g 1.79mmol) is dissolved in and adds sodium borohydride (0.074g) in the resulting solution of 15mL methyl alcohol Methylheptanoate.This mixture was at room temperature stirred 6 hours.After adding 1N HCl with this mixture of ethyl acetate extraction.Concentrate with the anhydrous magnesium sulfate drying organic layer, under reduced pressure and by purification by chromatography, use 50% EtOAc and hexane, use 100% EtOAc wash-out subsequently and obtain 7-{ (R)-2-[(E)-3-(3-bromo-phenyl)-3-hydroxyl-propenyl of 670mg]-5-oxo-tetramethyleneimine-1-yl }-Methylheptanoate.
Step 3:
7-{ (R)-2-[(E)-3-hydroxyl-3-(2 '-methyl-xenyl-3-yl)-propenyl]-5-oxo-tetramethyleneimine-1-yl }-Methylheptanoate
At room temperature to 7-{ (R)-2-[(E)-3-(3-bromo-the phenyl)-3-hydroxyl-propenyl that stirs]-5-oxo-tetramethyleneimine-1-yl }-(0.2g 0.46mmol) is dissolved in the resulting solution of 10mL DME and adds Pd (Ph Methylheptanoate 3P) 4(0.03g, 0.05 equivalent).The 2M Na that after stirring 5 minutes, adds o-tolyl boric acid (0.12g, 2 equivalents) 2CO 3Solution (0.6mL, 2.5 equivalents) and with this mixture at N 2Reflux in the compression ring border and spend the night.This reaction mixture is cooled to room temperature, uses 25%NH 4Oac (10mL) dilutes, stirred 5 minutes and uses ethyl acetate extraction then, uses MgSO 4(anhydrous) dry organic layer, under reduced pressure, concentrate and purifying and obtain 7-{ (R)-2-[(E)-3-hydroxyl-3-(2 '-methyl-xenyl-3-yl)-propenyl of 87mg]-5-oxo-tetramethyleneimine-1-yl-Methylheptanoate.
Step 4:
7-{ (R)-2-[(E)-3-hydroxyl-3-(2 '-methyl-xenyl-3-yl)-propenyl-5-oxo-tetramethyleneimine-1-yl } enanthic acid
Figure A0281409100561
To 7-{ (R)-2-[(E)-3-hydroxyl-3-(2 '-methyl biphenyl-3-yl)-propenyl]-5-oxo-tetramethyleneimine-1-yl }-add the aqueous solution (2.5mL) of LiOH monohydrate in the methanol solution (5mL) of Methylheptanoate (87mg).This reaction mixture was stirred 6 hours and was concentrated into then to remove methyl alcohol.Use CH 2Cl 2Hour this aqueous concentrates and with adding 1N HCl, use CH 2Cl 2Extract and use MgSO 4Dry.This mixture filtered and is concentrated into 7-{ (R)-2-[(E)-3-hydroxyl-3-of obtaining 62mg (2 '-methyl-xenyl-3-yl)-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid, be oily matter (42) (50) .MS:435[(M+H) +].
Prepare following compounds with the o-tolyl boric acid in the phenyl-boron dihydroxide step of replacing 3 that suitably replaces similarly:
7-[(R)-2-((E)-3-xenyl-3-base-3-hydroxyl-propenyl)-5-oxo-tetramethyleneimine-1-yl]-enanthic acid (43), MS:m/z422[(M + 1) +];
7-{ (R)-2-[(E)-3-(2 '-oxyethyl group-xenyl-3-yl)-3-hydroxyl-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid (44), MS:m/z466[(M + 1) +];
7-{ (R)-2-[(E)-3-(2 '-chloro-xenyl-3-yl)-3-hydroxyl-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid (45), MS:m/z 457[(M + 1) +];
7-{ (R)-2-[(E)-3-(4 '-chloro-xenyl-3-yl)-3-hydroxyl-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid (46), MS:m/z 457[(M + 1) +];
7-{ (R)-2-[(E)-3-(3 '-chloro-xenyl-3-yl)-3-hydroxyl-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid (47), MS:m/z 457[(M + 1) +];
7-{ (R)-2-[(E)-3-(4 '-chloro-2 '-methyl-xenyl-3-yl)-3-hydroxyl-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid (48), MS:m/z471[(M + 1) +];
7-{ (R)-2-[(E)-3-(4 '-hydroxyl-2 '-methyl-xenyl-3-yl)-3-hydroxyl-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid (49), MS:m/z 452[(M + 1) +];
7-{ (R)-2-[(E)-3-(4 '-chloro-2-methyl-xenyl-3-yl)-3-hydroxyl-propyl group]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid [(50), hydrogenation in step 1 (uses 1atm hydrogen and 10% palladium/carbon in EtOAc, 1.5 hour) the back preparation), MS:m/z 473[(M + 1) +];
7-{ (S)-2-[(R)-3-hydroxyl-3-(4 '-hydroxyl-2 '-methyl-xenyl-3-yl)-propyl group]-5-oxo-tetramethyleneimine-1-yl }-[(51) are according to step 3 but the processing described in carry out step 2 for enanthic acid; Use 1atm hydrogen, catalyzer 10% palladium/carbon carried out in EtOAc 1.5 hours and contact E.J.Corey etc. then at " Journal of the American Chemical Society " (J.Am.Chem.Soc.) 1987,109, reductive condition described in the 7925-7926, use (S)-2-methyl-CBS catalyzer from Aldrich, the 1M toluene solution is produced], MS:m/z 454[(M + 1) +].
Use [2-(3-bromo-4-methyl-phenyl)-2-oxo-ethyl] dimethyl phosphonate in the step 1 to obtain 7-{ (R)-2-[(E)-3-(6 similarly, 2 '-dimethyl-xenyl-3-yl)-3-hydroxyl-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid (52), MS:362[(M+H) +].
