RU2207858C2 - Derivatives of prostaglandins without adverse effects for glaucoma treatment - Google Patents

Abstract

FIELD: medicine, ophthalmology. SUBSTANCE: invention describes composition used for treatment of glaucoma and intraocular hypertensions and the use of EP₁ agonists of prostanoid receptors that reduce intraocular pressure effectively but do not or reduce the pigmentation effect or iris. Prostaglandin analog as a EP₁ selective agonist is applied on eye topically. Invention provides attenuation of adverse effect expressing as melanogenesis. EFFECT: enhanced and valuable properties of prostaglandins. 4 cl, 5 tbl, 7 ex

Description

 The invention relates to a method for the treatment of glaucoma and intraocular hypertension using analogues of prostaglandins or their derivatives, which do not have or have a reduced melanogenic effect on the eye. The present invention also relates to ophthalmic compositions containing prostaglandin compounds that do not have or have a reduced melanogenic effect on the eye.

 Glaucoma is an eye disease characterized by an increase in intraocular pressure, excavation of the optic disc and gradual loss of the visual field. Abnormally high intraocular pressure is known to be harmful to the eye, and there are clear signs that intraocular pressure in glaucoma is the most important factor causing degenerative changes in the retina and optic disc. However, the exact pathophysiological mechanism of open-angle glaucoma is still unknown. If untreated, glaucoma can lead to blindness, and, as a rule, the disease progresses slowly with progressive loss of vision.

Intraocular pressure (IOP) can be determined according to formula (1):
(1) IOP = Fe + (Ft-Fu) • R,
where Re is episcleral venous pressure, Ft is the formation of intraocular fluid, Fu is the portion of intraocular fluid that leaves the eye through the uveoscleral abduction, and R is resistance in the trabecular abduction. Intraocular fluid is formed in the anterior and posterior ocular chambers by the ciliary processes behind the iris. Then the fluid flows through the pupil into the anterior chamber and normally leaves the eye through the trabecular network (fountain spaces) and Schlemm's canal into the episcleral veins located outside the eyeball. However, part of the intraocular fluid may leave the eye along the uveoscleral abduction path. It is believed that the flow along this pathway is minimally affected by intraocular pressure (Bill, 1975). Normal intraocular pressure in humans is in the range of 12-22 mm RT. Art. At higher pressure, i.e. above 22 mm RT. Art., there is an increased risk that the eye may be damaged. However, with one particular form of glaucoma, normal tension glaucoma, damage can also occur with intraocular pressure within the physiological norm. Opposite situations are also known, i.e. in some individuals, an abnormally high intraocular pressure may be observed without the appearance of any defects in the field of vision or the optic nerve head. Such conditions are usually referred to as intraocular hypertension.

 Glaucoma can be treated with medication, a laser, or surgery. In drug treatment, the goal is either to reduce the formation of intraocular fluid (Ft), or to reduce the resistance to outflow of intraocular fluid (R), which according to the above formula 1 will lead to a decrease in intraocular pressure, alternatively, to increase the outflow of intraocular fluid along the uveoscleral pathway, which according to formula 1 also leads to to a decrease in intraocular pressure.

Prostaglandins and, as a rule, PGF _2α , their esters and analogues reduce intraocular pressure, mainly by increasing the uveoscleral outflow of intraocular fluid (Crawford and Kaufman, 1987; Nilsson et al., 1989; Toris et al., 1993; Stjernschantz et al. , 1995). The use of prostaglandins and their derivatives is described in several patent applications and patents, for example in US 4,599,353 (Bito), US 4952581 (Bito), WO89 / 03384 (Resul and Stjernschantz), EP 170258 (Cooper), EP 253094 (Goh) and in EP 308135 (Ueno).

Соответственно простагландины несут циклопентановое кольцо, к которому присоединены две углеродные цепи, причем верхнюю цепь обычно называют альфа-цепью, а нижнюю обычно называют омега-цепью. Простагландины подразделяют на подгруппы А, В, С, D, Е, F, G, Н, I и J в зависимости от структуры и заместителей циклопентанового кольца:

Альфа-цепь является 7-углеродной алифатической цепью с карбоксильной группой на конце, в то время как омега-цепь является 8-углеродной алифатической цепью с метильной группой на конце. В зависимости от числа двойных связей в этих цепях им присваиваются нижние индексы от 1 до 3. В простагландинах с нижним индексом 1, например PGF_1α, двойная связь расположена между 13 и 14 углеродами омега-цепи, и в простагландинах природного происхождения имеет трансконфигурацию. В простагландинах с нижним индексом 2, например PGF_2α, дополнительная двойная связь в цис-конфигурации расположена между 5 и 6 атомом алифатической цепи и, наконец, в простагландинах с нижним индексом 3, третья двойная связь расположена между 17 и 18 углеродами в омега-цепи. В природных простагландинах эта двойная связь находится также в цис-конфигурации. Все природные простагландины имеют гидроксильную группу при 15 атоме углерода, которая является важной для биологической активности.Prostaglandins are fatty acids, usually formed from precursors such as eicosatrienoic, eicosatetraenoic and eicosapentaenoic acid, during a series of metabolic stages, including oxygenation. Natural prostaglandins, as a rule, have a common structure:

Accordingly, prostaglandins carry a cyclopentane ring to which two carbon chains are attached, with the upper chain usually called the alpha chain and the lower chain usually called the omega chain. Prostaglandins are divided into subgroups A, B, C, D, E, F, G, H, I and J depending on the structure and substituents of the cyclopentane ring:

The alpha chain is a 7-carbon aliphatic chain with a carboxyl group at the end, while the omega-chain is an 8-carbon aliphatic chain with a methyl group at the end. Depending on the number of double bonds in these chains, they are assigned subscripts from 1 to 3. In prostaglandins with a subscript of 1, for example, PGF _1α , the double bond is located between 13 and 14 carbons of the omega chain, and in natural prostaglandins it has a trans configuration. In prostaglandins with a subscript of 2, for example PGF _2α , the additional double bond in the cis configuration is located between the 5th and 6th atoms of the aliphatic chain, and finally in prostaglandins with a subscript of 3, the third double bond is located between 17 and 18 carbons in the omega chain . In natural prostaglandins, this double bond is also in the cis configuration. All natural prostaglandins have a hydroxyl group at 15 carbon atoms, which is important for biological activity.

The receptor system of natural prostaglandins has been identified only recently. Thus, most prostaglandin receptors are pharmacologically characterized and their molecular structure is identified using molecular biological techniques (Coleman et al., 1994). For natural prostaglandins, specific receptors exist. The receptors PGD, PGE, PGF, PGI ₂ (prostacyclin) and TxA ₂ (thromboxane) correspond to the abbreviations DP, EP, FP, IP and TP, respectively. It was further shown that EP receptors can be subdivided into four receptors, namely, EP ₁ , EP ₂ , EP ₃ and EP ₄ receptors. Individual tissues or cells may express few or many of these receptors, depending on the evolutionary development of the given physiologically active substances system in various species. For example, it has been shown that the cat's iris sphincter muscle expresses mainly FP receptors that are functionally conjugated and mediate pupil constriction, while the corresponding smooth muscle of the bovine eye expresses EP ₁ and TP receptors, the activation of which leads to a reduction the muscles. A compound that binds to and activates a specific receptor is called an agonist, while a substance that binds to a receptor without activating it is called an antagonist.

