CN1169528C

CN1169528C - Prostaglandin derivatives devoid of side-effects for treatment of glaucoma

Info

Publication number: CN1169528C
Application number: CNB988070456A
Authority: CN
Inventors: J; J·斯特杰恩斯查茨; ն�; B·里苏尔; S·莱克
Original assignee: Pharmacia and Upjohn AB
Current assignee: Pfizer Health AB
Priority date: 1997-07-11
Filing date: 1998-07-10
Publication date: 2004-10-06
Anticipated expiration: 2018-07-10
Also published as: BR9815501A; EP1014991A1; TR200000008T2; NO20000062L; JP2002509543A; CN1262623A; NO20000062D0; HK1029942A1; CA2294779A1; IL133871A0; NZ501834A; WO1999002165A1; HUP0003106A2; KR20010021682A; AU739828B2; HUP0003106A3; SK183499A3; SE9702706D0; RU2207858C2; PL337940A1

Abstract

A new method and compositions for the treatment of glaucoma and ocular hypertension are described. The method is based on the usage of EP1 prostanoid receptor agonists which effectively reduce the intraocular pressure but have no, or reduced effect on iris pigmentation. The prostaglandin analogue which is an EP1 selective agonist is applied topically on the eye.

Description

To treating the derivatives of prostaglandins that glaucoma has no side effect

The present invention relates to use the too high method of prostaglandin analogue or derivatives to treat glaucoma and borehole pressure, described analog or derivant do not have melanocyte to generate effect to eye or the effect of reduction are arranged.The invention still further relates to the ophthalmic composition of prostaglandin-containing chemical compound, described chemical compound does not have melanocyte to generate effect to eye or the effect of reduction is arranged.

Glaucoma is a kind of oculopathy, it is characterized in that the increase of intraocular pressure, the pouch of papilla of optic nerve and the forfeiture gradually in the visual field.Usually the intraocular pressure that known exception is high is harmful to eye, and has clearly that indication shows, intraocular pressure is the greatest factor that causes retina and papilla of optic nerve degeneration variation in the glaucoma.Yet, also do not know the accurate pathophysiological mechanism of open-angle glaucoma.Unless treatment, glaucoma can cause losing one's sight, and this sick course of disease generally slows down along with the carrying out property forfeiture of vision.

Intraocular pressure (IOP) can be represented by following formula (1):

(1) IOP=Pe+ (Ft-Fu) * R wherein Pe be episcleral veins pressure, Ft is hydatoid formation, Fu is the aqueous humour part that flows out eyes along uvea sclera flow pass, R then is the resistance in the girder flow pass.Aqueous humour in the anterior eye and the back eye-chamber produces by retro-iridian ciliary processes.This aqueous humour flows into anterior eye by pupil then, and normally passes trabecular reticulum and sinus venous sclerae and flow out and enter extrabulbar episcleral veins from eyes.But the part aqueous humour may be left eyes by uvea sclera flow pass.Think that flowing in this passage just is subjected to minimum degree the influence (Bill, 1975) of intraocular pressure.People's intraocular pressure is generally in the scope of 12～22mmHg.Under high pressure (for example more than the 22mmHg) more, the danger that eyes may damaged will increase.Yet, under a kind of situation of glaucoma (being the normal pressure glaucoma) of form, damage may appear when the intraocular pressure level in the normal physiological scope.Also see opposite situation, promptly some individuality may show unusual high intraocular pressure and aspect the visual field or papilla of optic nerve without any obvious defects.It is too high that these situations are commonly called borehole pressure.

Glaucoma can pass through medicine, laser or surgical operation therapy.In Drug therapy, purpose is to reduce hydatoid formation (Ft) or reduce hydatoid resistance to outflow (R), will cause the reduction of intraocular pressure like this by following formula (1); Also can increase the discharge of aqueous humour, also reduce intraocular pressure by formula (1) like this via uvea sclera approach.

Prostaglandin (PGF typically _{2 α}, its ester and analog) mainly reduce intraocular pressure (Crawford and Kaufman, 1987 by the discharge that increases hydatoid uvea sclera; Nilsson etc., 1989; Toris etc., 1993; Stjernschantz etc., 1995).The application of prostaglandin and derivant thereof is described in several parts of patents and the patent application, for example at US4,599,353 (Bito), US4, among 952,581 (Bito), WO89/03384 (Resul and Stjernschantz), EP170258 (Cooper), EP253094 (Goh) and the EP308135 (Ueno).

Prostaglandin is a fatty acid, derives from precursor eicosatrienoic acid, eicosatetraenoic acid and eicosapentaenoic acid by the metabolism step that comprises Oxygenation usually.Natural prostaglandins has the population structure shown in Fig. 1 usually.

Fig. 1

So prostaglandin has a Pentamethylene. ring, be connected with two carbochains above it, the chain of top is commonly called the α chain, and the chain of below is commonly called the ω chain.According to the structure of this Pentamethylene. ring and substituent group and prostaglandin is divided into A, B, C, D, E, F, G, H, I and J subclass, as shown in Figure 2.

Fig. 2

The α chain is the aliphatic chain of 7 carbon, carboxy blocking, and the ω chain then is the aliphatic chain of 8 carbon, methyl blocking.Provide 1～3 subscript according to the double key number in these chains.At (the PGF for example of the prostaglandin with subscript 1 _{1 α}) in, between the carbon 13 and carbon 14 of double bond position in the ω chain, and it presents anti-configuration in natural prostaglandins.At (the PGF for example of the prostaglandin with subscript 2 _{2 α}) in, be between the carbon 5 and carbon 6 of another double bond position in the α chain of cis-configuration, and last in prostaglandin with subscript 3, and the 3rd double bond position is between the carbon 17 and carbon 18 of ω chain.This pair key also presents cis-configuration in natural prostaglandins.All prostaglandins all have a hydroxyl on carbon 15, it is that biological activity is necessary.

The receptor system of natural prostaglandins has just just been set forth in the recent period.So most of prostaglandin receptors have been characterized on pharmacology, and have identified their molecular structure (Coleman etc., 1994) by molecular biotechnology.Specific receptor is all arranged for natural prostaglandins.PGD, PGE, PGF, PGI ₂(prostacyclin) and TxA ₂The receptor of (thromboxane) is respectively DP, EP, FP, IP and the TP of abbreviation.In addition, confirmed that the EP receptor can be subdivided into four kinds of receptors, i.e. EP ₁, EP ₂, EP ₃And EP ₄Receptor.Specific tissue or cell may only be expressed several or be expressed multiple these receptors, and this depends on the evolutionary development of this autacoid system in the different plant species.So, for example having confirmed the FP receptor of contraction of link coupled and mediation pupil on the main expressive function of cat iris sphincter, corresponding buphthalmos smooth muscle is then expressed EP ₁With the TP receptor, they any activation all will cause the contraction of muscle.Be called as analeptic with a kind of specific receptors bind and the chemical compound that activates it, but the chemical compound that does not only activate it with receptors bind then is called as antagonist.