Embodiment 4
7-{ (S)-2-[3-(1-benzyl-1H-pyrazoles-4-yl)-3-hydroxyl-propyl group]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid (53)
Figure A0281409100581
Step 1:
[2-(1-benzyl-1H-pyrazoles-4-yl)-2-oxo-ethyl]-dimethyl phosphonate
Use at ambient temperature bromotoluene (1.9mL, 15.7mmol) handle 4-pyrazole carboxylic acid ethyl ester (2.2g, 15.7mmol) and cesium carbonate (5.2g 15.7mmol) is dissolved in the resulting suspension of dimethyl formyl ammonium (100mL).With this mixture heating up to 90 ℃ following 45 minutes, be cooled to envrionment temperature and be distributed in water (400mL) and 1: 1 hexane: ethyl acetate is (between 4 * 150mL).(2 * 100mL) wash and store jointly with anhydrous magnesium sulfate with salt solution with the organic extraction that merges.Remove volatile matter and make silicagel column on the resistates.With 3: 1 hexanes: eluent ethyl acetate obtained required product, is white solid (3.4g).(Aldrich, 1.6mL, tetrahydrofuran (THF) 15mmol) (80mL) solution are cooled to-78 ℃, and also (6.0mL 15mmol) handles with n-Butyl Lithium with dimethyl methyl phosphonate in independent container.Add after 45 minutes above-mentioned ester (2.3g, (20mL) solution of tetrahydrofuran (THF) 10mmol) and in 30 minutes with this mixture temperature to 0 ℃.(2 * 100mL) extract with this mixture impouring aqueous ammonium chloride solution and with ethyl acetate.With the organic extraction that merges with new water (2 * 50mL) and store with the salt water washing and with anhydrous sodium sulphate then.Use rotatory evaporator to remove volatile matter and make silicagel column on the resistates.With 20: 1 ethyl acetate: [2-(1-benzyl-1H-pyrazoles-4-yl)-2-oxo-ethyl]-dimethyl phosphonate that methanol-eluted fractions is required also obtained oily matter (1.68g).
Step 2:
7-{ (R)-2-[(E)-4-(1-benzyl-1H-pyrazoles-4-yl)-3-oxo-but-1-ene base]-5-oxo-tetramethyleneimine-1-yl } oil of cognac
Be dissolved in [2-(1-benzyl-1H-pyrazoles-4-yl)-2-oxo-ethyl]-dimethyl phosphonate (820mg of glycol dimethyl ether according to embodiment 1 step 3, use; 2.66mmol) and sodium hydride (95%; 70mg; 2.66mmol) and 7-((R)-2-formyl radical-5-oxo-tetramethyleneimine-1-yl)-oil of cognac (about 800mg 2.8mmol) produces 7-{ (R)-2-[(E)-4-(1-benzyl-1H-pyrazoles-4-yl)-3-oxo-but-1-ene base]-5-oxo-tetramethyleneimine-1-yl }-oil of cognac.(419mg 0.93mmol), is oily matter to separate required ketenes.
Step 3:
7-{ (R)-2-[(E)-4-(1-benzyl-1H-pyrazoles-4-yl)-3-oxo-but-1-ene base]-5-oxo-tetramethyleneimine-1-yl } enanthic acid
Figure A0281409100601
To contain pyrazoles ketenes (210mg, 0.46mmol) be dissolved in methyl alcohol (5mL), be cooled to 0 ℃ and with sodium borohydride (50mg 1.3mmol) handles.After stirring 15 minutes at ambient temperature, add acetone (2mL) and remove volatile matter.Add methyl alcohol again and remove volatile matter once more.Resistates is suspended in the 0.05M aqueous phosphatic (about 50mL) of pH6.5 and (Sigma 2g) handles and vigorous stirring 2 hours at ambient temperature with VII type lipase.Dilute this suspension and pass through the filtration of C salt pad with ether (about 25mL).Separate each layer and wash water layer once more with ether.(4 * 25mL) extract with the Glacial acetic acid acidifying and with ethyl acetate with water layer.The organic extraction that merges is stored with anhydrous sodium sulphate.Remove volatile matter after the filtration and obtain required 7-{ (R)-2-[(E)-4-(1-benzyl-1H-pyrazoles-4-yl)-3-oxo-but-1-ene base]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid (53) (70) (109mg, 0.25mmol): MS:428[(M+H) +].
Embodiment 5
7-{ (S)-2-[3-hydroxyl-3-(5-o-tolyl-furans-2-yl)-propyl group]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid (54)
Step 1
[2-(5-bromo-furans-2-yl)-2-oxo-ethyl]-dimethyl phosphonate
When handling, prepare 5-bromo-2-methylfuroate with the trimethylsilyl diazomethane.(10.2g 47mmol) is dissolved in tetrahydrofuran (THF) (40mL) and joining in-78 ℃ dimethyl methyl phosphonate (90mmol) solution of lithiumation with this ester.Separate as mentioned above required [2-(5-bromo-furans-2-yl)-2-oxo-ethyl]-dimethyl phosphonate (5.83g, 19.5mmol).
Step 2:
7-{ (R)-2-[(E)-3-(5-bromo-furans-2-yl)-3-oxo-propenyl]-5-oxo-tetramethyleneimine-1-yl }-oil of cognac
Figure A0281409100611
It is described to go into embodiment 4 steps 1; use 5-bromo-2-furoyl base phosphonic acid ester (1.12g; 3.8mmol) glycol dimethyl ether solution (95mL); sodium hydride (95%; 91mg; 3.6mmol) prepare above-mentioned 7-{ (R)-2-[(E)-3-(5-bromo-furans-2-yl)-3-oxo-propenyl]-5-oxo-tetramethyleneimine-1-yl-oil of cognac and use then 7-((R)-2-formyl radical-5-oxo-tetramethyleneimine-1-yl)-Methylheptanoate (1.2g 4mmol) handles and obtains 7-{ (R)-2-[(E)-3-(5-bromo-furans-2-yl)-3-oxo-propenyl]-5-oxo-tetramethyleneimine-1-yl-oil of cognac MS:442 (M +1, use 81Br), 440 (M +1, use 79Br).
Step 3:
7-{ (S)-2-[3-hydroxyl-3-(5-o-tolyl-furans-2-yl)-propyl group]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid
Figure A0281409100621
In ar gas environment with 7-{ (R)-2-[(E)-3-(5-bromo-furans-2-yl)-3-oxo-propenyl]-5-oxo-tetramethyleneimine-1-yl-oil of cognac is dissolved in anhydrous 1,4-two  alkane (3mL), usefulness salt of wormwood (130mg, 0.94mmol), 2-aminomethyl phenyl boric acid (64mg, 0.47mmol) and molybdenyl dichloride (triphenyl phosphine) palladium (33mg, 0.047mmol) processing.Should yellow suspension temperature to 55 ℃ following 15 hours and remove volatile matter then.Also (about 35mg 0.9mmol) stirred together 20 minutes and handles with acetone (1mL) with sodium borohydride at ambient temperature then this mixture to be dissolved in methyl alcohol (10mL).After removing volatile matter, handle resistates and remove volatile matter again one time with methyl alcohol.The silica-gel plate that 1mm is thick on the resistates also should be launched 2 times by flat board with the dichloromethane solution of 3% Virahol.Obtain 7-{ (S)-2-[3-hydroxyl-3-(5-o-tolyl-furans-2-yl)-propyl group]-5-oxo-tetramethyleneimine-1-yl }-oil of cognac (54mg), be oily matter.