 Regarding the practical applicability of many prostaglandins and their derivatives as suitable drugs for the treatment of glaucoma or intraocular hypertension, a limiting factor may be their ability to increase pigmentation of the iris (Stjernschantz and Aim, 1996). So, during chronic treatment of monkeys or humans, the color of the iris tends to become darker, turning brown. And if this does not have any medical consequences, then when considered from a cosmetic point of view, this is an understandable drawback especially in patients undergoing treatment in only one eye. Thus, it would be desirable to identify prostaglandins that effectively reduce intraocular pressure and do not cause a side effect of increased iris pigmentation.

The authors of the present invention unexpectedly found that derivatives and analogues of prostaglandins, which are selective agonists for the EP ₁ subgroup of prostaglandin receptors, meet the criteria for a prostaglandin analog that effectively reduces intraocular pressure without causing increased pigment formation (melanogenesis) in the iris of the eye. The premise of this finding was that when studying to identify subtypes of prostanoid receptors in human iris melanocytes, the authors of the present invention found that these cells express FP, EP ₂ and EP ₃ receptors, but not EP ₁ and TP receptors. In addition, the authors of the present invention investigated the effect of lowering the intraocular pressure of several relatively selective EP ₁ agonists and found that these prostaglandin analogs effectively and strongly reduce intraocular pressure in both cats and monkeys.

Thus, it is now obvious that by using selective agonists of EP ₁ receptors, the intraocular pressure in primates and thus also in humans can be reduced, without or with a significant decrease in melanogenesis as a side effect, since melanin-producing cells melanocytes do not have a specific receptor necessary for transmembrane signal transmission to the cell. Although at present the authors of the present invention do not have clinical evidence that such selective agonists of EP ₁ do not lead to an increase in pigmentation of the iris, since the time of occurrence of this phenomenon is often 6-12 months, and therefore, extremely long and expensive experiments are required on primates, however, the authors of the present invention can conclude from relevant in vitro studies that such increased pigmentation does not occur in the presence of specific transmitting Ignals of receptors in the cell membrane of melanocytes.

Accordingly, high selectivity or specificity for the EP ₁ receptor compared to other prostaglandin receptors of the eye characterizes the compounds useful in the method or compositions of this invention. Needless to say, the more selective the compound with respect to the EP ₁ receptor, the better the results obtained, but some advantage was also achieved in cases of some interactions with other receptors. High selectivity in this regard means that the effect on the EP ₁ receptor is at least 5 times, especially more than 10 times and, in particular, more than 100 or 1000 times greater than the effect on other prostaglandin receptors.

где волнистые связи изображают α- или β-конфигурацию, а пунктирные связи представляют собой простую связь, тройную связь или двойную связь в цис- или транс-конфигурации;
R представляет собой водород, насыщенный или ненасыщенный алкил, предпочтительно C_1-10 алкил, циклоалкил, предпочтительно С_3-8 циклоалкил, арил, арилалкил, предпочтительно арил-С_2-5 алкил, или гетероарил;
R₁ представляет собой насыщенную или ненасыщенную алкильную группу, содержащую 2-5 атомов углерода, необязательно прерванную гетероатомами, выбранными из кислорода, серы и азота, циклоалкил, предпочтительно С_3-7 циклоалкил, циклоалкенил, предпочтительно С_3-7 циклоалкенил, арил или гетероарил;
Х представляет собой С-ОН или С=O;
R₂ представляет собой водород, гидрокси, метил, этил, метокси или OCOR₄, где R₄ представляет собой неразветвленную или разветвленную цепь насыщенной или ненасыщенной алкильной группы, предпочтительно C_1-10 алкил, особенно C_1-6 алкил, или циклоалкил, предпочтительно С_3-8 циклоалкил, или арильную группу;
R₃ представляет собой неразветвленную или разветвленную цепь насыщенной или ненасыщенной алкильной группы, предпочтительно содержащую 3-8 атомов углерода, особенно 3-5 атомов углерода, необязательно прерванную одним или более гетероатомами, выбранными из кислорода, серы и азота, причем каждый атом углерода необязательно замещен заместителем, выбранным из C_1-5 алкильной, гидроксильной и карбонильной групп, причем гидрокси и карбонил предпочтительно присоединены к 15 атому углерода простагландиновой структуры, и указанная алкильная группа необязательно содержит циклоалкильную, предпочтительно С_3-8 циклоалкильную, арильную или гетероарильную группу, которая может быть замещена одним из или независимо C_1-3 алкилом, C_1-3 алкокси, гидрокси, нитро, трифторметилом или галогеном; или его фармацевтически приемлемой солью или сложным эфиром, которое представляет собой селективный агонист EP₁-простаноидных рецепторов, и офтальмологически совместимый носитель.In accordance with the first implementation of the present invention relates to an ophthalmic composition for the treatment of glaucoma and intraocular hypertension without increasing or decreasing the side effect, expressed in melanogenesis, which includes a therapeutically active and physiologically acceptable amount of a compound of the general formula:

where the wavy bonds represent the α or β configuration, and the dashed bonds represent a single bond, a triple bond or a double bond in a cis or trans configuration;
R represents hydrogen, saturated or unsaturated alkyl, preferably C _1-10 alkyl, cycloalkyl, preferably C _3-8 cycloalkyl, aryl, arylalkyl, preferably aryl-C _2-5 alkyl, or heteroaryl;
R ₁ represents a saturated or unsaturated alkyl group containing 2-5 carbon atoms, optionally interrupted by heteroatoms selected from oxygen, sulfur and nitrogen, cycloalkyl, preferably C _3-7 cycloalkyl, cycloalkenyl, preferably C _3-7 cycloalkenyl, aryl or heteroaryl ;
X represents C — OH or C = O;
R ₂ is hydrogen, hydroxy, methyl, ethyl, methoxy or OCOR ₄ , where R ₄ is a straight or branched chain saturated or unsaturated alkyl group, preferably C _1-10 alkyl, especially C _1-6 alkyl, or cycloalkyl, preferably C _3-8 cycloalkyl, or an aryl group;
R ₃ represents a straight or branched chain saturated or unsaturated alkyl group, preferably containing 3-8 carbon atoms, especially 3-5 carbon atoms, optionally interrupted by one or more heteroatoms selected from oxygen, sulfur and nitrogen, with each carbon atom optionally substituted a substituent selected from C _1-5 alkyl, hydroxyl and carbonyl groups, with hydroxy and carbonyl being preferably attached to the 15 carbon atom of the prostaglandin structure, and said alkyl group optionally contains a cycloalkyl, preferably a C _3-8 cycloalkyl, aryl or heteroaryl group, which may be substituted with one or independently C _1-3 alkyl, C _1-3 alkoxy, hydroxy, nitro, trifluoromethyl or halogen; or a pharmaceutically acceptable salt or ester thereof, which is a selective agonist of EP ₁ -protanoid receptors, and an ophthalmologically compatible carrier.