As for the practical application of many prostaglandins and their derivant as the too high suitable drug of treatment glaucoma or borehole pressure, a limiting factor may be the performance that increases (Stjernschantz and Alm, 1996) that they cause ophthalmic iris pigment calmness.So in monkey and people's long-term treatment process, it is darker that the color of iris is tended to become, and changes into brown.Even now does not obviously have passive medical outcome, but considers that from the beauty treatment angle it is a significant disadvantages, especially in the patient who only treats an eye.Thereby wish to determine such prostaglandin: they can reduce this side effect that increases that intraocular pressure does not cause the iris pigment calmness again effectively.We now have been surprised to find that, as the EP of prostaglandin receptoroid ₁This criterion that the derivatives of prostaglandins of the selective excitement agent of subclass and analog meet prostaglandin analogue promptly reduces intraocular pressure effectively and does not cause in the iris increase of the pigment (melanocyte generation) that produces.The background of this discovery is, in the research of the melanocytic prostaglandin receptoroid of surveyor's iris subclass, we have found that these cells express FP, EP in their cell membrane ₂And EP ₃Receptor, but do not express EP ₁With the TP receptor.In addition, we have studied the EP of several relative selectivities ₁Anti-depressant intraocular pressure reduces effect, and has found that these prostaglandin analogues effectively and have effectively reduced the intraocular pressure of cat and monkey.

Therefore, now show, by application choice EP ₁Receptor agonist, can reduce the intraocular pressure of primate, so also can reduce people's intraocular pressure, and can not increase melanocyte nucleus formation as side effect, perhaps have only this effect of obvious reduction, go into the required specific receptor of cell because produce cell (melanocyte) the shortage transmembrane signal granting of melanocyte.Though we do not have clinical evidence to show these selectivitys EP at present ₁Analeptic can not cause increasing of iris pigment calmness, because the induction time normally 6～12 months of this phenomenon takes place, so must carry out test of a specified duration especially, that expense is high to primate, but we can sum up from relevant in vitro study, and this Pigmented increasing under the situation that can not exist specific signals to provide receptor in melanocytic cell membrane occurs.

Therefore, compare with other prostaglandin receptor of ophthalmic, to EP ₁The high selectivity of receptor or specificity become the feature that is applied to the chemical compound in method of the present invention or the compositions.Much less, described chemical compound is to EP ₁The selectivity of receptor is high more, and then the result of Huo Deing is good more, but has also obtained certain effect under some interaction with other receptor certainly.In this respect, high selectivity is represented EP ₁The effect that the effect of receptor is compared other prostaglandin receptor is high at least 5 times, and is especially high 10 times, particularly high 100 times or 1000 times.

The concrete prostaglandin analogue that we are used to illustrate and verify in the present invention is: PGF _{2 β}(1), PGF _{2 β}Isopropyl ester (2), 17-phenyl-18,19,20-three nor--PGE ₂(3), 17-phenyl-18,19,20-three nor--PGE2 isopropyl esters (4), 15 (R, S)-16,16-propylidene-PGE ₂(5), 15 (R, S)-16,16-propylidene-PGE ₂Methyl ester (6), and 13,14-dihydro-17-(3-fluorophenyl)-18,19,20-three nor--PGE ₂-isopropyl ester (7).All these analog all are the EP of relative selectivity ₁Receptor agonist.The receptor overall picture of test compound is given in the Table I.

Table I. the receptor overall picture of the prostaglandin analogue of test (the EC-50 value of in the functional receptor analysis, representing) with mol/l

Prostaglandin F P EP ₁EP ₂EP ₃DP/IP TP

1 50×10 ^-6 10 ^-6 10 ^-5 ＞10 ^-4 ＞10 ^-3 ＞10 ^-3

3 10 ^-7 2×10 ^-8 ＞10 ^-4 ＞10 ^-4 ＞10 ^-4 ＞10 ^-4

5 2×10 ^-5 6×10 ^-9 2×10 ^-7 3×10 ^-8#?＞10 ^-4 ＞10 ^-4

7 6×10 ^-7 4×10 ^-8 5×10 ^-5 10 ^-6# ＞10 ^-4 ＞10 ^-4

# estimates based on the difference between Cavia porcellus deferent duct in the receptor assay and the chickling ileum.

On the one hand, the present invention relates to not have melanocyte generate effect, selective prostaglandins EP ₁The application of receptor agonist in the too high treatment of glaucoma or borehole pressure.The treatment glaucoma comprises that with the too high method of borehole pressure the surface that makes eye contacts the compositions that intraocular pressure reduces effective dose, and described compositions contains aforementioned EP ₁Selective prostaglandins is to reduce intraocular pressure and described pressure to be remained on the level of reduction.Said composition contains 0.1～100 μ g that has an appointment usually, especially the each active substance of using of 1～30 μ g.Said composition was locally applied on the eye for 1～3 time by every day.

Carrier compatible on derivatives of prostaglandins and the original known opthalmological is mixed.The carrier that can be used to prepare compositions of the present invention comprises aqueous solution for example normal saline, oil solution or ointment.Described carrier also can contain for example Benasept of antiseptic compatible on the opthalmological, and surfactant is Spheron MD 30/70 for example, and liposome or polymer be methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone and hyaluronic acid for example; These materials can be used to improve viscosity.In addition, it also may using soluble or insoluble medicine insert.

On the other hand, the present invention relates to cure glaucoma or the too high ophthalmic pharmaceutical compositions of borehole pressure, said composition comprises and reduces the prostaglandin analogue of effective dose by intraocular pressure (it is previously defined EP ₁The selective excitement agent of receptor) compatible carrier and on the opthalmological.Described effective dose generally includes the dosage of about 0.1～100 μ g in about 10～50 μ l compositionss.Compositions of the present invention improves significantly than prior art prostaglandin composition, and this is owing to described reactive compound and other prostaglandin receptor is compared EP ₁The selectivity of receptor has been eliminated or has at least greatly been reduced Pigmented danger.

Aspect another, the present invention relates to prostaglandin analogue and be used for the treatment of application aspect the too high medicament of glaucoma and borehole pressure in preparation.

Preferably, described prostaglandin analogue derives from PGF or PGE prostanoid.Specifically, this prostaglandin analogue is the chemical compound of following general formula:

Wherein:

The ripple key table shows α or beta comfiguration, and empty key table shows the two keys in singly-bound, triple bond or cis or the anti-configuration;

R is a hydrogen, saturated or unsaturated alkyl, preferably C _1-10Alkyl, cycloalkyl, preferably C _3-8Cycloalkyl, aryl, aryl alkyl, preferably aryl-C _2～5Alkyl, or heteroaryl;

R1 has the saturated or unsaturated alkyl that 2～5 carbon atoms, the optional hetero atom that is selected from oxygen, sulfur and nitrogen have separated, cycloalkyl, preferably C _3-7Cycloalkyl, cycloalkenyl group, preferably C _3-7Cycloalkenyl group, aryl or heteroaryl;

X is C-OH or C=O;

R2 is hydrogen, hydroxyl, methyl, ethyl, methoxyl group or OCOR4, and wherein R4 is the saturated or unsaturated alkyl of straight or branched, preferably C _1-10Alkyl, especially C _1-6Alkyl, perhaps cycloalkyl, preferably C _3-8Cycloalkyl, perhaps aryl;

R3 preferably has 3～8 carbon atoms, 3～5 carbon atoms especially, the saturated or unsaturated alkyl of straight or branched that one or more hetero atoms that optional quilt is selected from oxygen, sulfur and nitrogen have separated, the optional C that is selected from of each carbon atom _1-5The substituent group of alkyl, hydroxyl and carbonyl has replaced, and hydroxyl and carbonyl preferably are connected on the carbon 15 of prostaglandin structure, and optional cycloalkyl, the preferably C of containing of described alkyl _3～8Cycloalkyl, aryl or heteroaryl, it can be by C _1-3Alkyl, C _1-3Alkoxyl, hydroxyl, nitro, trifluoromethyl or halogen list replace or are polysubstituted independently;

Perhaps its pharmaceutically acceptable salt or ester.