This ester (54mg) is dissolved in methyl alcohol (3mL) also to be handled and stirred at ambient temperature 1 hour with 5M aqueous sodium hydroxide solution (0.5mL).Obtain 7-{ (S)-2-[3-hydroxyl-3-(5-o-tolyl-furans-2-yl)-propyl group with the processing of 1M aqueous hydrochloric acid and with ethyl acetate extraction]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid (54) (71) (45mg, 0.10mmol): MS:428[(M+H) +].
Embodiment 6
7-{ (R)-5-[(E)-3-hydroxyl-3-(5-trifluoromethyl-furans-2-yl)-propenyl]-3,3-dimethyl-2-oxo-tetramethyleneimine-1-yl }-enanthic acid (55)
Step 1:
(R)-and 5-(1-oxyethyl group-ethoxyl methyl)-3,3-dimethyl-pyrrolidin-2-one
To as " tetrahedron " (Tetrahedron) 1998, (the R)-5-hydroxymethyl-3 for preparing described in the 5410295-10307,3-dimethyl-pyrrolidin-2-one (4.0g, 28mmol) and ethyl vinyl ether (4mL 42mmol) is dissolved in the resulting solution of chloroform (26mL) trifluoroacetic acid (0.056mL) that adds the catalysis beam and this reaction mixture was at room temperature stirred 4 hours.Then with saturated sodium bicarbonate and this solution of salt water washing and use dried over mgso.By using hexane: the thick oily matter that ethyl acetate silica gel chromatography purifying evaporating solvent as solvent after obtains at 1: 1 obtains (R)-5-(1-oxyethyl group-ethoxyl methyl)-3 of 2.6g, 3-dimethyl-pyrrolidin-2-one.
Step 2:
7-((R)-5-hydroxymethyl-3,3-dimethyl-2-oxo-tetramethyleneimine-1-yl)-oil of cognac
0 ℃ down and in the nitrogen environment with (R)-5-(1-oxyethyl group-ethoxyl methyl)-3,3-dimethyl-pyrrolidin-2-one (2.58g, 11.2mmol) be dissolved in the resulting solution of dimethyl formyl ammonium (4mL) and slowly join sodium hydride 60% (450mg, 11.2mmol) and potassiumiodide (2.27g 13.7mmol) is dissolved in the resulting suspension of dimethyl formyl ammonium (13mL).After at room temperature stirring 1 hour, (2.66mL 13.7mmol) is dissolved in the resulting solution of dimethyl formyl ammonium (5mL) and with flask temperature to 50 ℃ following 72 hours to add ethyl-7-bromine heptanoate in this reaction mixture.Then in a vacuum except that desolvating and resistates being dissolved in ethyl acetate.With this solution of salt water washing and use dried over mgso.
After concentrating, the resistates that obtains is dissolved in methyl alcohol (40mL) and in this solution, adds the tosic acid monohydrate (170mg) of catalytic amount.With this reaction mixture stir 7 hours complete to deprotection.Then in a vacuum except that desolvating and resistates being dissolved in ethyl acetate.With saturated sodium bicarbonate and this solution of salt water washing and use dried over mgso.By using hexane: ethyl acetate 2: 1-1: the crude product that obtains after the 2 silica gel chromatography purifying as solvent concentrate in a vacuum obtains 7-((R)-5-hydroxymethyl-3 of 2.3g, 3-dimethyl-2-oxo-tetramethyleneimine-1-yl)-and oil of cognac, be transparent oily matter.
Step 3:
7-((R)-5-formyl radical-3,3-dimethyl-2-oxo-tetramethyleneimine-1-yl)-oil of cognac
In nitrogen environment with methyl-sulphoxide (0.93mL, 12mmol) be dissolved in the resulting solution of methylene dichloride (40mL) and be cooled to-78 ℃ and (0.820mL 9.4mmol) is dissolved in the resulting solution of methylene dichloride (3mL) to wherein adding oxalyl chloride in 2 minute time limit.This reaction mixture is kept down stirring 30 minutes at-78 ℃.(2.25g 7.5mmol) is dissolved in the resulting solution of methylene dichloride (20mL) slowly to add 7-((R)-5-hydroxymethyl-3,3-dimethyl-2-oxo-tetramethyleneimine-1-yl)-oil of cognac.When interpolation is finished, this reaction flask content was stirred 15 minutes down at-78 ℃.In this reaction flask, slowly add at last triethylamine (2.1mL, 15.0mmol); Make it reach room temperature and restir 15 minutes.Make this reaction all standing and use dichloromethane extraction by adding 20mL water and 20mL ether then.With the dry organic phase of salt of wormwood and be concentrated into dried.By using hexane: ethyl acetate as the silica gel chromatography purifying crude mixture of solvent obtains 7-((R)-5-formyl radical-3,3-dimethyl-2-oxo-tetramethyleneimine-1-yl)-oil of cognac of 1.5g at 2: 1.
Step 4:
7-{ (R)-3,3-dimethyl-2-oxo-5-[(E)-3-oxo-3-(5-trifluoromethyl-furans-2-yl)-propenyl]-tetramethyleneimine-1-yl }-oil of cognac
To 7-((the R)-5-formyl radical-3 that stirs; 3-dimethyl-2-oxo-tetramethyleneimine-1-yl)-oil of cognac (360mg; 1.21mmol) and [2-oxo-2-(5-trifluoromethyl-furans-2-yl)-ethyl]-dimethyl phosphonate (344mg; 1.21mmol) (as described herein by the preparation of 5-trifluoromethyl-furans-2-formic acid) be dissolved in the resulting solution of acetonitrile (14mL) and add lithium chloride (62mg; 1.21mmol) and diisopropylethylamine (0.214mL, 1.21mmol).In this week, this reaction flask is kept at room temperature stirring.Make this reaction all standing and use ethyl acetate extraction with saturated ammonium chloride solution then.Then with salt water washing organic phase and with dried over mgso and by using hexane: 2: 1 silica gel chromatography purifying crude products of ethyl acetate as solvent.Evaporating solvent obtains the 7-{ (R)-3 of 280mg, 3-dimethyl-2-oxo-5-[(E)-3-oxo-3-(5-trifluoromethyl-furans-2-yl)-propenyl]-tetramethyleneimine-1-yl }-oil of cognac.
Step 5:
7-{ (R)-5-[(E)-3-hydroxyl-3-(5-trifluoromethyl-furans-2-yl)-propenyl]-3,3-dimethyl-2-oxo-tetramethyleneimine-1-yl }-oil of cognac
Figure A0281409100661
Under-20 ℃ with sodium borohydride (37mg, 0.98mmol) slowly join 7-{ (R)-3,3-dimethyl-2-oxo-5-[(E)-3-oxo-3-(5-trifluoromethyl-furans-2-yl)-propenyl]-tetramethyleneimine-1-yl }-(280mg 0.61mmol) is dissolved in the resulting solution of methyl alcohol (4mL) oil of cognac.With this reaction flask remain on-10 ℃ following 45 minutes.When interpolation is finished, with this reaction vessel remain on-10 ℃ following 40 minutes.When reacting, make this reaction all standing and be concentrated into dried with acetone.Resistates is dissolved in ethyl acetate, also dry with the salt water washing.Concentrate the back by the use hexane: 1: 1 silicagel column purifying crude mixture as solvent of ethyl acetate obtains 7-{ (R)-5-[(E)-3-hydroxyl-3-(5-trifluoromethyl-furans-2-yl)-propenyl of 90mg]-3,3-dimethyl-2-oxo-tetramethyleneimine-1-yl }-oil of cognac.