According to a first embodiment, the present invention relates to the use of a prostaglandin analog, which is a selective agonist of EP ₁ prostanoid receptors, as defined above, for the preparation of a medicament for the treatment of glaucoma or intraocular hypertension without amplification or amelioration of the side effect of melanogenesis.

Specific prostaglandin analogues that the authors of the present invention used to illustrate and prove the present invention were PGF _2β (1), isopropyl ether PGF _2β (2), 17-phenyl-18,19,20-trinor-PGE ₂ (3), isopropyl 17-phenyl-18,19,20-trinor-PGE ₂ (4), 15 (R, S) -16,16-trimethylene-PGE ₂ (5) ether, 15 (R, S) -16,16 methyl ether -trimethylene-PGE ₂ (6) and 13,14-dihydro-17- (3-fluorophenyl) -18,19,20-trinor-PGE ₂ isopropyl ether (7). All of these analogs are relatively selective EP ₁ receptor agonists. The receptor profiles of the tested compounds are presented in table I.

On the one hand, the invention relates to the use of agonists, selective prostaglandin EP ₁ receptors lacking a melanogenic effect, for the treatment of glaucoma or intraocular hypertension. A method of treating glaucoma or intraocular hypertension involves contacting the surface of the eye with an effective intraocular pressure-reducing amount of a composition that contains said prostaglandin EP ₁ in order to reduce intraocular pressure and keep said pressure low. The composition usually contains about 0.1-100 μg, mainly 1-30 μg per single application of the active principle. The composition is topically applied to the eye 1-3 times a day.

 The prostaglandin derivative is mixed with an ophthalmologically compatible carrier known in the art. A carrier that can be used to prepare the compositions of this invention includes aqueous solutions, for example, physiological solutions of salts, solutions of oils or ointments. Moreover, the carrier may contain ophthalmologically compatible preservatives, such as, for example, benzalkonium chloride, surfactants, such as polysorbate 80, liposomes or polymers, for example methyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone and hyaluronic acid; they can be used to increase viscosity. Moreover, soluble or insoluble drug additives may be used.

On the other hand, the present invention relates to an ophthalmic composition for the medicamentous treatment of glaucoma or intraocular hypertension, which comprises effectively reducing the intraocular pressure of a quantity of the prostaglandin analog, which, as defined above, is a selective EP ₁ receptor agonist and an ophthalmologically compatible carrier. Effective amounts typically include a dose of about 0.1-100 μg in about 10-50 μl of the composition. The compositions of the present invention have obvious advantages over existing prostaglandin compositions due to the selectivity of the active compound to EP ₁ receptors compared to other prostaglandin receptors with an eliminated or at least significantly reduced risk of pigmentation.

 And in yet another aspect, the present invention relates to the use of prostaglandin analogs for the preparation of drugs for the treatment of glaucoma and intraocular hypertension.

где волнистые связи изображают α- или β-конфигурацию, а пунктирные связи представляют собой простую связь, тройную связь или двойную связь в цис- или транс-конфигурации;
R представляет собой водород, насыщенный или ненасыщенный алкил, предпочтительно C_1-10 алкил, циклоалкил, предпочтительно С_3-8 циклоалкил, арил, арилалкил, предпочтительно арил-С_2-5 алкил, или гетероарил;
R₁ представляет собой насыщенную или ненасыщенную алкильную группу, содержащую 2-5 атомов углерода, необязательно прерванную гетероатомами, выбранными из кислорода, серы и азота, циклоалкила, предпочтительно С_3-7 циклоалкила, циклоалкенила, предпочтительно С_3-7 циклоалкенила, арила или гетероарила;
Х представляет собой С-ОН или С=O;
R₂ представляет собой водород, гидрокси, метил, этил, метокси или OCOR₄, где R₄ представляет собой неразветвленную или разветвленную цепь насыщенной или ненасыщенной алкильной группы, предпочтительно C_1-10 алкил, особенно C_1-6 алкил, или циклоалкил, предпочтительно С_3-8 циклоалкил, или арильную группу;
R₃ представляет собой неразветвленную или разветвленную цепь насыщенной или ненасыщенной алкильной группы, предпочтительно содержащую 3-8 атомов углерода, особенно 3-5 атомов углерода, необязательно прерванную одним или более гетероатомами, выбранными из кислорода, серы и азота, причем каждый атом углерода необязательно замещен заместителем, выбранным из C_1-5 алкильной, гидроксильной и карбонильной групп, причем гидрокси и карбонил предпочтительно присоединены к 15 атому углерода простагландиновой структуры, и указанная алкильная группа необязательно содержит циклоалкильную, предпочтительно С_3-8 циклоалкильную, арильную или гетероарильную группу, которая может быть замещена одним из или независимо C_1-3 алкилом, C_1-3 алкокси, гидрокси, нитро, трифторметилом или галогеном, или его фармацевтически приемлемой солью, или сложным эфиром.Preferably, the prostaglandin analog is derived from prostaglandins PGF or PGE types. In particular, the prostaglandin analog is a compound usually having the following formula:

where the wavy bonds represent the α or β configuration, and the dashed bonds represent a single bond, a triple bond or a double bond in a cis or trans configuration;
R represents hydrogen, saturated or unsaturated alkyl, preferably C _1-10 alkyl, cycloalkyl, preferably C _3-8 cycloalkyl, aryl, arylalkyl, preferably aryl-C _2-5 alkyl, or heteroaryl;
R ₁ represents a saturated or unsaturated alkyl group containing 2-5 carbon atoms, optionally interrupted by heteroatoms selected from oxygen, sulfur and nitrogen, cycloalkyl, preferably C _3-7 cycloalkyl, cycloalkenyl, preferably C _3-7 cycloalkenyl, aryl or heteroaryl ;
X represents C — OH or C = O;
R ₂ is hydrogen, hydroxy, methyl, ethyl, methoxy or OCOR ₄ , where R ₄ is a straight or branched chain saturated or unsaturated alkyl group, preferably C _1-10 alkyl, especially C _1-6 alkyl, or cycloalkyl, preferably C _3-8 cycloalkyl, or an aryl group;
R ₃ represents a straight or branched chain saturated or unsaturated alkyl group, preferably containing 3-8 carbon atoms, especially 3-5 carbon atoms, optionally interrupted by one or more heteroatoms selected from oxygen, sulfur and nitrogen, with each carbon atom optionally substituted a substituent selected from C _1-5 alkyl, hydroxyl and carbonyl groups, with hydroxy and carbonyl being preferably attached to the 15 carbon atom of the prostaglandin structure, and said alkyl group optionally contains a cycloalkyl, preferably a C _3-8 cycloalkyl, aryl or heteroaryl group, which may be substituted by one or independently C _1-3 alkyl, C _1-3 alkoxy, hydroxy, nitro, trifluoromethyl or halogen, or a pharmaceutically acceptable salt thereof, or ester.