Phenyl that aryl preferably replaces or unsubstituted.

Heteroaryl for example has: thiophene, furan, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine.

Aryl, heteroaryl and cycloalkyl can be by C _1-3Alkyl, C _1-3Alkoxyl, hydroxyl, nitro, trifluoromethyl or halogen list replace or two replacements or polysubstituted independently.

Unsaturated alkyl can contain one or more pairs of keys and/or triple bond.

Halogen is fluorine, chlorine, bromine or iodine, especially fluorine, chlorine or bromine.

Described prostaglandin can be the epimer form of mixtures and be independent epimer form.

Set forth the present invention by following non-restrictive example:

The evaluation of prostaglandin receptorProstaglandin receptor is to use reverse transcriptase-polymerase chain reaction (RT-PCR) technical appraisement.Be FP, EP ₁, EP ₂, EP ₃Designed Auele Specific Primer with the TP receptor.The primer that is used for this analysis is listed in the Table II.RT-PCR is carrying out from the isolating mRNA of human iris's melanocyte that cultivates.Described cultured cells is used to prepare mRNA.The RT-PCR mixture is analyzed on agarose gel, and the band of desired size is cloned and checked order.Analyze the sequence of supposition and the similarity of each prostaglandin receptor sequence.

MethodSeparate and cultivate human iris's melanocyte and be used for going down to posterity in early days by the method for (1993) such as Hu.Cell grows to and is paved with the back collection for the mRNA enrichment.

Use Dynals mRNA Direct System (Dynal A/S, Norway) separating mRNA by manufacturer's indication.100.000～200.000 people's melanocytes are used for enrichment.MRNA is connected on the Dynabead of oligodeoxythymidylic acid labelling with covalent bond.Using reverse transcriptase is reverse transcriptase primer directly synthetic first chain cDNA on described Dynabeads with the oligodeoxythymidylic acid.Application derives from the synthetic second chain cDNA of known 3 ' aligning primer of prostaglandin receptor separately, forms double-stranded cDNA.Same group of Dynabeads is used for every kind of receptor RT-PCR.Indication by the manufacturer is used for the receptor-specific primer to begin pcr amplified dna from the bonded cDNA of Dynabead.As for FP and EP3 receptor response, PCR carries out in containing 50 μ l final volumes of 5%DMSO, 200 μ MdNTPs and every kind of primer of 20 picomoles.As for other receptor, (Perkin Elmer, hot initial being used to USA) contains in the 75 μ l final volumes of 5%DMSO, 200 μ M dNTPs and every kind of primer of 20 picomoles will to contain the AmpliWax pill.

Table II. the prostaglandin receptor Auele Specific Primer.

The FP primer:

Elementary primer; CAC AAC CTG CCA GAC GGA AAA C and CCA GTC TTTGAT GTC TTC TGT G

Secondary primer; CAG TAA TCT TCA TGA CAG TGG G and TTG TAG AAACAC CAG GTC CTG G

EP ₁Primer:

Elementary primer; TGT GGC ATG GCC GTG GAG and ACC AAC ACC AGC ATTGGG C

Secondary primer; CTG CAG GGA GGT AGA GCT C and GGC ACG TGG TGCTTC ATC G

EP ₂Primer:

Elementary primer; CAA CCA TGC CTA TTT CTA CAG C and TCT CGC TCC AAACTT GGC TG

Secondary primer; CTA CGT GGA CAA GCG ATT GGC and TGG TTG ACGAAC ACT CGC AC

EP ₃Primer:

Elementary primer; GGG ATC CAA GAT CTG GTT CAG and GCC TTC CCG ATCACC ATG CTG

Secondary primer; CGC AAG AAG TCG TTC CTG CTG and CAC CAA GTCCCG GGC CAC TG

The TP primer:

Elementary primer; CTG GTG ACC GGT ACC ATC GTG GTG T and GTA GAT CTACTG CAG CCC GGA GCG C

Secondary primer; TCG CTA CAC CGT GCA ATA CC and GGC TGG AGG GACAGC GAC

The PCR mixture of these reactions is that (BioRadLaboratories USA) upward analyzes at the 1%LMP agarose gel.The dna fragmentation of desired size is to use indication (the Invitrogen Inc. of TA-clone box by the manufacturer, USA) carry out the TA clone's, and (AppliedBiosystems Inc. USA) goes up order-checking at Applied Biosystem 373A type dna sequencing system about their Taq Dye Dioxy Terminator cycle sequencing box scheme to press Applied Biosystems.Application derives from Genetics ComputerGroupInc., Madison, USA[Devereux, J. etc., nucleic acids research (Nucleic AcidResearch) 12 (1): 387～395 (1984)] the sequence analysis program on the VAX computer, handle the initial data that produces.

The result: in the human iris's melanocyte of RT-PCR based on us, we can confirm FP, EP ₂And EP ₃Receptor expression.But we can not confirm EP ₁Exist (Table III) with the TP receptor.As positive control, we are with the same primers as that the derives from people's kidney cDNA library desired EP that increased ₁With the TP fragment.We from the enrichment of two isolating human iris's melanocytes of different time polyadenylic acid mRNA and carried out PCR reaction for several times, obtain identical result.

Table III. the RT-PCR (secondary PCR primer) of human iris's melanocyte mRNA that application prostaglandin receptor Auele Specific Primer (seeing Table II) carries out.

The correct fragment chi of gene sequence analysis

Very little (bp)

The expectation of observation

FP+489 are identical with FP

EP ₁ - 397 -

EP ₂+ 501 and EP ₂Identical

EP ₃+ 372 and EP ₃Identical

TP - 484 -

Synthesizing of derivatives of prostaglandins

The structure of the target compound for preparing among the embodiment has been shown in the sketch map 1 that this description is enclosed later.

Implement 1:PGF _{2 β}(chemical compound 1)

This title compound is from Cayman Chemicals Company, Ann ArborMichigan, and USA buys.

Embodiment 2: PGF _{2 β}Isopropyl ester (chemical compound 2)

0 ℃ and stir under, (163.5mg 1.01mmol) is added to PGF with DBU _{2 β}(CaymanChemicals) (60mg is 0.169mmol) in the solution of acetone (20ml).Allow this mixture be warmed to room temperature, this moment drip 2-iodopropane (222.6mg, 1.34mmol).Behind the 48h (TLC monitoring), (40ml) dilutes this mixture with ethyl acetate, with saline (30ml), 3% citric acid (2 * 40ml) and 5% sodium bicarbonate (2 * 30ml) washings, dry on anhydrous sodium sulfate.Remove in a vacuum and desolvate, use the ethyl acetate of 3:1: acetone is that eluent carries out chromatography to residue on silica gel.Get colorless oil, output is 46mg (68%). ¹H NMR (CDCl ₃) d1.3 (d, 6H), 1,6-1,7 (dm, 4H), 2.0-2.2 (dm, 6H), 2.3 (t, 2H), 4.0-4.1 (m, 3H), 5.0 (split swarming, 1H), 5.5 (m, 2H), 5.6 (m, 2H). ¹³CNMR (CDCl ₃) d135.9,132.2,130.5,128.0,75.3,74.8,72.85,67.6,56.23,52.25,51.59,42.32,37.35,33.44,31.74,29.14,26.66,24.79,22.6,21.8,14.03.