Step 6:
7-{ (R)-5-[(E)-3-hydroxyl-3-(5-trifluoromethyl-furans-2-yl)-propenyl]-3,3-dimethyl-2-oxo-tetramethyleneimine-1-yl }-enanthic acid
With 7-{ (R)-5-[(E)-3-hydroxyl-3-(5-trifluoromethyl-furans-2-yl)-propenyl]-3,3-dimethyl-2-oxo-tetramethyleneimine-1-yl }-(89mg 0.2mmol) is dissolved in methyl alcohol (3mL) and also this solution is cooled off in ice bath oil of cognac.(0.280mL 1.4mmol) and when adding when finishing, at room temperature keeps stirring to spend the night this reaction flask content slowly to add 20% sodium hydroxide solution.Concentrate this reaction soln in a vacuum; Resistates is suspended in the 0.1N sodium hydroxide solution of 5mL and uses the ether washed twice.Also use ethyl acetate extraction three times with this solution of 1N hcl acidifying then.Also after concentrating, obtain 7-{ (R)-5-[(E)-3-hydroxyl-3-(5-trifluoromethyl-furans-2-yl)-propenyl of 55mg with dried over mgso with salt water washing organic layer]-3,3-dimethyl-2-oxo-tetramethyleneimine-1-yl }-enanthic acid (55) (80) .MS:432[(M+H) +].
The compound that replaces the following suitable following general formula I of intermediate preparation similarly:
Use (the 2-oxygen heptyl) dimethyl phosphonate in the step 4 to obtain 7-[(R)-5-((E)-3-hydroxyl-Xin-1-thiazolinyl)-3,3-dimethyl-2-oxo-tetramethyleneimine-1-yl]-enanthic acid (56), MS:m/z 368 (M + 1);
Use 4 in the step 1,4-dimethyl-5-hydroxymethyl-2-Pyrrolidone obtains 7-[2-((E)-3-hydroxyl-Xin-1-thiazolinyl)-3,3-dimethyl-5-oxo-tetramethyleneimine-1-yl]-enanthic acid (57), MS:m/z 368 (M + 1);
Use [2-(cyclobutyl-ethyl)-2-oxo-ethyl] dimethyl phosphonate in the step 4 to obtain 7-[(R)-5-((S)-(E)-5-cyclobutyl-3-hydroxyl-penta-1-thiazolinyl)-3,3-dimethyl-2-oxo-tetramethyleneimine-1-yl]-enanthic acid (58), MS:m/z 380 (M + 1);
Use in the step 4 2-[(3-methoxymethyl-phenyl) methyl]-2-oxo-ethyl dimethyl phosphonate obtains 7-{ (R)-5-[(E)-3-hydroxyl-4-(3-methoxymethyl-phenyl)-but-1-ene base]-3,3-dimethyl-2-oxo-tetramethyleneimine-1-yl }-enanthic acid (59), MS:m/z 432 (M + 1);
Use { 2-[3-(4-methoxy-benzyl)-phenyl]-2-oxo-ethyl } dimethyl phosphonate in the step 4 obtain 7-((R)-5-{ (E)-3-hydroxyl-3-[3-(4-methoxyl group-benzyl)-phenyl]-propenyl-3,3-dimethyl 2-oxo-tetramethyleneimine-1-yl)-and enanthic acid (60), MS:m/z 494 (M + 1); Or
Use in the step 4 [2-(4 '-chloro-2 '-methyl-xenyl-3-yl)-2-oxo-ethyl] dimethyl phosphonate obtain 7-{ (R)-5-[(E)-3-(4 '-chloro-2 '-methyl-xenyl-3-yl)-3-hydroxyl-propenyl]-3,3-dimethyl-2-oxo-tetramethyleneimine-1-yl }-enanthic acid (61), MS:m/z499 (M + 1).
Embodiment 7
7-((R)-2-{ (E)-3-[3-(3-fluoro-phenoxy group)-phenyl]-3-hydroxyl-propenyl }-5-oxo-tetramethyleneimine-1-yl)-enanthic acid (62)
Figure A0281409100681
Present embodiment illustrates the phosphonic acid ester by the synthetic above-mentioned general formula of the method described in the reaction process B.
Step 1:
Figure A0281409100682
Under envrionment temperature and environmental stress, stir 3-methyl hydroxybenzoate (5.4g, 35.5mmol), 3-fluorophenyl boric acid (5.5g, 35.5mmol), venus crystals (7.1g, 35.5mmol), 3  molecular sieves (9g), pyridine (12mL, 145mmol) be dissolved in the resulting suspension of methylene dichloride (220mL), after 11 days, this mixture is filtered and removes volatile matter by C salt from filtrate.Use 5: 1 hexanes: ethyl acetate required ester (3.68g) and be used for next step under the wash-out from the silicagel column.
Step 2:
Figure A0281409100683
(4.0mL, tetrahydrofuran (THF) 37.5mmol) (100mL) solution are cooled to-78 ℃, and also (45 minutes are handled and stirred to 15.0mL, 2.5M hexane solution 37.5mmol) with n-Butyl Lithium with dimethyl methyl phosphonate in ar gas environment.(4.62g 18.7mmol) is dissolved in tetrahydrofuran (THF) (15mL) and joining in the described solution and with the gained mixture and stirred 1 hour down at 0 ℃ under-78 ℃ with the ester that obtains in the step 1.Be distributed between aqueous ammonium chloride solution (100mL) and the ether (200mL) yellow solution this moment.With new water (3 * 30mL), store with salt water washing organic moiety and with anhydrous sodium sulphate then.Filtration obtains required beta-keto phosphonic acid ester (5.8g) after also removing volatile matter in a vacuum, is viscous oil:
1H NMR(300MHz，CDCl 3)□7.78(dt，J＝0.6，0.9，7.8Hz，1H)，7.63(t，J＝2.1Hz，1H)，7.48(t，J＝8.1Hz，1H)，7.32-7.26(m，2H)，6.90-6.78(m，2H)，6.70(dt，J＝2.4，9.91H)，3.80(d，J＝11.2Hz，6H)，3.61(d，J＝22.6，2H).