 Aryl is preferably substituted or unsubstituted phenyl.

 Typical heteroaryl groups are thiophene, furan, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine.

Aryl, heteroaryl and cycloalkyl can be mono-, independently di-, or multisubstituted with C _1-3 alkyl, C _1-3 alkoxy, hydroxy, nitro, trifluoromethyl or halogen.

 Unsaturated alkyl may contain one or more double and / or triple bonds.

 Halogen is fluoro, chloro, bromo or iodo, especially fluoro, chloro or bromo.

 Prostaglandins can be in the form of epimeric mixtures in the same way as in the form of individual epimers.

 The invention is illustrated by the following non-limiting examples.

 Identification of prostaglandin receptors.

Prostaglandin receptors were identified using the reverse transcriptase polymerase chain reaction (RT-PCR) technique. Specific primers were designed for receptors FP, EP ₁ , EP ₂ , EP ₃ and TP. The primers used in the studies are presented in table II. RT-PCR was performed on mRNA isolated from human iris melanocytes in culture. Cultured cells were used to prepare mRNA. The RT-PCR mixture was analyzed on an agarose gel, and bands of the expected size were cloned and sequenced. These sequences were analyzed for similarity with the sequence of each prostaglandin receptor.

 Ways. Human iris melanocytes were isolated and cultured according to Ni et al. (1993) and used in the early passages. Cells were grown to form a confluent culture and harvested to enrich mRNA.

mRNA was isolated using the Dynals Direct System mRNA (Dynal A / S, Norway) according to the manufacturer's instructions. For enrichment, 100,000-200,000 human melanocyte cells were used. mRNA covalently binds to labeled oligo-dT Dynabead. Using reverse transcriptase, the first cDNA strand is directly synthesized by Dynabead with oligo-dT as a reverse transcriptase primer. A second cDNA strand is synthesized using the 3'-primer of the corresponding prostaglandin receptor sequence to produce double-stranded DNA. The same Dynabead kit was used for each RT-PCR receptor. Receptor-specific primers were used for PCR amplification of DNA from cDNA associated with Dynabead, according to the manufacturer's instructions. For FP and EP ₃ receptor reactions, PCR was performed in a final volume of 50 μl containing 5% DMSO, 200 μM dNTP and 20 pmol of each primer. For other receptors, a hot start was used using AmpliWax pellets (Perkin Elmer, USA) in a final volume of 75 μl containing 5% DMSO, 200 μM dNTP and 20 pmol of each primer (see Table II).

A PCR mixture of these reactions was analyzed on a 1% LMP agarose gel (BioRad Laboratories, USA). Expected DNA fragments were TA-cloned using a TA-cloning kit according to the manufacturer's instructions (Invitrogen Inc., USA) and sequenced on an Applied Biosystem Model 373A DNA sequencing system (Applied Biosystems Inc., USA) according to the Applied Biosystems' protocol for their Taq Dye Dioxi Termination Cycle Sequencing Kit. The obtained primary data was processed on a VAX computer using sequence analysis programs from Genetics Computer Group Inc. , Madison, USA (Devereux, J., et al., Nucleic Acids Research 12 (1): 387-395 (1984). Results: Based on RT-PCR data, the authors were able to show the expression of FP, EP ₂ and EP ₃ receptors in human iris melanocytes, however, the authors were unable to show the presence of EP ₁ and TP receptors (Table III). As expected controls, the expected EP ₁ and TP fragments with the same primers from the typical human cDNA library were amplified. Enriched poly-A mRNA from isolated melanocytes human iris twice and PCR reactions were performed several times with the same result.

Synthesis of Prostaglandin Derivatives
The structures of the final compounds obtained in the examples are shown in Scheme 1, presented at the end of the description.

Example 1. PGF _2β (compound 1)
The title compound was purchased from Cayman Chemicals Company, Ann Arbor Michigan, USA.

Example 2. Isopropyl ether PGF _2β (compound 2)
DBU (163.5 mg, 1.01 mmol) was added to a stirred solution of PGF _2β (Cayman Chemicals) (60 mg, 0.169 mmol) in acetone (20 ml) at 0 ^° C. The mixture was allowed to warm to room temperature, was added dropwise isopropyl iodide (222.6 mg, 1.34 mmol). After 48 hours (monitoring by TLC), the mixture was diluted with ethyl acetate (40 ml), washed with brine (30 ml), 3% citric acid (2 • 40 ml) and 5% sodium bicarbonate (2 • 30 ml) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was chromatographed on silica gel using ethyl acetate: acetone 3: 1 as the eluent. This gave a colorless oil in 46 mg (68%) yield.

¹ H NMR (CDCl ₃ ) d 1.3 (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 (sept, 1H), 5.5 (m, 2H), 5.6 (m, 2H). ¹³ C NMR (CDCl ₃ ) d 135.9, 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.

Example 3. 17-Phenyl-18,19,20-trinor-PGE ₂ (compound 3)
The title compound was purchased from Cayman Chemicals Company, Ann Arbor Michigan, USA.

Example 4. Isopropyl ether 17-phenyl-18,19,20-trinor-PGE ₂ (compound 4)
DBU (43.5 mg, 0.29 mmol) in acetonitrile (1 ml) was added dropwise to a stirred solution of compound 3 (22.1 mg, 0.057 mmol) in acetonitrile (3 ml) at 0 ^° C. The mixture was allowed to warm to room temperature, after which isopropyl iodide (78.0 mg, 0.46 mmol) in acetonitrile (2 ml) was added dropwise. After stirring for 12 hours (monitoring by TLC), the reaction mixture was quenched with water (8 ml), the mixture was extracted with ethyl acetate (2 x 50 ml) and the extract was washed with brine (10 ml), 3% citric acid (10 ml) and, finally 5% sodium bicarbonate (10 ml). After drying over anhydrous sodium sulfate, the solvent was removed in vacuo and the residual oil was chromatographed on silica gel using ethyl acetate as the eluent. This made it possible to obtain 230 mg of the product (69%) of the title compound as a colorless oil: R _f = 0.516 (ethyl acetate: acetone: HOAc 1: 1: 0.02).

¹ H NMR (CDCl ₃ ) d 0.89 (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). ¹³ C NMR (CDCl ₃ ) d 10.9, 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.

Example 5. 15RS-16,16-trimethylene-PGE ₂ (compound 5)
Lipase VII (40 mg) was added to a stirred solution of 15RS-16,16-trimethylene-PGE ₂ methyl ester (52 mg, 0.13 mmol) in acetone (0.4 ml) and phosphate buffer pH 7 (4 ml). The mixture was stirred at room temperature for 24 hours (monitoring by TLC). The mixture was quenched with ethanol (3 ml) and extracted with ethyl acetate (2 x 10 ml). The organic layer was washed with brine, dried (sodium sulfate) and concentrated in vacuo to give 46 mg of the product as an oil.