Embodiment 3: 17-phenyl-18,19,20-three nor--PGE ₂(chemical compound 3)

Embodiment 4: 17-phenyl-18,19,20-three nor--PGE ₂Isopropyl ester (chemical compound 4)

0 ℃ and stir under, (43.5mg, 0.29mmol) drips of solution in acetonitrile (1ml) is added to chemical compound 3 (22.1mg is 0.057mmol) in the solution of acetonitrile (3ml) with DBU.Allow this mixture be warmed to room temperature, drip 2-iodopropane (78.0mg, 0.46mmol) solution in acetonitrile (2ml) then.After stirring 12h (TLC monitoring), this reactant mixture of water (8ml) quencher, (2 * 50ml) extract this mixture, with saline (10ml), 3% citric acid (10ml) and last with 5% sodium bicarbonate (10ml) washing extracting solution with ethyl acetate.After drying on the anhydrous sodium sulfate, remove in a vacuum and desolvate, using ethyl acetate is that eluent carries out chromatography to remaining grease on silica gel.Get the product (69%) of 230mg colorless oil title compound: R _f=0.516 (ethyl acetate: acetone: HOA _C=1: 1: 0.02); ¹H NMR (CDCl ₃) d0.89 (m, 3H), 1.3 (d, 6H), 2.6-2.8 (m, 2H), 4.1 (m, 2H), 5.0 (m, 1H), 5.3-5.7 (dm, 4H), 7.2 (m, 5H). ¹³C NMR (CDCl ₃) d10.9,13.9,21.8,22.9,23.8,24.49,24.8,25.17,25.6,26.68,28.93,30.45,31.77,33.90,34.01,34.07,38.8,46.22,53.3,54.48,66.83,67.62,68.18,71.77,72.21,76.35,77.00,77.2,77.64,125.93,126.46,128.39,128.44,128.79,130.63,130.81,131.04,137.79,213.88.

Embodiment 5: 15RS-16,16-propylidene-PGE ₂(chemical compound 5)

Under agitation past 15RS-16,16-propylidene-PGE ₂(52mg is 0.13mmol) in acetone (0.4ml) and phosphate buffer (pH7, interpolation lipase VII (40mg) in solution 4ml) for methyl ester.At room temperature stir this mixture and reach 24h (TLC monitoring).(2 * 10ml) extract with this mixture of ethanol (3ml) quencher and with ethyl acetate.With salt water washing organic layer, dry (sodium sulfate), vacuum concentration gets 46mg oily product.

Embodiment 6: 15RS-16,16-propylidene-PGE ₂Methyl ester (chemical compound 6)

15RS-16,16-propylidene prostaglandin E ₂Synthetic (Skotnicki, S. etc., 1977) diagrammatize in sketch map 2.Separately structure in the numeral sketch map 2 hereinafter.

2,2-propylidene ethyl hexanoate (9)

-78 ℃ and stir under, toward N-isopropyl cyclohexylamine (56,2g, 398mmol) interpolation n-BuLi (159ml, 398mmol is 2.5M in hexane) the rapidly solution in THF (400ml) in.(50g 390mmol) and stirred 30 minutes, is warmed to 0 ℃ then, and this solution is splashed into n-butyl iodide, and (159ml, 398mmol are in hexane, 2.5mol) in the solution of DMSO (200ml) to drip cyclobutane carboxylate (8) in the solution that forms.At room temperature stir this reactant mixture and reach 1h (TLC monitoring).Remove by filter salt, vacuum concentrated filtrate.Residue is dissolved in hexane, dry on sodium sulfate then with 2%HCl, saline and water washing, vacuum evaporation.The remaining grease of distillation (49～56 ℃, 1mm Hg) gets 26.5g (37%) product.

¹H?NMR(CDCl ₃)d0.9(t，3H)，1.2(t，3H)，1.8-2.0(dm，5H)，2.2-2.5(m，3H)，4.2(m，2H).

2, the 2-propylidene oneself-1-alcohol (10)

0 ℃ and stir under, toward 2,2-propylidene ethyl hexanoate (9) (26.5g, 144mmol) in the solution of dry toluene (100ml) in dropping DIBAL-H (206ml, 298mmol is in toluene, 1.4mol).At room temperature stir the solution that forms and reach 3h (TLC monitoring), among then that this solution impouring is the ice-cold 5%HCl.Separate organic layer,, filter with 5%HCl, salt water washing, drying, concentrate 30g oily product. ¹H?NMR(CDCl ₃)d0.9(t，3H)，1.8～2.0(dm，5H)，2.5(m，1H)，3.0(m，1H)，3.6(m，2H)。

2,2-propylidene hexanal (11)

Toward 2, the 2-propylidene oneself-1-alcohol (10) (30g, 210mmol) in the solution of DME (400ml), add bicyclohexane carbodiimides (DCC) (130g, 630mmol), DMSO (120ml) and orthophosphoric acid (10.3g).At room temperature stir this mixture and reach 3h (TLC monitoring), filter.With dichloromethane (300ml) dilution filtrate, wash with water again.Separate organic layer.Remove by filter residue.With saline (100ml) wash filtrate, drying, vacuum concentration.Use hexane and on silica gel, pass through column chromatography purification residue, get oily title product (17.3g) as eluent. ¹HNMR(CDCl ₃)d0.9(t，3H)，1.2(t，3H)，1.8～2.0(dm，5H)，8.8(s，1H)。

4,4-propylidene-1-octyne-3-alcohol (12)

At 0 ℃ and N ₂It is past in the atmosphere that the ethynylation lithium-(12.2g 132mmol) adds 2 to the ethylenediamine complex in the solution of DMSO (10ml), 2-propylidene hexanal (11) (17g, 120mmol) solution in DMSO (20ml).At room temperature stir this mixture and reach 24h (TLC monitoring), in then that its impouring is ice-cold 2%HCl (50ml) and the ether (50ml).Separate organic layer, extract water layer,, filter vacuum concentration with the organic facies that the salt water washing merges, drying with ether (50ml).Use 5: 1 hexane: ethyl acetate is used the chromatography purification residue as eluent on silica gel, gets grease 12 (7.6g, 38%).

E-tributyl tin-4,4-propylidene-1-octene-3-alcohol (13)

Under 130 ℃ with 4,4-propylidene-1-octyne-3-alcohol (12) (5.0g, 30mmol), tributyltin hydride (14.6ml, 54.2mmol) and the mixture of AIBN (30mg) stir 24h (TLC monitoring).Use the hexane of hexane and 9: 1 respectively: ether is handled residue with chromatography as eluent on silica gel, oily title compound (13) (12.54g, 91.4%).