According to the method described in the embodiment 1 will 2-[3-fluoro-phenoxy group)-phenyl]-2-oxo-ethyl-dimethyl phosphonate be used to prepare 7-((R)-2-{ (E)-3-(3-(3-fluoro-phenoxy group)-phenyl]-3-hydroxyl-propenyl-5-oxo-tetramethyleneimine-1-yl)-enanthic acid (62) (90), MS m/z 456 (M + 1).
The compound for preparing following general formula I similarly with the 3-fluorophenyl boric acid in the phenyl-boron dihydroxide step of replacing 1 that suitably replaces:
Phenyl-boron dihydroxide obtains 7-((R)-2-{ (E)-3-(3-phenoxy group)-phenyl-3-hydroxyl-propenyl }-5-oxo-tetramethyleneimine-1-yl)-enanthic acid (63), MS m/z 438 (M + 1);
4-anisole ylboronic acid obtain 7-((R)-2-{ (E)-3-hydroxyl-3-[3-(4-methoxyl group-phenoxy group) phenyl]-propenyl-5-oxo-tetramethyleneimine-1-yl)-enanthic acid (64), MS:m/z 468 (M + 1);
4-fluorophenyl boric acid (follow-up use 1atm hydrogen and 10% palladium/hydrocarbonize) obtain 7-((S)-2-{ (E)-3-hydroxyl-3-[3-(4-fluoro-phenoxy group) phenyl]-propyl group-5-oxo-tetramethyleneimine-1-yl)-enanthic acid (65), MS:458m/z (M + 1);
Between tolyl boric acid obtain 7-((R)-2-[(E)-3-hydroxyl-3-(tolyloxy-phenyl between 3-)-propenyl]-5-oxo-tetramethyleneimine-1-yl)-enanthic acid (66), MS:m/z 452 (M + 1);
3-anisole ylboronic acid obtain 7-((R)-2-{ (E)-3-hydroxyl-3-[3-(3-methoxyl group-phenoxy group)-phenyl]-propenyl-5-oxo-tetramethyleneimine-1-yl)-enanthic acid (67), MS:m/z 468 (M + 1);
The 4-trifluoromethyl phenyl boronic acid obtain 7-((R)-2-{ (E)-3-hydroxyl-3-[3-(4-trifluoromethyl-phenoxy group)-phenyl]-propenyl-5-oxo-tetramethyleneimine-1-yl)-enanthic acid (68), MS:m/z 506 (M + 1);
O-tolyl boric acid obtains 7-((R)-2-[(E)-3-hydroxyl-3-(3-oxy-o-cresyl-phenyl)-propenyl]-5-oxo-tetramethyleneimine-1-yl)-enanthic acid (69), MS:m/z 452 (M + 1);
The 3-trifluoromethyl phenyl boronic acid obtain 7-((R)-2-{ (E)-3-hydroxyl-3-[3-(3-trifluoromethyl-phenoxy group)-phenyl]-propenyl-5-oxo-tetramethyleneimine-1-yl)-enanthic acid (70), MS:m/z 506 (M + 1);
2-anisole ylboronic acid obtain 7-((R)-2-{ (E)-3-hydroxyl-3-[3-(2-methoxyl group-phenoxy group)-phenyl]-propenyl-5-oxo-tetramethyleneimine-1-yl)-enanthic acid (71), MS:m/z 468 (M + 1);
P-methylphenyl boric acid obtains 7-((R)-2-[(E)-3-hydroxyl-3-(3-is to tolyloxy-phenyl)-propenyl]-5-oxo-tetramethyleneimine-1-yl)-enanthic acid (72), MS:m/z 452 (M + 1);
4-fluorophenyl boric acid obtain 7-((R)-2-{ (E)-3-[3-(4-fluoro-phenoxy group)-phenyl]-3-hydroxyl-propenyl-5-oxo-tetramethyleneimine-1-yl)-enanthic acid (73), MS:m/z 456 (M + 1);
The 4-chlorophenylboronic acid obtain 7-((R)-2-{ (E)-3-[3-(4-chloro-phenoxy group)-phenyl]-3-hydroxyl-propenyl-5-oxo-tetramethyleneimine-1-yl)-enanthic acid (74), MS:m/z 473 (M + 1); Or
The 3-chlorophenylboronic acid obtain 7-((R)-2-{ (E)-3-[3-(3-chloro-phenoxy group)-phenyl]-3-hydroxyl-propenyl-5-oxo-tetramethyleneimine-1-yl)-enanthic acid (75), MS:m/z 473 (M + 1).
Embodiment 8
4-{2-[(R)-and 2-((E)-3-hydroxyl-Xin-1-thiazolinyl)-5-oxo-tetramethyleneimine-1-yl] ethyl }-phenylformic acid (76)
Figure A0281409100701
Step 1:
Figure A0281409100711
At 0 ℃ of following and N 2DMF with 40mL in the environment joins among 1.27g (31.67mmol, 60% mineral oil dispersion liquid) NaH and 5.26g (31.67mmol) KI.Dropwise add 3.50g (30.16mmol) of (S)-(+)-dihydro-5-hydroxymethyl-2 (3H) furanone (Aldrich) then and be dissolved in the resulting solution of 15mL DMF.This slurry temperature to room temperature and stirred 2.5 hours, is dropwise added 5.4mL (45.24mmol) bromotoluene and then with mixture heating up to 50 ℃ and stirred 16 hours.Be that this reaction system is distributed in the saturated NH of 250mL 4Between Cl (aqueous solution) and the 250mL ethyl acetate/hexane (60%).Water (3 * 200mL), 200mL salt water washing organic layer, concentrate with dried over mgso and under reduced pressure.By the thick resistates of purification by chromatography, obtain with 35% ethyl acetate/hexane wash-out 3.37g (16.34mmol, 54% productive rate) (S)-O-benzyl-dihydro-5-hydroxymethyl-2 (3H) furanone, be yellow oil.
Step 2:
With 1.98g (9.59mmol) (S)-O-benzyl-dihydro-5-hydroxymethyl-2 (3H) furanone and 3.14g (16.25mmol) be dissolved in 50mL THF to the amino-ethyl ethyl benzoate and stirred 20 hours down at 50 ℃.This reaction system is concentrated and, obtain 2.24g (5.61mmol, 58% productive rate) N '-[2-(4-carbethoxy phenyl) ethyl]-5-benzyloxy-4-hydroxyl valeramide, be white solid with 50% ethyl acetate/hexane wash-out by the thick resistates of purification by chromatography.
