RU2392941C2 - Prostaglandin derivatives for treating gastrointestinal disorders - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly to gastroenterology, and concerns treating gastrointestinal disorders. That is ensured by administration of the effective amount of a halogenated prostaglandin compound and/or its tautomer.

EFFECT: method provides effective treatment in patients of any age and sex without involving electrolyte balance even in long-term introduction for 1 to 6 months and more.

54 cl, 8 tbl, 14 dwg, 6 ex

Description

FIELD OF THE INVENTION

The invention relates to a method and composition for the long-term treatment of gastrointestinal disorders in humans.

In addition, the present invention relates to a method and composition for treating gastrointestinal disorders in both women and men.

The present invention also relates to a method and composition for treating gastrointestinal disorders in people 65 years of age and older.

In addition, the present invention relates to a method and composition for improving the quality of life of people with gastrointestinal disorders.

State of the art

Constipation is usually defined as a rare and difficult discharge of feces. According to medical estimates, one in every 50 people in the United States suffers from constipation. Thus, this violation is one of the main problems among residents of the United States. It is most likely that constipation affects women more often than men and is more common in older people, showing an exponential increase in the disease in people over 65 years of age. The actual number of cases of constipation seems to exceed the number of reports of this violation, since a large number of people suffer from it at home and do not seek professional help.

Although in some cases, constipation may be caused by obstruction, the largest number of disorders of this kind may be associated with factors such as eating with insufficient amounts of soluble and insoluble fibers, insufficient physical activity, taking medications (especially opium analgesics, anticholinergic antidepressants, antihistamines preparations and vinca alkaloids), intestinal disorders, neuromuscular disorders, metabolic disorders, low intraperitoneal pressure or muscle aton and I.

It is difficult to give an exact quantitative definition of constipation, which is associated with a broad concept of "normal" intestinal activity, as well as a variety of symptoms and signs associated with constipation. It should be noted that the FDA recognized the need for mandatory treatment for cases of recurrent constipation.

Prostaglandins (hereinafter PGs) belong to the class of organic carboxylic acids contained in the tissues or organs of humans or other mammals and possessing wide physiological activity. Natural PGs (primary PGs) with the framework of prostanoic acid depicted in the formula (A)

(α-chain)

(ω-chain)

PGs are divided into several types depending on the structure and substituents in the five-membered ring, for example:

Prostaglandins Series A (PGAs)

Prostaglandins Series B (PGBs)

Prostaglandins Series C (PGCs)

Prostaglandins Series D (PGDs)

Prostaglandins Series E (PGEs)

F-Series Prostaglandins (PGFs)

etc. In addition, they are subdivided into the group PG ₁ S containing a 13.14 double bond; PG ₂ s containing 5,6- and 13,14-double bonds; and PG ₃ s containing 5.6, 13.14 and 17.18 double bonds. PGs are known to have various pharmacological and physiological activities, for example, such as vasodilation, including inflammation, platelet aggregation, uterine muscle stimulation, intestinal muscle stimulation, antiulcer effect, etc. The major prostaglandins that form in the human gastrointestinal system (GI) are of the E, I, and F series (Sellin, Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis and Management. (WB Saunders Company, 1998); Robert, Physiology of the Gastrointestinal Tract 1407-1434 (Raven, 1981); Rampton, Prostaglandins: Biology and Chemistry of Prostaglandins and Related Eicosanoids 323-244 (Churchill Livingstone, 1988); Hawkey et al., Gastroenterology, 89: 1162-1188 (1985); Eberhart et al ., Gastroenterology, 109: 285-301 (1995)).