E-tributyl tin-4,4-propylidene-3-trimethyl silyloxy-1-octene (14)

Toward E-tributyl tin-4,4-propylidene-1-octene-3-alcohol (13) (7g, 15.3mmol) in the mixture of DMF (100ml), add imidazoles (2.1g, 30.6mmol) and trimethylsilyl chloride (2.5g, 23.0mmol).At room temperature stir this reactant mixture and reach 1h (TLC monitoring).This mixture is distributed between water (200ml) and the ether (200ml).Dry organic facies, vacuum evaporation.Use hexane and on silica gel, handle residue, get 14 (5.53g) with chromatography as eluent.

11, two (the trimethyl silyloxies)-16 of 15-, 16-propylidene-5,6-two dehydrogenations- PGE2 methyl ester (17)

Packing in a dried 100ml three-necked bottle, (928mg is 10.4mmol) with a magnetic stirring bar for copper cyanider (I).Cover this flask and heating in vacuum with rubber septum and remove the water of trace, again at N ₂In be cooled to 0 ℃.Add anhydrous THF by syringe, (14ml, 22.4mmol is in ether, 1.6mol) then to add lithium methide.Stir this mixture down at 0 ℃ and reach 15 minutes, in whipping process, it is limpid and even that this suspension becomes.Add E-tributyl tin-4 by syringe under 0 ℃, (5.9g, the 11.2mmol) solution in THF (10ml) at room temperature stirred 30 minutes 4-propylidene-3-trimethyl silyloxy-1-octene (14) again.Under-70 ℃, in the solution that forms, add 4-(tert-butyl group dimethyl methyl siloxy)-cyclopentenone (15) (1.7g in succession, 8mmol) solution in THF (6ml), trimethylsilyl chloride (4.35g, 40mmol) and triethylamine (8.1g, 80mmol), stirred 15 minutes down at-70 ℃ again, stirred 15 minutes down at 0 ℃ then.This mixture is distributed between hexane (600ml) and the water (300ml).Separate organic layer, dry on sodium sulfate, filter final vacuum and concentrate, get the limpid thick silicyl enol ether of oily.Under agitation, at-30 ℃ and N ₂In in the solution of THF (50ml), add lithium methide (7.7ml toward this silicyl enol ether, 12.3mmol in ether, 1.6mol), stirred 30 minutes, then add freshly prepd 1-trifluoromethanesulfonic acid-2-hexynic acid methyl ester (16) (Erhardt, P.W. etc. 1987; Caldwell A.G. etc. 1979), stirred 5 minutes at-40 ℃.With the solution that saturated aqueous ammonium chloride (30ml) quencher forms, (3 * 100ml) extract the reuse ether, dry on sodium sulfate, filter final vacuum and concentrate.Use hexane: ethyl acetate (1: 1) is handled residue with chromatography as eluent on silica gel, gets limpid oily 15RS isomer mixture (2.71g, 57.3%) R _f=0.36 (SiO ₂, ether: hexane=1: 1), ¹H NMR (CDCl ₃) d0.2 (dm, 12H), 0.8～0.9 (ms, 18H), 1.8 (m, 2H), 2.3 (m, 4H), 3.7 (s, 3H), 3.9～4.1 (dm, 2H), 5.5～5.6 (2H).Also to the desilylation analog (16,16-propylidene-5,6-two dehydrogenations-PGE ₂Methyl ester) carried out ¹HNMR. ¹H?NMR(CDCl ₃)d0.9(t，3H)，1.2～1.3(m，3H)，1.9～2.1(m，4H)，3.7(s，3H)，4.1(m，2H)，5.6～5.9(dm，2H)。

11, two (the trimethyl silyloxies)-16 of 15-, 16-propylidene-PGE2 methyl ester

Under agitation, toward 11, two (the trimethyl silyloxies)-16 of 15-, 16-propylidene-5,6-two dehydrogenations-PGE ₂(500mg is 0.8mmol) in 1: 1 benzene: add Pd-BaSO in the solution of cyclohexane extraction (50ml) for methyl ester (17) ₄(250mg) and quinoline (250mg), and at-40 ℃ H ₂Stir 5h (TLC monitoring) in the atmosphere.Dilute this reactant mixture with ether, filter vacuum concentration by celite.Use 9: 1 hexane: ethyl acetate is handled residue with chromatography on silica gel, gets the corresponding product of 442mg.

16,16-propylidene-PGE2 methyl ester (6)

Under 0 ℃, toward 11, two (the trimethyl silyloxies)-16 of 15-, 16-propylidene-PGE ₂(374mg 0.589mmol) adds THF (1ml) solution of 40%HF (3.5ml) to methyl ester in the solution of THF (18ml).In the mixture with its impouring 5% sodium bicarbonate (30ml) and ethyl acetate (50ml) behind this reactant mixture stirring 5h (TLC monitoring).Separate organic layer, with ethyl acetate (2 * 30ml) washing water layers.Merge organic layer, dry on sodium sulfate, vacuum concentration.1: 1 hexane of sequential use: ethyl acetate and ethyl acetate are handled residue with chromatography on silica gel, get grease 6 (75mg, 31%). ¹H?NMR(CDCl ₃)d0.9(t，3H)，1.3(t，6H)，2.0-2.6(mm，9H)，(dm，5H)，3.6(s，3H)，4.1(m，2H)，5.4(m，2H)，5.6-5.8(dm，2H)； ¹³C?NMR(CDCl ₃)d14.222，14.9，23.7，24.7，25.2，26.2，26.5，26.6，26.8，29.7，33.4，36.5，44.9，46.0，51.6，54.0，54.6，71.9，76.7，77.06，77.1，77.38，126.5，126.9，127.7，130.9，132.5，132.9，133.36，133.46，174.15，214.32.

Embodiment 7: 13,14-dihydro-17-(3-fluorophenyl)-18,19,20 ,-three nor-PGE ₂Synthesizing of isopropyl ester (chemical compound 7)

The synthetic of this title compound diagrammatizes in sketch map 3.Separately structure in the numeral sketch map 3 hereinafter.

2-oxo-4-(3-fluorophenyl butyl) dimethyl phosphonate

In room temperature with under stirring, (4.17g 138mmol) drips 2-oxo-propyl phosphonic acid methyl ester (23.12g, 132.3mmol) solution in THF (110ml) in the suspension of anhydrous THF (250ml) toward using the washed sodium hydride of pentane in advance.Stir this reactant mixture and reach 2h, cool off in ice bath then, (10.2g, the 158.7mmol) solution-treated in hexane make to become dark-brown solution with n-BuLi.Stir 2h down at 0 ℃, then drip 3-fluoro benzyl bromide (25g, 132.3mmol) solution in THF (50ml).Allow this reactant mixture be warmed to room temperature gradually, behind the 3h (TLC monitoring), with 10%HCl (20ml) quencher.In this mixture impouring frozen water (200ml), use CHCl ₃(2 * 150ml) extract, and collected organic layer is with saline (150ml) washing, sequential use CH ₂Cl ₂On silica gel, handle as eluent with EtOAc, get the faint yellow oily thing of 19.5g with chromatography.R _f=0.37 (silica gel, 1: 1 EtOAc: acetone).