Step 3:
Figure A0281409100721
2.24g (5.61mmol) N '-[2-(4-carbethoxy phenyl) ethyl]-5-benzyloxy-4-hydroxyl valeramide is dissolved in 40mL THF and 1.17mL (8.43mmol) triethylamine and stirred 10 minutes.Dropwise add 0.57mL (7.30mmol) methylsulfonyl chloride then and this reaction mixture was stirred 2.5 hours, filter out precipitation and with 3mL THF debris.Adding 1.33g (11.85mmol) t-BuOK in filtrate also at room temperature stirred this reaction system 2 hours.When reaction is finished, make this reaction system be distributed in the saturated NH of 200mL 4Between Cl (aqueous solution) and the 250mL ethyl acetate.Use 100mL H 2O, 200mL salt water washing organic layer, use MgSO 4Dry and concentrated under reduced pressure.By the purification by chromatography crude product, use 1% MeOH/CH 2Cl 2Wash-out and obtain (R) N '-[2-(4-carbethoxy phenyl) ethyl]-5-benzyloxymethyl-2-Pyrrolidone of 1.78g (4.69mmol, 83% productive rate) is a clarification oily matter.
Step 4:
Figure A0281409100722
With 1.78g (4.69mmol) (R) N '-[2-(4-carbethoxy phenyl) ethyl]-5-benzyloxymethyl-2-Pyrrolidone be dissolved in 20mL ethanol.In this reaction system, spray argon gas, after this add 0.63g 10% Pd/C and 0.095g (0.55mmol) tosic acid.Emptying reaction vessel and with hydrogen cleaning and at room temperature stirred 4 hours, then by the filtration of C salt then.Concentrated filtrate obtains (R) N-[2-(4-carbethoxy phenyl) ethyl of 1.35g (4.63mmol, 98% productive rate)]-5-hydroxymethyl-2-Pyrrolidone, be clear colorless oil shape thing.
Step 5:
Then by the step described in the above-mentioned reaction process A, use E.J.Corey etc. at " Journal of the American Chemical Society " (J.Am.Chem.Soc.) 1987 simultaneously, 109, the combination of (R)-2-methyl-" the CBS "-oxazaborolidine of the catalytic amount described in the 7925-7926 and the borine-methyl-sulfide of stoichiometry with the alcohol that obtains in the above-mentioned steps change into required ester and acid and the alcohol-ester shown in obtaining: [(M+H) +=388].
Figure A0281409100731
The above-mentioned ester of hydrolysis and obtain phenylformic acid (76) as mentioned above, MS:m/z 360 (M+1) is white powder.
Ethyl in the step of replacing 2-amino-ethyl benzoic ether the is prepared compound of following general formula I:
Right-(3-aminopropyl) methyl benzoate obtains 4-{3-[(R)-2-((E)-3-hydroxyl-Xin-1-thiazolinyl)-5-oxo-tetramethyleneimine-1-yl]-propyl group }-phenylformic acid (77), MS:m/z 374 (M+1) +
Between-(3-aminopropyl) methyl benzoate obtains 3-{3-[(R)-2-((E)-3-hydroxyl-Xin-1-thiazolinyl)-5-oxo-tetramethyleneimine-1-yl]-propyl group }-phenylformic acid (78), MS:m/z 374 (M+1) +
Neighbour-(3-aminopropyl) methyl benzoate obtains 2-{3-[(R)-2-((E)-3-hydroxyl-Xin-1-thiazolinyl)-5-oxo-tetramethyleneimine-1-yl]-propyl group }-phenylformic acid (79), MS:m/z 374 (M+1) +
1-(2-amino-ethyl)-1H-pyrazoles-4-formic acid obtains 1-{2-[(R)-2-((E)-3-hydroxyl-Xin-1-thiazolinyl)-5-oxo-tetramethyleneimine-1-yl]-ethyl }-1H-pyrazoles-4-formic acid (80), MS:m/z 349 (M+1) +
Alternatively, with [2-(4 ' chloro-2 '-methyl-biphenyl-3-yl)-2-oxo-ethyl]-dimethyl phosphonic acids as raw material, use the hydrogen of 1atm subsequently, catalyzer 10% palladium/carbon was EtOAc reduction 1.5 hours and use then from the 1M toluene solution contact E.J.Corey of (S)-2-methyl-CBS catalyzer of Aldrich etc. at " Journal of the American Chemical Society " (J.Am.Chem.Soc.) 1987,109, reductive condition described in the 7925-7926 and obtain 4-(2-{ (S)-2-[(R)-3-(4 '-chloro-2 '-methyl-xenyl-3-yl)-3-hydroxyl-propyl group]-5-oxo-tetramethyleneimine-1-yl-ethyl)-phenylformic acid (81), MS:m/z493 (M+1) +Or use ethyl 5-(2-amino-ethyl)-thiophene-2-carboxylic acid to obtain 5-[(R)-2-((E)-3-hydroxyl-Xin-1-thiazolinyl)-5-oxo-tetramethyleneimine-1-yl]-ethyl)-thiophene-2-carboxylic acid (82), MS:m/z366 (M+1)+.
Embodiment 9
Be the representational pharmaceutical preparation that contains compound of Formula I below.
Tablet
Following component is closely mixed and is pressed into single scored tablet.
The amount of each component Sheet, mg
Compound W-Gum croscarmellose sodium lactose Magnesium Stearate of the present invention 400 50 25 120 5
Capsule
The closely mixed and hard-shell capsule of packing into following component.
The consumption of each component Capsule, mg
The spray-dired lactose Magnesium Stearate of compound of the present invention 200 148 2
Suspensoid
Following component is blended into the suspensoid that is used for oral administration.
Component Consumption
Compound fumaric acid sodium chloride methyl p-hydroxybenzoate propylparaben sugar granulated sorbitol (70% solution) Veegum K (Vanderbilt Co.) flavouring colouring agent distilled water of the present invention 1.0g 0.5g 2.0g 0.15g 0.05g 25.5g 12.85g 1.0g 0.035mL 0.5mg is in right amount to 100mL
Injection
Following component is blended into injection.
Component Consumption
Compound sodium acetate buffer solution HCl of the present invention (1N) or NaOH (1N) water (distillation, aseptic) 0.4mg 0.4M 2.0mL capacity to suitable pH capacity to 20mL
Embodiment 10
EP by luciferase test detection 4(or EP 2) functionally active of acceptor
EP with expression of receptor 4(or EP 2) cell contain 10% FBS (Gibco, BRL) and the F12 of 25mM Hepes (Gibco BRL) goes down to posterity in the substratum and is cultured to 96-hole flat board (Packard) and incubated overnight.Remove substratum second day morning.With the Hanks damping fluid with twice of cell washing and replenish again and contain in the F12 substratum of 0.1%BSA.Described culture pre-incubation after 1.5-3 hour, is being added the compound of being paid close attention to and will be incubated lasting 3 hours again in culture.The scheme of using LucLite that Packard produces, recommending according to Packard is measured the activity of luciferase in the cell.