Example 6. Methyl ester 15RS-16,16-trimethylene-PGE ₂ (compound 6)
The synthesis of 15RS-16,16-trimethylene prostaglandin E ₂ (Skotnicki, S. et al., 1977) is shown schematically in Scheme 2. The following figures in bold refer to the corresponding structures in Scheme 2.

Ethyl 2,2-trimethylenehexanoate (9)
To a stirred solution of N-isopropylcyclohexylamine (56.2 g, 398 mmol) in THF (400 ml) at -78 ^° C, n-BuLi (159 ml, 398 mmol, 2.5 M in hexane) was quickly added. Ethyl cyclobutanecarboxylate (8) (50 g, 390 mmol) was added dropwise to the resulting solution and stirred for 30 minutes, then heated to 0 ^{° C.} and dropped into a solution of n-butyl iodide (159 ml, 398 mmol, 2.5 mol in hexane) in DMSO (200 ml). The reaction mixture was stirred for 1 h at room temperature (monitoring by TLC). The salt was removed by filtration and the filtrate was concentrated in vacuo. The residue was dissolved in hexane and washed with 2% HCl, brine and water, then dried over sodium sulfate and evaporated in vacuo. The residual oil was distilled (49-56 ^{° C.} , 1 mmHg) to obtain 26.5 g (37%) of the product.

¹ H NMR (CDCl ₃ ) d 0.9 (t, 3H), 1.2 (t, 3H), 1.8-2.0 (dm, 5H), 2.2-2.5 (m, 3H) ), 4.2 (m, 2H).

2,2-Trimethylenehexan-1-ol (10)
To a stirred solution of ethyl 2,2-trimethylene hexanoate (9) (26.5 g, 144 mmol) in dry toluene (100 ml) was added dropwise DIBAL-H (206 ml, 289 mmol, 1.4 mol in toluene) at 0 ^o C. The resulting solution was stirred at room temperature for 3 hours (monitoring by TLC) and then poured into 5% ice-cold HCl. The organic layer was separated and washed with 5% HCl, brine, dried, filtered and concentrated to give 30 g of the product as an oil. ¹ H NMR (CDCl ₃ ) d 0.9 (t, 3H), 1.8-2.0 (dm, 5H), 2.5 (m, 1H), 3.0 (m, 1H), 3, 6 (m, 2H).

2,2-Trimethylene Hexaldehyde (11)
To a solution of 2,2-trimethylenehexan-1-ol (10) (30 g, 210 mmol) in DME (400 ml) was added dicyclohexanecarbodiimide (DCC) (130 g, 630 mmol), DMSO (120 ml) and orthophosphoric acid (10 , 3 g). The mixture was stirred at room temperature for 3 hours (monitoring by TLC) and filtered. The filtrate was diluted with dichloromethane (300 ml) and washed with water. The organic layer was separated. The residue was removed by filtration. The filtrate was washed with brine (100 ml), dried and concentrated in vacuo. The residue was purified by silica gel column chromatography using hexane as an eluent to obtain the title product (17.3 g) as an oil.

¹ H NMR (CDCl ₃ ) d 0.9 (t, 3H), 1.2 (t, 3H), 1.8-2.0 (dm, 5H), 8.8 (s, 1H).

4,4-Trimethylene-1-octin-3-ol (12)
To a solution of lithium acetylide-ethylene diamine complex (12.2 g, 132 mmol) in DMSO (10 ml) was added a solution of 2,2-trimethylenehexaldehyde (11) (17 g, 120 mmol) in DMSO (20 ml) at 0 ^{° C.} atmosphere N ₂ . The mixture was stirred at room temperature for 24 hours (monitoring by TLC) and then poured into ice-cold 2% Hcl (50 ml) and ether (50 ml). The organic layer was separated and the aqueous layer was extracted with ether (50 ml), the combined organic phases were washed with brine, dried, filtered and concentrated in vacuo. The residue was chromatographed on silica gel using hexane: ethyl acetate 5: 1 as the eluent to give 12 (7.6 g, 38%) as an oil.

E-Tributyltin-4,4-trimethylene-1-octen-3-ol (13)
A mixture of 4,4-trimethylene-1-octin-3-ol (12) (5.0 g, 30 mmol), tributyltin hydride (14.6 ml, 54.2 mmol) and AIBN (30 mg) was stirred at 130 ^o C for 24 hours (monitoring by TLC). The residue was chromatographed on silica gel using hexane and hexane: ether 9: 1, respectively, as an eluent, to give the title compound (13) (12.54 g, 91.4%) as an oil.

E-Tributyltin-4,4-trimethylene-3-trimethylsilyloxy-1-octene (14)
To a mixture of E-tributyltin-4,4-trimethylene-1-octene-3-ol (13) (7 g, 15.3 mmol) in DMF (100 ml) was added imidazole (2.1 g, 30.6 mmol) and trimethylsilyl chloride (2.5 g, 23.0 mmol). The reaction mixture was stirred at room temperature for 1 h (monitoring by TLC). The mixture was partitioned between water (200 ml) and ether (200 ml). The organic phase was dried and evaporated in vacuo. The residue was chromatographed on silica gel using hexane as an eluent to give 14 (5.53 g).

11,15-bis trimethylsilyloxy-16,16-trimethylene-5,6-didehydro-PGE ₂ methyl ester (17)
Copper (I) cyanide (928 mg, 10.4 mmol) and a magnetic stirrer were charged into a dry 100 ml three-necked flask. The flask was closed with a rubber stopper and heated in vacuo to remove traces of water, and cooled to 0 ^° C in an N ₂ atmosphere. Dry THF was then added to methyl lithium (14 ml, 22.4 mmol, 1.6 mol in diethyl ether) using a syringe. The mixture was stirred at 0 ^{° C. for} 15 minutes, during which time the suspension became clear and homogeneous. A solution of E-tributyltin-4,4-trimethylene-3-trimethylsilyloxy-1-octene (14) (5.9 g, 11.2 mmol) in THF (10 ml) was added via syringe at 0 ^{° C.} and stirred at room temperature temperature for 30 minutes To the resulting solution was added a solution of 4- (tert-butyl-dimethylsilyloxy) cyclopentenone (15) (1.7 g, 8 mmol) in THF (6 ml), trimethylsilyl chloride (4.35 g, 40 mmol) and triethylamine (8.1 g, 80 mmol) at -70 ^{° C.} sequentially and stirred at -70 ^{° C.} for another 15 minutes, then for 15 minutes at 0 ^° C. The mixture was partitioned between hexane (600 ml) and water (300 ml). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to give the crude silylenol ester as a clear oil. To a stirred solution of silylenol ether in THF (50 ml) in an atmosphere of N ₂ at -30 ^° C was added a solution of methyl lithium (7.7 ml, 12.3 mmol, 1.6 mol in diethyl ether) and stirred for 30 min followed by by adding freshly prepared methyl 1-triflate-2-hexinoate (16) (Erhardt, PW, et al., 1987; Caldwell AG, et al., 1979) and stirred at -40 ^° C for 5 minutes. The resulting solution was quenched with a saturated aqueous solution of ammonium chloride (30 ml) and extracted with ether (3 • 100 ml), dried on sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel using hexane: ethyl acetate (1: 1) as an eluent to obtain a clear oil from a mixture of 15RS isomers (2.71 g, 57.3%) R _f = 0.36 (SiO ₂ , ether: hexane 1: 1).