(1S, 5R, 6R, 7R)-6-formyl-7-(4-Phenylbenzoic acid base)-2-oxa-is two Ring [3.3.0] octane-3-ketone (19)

Toward be cooled to 18 ℃ alcohol 18 (19.0g, 53.9mmol) in the solution of DME (100ml), add dicyclohexyl carbodiimide (DCC) (33.3,161.8mmol), DMSO (38.2ml) and phosphoric acid (1.43ml, 21.28mmol).The temperature of this reactant mixture is kept below 25 ℃ reach 30 minutes.At room temperature stir this reactant mixture again and reach 2 hours (TLC monitoring), the filtering precipitate is with ether (2 * 50ml) washings.(organic layer that 2 * 50ml) washings merge extracts aqueous solution with ether (100ml), and collected organic layer is also dry on sodium sulfate, filters, and is directly used in down-go on foot for water (50ml) and saline.TLC R _f=0.37 (silica gel, 2: 1 EtOAc: toluene).

(1S, 5R, 6R, 7R)-6-{3-oxo-5-(3-fluorophenyl)-1-E-pentenyl }- 7-(4-Phenylbenzoic acid base)-2-oxabicyclo [3.3.0] octane-3-ketone (20)

In nitrogen and under stirring, toward using the washed NaH (1.9g of pentane in advance, 65.1mmol) dropping 2-oxo-4-(3-fluorophenyl) butyl phosphine dimethyl phthalate (Wadsworth in the suspension of DME (130ml), Jr., W.S., Deng 1961) (19.3g, 70.5mmol) solution in DME (100ml) and at room temperature vigorous stirring 1h.This mixture is cooled to-10 ℃ then, drips the solution of thick aldehyde 19.0 ℃ 30 minutes and behind room temperature 2h (TLC monitoring), with acetic acid this reactant mixture that neutralizes, remove in a vacuum and desolvate, residue is dissolved in EtOAc (200ml), water (50ml) and saline (50ml) wash.Dry organic layer on anhydrous sodium sulfate filters vacuum evaporation.Residue is stirred with ether (100ml), leach the white precipitate of formation,, get white crystalline material, output 17g (58.5%) R with the cold diethyl ether washing _f=0.56 (silica gel, 2: 1 ethyl acetate: toluene).

(1S, 5R, 6R, 7R)-6-(3S-3-hydroxyl-5-(3-fluorophenyl)-1-pentenyl) -7-(4-Phenylbenzoic acid base)-2-oxabicyclo [3.3.0] octane-3-ketone (21)

(17.1g is 34.3mmol) in THF (20ml) and cerium chloride (CeCl toward the ketenes 20 that is cooled to-20 ℃ in nitrogen ₃7H ₂O) (3.8g, 10.3mmol) in 1: 2 THF: be divided in the agitating solution in the ether (60ml) fraction ground add sodium borohydride (0.8g, 20.57mmol).This reactant mixture is stirred 2h (TLC monitoring).Raise the temperature to ± 0 ℃, the aqueous solution that passes through then to add water (20ml) and 10%HCl is to the pH4 quencher, and reuse EtOAc (50ml) extracts.Separate organic layer, use the salt water washing, dry on anhydrous sodium sulfate, vacuum concentration, the toluene of sequential use 2: 1 and 1: 1: EtOAc handles twice with chromatography as eluent on silica gel, must white crystal product 4 (5g), R _f=0.32 (silica gel, 2: 1 EtOAc: toluene).

(1S, 5R, 6R, 7R)-6-{3R-3-hydroxyl-5-(3-fluorophenyl)-1-amyl group }- 7-(4-Phenylbenzoic acid base)-2-oxabicyclo [3.3.0] octane-3-ketone (22)

Toward 10%Pd/C (0.1g) in sodium nitrite (3.6ml, 1.8mmol) and add 21 (3g, 6.0mmol) solution in ethanol (6.0ml) in the suspension of ethanol (15ml).In nitrogen atmosphere, stir this mixture and reach 6h (TLC monitoring), with the quencher of 1M HCl solution.Remove by filter catalyst by the celite pad, with absolute ethanol (15ml) washing.Remove in a vacuum and desolvate.The grease that forms is dissolved in EtOAc (100ml), washs with 15% saline (30ml).With EtOAc (40ml) washing water.The dry organic extract that merges filters on sodium sulfate.Remove in a vacuum and desolvate.Use EtOAc and on silica gel, handle residue, get 5 (2.94g), R with chromatography as eluent _f=0.25 (silica gel, EtOAc).

(1S, 5R, 6R, 7R)-6-{3R-3-hydroxyl-5-(3-fluorophenyl)-1-amyl group } -7-R-hydroxyl-2-oxabicyclo [3.3.0] octane-3-ketone (23)

(2.8g, (0.47g 3.3mmol), at room temperature stirs this mixture and reaches 6h (TLC monitoring) 5.65mmol) to add potassium carbonate in the solution of methanol (15ml) toward lactone 22.With 10%HCl aqueous solution this mixture that neutralizes, (2 * 30ml) extract reuse EtOAc.Dry organic facies on anhydrous sodium sulfate is evaporated to dried.Use 1: 1 EtOAc: acetone is handled crude product with chromatography as eluent on silica gel.Get the title compound 23 of white crystal product form; Output is 1.6g, R _f=0.17 (silica gel, EtOAc); ¹H NMR (CDCl ₃) d 1.2-1.4 (m, 1H), 1.54 (m, 3H), 1.8 (m, 3H), 2.1 (m, 1H), 2.2 (m, 1H), 2.3 (m, 1H), 2.6 (m, 2H), 2.67 (m, 1H), 2.8 (m, 2H), 3.60 (m, CH ₂CHOHCH ₂), 4.0 (m, CHOH), 4.92 (m, CHOC=O), 6.8-7.0 (m, 3H), 7.28 (m, 1H).

(1S, 5R, 6R, 7R)-6-{3R-3-tert-butyl group dimethyl methyl siloxy-5-(3- Fluorophenyl)-the 1-amyl group }-7-R-tert-butyl group dimethyl methyl siloxy-2-oxabicyclo [3.3.0] octane-3-ketone (24)

With tert-butyl group dimethyl chloride monosilane (2.3g, 14.9mmol) add glycol 23, triethylamine (2.1ml once, 14.8mmol) and 4-dimethylamino naphthyridine (0.06g, 0.1mmol) solution in dichloromethane (20ml), vigorous stirring 24h at room temperature, this reactant mixture of vacuum concentration.Crude product is dissolved in ethyl acetate (50ml), aqueous solution (20ml) washing of water (20ml) and 5% sodium bicarbonate.Dry organic facies on sodium sulfate is filtered vacuum concentration.Use dichloromethane and on silica gel, handle residue, get 3g oily product with chromatography as eluent.R _f=0.68 (silica gel, ether).

(1S, 5R, 6R, 7R)-6-{3R-3-tert-butyl group dimethyl methyl siloxy-5-(3- Fluorophenyl)-the 1-amyl group }-7-R-tert-butyl group dimethyl methyl siloxy-2-oxabicyclo [3.3.0] octane-3-alcohol (25)

-72/-80 ℃ and stir under, (1.1g, 7.43mmol) drips of solution in dry toluene (5.3ml) is added to lactone 24 (2.7g is 4.95mmol) in the solution of anhydrous THF (30ml) with diisobutyl aluminium hydride (DIBAL).Behind the 1h (TLC monitoring), with methanol (5ml) this reactant mixture of quencher and be warmed to room temperature, add water (50ml), 10%HCl aqueous solution (50ml), (2 * 50ml) extract with EtOAc.Use the dried over sodium sulfate organic layer, filter, remove in a vacuum and desolvate, use the EtOAc of EtOAc and 1: 1 respectively: acetone is handled residue with chromatography as eluent on silica gel, yellow oil product (2.7g), R _f=0.85 (silica gel, 1: 1 ethyl acetate).