Embodiment 11
[ 3H] PGE 2With rEP 1Or rEP 3The CBA of acceptor
Cell is maintained in the substratum, when merging, collect then.By two times centrifugal (12,000xg, 15 minutes) preparation film, contain 1mM EDTA, 10mMMgCl at 4 ℃ of following 10 volumes subsequently 2, the 20uM indomethacin the 20mM Hepes of pH7.4 in by polytron homogenize lysing cell.At the above-mentioned 3nM[that contains 3H] PGE 2, the compound of 2% DMSO, different concns and 25ug from take place in the proteinic damping fluid of film fraction compound [ 3H] PGE 2In conjunction with the restraining effect in the test.Be incubated 1 hour down at 30 ℃, after this by quick filtering separation combination and free radioligand.By liquid scintillation counting(LSC) pair and filter membrane bonded remnants [ 3H] PGE 2Quantitatively.Any Ki by Prism in conjunction with computation program computerized compound.
Compound EP4(Ki)
7-{5-[(E)-and 3-hydroxyl-4-(3-methoxymethyl-phenyl)-but-1-ene base]-3,3-dimethyl-2-oxo-tetramethyleneimine-1-yl }-enanthic acid 0.07
7-((R)-5-{ (E)-3-hydroxyl-3-[3-(4-methoxyl group-benzyl)-phenyl]-propenyl }-3,3-dimethyl-2-oxo-tetramethyleneimine-1-yl)-enanthic acid 0.080
7-((R)-2-{ (E)-3-[3-(4-chloro-phenoxy group)-phenyl]-3-hydroxyl-propenyl }-5-oxo-tetramethyleneimine-1-yl)-enanthic acid 0.010
7-{ (R)-2-[(E)-3-(4 '-chloro-2 '-methyl-xenyl-3-yl)-3-hydroxyl-propenyl]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid 0.003
7-{ (R)-2-[3-(4 '-chloro-2 '-methyl-xenyl-3-yl)-3-hydroxyl-propyl group]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid 0.008
Embodiment 12
Bone density test (Bone Mass Density Assay)
Estimate the effect of The compounds of this invention to sclerotin in the ovariectomized rat body.
By Charles River grow up Sprague-Dawley or Wistar Hanover female rats are implemented sham-operation (sham operated) or implemented ovariectomy.When undergoing surgery, make the rat pair fed in be controlled indoor of environment and make them adapt at least one week.Feeding animals makes them raise at a place simultaneously in pairs.
Once a day through subcutaneous 10% EtOH/ salt solution or the 20mM phosphate buffered liquor that gives test compounds, continued for 5 weeks from beginning in postoperative 20 days.
Before treatment and treatment when finishing, use high resolution software package scanning rat on the Hologic QDR-4500 bone density meter to measure bmd (BMD).Use the concern district of following name that scanning is analyzed then: complete femur; Near end of thighbone; The femur backbone; Distal femur; The distal femur metaphysis; Proximal tibia; The shin bone PM; The L2-L4 vertebra; The L5 vertebra.
In order to verify the influence of ovariectomy, use Si Shi (student) t-check relatively more false and OVX sample vehicle group to sclerotin.Compare the OVX group by One-way ANOVA (ANOA), compare each treatment group and vehicle group by Fisher ' s LSD subsequently, the overall function of this moment has significance,statistical.Can carry out classification to data, after this carry out above-mentioned analysis and corresponding distribution free analysis (Wilcoxon rank-sum test or Kruskal-Wallis).
Ovariectomy is brought out mainly the significantly total bone mass loss from trabecular bone (trabecular bone).Total BMD is lower than the 5-20% of Sham-operated control group.

Claims (32)

1. the racemoid or the non-racemic mixture of the compound of general formula I or its pharmaceutically acceptable salt or solvate, its individual isomer or isomer:
Wherein:
A is-CH 2-CH 2-, or-CH=CH-;
B does not exist, is aryl or heteroaryl;
Z is-C (O) OR ' ,-C (O) NR ' R " ,-C (O) NSO 2R ' ,-PR ' (O) (OR ') ,-PO (OR ') 2, or tetrazolium-5-base; Wherein R ' and R " are hydrogen or (C independently of one another 1-C 6) alkyl;
M is 1,2,3,4,5 or 6;
R 1Be alkyl, alkenyl, alkynyl, cycloalkylalkyl, heterocyclic radical alkyl, aryl, arylalkyl or heteroaryl, when B is aryl or heteroaryl and R 3, R 4, R 5And R 6When being not hydrogen simultaneously, or R 1Be heterocyclic radical alkyl, aryl or heteroaryl, when B does not exist and R 3, R 4, R 5And R 6When being hydrogen simultaneously;
R 2Be hydrogen or (C 1-C 6) alkyl, (C 1-C 6) alkenyl or (C 1-C 6) alkynyl;
R 3, R 4, R 5And R 6A is hydrogen or (C independently of one another 1-C 6) alkyl; Or R 3And R 4, R 5And R 6Or R 3And R 5Can form (C with the atom that they connected 3-C 7) the alkyl ring.
2. the described compound of claim 1, wherein B does not exist and R 1Be optional be selected from trifluoromethyl, halogen ,-Y-R a,-Y-OR aWith-Y-C (O) R aThe aryl that the substituting group of the group of forming replaces; Y is key or (C 1-C 3) alkylidene group and R aBe (C 1-C 6) alkyl, aryl, heterocyclic radical, heteroaryl or heterocyclic radical.
3. claim 1 or 2 described compound, wherein R 1It is unsubstituted phenyl.
4. claim 1 or 2 described compound, wherein R 1Be selected from trifluoromethyl, halogen ,-Y-R a,-Y-OR aWith-Y-C (O) R aThe phenyl that the substituting group of the group of forming replaces; Y is key or (C 1-C 3) alkylidene group and R aBe (C 1-C 6) alkyl, aryl, heterocyclic radical, heteroaryl or heterocyclic radical.
5. any described compound, wherein a R among the claim 1-4 aBe to choose wantonly to be selected from (C 1-C 6) alkyl, (C 1-C 6) phenyl that replaces of the substituting group of the group formed of alkoxyl group, trifluoromethyl and halogen.
6. any described compound, wherein a R among the claim 1-5 1By at least one-Y-R aThe phenyl that replaces, wherein Y is key or (C 1-C 3) alkylidene group; R aBe to choose wantonly to be selected from (C 1-C 6) alkyl, (C 1-C 6) phenyl that replaces of the substituting group of the group formed of alkoxyl group, trifluoromethyl and halogen.
7. any described compound, wherein a R among the claim 1-6 1By at least one-Y-R aThe phenyl that replaces; Wherein Y is key or (C 1-C 3) alkylidene group; R aIt is the optional heteroaryl that replaces.
8. any described compound, wherein a R among the claim 1-7 1By at least one-Y-OR aThe phenyl that replaces, wherein Y is key or (C 1-C 3) alkylidene group and R aBe to choose wantonly to be selected from (C 1-C 6) alkyl, (C 1-C 6) phenyl that replaces of the substituting group of the group formed of alkoxyl group, trifluoromethyl and halogen.