Under normal physiological conditions, endogenous-produced prostaglandins play an important role in maintaining GI function, including regulation of intestinal motility and passage of contents through the intestines, and regulation of stool consistency (Sellin, Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis and Management. (WB Saunders Company, 1998); Robert, Physiology of Gastrointestinal Tract 1407-1434 (Raven, 1981); Rampton, Prostaglandins: Biology and Chemistry of Prostaglandins and Related Eicosanoids 323-244 (Churchill Livingstone, 1988); Hawkey et al., Gastroenterology, 89: 1162-1188 ( 1985); Eberhart et al., Gastroenterology, 109: 285-301 (1995); Robert, Adv Prostaglandin Thromboxane Res, 2: 507-520 (1976); Main et al., Postgard Med J, 64 Suppl 1: 3- 6 (1988); Sanders, Am J Physiol, 247: G117 (1984); Pairet, et al., Am J Physiol., 250 (3 pt I): G302-G308 (1986); Gaginella, Textbook of Secretory Diarrhea 15-30 (Raven Press, 1990)) . When taken in pharmacological doses, both PGE ₂ and PGF _{2α have} been shown to stimulate the passage of contents through the intestines and cause diarrhea (Robert, Physiology of the Gastrointestinal Tract 1407-1434 (Raven, 1981); Rampton, Prostaglandins: Biology and Chemistry of Prostaglandins and Related Eicosanoids 323-344 (Churchill Livingstone, 1988); Robert, Adv Prostaglandin Thromboxane Res, 2: 507-520 (1976)). In addition, diarrhea is the most commonly known side effect of misoprostol, an analogue of PGE ₁ , designed to treat stomach and duodenal ulcers (Monk et al., Drugs 33 (1): 1-30 (1997)).

PGE or PGF can stimulate the activity of the intestine and cause its contraction, however, they have a weak effect on the ability to concentrate feces in the intestine. Therefore, PGEs or PGFs cannot be used as a laxative due to side effects associated with stomach pain caused by bowel contraction.

Multiple mechanisms, including modified reactions of the intestinal nerves, changes in smooth muscle contraction, stimulation of mucus secretion, stimulation of cellular ion transport (especially Cl ^- electrogenic transport), and increased gastric fluid volume have been reported to contribute to the effects of prostaglandins in GI (Robert, Physiology of the Gastrointestinal Tract 1407-1434 (Raven, 1981); Rampton, Prostaglandins: Biology and Chemistry of Prostaglandins and Related Eicosanoids 323-244 (Churchill Livingstone, 1988); Hawkey et al., Gastroenterology, 89: 1162-1188 (1985); Eberhart et al., Gastroenterology, 109: 285-301 (1995); Robert, Adv Prostaglandin Thromboxane Res, 2: 507-520 (1976); Main et al., P ostgrad Med J, 64 Suppl 1: 3-6 (1988); Sanders, Am J Physiol, 247: G117 (1984); Pairet et al., Am J Physiol, 250 (3 pt 1): G302-G308 (1986) ; Gaginella, Textbook of Secretory Diarrhea 15-30 (Raven Press, 1990); Federal Register Vol.50, No.10 (GPO, 1985); Pierce et. Al, Gastroenterology 60 (1): 22-32 (1971); Beubler et al., Gastroenterology, 90: 1972 (1986); Clarke et al., Am J Physiol 259: G62 (1990); Hunt et al., J Vet Pharmacol Ther, 8 (2): 165-173 (1985); Dajani et al., Eur J Pharmacol, 34 (1): 105-113 (1975); Sellin, Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis and Management (WB Saunders Company, 1998). It has also been shown that prostaglandins have cytoprotective effects (Sellin, Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis and Management (WB Saunders Company, (1998): Robert, Physiology of the Gastrointestinal Tract 1407-1434 (Raven, 1981); Robert, Adv Prostaglandin Thromboxane Res, 2: 507-520 (1976); Wallace et al., Aliment Pharmacol Ther 9: 227-235 (1995)).

U.S. Patent No. 5317032, registered by Ueno et al., Describes laxatives based on a prostaglandin analogue including their bicyclic tautomers, and U.S. Patent No. 6416016, registered by Ueno, describes bicyclic tautomers of a prostaglandin analogue with pronounced anti-constipation activity. Bicyclic tautomers of a prostaglandin analog substituted at position C-16 with one or more halogen atoms, especially fluorine atoms, can be used in small doses to alleviate symptoms of constipation.

U.S. Patent Publication No. 2003/0130352, registered by Ueno et al., Describes that a prostaglandin compound opens and activates chlorine channels, especially ClC channels, and especially ClC-2 channels.

US Patent publication No.2003 / 0119898, registered by Ueno et al., Describes a special halogenated prostaglandin analog composition for the treatment and prevention of constipation.