¹ H NMR (CDCl ₃ ) d 0.2 (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).

¹ H NMR was also performed on a desilylated analogue, 16.16-trimethylene-5,6-didehydro-PGE ₂ methyl ester.

¹ H NMR (CDCl ₃ ) d 0.9 (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).

11,15-bis trimethylsilyloxy-16,16-trimethylene-PGE ₂ methyl ester
To a stirred solution of 11,15-bis trimethylsilyloxy-16,16-trimethylene-5,6-didehydro-PGE ₂ methyl ester (17) (500 mg, 0.8 mmol) in a benzene: cyclohexane 1: 1 mixture (50 ml) Pd-BaSO ₄ (250 mg) and quinoline (250 mg) were added and stirred at -40 ^° C in an H ₂ atmosphere for 5 hours (monitoring by TLC). The reaction mixture was diluted with ether and filtered through celite and concentrated in vacuo. The residue was chromatographed on silica gel using hexane: ethyl acetate 9: 1 to give 442 mg of the corresponding product.

16,16-trimethylene-PGE ₂ methyl ester (6)
To a solution of 11,15-bis trimethylsilyloxy-16, 16-trimethylene-PGE ₂ methyl ester (374 mg, 0.589 mmol) in THF (18 ml) was added 40% HF (3.5 ml) in THF (1 ml) at 0 ^o C. The reaction mixture was stirred for 5 hours (monitoring by TLC) and then poured into a mixture of 5% sodium bicarbonate (30 ml) and ethyl acetate (50 ml). The organic layer was separated and the aqueous layer was washed with ethyl acetate (2 x 30 ml). The organic layers were combined and dried on sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel using hexane: ethyl acetate 1: 1 and ethyl acetate successively to obtain 6 (75 mg, 31%) as an oil.

¹ H NMR (CDCl ₃ ) d 0.9 (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); ¹³ C NMR (CDCl ₃ ) d 14.222, 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.

Example 7. Synthesis of isopropyl ether 13,14-dihydro-17- (3-fluorophenyl) -18,19,20-trinor PGE ₂ (compound 7)
The synthesis of the title compound is shown schematically in scheme 3. Highlighted bold figures refer to the corresponding structures of scheme 3.

Dimethyl- (2-oxo-4- (3-fluorophenylbutyl) phosphonate
To a stirred suspension of sodium hydride (4.17 g, 138 mmol), previously washed with n-pentane, in dry THF (250 ml), a solution of dimethyl 2-oxopropylphosphonate (23.12 g, 132.3 mmol) was added dropwise at room temperature. ) in THF (110 ml). The reaction mixture was stirred for 2 hours, then cooled in an ice bath and treated with a solution of n-BuLi (10.2 g, 158.7 mmol) in hexane, which led to the formation of a dark brown solution. Stirring was continued for 2 hours at 0 ^{° C.} , followed by dropwise addition of 3-fluorobenzyl bromide (25 g, 132.3 mmol) in THF (50 ml). The reaction mixture was gradually warmed to room temperature and after 3 h (monitoring by TLC), it was quenched with 10% Hcl (20 ml). The mixture was poured into ice water (200 ml), extracted with CHCl ₃ (2 • 150 ml), the organic layers were collected, washed with brine (150 ml), chromatographed on silica gel using successively CH ₂ Cl ₂ and EtOAc as eluent, giving 19 5 g of a yellowish oil. R _f = 0.37 (silica gel, EtOAc: acetone 1: 1).

(1S, 5R, 6R, 7R) -6-Formyl-7- (4-phenylbenzoyloxy) -2-oxabicyclo [3.3.0] octan-3-one (19)
To a solution of alcohol 18 (19.0 g, 53.9 mmol) in DME (100 ml) cooled to 18 ^{° C. was} added dicyclohexylcarbodiimide (DCC) (33.3, 161.8 mmol), DMSO (38.2 ml ) and phosphoric acid (1.43 ml, 21.28 mmol). The temperature of the reaction mixture was kept below 25 ^{° C.} for 30 minutes. The reaction mixture was stirred at room temperature for an additional 2 hours (monitoring by TLC) and the precipitate was removed by filtration and washed with ether (2 x 50 ml). The combined organic layer was washed with water (50 ml) and brine (2 x 50 ml), the aqueous solution was extracted with ether (100 ml), the organic layers were collected and dried over sodium sulfate, filtered and used directly for the next step. TLC R _f = 0.37 (silica gel, EtOAc: 2: 1 toluene).

(1S, 5R, 6R, 7R) -6- {3-Oxo-5- (3-fluorophenyl) -1-E-pentenyl} -7- (4-phenylbenzoyloxy) -2-oxabicyclo [3.3.0] octane- 3-on (20)
To a stirred suspension of NaH (1.9 g, 65.1 mmol), previously washed with n-pentane, in DME (130 ml) under nitrogen atmosphere was added dropwise dimethyl-2-oxo-4- (3-fluorophenyl) butylphosphonate (Wadsworth , Jr., WS, et al. 1961) (19.3 g, 70.5 mmol) in DME (100 ml) and stirred vigorously for 1 h at room temperature. The mixture was then cooled to -10 ^{° C.} and a crude aldehyde 19 solution was added dropwise. After 30 minutes at 0 ^{° C.} and 2 hours at room temperature (monitoring by TLC), the reaction mixture was neutralized with acetic acid, the solvent was removed in vacuo and the residue was dissolved in EtOAc (200 ml) and washed with water (50 ml) and brine (50 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The residue was stirred with ether (100 ml), the resulting white precipitate was filtered and washed with cold ether, obtaining a white crystalline substance (17 g, 58.5%). R _f = 0.56 (silica gel, ethyl acetate: toluene 2: 1).

(1S, 5R, 6R, 7R) -6- (3S-3-Hydroxy-5- (3-fluorophenyl) -1-pentenyl) -7- (4-phenylbenzoyloxy) -2-oxabicyclo [3.3.0] octane- 3-on (21)
To a stirred solution of enon 20 (17.1 g, 34.3 mmol) in THF (20 ml) and cerium chloride (CeCl ₃ • 7H ₂ O) (3.8 g, 10.3 mmol) in a mixture of THF: ether 1 : 2 (60 ml), cooled to -20 ^o C, in a nitrogen atmosphere was added sodium borohydride (0.8 g, 20.57 mmol) in small portions. The reaction mixture was stirred for 2 hours (monitoring by TLC). The temperature was raised to ± 0 ^° C, then quenched by addition of water (20 ml) and an aqueous solution of 10% Hcl to pH 4 and extracted with EtOAc (50 ml). The organic layer was separated and washed with brine, dried on anhydrous sodium sulfate, concentrated in vacuo, and chromatographed twice on silica gel using successively toluene: EtOAc 2: 1 and 1: 1 as eluent, to give 4 (5 g) as a white crystalline product R _f = 0.32 (silica gel, EtOAc: 2: 1 toluene).