9. any described compound, wherein a R among the claim 1-8 1By at least one-Y-C (O) R aThe phenyl that replaces; Wherein Y is key or (C 1-C 3) alkylidene group and R aBe to choose wantonly to be selected from (C by at least one 1-C 6) alkyl, (C 1-C 6) phenyl that replaces of the substituting group of the group formed of alkoxyl group, trifluoromethyl and halogen.
10. any described compound among the claim 1-9, wherein B does not exist and R 1It is heteroaryl.
11. any described compound, wherein a R among the claim 1-10 1Be selected from trifluoromethyl, halogen ,-Y-R a,-Y-OR aWith-Y-C (O) R aThe heteroaryl that the substituting group of the group of forming replaces, wherein Y is key or (C 1-C 3) alkylidene group and R aBe (C 1-C 6) alkyl, aryl, heterocyclic radical, heteroaryl or heterocyclic radical.
12. any described compound among the claim 1-11, wherein B does not exist, R 3And R 4Be (C 1-C 6) alkyl.
13. any described compound, wherein a R among the claim 1-12 1Be optional be selected from trifluoromethyl, halogen ,-Y-R a,-Y-OR aWith-Y-C (O) R aThe phenyl that the substituting group of the group of forming replaces; Y is key or (C 1-C 3) alkylidene group and R aBe (C 1-C 6) alkyl, aryl, heterocyclic radical, heteroaryl or heterocyclic radical.
14. any described compound, wherein a R among the claim 1-13 1Be optional be selected from trifluoromethyl, halogen ,-Y-R a,-Y-OR aWith-Y-C (O) R aThe heteroaryl that the substituting group of the group of forming replaces; Y is key or (C 1-C 3) alkylidene group and R aBe (C 1-C 6) alkyl, aryl, heterocyclic radical, heteroaryl or heterocyclic radical.
15. any described compound, wherein a R among the claim 1-14 1It is the alkyl or cycloalkyl alkyl.
16. any described compound among the claim 1-15, wherein A is-CH 2-CH 2
17. any described compound among the claim 1-16, wherein B does not exist and A is-CH 2-CH 2
18. any described compound among the claim 1-17, wherein B does not exist and R 1Be optional be selected from trifluoromethyl, halogen ,-Y-R a,-Y-OR aWith-Y-C (O) R aThe phenyl that the substituting group of the group of forming replaces; Wherein Y is key or (C 1-C 3) alkylidene group and R aBe (C 1-C 6) alkyl, aryl, heterocyclic radical, heteroaryl or heterocyclic radical.
19. any described compound among the claim 1-16, wherein B is an aryl, and m is 1 or 2 and R 1Be alkyl, aryl or heteroaryl.
20. any described compound, wherein a R among the claim 1-19 1It is the optional phenyl that replaces.
21. any described compound, wherein a R among the claim 1-19 1It is alkyl.
22. any described compound among the claim 1-21, wherein B is a heteroaryl, and m is 1 or 2 and R 1It is alkyl.
23. any one compound among the claim 1-22 is selected from the group that following compounds is formed:
7-{ (R)-2-[(E)-3-(4 '-chloro-2 '-methyl-xenyl-3-yl)-3-hydroxyl-propyl group]-5-oxo-tetramethyleneimine-1-yl }-enanthic acid;
7-{ (R)-5-[(E)-3-hydroxyl-3-(5-trifluoromethyl-furans-2-yl)-propenyl]-3,3-dimethyl-2-oxo-tetramethyleneimine-1-yl }-enanthic acid;
7-{ (R)-5-[(E)-3-hydroxyl-4-(3-methoxymethyl-phenyl)-but-1-ene base]-3,3-dimethyl-2-oxo-tetramethyleneimine-1-yl }-enanthic acid;
7-(R)-2-{ (E)-3-[3-(4-chloro-phenoxy group)-phenyl]-3-hydroxyl-propenyl }-5-oxo-tetramethyleneimine-1-yl)-enanthic acid;
4-{2-[(R)-2-((E)-3-hydroxyl-Xin-1-thiazolinyl)-5-oxo-tetramethyleneimine-1-yl]-ethyl }-phenylformic acid;
4-(2-{ (S)-2-[(R)-3-(4 '-chloro-2 '-methyl-xenyl-3-yl)-3-hydroxyl-propyl group]-5-oxo-tetramethyleneimine-1-yl }-ethyl)-phenylformic acid; With
5-[(R)-2-((E)-3-hydroxyl-Xin-1-thiazolinyl)-5-oxo-tetramethyleneimine-1-yl]-ethyl)-thiophene-2-carboxylic acid.
24. the preparation method of any one compound among the claim 1-23, this method comprises the following steps:
Make general formula aCompound and general formula mPhosphonate reaction,
Its formula of aThe structural formula of compound as follows:
Figure A028140910005C1
Wherein m, R 3, R 4, R 5And R 6As defined in claim 1 and wherein R ' is methyl or ethyl;
Its formula of mStructural formula as follows:
R wherein 1Such as claim 1 definition;
Reduce subsequently and optional being hydrolyzed and obtain the compound of general formula I:
Figure A028140910006C1
R wherein 2Be hydrogen and m, R 1, R 3, R 4, R 5, R 6With Z such as claim 1 definition.
25. any one compound among the claim 1-23 is as therapeutic active substance.
26. any one compound among the claim 1-23 is used for being used to prevent the medicine of the disease relevant with bone disorder with treatment in production.
27. any one compound is used for the treatment of application in the medicine of the disease relevant with bone disorder with prevention in production among the claim 1-23.
28. according to any one compound among the claim 1-23 of claim 24 preparation.
29. pharmaceutical composition comprises any one compound among the claim 1-23 with the treatment significant quantity of at least a suitable carriers, thinner or mixed with excipients.
30. can be by giving selectivity EP 4The methods of treatment of the mammalian diseases of prostaglandin agonists treatment, this method comprises the step of described Mammals being treated compound any among the claim 1-23 of significant quantity.
31. the described method of claim 30, wherein said disease is relevant with bone disorder.
32. the present invention as indicated above.
CN 02814091 2001-07-16 2002-07-08 8-aza-11-deoxy prostaglandin analogues Pending CN1863768A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106748951A (en) * 2012-07-19 2017-05-31 开曼化学股份有限公司 As the difluoro lactam compound of the EP4 receptor selective agonists used in the disease and symptom that treatment EP4 is mediated

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106748951A (en) * 2012-07-19 2017-05-31 开曼化学股份有限公司 As the difluoro lactam compound of the EP4 receptor selective agonists used in the disease and symptom that treatment EP4 is mediated

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