13,14-dihydro-11,15-di-t-butyl dimethyl methyl siloxy-17-(3-fluorobenzene Base)-18,19,20-three nor--PGF2 α (26)

Under 0～5 ℃, in the nitrogen, (8.78g, (3.89g 34.6mmol), at room temperature stirs this mixture and reaches 30 minutes 19.82mmol) to add potassium tert-butoxide in the stirred suspension of THF (50ml) toward 4-carboxybutyl three phenyl phosphonium bromides.-15/-10 ℃ down in the salmon pink that generates in the saline solution interpolation inner hemiacetal 25 (2.7g, the 4.95mmol) solution in THF (10ml) stir this mixture and reach 3～4h (TLC monitoring).Water (30ml) dilutes this reactant mixture, with ether (4 * 40ml) washings.To pH4, (2 * 50ml) extract with EtOAc with 5% aqueous citric acid solution acidify water layer.With saline (30ml) washing organic facies, dry on sodium sulfate, filter.Remove in a vacuum and desolvate, slurry 26 is directly used in next step without separation.

13,14-dihydro-11,15-di-t-butyl dimethyl methyl siloxy-17-(3-fluorobenzene Base)-18,19,20-three nor-PGF2 α isopropyl esters (27)

0 ℃ and stir under, (5.28g, (3.16g is 4.96mmol) in the solution of acetone (20ml) 34.7mmol) to be added drop-wise to thick product 26 with DBU.Allow this mixture be warmed to room temperature, and the dropping 2-iodopropane (5.05g, 29.7mmol).Behind the 4h (TLC monitoring), dilute this mixture with EtOAc (100ml), with saline (30ml), 3% citric acid (2 * 25ml) and 5% sodium bicarbonate (2 * 25ml) washings, dry on anhydrous sodium sulfate.Remove in a vacuum and desolvate, use 1: 2 ether: petroleum ether is handled residue with chromatography as eluent on silica gel.Get colorless oil, output is 1.7g, R _f=0.43 (silica gel, 1: 2 ether: petroleum ether). ¹H NMR (CDCl ₃) d0.1 (m, 9H), 0.9 (m, 16H), 1.2 (m, 9H), 1.6-1.8 (mm, 10H), 2.12 (m, 2H), 2.22-2.33 (m, 2H), 2.6-2.9 (dm, 2H), 3.65 (m, CH ₂CHOHCH ₂), 3.94 (m, CH ₂CHOH), 4.16 (m, CH ₂CHOH), 5.0 (splitting swarming 1H), 5.38 (m, db), 5.47 (m, db), 6.8-7.0 (dm, Ar, 3H), 7.2 (m, Ar, 1H).

13,14-dihydro-11,15-di-t-butyl dimethyl methyl siloxy-17-(3-fluorobenzene Base)-18,19,20-three nor-PGE2 isopropyl esters (28)

To be carried on two chloro-chromic acid pyridines on the aluminium oxide (20g) is divided into fraction ground and adds 27 to (1.7g is 2.5mmol) in the solution of dichloromethane (30ml).At room temperature stir this mixture (TLC monitoring), filter, with 2: 1 ether: the ethyl acetate washing precipitation.Remove in a vacuum and desolvate.With ether (100ml) dilution residue, water (30ml), 5%NaHCO ₃(3 * 20ml) washings separate organic facies to aqueous solution, and dry on sodium sulfate, vacuum evaporation gets grease 28 (1.3g).R _f=0.72 (silica gel, ethyl acetate).

13,14-dihydro-17-(3-fluorophenyl)-18,19,20-three nor-PGE2 isopropyl esters (7)

(12ml) adds in the acetonitrile solution of 28 (314mg) with 15% fluohydric acid gas.At room temperature stir this mixture and reach 4h (TLC monitoring).(100ml) dilutes this reactant mixture with ethyl acetate, water (3 * 20ml) washings, drying and vacuum evaporation.Use ethyl acetate and on silica gel, handle residue, get grease 7 (64mg), R with chromatography as eluent _f=0.43 (silica gel, ethyl acetate). ¹H NMR (CDCl ₃) d 1.2 (d, 6H), 1.6-1.8 (m, 6H), 1.8 (m, 2H), 2.12 (m, 2H), 2.2-2.3 (m, 2H), 2.6-2.8 (dm, 2H), 3.6 (m, CH ₂CHOHCH ₂), 4.16 (m, CH ₂CHOH), 5.0 (splitting swarming .1H), 5.38 (m, db), 5.47 (m, db), 6.8-7.0 (dm, Ar, 3H), 7.2 (m, Ar, 1H).

The pharmacology

Test compound reduces effect to the intraocular pressure of cat and monkey

Tested the intraocular pressure reduction effect of described chemical compound to animal model.Intraocular pressure is measured with gauged pneumotometer (pneumotonometer).Europe domestic cat and macaque are used as experimental animal.Anaesthetize cornea with benoxinate before the test.Use PGF _{2 β}Isopropyl ester (2), 17-phenyl-18,19,20-three nor--PGE ₂Isopropyl ester (4), 15RS-16,16-propylidene methyl ester (6) and 13,14-dihydro-17-(3-fluorophenyl)-18,19,20-three nor--PGE ₂Intraocular pressure reduction effect after isopropyl ester (7) Local treatment is illustrated among Table IV and the V.

Table IV.1～10 μ g test compound is (to EP ₁The prostaglandin receptoroid has effect) intraocular pressure of cat is reduced effect.The contrast eyes are only accepted carrier.(n=5～6; Meansigma methods ± SEM).

Prostaglandin/eyes baseline pressure is handled the pressure of back 3h

(mmHg) (mmHg)

2

Test eye 24.2 ± 2.3 15.1 ± 2.8 ^*

Contrast eyes 24.5 ± 2.7 22.5 ± 3.4

4

Test eye 22.0 ± 1.7 14.2 ± 1.7 ^*

Contrast eyes 21.5 ± 1.7 18.7 ± 1.9

6

Test eye 19.2 ± 1.7 9.5 ± 0.5 ^*

Contrast eyes 19.3 ± 1.7 17.0 ± 1.3

7

Test eye 20.4 ±-2.0 14.2 ± 0.9 ^*

Contrast eyes 20.6 ±-1.8 18.4 ± 1.5

^*P＜0.01 (paired t check between the eyes)

Table V. test compound is (to EP ₁Receptor has effect) intraocular pressure of monkey is reduced effect.PGF _{2 β}The dosage of isopropyl ester is 30 μ g, and 17-phenyl-18,19,20-three nor--PGE ₂Isopropyl ester and 15RS-16,16-propylidene-PGE ₂The dosage of isopropyl ester then is 3 μ g.The contrast eyes are only accepted carrier (n=6; Meansigma methods ± SEM).