U.S. Patent publication No. 2004/0138308, registered by Ueno et al., Describes that a chlorine channel activator, in particular a prostaglandin compound, can be used to treat stomach discomfort, as well as to treat functional gastrointestinal disorders such like irritable bowel syndrome and functional dyspepsia.

MiraLax ™ (polyethylene glycol 3350, NF powder for solutions) is a synthetic polyglycol with an average molecular weight of 3350 and is used to treat recurrent constipation. This remedy is usually used within two weeks. Prolonged, frequent or excessive use of MiraLax ™ can lead to electrolyte imbalance and dependence on laxatives (see the package insert in the MiraLax ™ package). MiraLax ™ acts as an osmotic agent that creates an imbalance in the intestinal lumen and osmotically draws in fluid. An increased level of fluid softens the stool and promotes bowel movements.

It is also suggested that the above activators of ClC-2-chlorine channels function by stimulating the secretion of chlorine ions into the intestinal lumen, as a result of which water by the osmotic mechanism enters the intestinal lumen, which, in turn, contributes to defecation. Considering that a specific prostaglandin compound is an activator of ion channels, and is believed to work mainly by the osmotic mechanism similar to that of MiraLax ™, it can be assumed that the long-term use of this prostaglandin compound has the same disadvantages as in the case of MiraLax ™. In this regard, its use is limited to almost a couple of weeks, as when using MiraLax ™.

Zelnorm® (tegaserod maleate) is indicated for the short-term treatment of women with irritable bowel syndrome (IBS), the primary symptom of which is constipation. In two randomized, placebo-controlled, double-blind trials involving 288 male volunteers, no significant differences were found in the responses to placebo and Zelnorm®. The safety and efficacy of Zelnorm® administration by men with IBS accompanying constipation have not been established. In addition, analysis of subgroups of patients 65 years of age and older did not reveal a significant therapeutic effect of Zelnorm® compared with the placebo. In other words, the efficacy of Zelnorm® has not been established in patients aged 65 years and older suffering from chronic constipation of unknown origin. Moreover, if you stop taking Zelnorm®, your symptoms may return within 1 or 2 weeks (instructions in the Zelnorm® package).

SUMMARY OF THE INVENTION

Despite the predominance of the osmotic mechanism of action, the inventor unexpectedly found that with prolonged use of certain halogenated prostaglandin compounds in humans, redistribution of electrolytes does not occur.

The inventor also found that halogenated prostaglandin compounds are effective in long-term treatment, and even after termination of long-term treatment with said compound, symptoms generally do not recur.

The inventor also found that halogenated prostaglandin compounds improve the quality of life of patients with gastrointestinal disorders and are equally effective in treating both women and men and even patients aged 65 years and older.

That is, the present invention provides a method for the long-term treatment of gastrointestinal disorders in humans, comprising administering to the patient an effective amount of a prostaglandin compound represented by formula (I) and / or its tautomer

where wi and ws are

,

или

(a)

,

or

(a)

R ₃ and R ₄ are hydrogen; or one of the radicals is OH and the other is hydrogen;

X ₁ and X ₂ represent hydrogen, lower alkyl or halogen, provided that at least one of them is halogen;

R ₂ represents hydrogen or alkyl;

Y represents a saturated or unsaturated C _2-10 hydrocarbon chain which is unsubstituted or substituted by oxo, halogen, alkyl, hydroxy or aryl;

A represents —CH ₂ OH, —COCH ₂ OH, —COOH, or functional derivatives thereof;

R ₁ represents a saturated or unsaturated, linear chain, branched chain, or cyclic lower hydrocarbon which is unsubstituted or substituted with halogen, oxo, hydroxy, lower alkyl, lower alkoxy, lower alkanoyloxy, lower cycloalkyl, lower cycloalkyloxy, aryl or aryloxy; lower cycloalkyl; lower cycloalkyloxy; aryl; or aryloxy;

the bond between C-13 and C14 is a double or single bond, and the steric configuration of the C-15 position is the R, S configuration, or a mixture thereof.

The present invention also provides a method for treating gastrointestinal disorders in men or men 65 years of age or older, which comprises administering to a patient in need of treatment an effective amount of a prostaglandin compound of formula (I) and / or its tautomer.