(1S, 5R, 6R, 7R) -6- {3R-3-Hydroxy-5- (3-fluorophenyl) -1-pentyl} -7- (4-phenylbenzoyloxy) -2-oxabicyclo [3.3.0] octane- 3-on (22)
To a suspension of 10% Pd / C (0.1 g) in sodium nitrite (3.6 ml, 1.8 mmol) and ethanol (15 ml) was added a solution of 21 (3 g, 6.0 mmol) in ethanol (6, 0 ml). The mixture was stirred in a hydrogen atmosphere for 6 hours (monitoring by TLC) and quenched with a 1M HCl solution. The catalyst was removed by filtration through a pad of celite, washed with absolute ethanol (15 ml). The solvent was removed in vacuo. The resulting oil was dissolved in EtOAc (100 ml) and washed with 15% saline (30 ml). The aqueous phase was washed with EtOAc (40 ml). The combined organic extracts were dried over sodium sulfate and filtered. The solvent was removed in vacuo. The residue was chromatographed on silica gel using EtOAc as eluent to give 5 (2.94 g), R _f = 0.25 (silica gel, EtOAc).

(1S, 5R, 6R, 7R) -6- {3R-3-Hydroxy-5- (3-fluorophenyl) -1-pentyl} -7-R-hydroxy-2-oxabicyclo [3.3.0] octane-3- he (23)
To a solution of lactone 22 (2.8 g, 5.65 mmol) in methanol (15 ml) was added potassium carbonate (0.47 g, 3.3 mmol) and the mixture was stirred at ambient temperature for 6 hours (monitoring using TLC). The mixture was neutralized with a 10% aqueous HCl solution and extracted with EtOAc (2 x 30 ml). The organic phase was dried on anhydrous sodium sulfate and evaporated to dryness. The crude product was chromatographed on silica gel using EtOAc: acetone 1: 1 as eluent. The title compound 23 was obtained as a white crystalline product; yield 1.6 g, R _f = 0.17 (silica gel, EtOAc).

4,0

4,92

6,8-7,0 (м, 3Н), 7,28 (м, 1Н). ¹ H 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

4.0

4.92

6.8-7.0 (m, 3H); 7.28 (m, 1H).

(1S, 5R, 6R, 7R) -6- {3R-3-tert-butyldimethylsilyloxy-5- (3-fluorophenyl) -1-pentyl} - 7-R-tert-butyldimethylsilyloxy-2-oxabicyclo [3.3.0] octan-3-one (24)
tert-Butyldimethylsilyl chloride (2.3 g, 14.9 mmol) was added in one portion to a solution of diol 23, triethylamine (2.1 ml, 14.8 mmol) and 4-dimethylaminopyridine (0.06 g, 0.1 mmol) in dichloromethane (20 ml) with vigorous stirring at room temperature for 24 hours and the reaction mixture was concentrated in vacuo. The crude product was dissolved in ethyl acetate (50 ml), washed with water (20 ml) and 5% aqueous sodium hydrogen carbonate solution (20 ml). The organic phase was dried on sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel using dichloromethane as an eluent to give 3 g of the product as an oil. R _f = 0.68 (silica gel, ether).

(1S, 5R, 6R, 7R) -6- {3R-3-tert-butyldimethylsilyloxy-5- (3-fluorophenyl) -1-pentyl} -7-R-tert-butyldimethylsilyloxy-2-oxabicyclo [3.3.0] octan-3-ol (25)
A solution of diisobutylaluminum hydride (DIBAL) (1.1 g, 7.43 mmol) in dry toluene (5.3 ml) was added dropwise to a stirred solution of lactone 24 (2.7 g, 4.95 mmol) in dry THF (30 ml) at -72 / -80 ^o С. After 1 h (monitoring by TLC), the reaction mixture was quenched with methanol (5 ml), and warmed to room temperature, and water (50 ml), 10% aqueous HC1 solution (50) was added. ml) was extracted with EtOAc (2 x 50 ml). The organic layer was dried with sodium sulfate, filtered, the solvent was removed in vacuo and the residue was chromatographed on silica gel using EtOAc and EtOAc: acetone 1: 1 respectively as an eluent to give a yellow oily product (2.7 g), R _f = 0.85 ( silica gel, ethyl acetate 1: 1).

13,14-dihydro-11,15-di-tert-butyldimethylsilyloxy-17- (3-fluorophenyl) -18,19,20-trinor-PGF _2α (26)
To a stirred suspension of 4-carboxybutyltriphenylphosphonium bromide (8.78 g, 19.82 mmol) in THF (50 ml) in a nitrogen atmosphere at 0-5 ^{° C.} were added potassium tert-butoxide (3.89 g, 34.6 mmol) and the mixture was stirred for 30 min at room temperature. To the resulting red-orange solution of ylide at -15 / -10 ^° C, lactol 25 (2.7 g, 4.95 mmol) in THF (10 ml) was added and the mixture was stirred for 3-4 hours (monitoring by TLC) . The reaction mixture was diluted with water (30 ml) and washed with ether (4 • 40 ml). The aqueous layer was acidified with a 5% aqueous citric acid solution to pH 4 and extracted with EtOAc (2 x 50 ml). The organic phase was washed with brine (30 ml), dried on sodium sulfate and filtered. The solvent was removed in vacuo and a liquid clay-like 26 was used directly without isolation in the next step.

13,14-dihydro-11,15-di-tert-butyldimethylsilyloxy-17- (3-fluorophenyl) -18, 19, 20-trinor-PGF _2α isopropyl ester (27)
DBU (5.28 g, 34.7 mmol) was added dropwise to a stirred solution of the crude product 26 (3.16 g, 4.96 mmol) in acetone (20 ml) at 0 ^° C. The mixture was allowed to warm to room temperature and isopropyl iodide (5.05 g, 29.7 mmol) was added dropwise. After 4 h (TLC monitoring), the mixture was diluted with EtOAc (100 ml), washed with brine (30 ml), 3% citric acid (2 • 25 ml) and 5% sodium bicarbonate (2 • 25 ml) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was chromatographed on silica gel using ether: 1: 2 petroleum ether as eluent. This made it possible to obtain a colorless oil, yield 1.7 g, R _f = 0.43 (silica gel, ether: 1: 2 petroleum ether).

3,94

4,16

5,0 (септ, 1Н), 5,38 (м, шир.д), 5,47 (м, шир.д), 6,8-7,0 (дм, Аr, 3Н), 7,2 (м, Аr, 1Н). ¹ H NMR (CDCl ₃ ) d 0.1 (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

3.94

4.16

5.0 (sept., 1H), 5.38 (m, br d), 5.47 (m, br d), 6.8-7.0 (dm, Ar, 3H), 7.2 ( m, Ar, 1H).