Prostaglandin/eyes baseline pressure is handled the pressure of back 4h

(mmHg) (mmHg)

2

Test eye 17.8 ± 1.4 14.1 ± 1.8 ^*

Contrast eyes 16.9 ± 1.2 17.5 ± 2.0

4

Test eye 14.1 ± 1.1 9.9 ± 0.9 ^*

Contrast eyes 13.9 ± 1.0 11.5 ± 0.8

6

Test eye 20.9 ± 1.6 15.3 ± 2.4 ^*

Contrast eyes 21.3 ± 1.5 19.0 ± 1.5

^*P＜0.05 (paired t check between the eyes)

As seen, in cat and monkey, select EP ₁All prostaglandin analogues of receptor have all significantly reduced intraocular pressure.

Therefore, the invention discloses EP ₁The chemical compound of the selective effect of stimulation of receptor can reduce intraocular pressure, and these chemical compounds can not have any melanocyte and generate effect in eye, perhaps have the melanocyte that greatly reduces at least and generate effect, because aberrant differentiation results in numerous (being melanocyte) lacks EP in the human body ₁Receptor.So, using EP ₁Receptor has the side effect that can avoid common iris pigment calmness to increase in the long-term treatment of prostaglandin optionally.

Sketch map 1

Sketch map 2

Reagent

A.N-isopropyl cyclohexylamine/THF, n-BuLi, cyclobutane carboxylate/DMSO

B.DIBAL-H/ toluene

c.DCC/DME，DMSO，H ₃PO ₄，

D. ethynylation lithium-ethylenediamine, DMSO

E. tri-butyl tin hydride, AIBN

F. chlorotrimethylsilane (TMSCl), imidazoles/DMF

G.Li ₂CuCN (CH ₃) ₂, TMSCl, triethylamine, the 4-tert-butyl group-dimethyl methyl siloxy-2-cyclopentenone, 1-tributyl tin-4,4-propylidene-3-trimethyl silyloxy-1-octene, 2-alkynes-8-methyl caprylate

H.Pd-BaSO ₄, quinoline

i.HF/THF

Sketch map 3

Reagent

a.DCC，DMSO，H ₂SO ₄，DME，H ₃PO ₄

B.NaH, 2-oxo-4-(3-fluorophenyl)-butyl phosphine dimethyl phthalate

c.NaBH ₄，CeCl ₃·7H ₂O/THF

d.Pd/C，NaNO ₂/THF

E.K ₂CO ₃/ methanol

F.TBDMS, TEA, 4-dimethylamino naphthyridine/dichloromethane

g.DIBAL-H/THF

H.4-carboxybutyl three phenyl phosphonium bromides, potassium tert-butoxide, THF

I.DBU, 2-iodopropane/acetone

J. pyridinium chlorochromate, aluminium oxide/dichloromethane

The k.HF/ acetonitrile

List of references

Bill，A.(1975)。Blood circulation and hydrodynamics in the eye, the physiology comments on (Physiol.Rev.), 55; 383～417.

Coleman, R.A., Smith, W.L. and Narumiya, S. (1994).VIII. international association classifies about the pharmacology of prostaglandin receptoroid: the performance of this receptor and subclass thereof, classification and structure.The pharmacology comments on (Pharmacol.Rev.), 46; 205～229.

Crawford, K. and Kaufman, P. (1987).Pilocarpine is antagonism PGF in monkey _{2 α}The borehole pressure that causes is too high.Ophthalmology's document (Arch.Ophthalmol.), 105; 1112～1116.

Ernhardt，P.W，Owens，A.H.(1987)。Form quaternary nitrogen heterocycles butane (azetidinium) chemical compound in the Triflation process of dialkyl amido propanol easily.Synthesising communication (Synth.Commun.), 17,469～475.

Caldwell，A，.G，.Harris，C.J.，Stepny，R.，Whittaker，N.(1979)。The hydantoin prostaglandin analogue, potential and anticoagulant optionally.Chemistry meeting will, chemical communication (J.C.S.Chem.Commun.), 561.

Skotnicki，S.，Schaub，E.，Weiss，J.(1977)。Prostaglandin and congener.14.dl-16, the synthetic and bronchodilatation activity of 16-propylidene prostaglandin.Pharmaceutical chemistry magazine (J.Med.Chem.), 20,1042.

Hu, D-N. etc. (1993).Ophthalmology and visual science research (InvestigativeOphthalmlogy and Visual Science), 34; 2210～2219.

Nilsson, S.F.E., Samuelsson, M., Bill, A. and Stjernschantz, J. (1989).Uvea sclera effluent increases conduct by prostaglandin F _{2 α}Isopropyl ester causes the possibility mechanism that borehole pressure is too high in macaque.Experimental eye research (Exp.Eye Res.), 48; 707～716.

Stjernschantz, J., Sel é n, G., Sj  quist, B. and Resul, B. (1995).The preclinical pharmacology of latanoprost.Prostaglandin, thromboxane and leukotriene progress (Advances in Prostaglandin, Thromboxane andLeukotriene Research), 23; 513～518.

Stjernschantz, J. and Alm, A. (1996).Latanoprost is as the new height in the glaucoma medical treatment.Current viewpoint among the ophthalmology (Current Opinion inOphthalmology), 7; 2:11～17.

Toris, C., Camras, C.B., and Yablonski, M.E. (1993).PhXA41-new prostaglandin F _{2 α}Analog is to human eye aqueous humour effect of kinetics.Ophthalmology (Ophthalmology), 10; 1297～1304.

Wodswarth，Jr.，W.S.，Emmon，W.D.(1961)。The effectiveness of phosphonate ester carbanion in alkene is synthetic.American Journal of the Chemical Society (J.Am.Chem.Soc.), 83,1733.

Claims

1. one kind as EP ₁The prostaglandin analogue of the selective excitement agent of prostaglandin receptoroid is used for the treatment of application in the too high medicament of glaucoma and borehole pressure in preparation, the pigment that described medicament does not increase as side effect produces, perhaps the pigment that significantly reduces as side effect produces, and wherein said prostaglandin analogue is the chemical compound of following general formula:

Wherein:

The ripple key table shows α or beta comfiguration, and empty key table shows the two keys in singly-bound or cis or the anti-configuration;

R is hydrogen or C _1～10Alkyl;

R1 is C _2-5Alkyl;

X is C-OH or C=O;

R2 is a hydroxyl;

R3 is the alkyl with 3～8 carbon atoms, and wherein the carbon 15 of prostaglandin structure is replaced by hydroxyl, and the optional C that contains of described alkyl _3～8Cycloalkyl, phenyl or the phenyl that is replaced by halogen; Perhaps its pharmaceutically acceptable salt or ester;

But following compounds forecloses:

17-phenyl-18,19,20-three nor--PGE ₂-isopropyl ester.

2. the application of claim 1, wherein R3 is the alkyl with 3-5 carbon atom.

3. the application of claim 1, the wherein said phenyl that is replaced by halogen is the 3-fluorophenyl.

4. the application of claim 1, wherein said prostaglandin analogue be 15 (R, S)-16,16-propylidene-PGE ₂Or its Arrcostab.

5. the application of claim 1, wherein said prostaglandin analogue is 13,14-dihydro-17-(3-fluorophenyl)-18,19,20-three nor--PGE ₂Or its Arrcostab.

6. each application of claim 1～5, wherein said medicament was locally applied on the eye for 1～3 time by every day.