13,14-dihydro-11,15-di-tert-butyldimethylsilyloxy-17- (3-fluorophenyl) -18,19,20-trinor-PGE ₂ isopropyl ether (28)
Pyridinium dichlorochromate (2.43 g, 11.25 mmol) on alumina (20 g) was added in small portions to a solution of 27 (1.7 g, 2.5 mmol) in dichloromethane (30 ml) and the mixture was stirred at room temperature ( monitoring by TLC), filtered and the precipitate was washed with a mixture of ether: ethyl acetate 2: 1. The solvent was removed in vacuo. The residue was diluted with ether (100 ml) and washed with water (30 ml), 5% aqueous NaHCO ₃ solution (3 • 20 ml), the organic phase was separated and dried over sodium sulfate and evaporated in vacuo to give 28 (1.3 g) in kind of oil. R _f = 0.72 (silica gel, ethyl acetate).

Isopropyl ether 13,14-dihydro-17- (3-fluorophenyl) -18,19,20-trinor-PGE ₂ (7)
Hydrogen fluoride 15% (12 ml) was added to a solution of 28 (314 mg) in acetonitrile. The mixture was stirred at room temperature for 4 hours (monitoring by TLC). The reaction mixture was diluted with ethyl acetate (100 ml) and washed with water (3 • 20 ml), dried and evaporated in vacuo. The residue was chromatographed on silica gel using ethyl acetate as an eluent to give 7 (64 mg) as an oil, R _f = 0.43 (silica gel, ethyl acetate).

4,16

5,0 (септ, 1Н), 5,38 (м, шир.д), 5,47 (м, шир.д), 6,8-7,0 (дм, Аr, 3Н), 7,2 (м, Аr, 1Н). ¹ H 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

4.16

5.0 (sept., 1H), 5.38 (m, br d), 5.47 (m, br d), 6.8-7.0 (dm, Ar, 3H), 7.2 ( m, Ar, 1H).

Pharmacology
The effect of reducing intraocular pressure from test compounds in cats and monkeys
Compounds were tested for the effect of lowering intraocular pressure in animal models. Intraocular pressure was measured with a calibrated pneumotonometer. European domestic cats and cynomolgus monkeys were used as experimental animals. Before measurement, the cornea was anesthetized with oxybuprocaine. Decreased intraocular pressure after topical treatment with PGF _2β -isopropyl ether (2), 17-phenyl-18,19,20-trinor-PGE ₂ -isopropyl ether (4), 15RS-16,16-trimethylene-methyl ether (6) and 13,14-dihydro-17- (3-fluorophenyl) -18,19, 20-trinor-PGE ₂ -isopropyl ether (7) are shown in tables IV and V.

As can be seen, in both cats and monkeys, all prostaglandin analogues with a preference for EP ₁ receptor significantly reduced intraocular pressure.

Thus, the present invention shows that compounds with a selective stimulatory effect on EP ₁ receptors reduce intraocular pressure and that such compounds may not have a melanogenic effect or at least have a significantly reduced effect in the eye, since pigment-producing cells, human melanocytes, do not have an EP ₁ receptor. Thus, the common side effect of increased iris pigmentation during chronic prostaglandin therapy selective for EP ₁ receptors can be avoided.

 For the purposes of the present description and the following claims, in a suitable context, the word “includes” and its variations should be understood as implying the inclusion of the indicated integer, or stage, or group of integers or stages, and not the exclusion of any other integer, or stage, or group integers or stages.

 Reference to any source of the prior art in the present description does not imply and should not be construed as a recognition or any form of assumption that the specified source from the prior art is part of the publicly available information in New Zealand.

Literature
Bill, A. (1975). Blood circulation and fluid dynamics in the eye. Physiol. Rev. 55; 383-417.

 Coleman, R.A., Smith, W.L. and Narumiya, S. (1994). Viii. International Union of Pharmacology classification of prostanoid receptors: Properties, distribution and structure of the receptors and their subtypes. Pharmacol Rev. 46; 205-229.

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Claims (4)

1. Ophthalmic composition for the treatment of glaucoma and intraocular hypertension without amplification or with the weakening of the side effect, expressed in melanogenesis, including a therapeutically active and physiologically acceptable amount of a compound of the general formula

where the wavy bonds represent the α or β configuration, and the dashed bonds represent a single bond, a triple bond or a double bond in a cis or trans configuration;
R represents hydrogen, saturated or unsaturated alkyl, preferably C _1-10 alkyl, cycloalkyl, preferably C _3-8 cycloalkyl, aryl, arylalkyl, preferably aryl-C _2-5 alkyl, or heteroaryl;
R1 represents a saturated or unsaturated alkyl group containing 2-5 carbon atoms, optionally interrupted by heteroatoms selected from oxygen, sulfur and nitrogen, cycloalkyl, preferably C _3-7 cycloalkyl, cycloalkenyl, preferably C _3-7 cycloalkenyl, aryl or heteroaryl;
X represents C — OH or C = O;
R2 is hydrogen, hydroxy, methyl, ethyl, methoxy or OCOR4, where R4 is a straight or branched chain saturated or unsaturated alkyl group, preferably C _1-10 alkyl, especially C _1-6 alkyl, or cycloalkyl, preferably C _{3- 8} cycloalkyl, or an aryl group;
R3 is a straight or branched chain saturated or unsaturated alkyl group, preferably containing 3-8 carbon atoms, especially 3-5 carbon atoms, optionally interrupted by one or more heteroatoms selected from oxygen, sulfur and nitrogen, with each carbon atom optionally substituted with a substituent selected from C _1-5 alkyl, hydroxyl and carbonyl groups, with hydroxy and carbonyl preferably attached to the 15th carbon atom of the prostaglandin structure, and said alkyl group optionally contains a cycloalkyl, preferably a C _3-8 cycloalkyl, aryl or heteroaryl group, which may be substituted by one or independently C _1-3 alkyl, C _1-3 alkoxy, hydroxy, nitro, trifluoromethyl or halogen,
or a pharmaceutically acceptable salt or ester thereof, which is a selective agonist of EP ₁ prostanoid receptors, and an ophthalmologically compatible carrier.  2. The composition according to claim 1, where the prostaglandin analogue is 15 (R, S) -16,16-trimethylene-PGE2 or its alkyl ester.  3. The composition of claim 1, wherein the prostaglandin analogue is 13,14-dihydro-17- (3-fluorophenyl) -18,19,20-trinor-PGE2 or an alkyl ester thereof. 4. The use of a prostaglandin analog, which is a selective agonist of EP ₁ -protanoid receptors, as defined in any one of claims 1 to 3, for the preparation of a medicament for the treatment of glaucoma or intraocular hypertension without amplification or with a weakening side effect, which is manifested in melanogenesis.

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