In addition, the present invention provides a method for improving the quality of life of a subject with gastrointestinal disorders, which comprises administering to a patient in need of treatment an effective amount of a prostaglandin compound of the formula (I) and / or its tautomer.

In each embodiment of the method of the present invention, the total daily dose of the PG compound may preferably be 6-96 μg.

The method of the present invention can be carried out by administering to a patient in need of treatment a pharmaceutical composition which comprises the aforementioned prostaglandin compound and / or its tautomer. Accordingly, in another aspect of the present invention, there is provided a pharmaceutical composition for the long-term treatment of gastrointestinal disorders in humans, comprising (i) an effective amount of a prostaglandin compound of formula (I) and / or its tautomer and (ii) a pharmaceutically acceptable excipient.

In addition, the present invention provides a pharmaceutical composition for treating a gastrointestinal disorder in patients of both male and female, or people 65 years of age or older, the composition comprising (i) an effective amount of a prostaglandin compound having the formula ( I), and / or its tautomer, and (ii) a pharmaceutically acceptable excipient.

The present invention also provides a pharmaceutical composition for improving the quality of life of a person with gastrointestinal disorders, which comprises (i) an effective amount of a prostaglandin compound having the formula (I) and / or its tautomer and (ii) a pharmaceutically acceptable excipient.

In another aspect of the present invention, there is provided the use of a prostaglandin compound having the formula (I) and / or its tautomer for the manufacture of the pharmaceutical composition described above.

Brief Description of the Drawings

Figure 1 is a graph showing the severity of constipation during treatment for 6 months.

Figure 2 is a graph showing the severity of constipation during treatment for 12 months.

Figure 3 is a graph showing an assessment of bloating during treatment for 6 months.

Figure 4 is a graph showing an assessment of bloating during treatment for 12 months.

Figure 5 is a graph showing an assessment of abdominal discomfort during treatment for 6 months.

Figure 6 is a graph showing an assessment of abdominal discomfort during treatment for 12 months.

Figure 7 is a graph showing the effect on the number of bowel movements per week.

Figure 8 is a graph showing the effect on bloating.

Figure 9 is a graph showing the effect on abdominal discomfort.

Figure 10 is a graph showing the effect on the severity of constipation.

Figure 11 is a graph showing the effect on the degree of straining during bowel movements.

Figure 12 is a graph showing the effect on stool consistency.

Figure 13 is a comparative graph showing the effect on bowel movements in male and female patients.

Figure 14 is a graph showing the effect of patient age on bowel movements.

DETAILED DESCRIPTION OF THE INVENTION

In the present invention, the term "effective amount" can be defined taking into account age, body weight, patient condition, desired therapeutic effect, method of application, treatment period, and the like. According to the present invention, the amount of prostaglandin compound administered to a patient may be 0.001-1000 μg / kg body weight, more preferably 0.01-100 μg / kg body weight and most preferably 0.1-10 μg / kg body weight . The frequency of administration may be one or more doses per day, preferably two or more doses per day. The usual amount of the drug administered to the patient is 6-96 mcg per day. In accordance with the description and the claims, the amount or dose administered is set for a patient with an approximate body weight of 60 kg.

Used in the text, the term "approximately", referring to the unit of measurement, can be defined as +/- 30%, preferably +/- 20%, particularly preferably +/- 10% of the measured value. So, for example, a total daily dose of about 6-96 μg preferably relates to the range of 5.4-105.6 μg. The preferred dose is in the range of 6-72 mcg. In a more preferred embodiment, the dose of the drug is in the range of 6-60 μg. So, for example, the dose of the halogenated compound may be about 8-48 μg.

(i) A prostaglandin compound having the formula (I)

In the present invention, a prostaglandin compound of the formula (I) is used

where W ₁ and W ₂ represent:

,

или

(a)

,

or

(a)

R ₃ and R ₄ are hydrogen; or one of the radicals is OH and the other is hydrogen;

X ₁ and X ₂ represent hydrogen, lower alkyl or halogen, provided that at least one of them is halogen;

R ₂ represents hydrogen or alkyl;

Y represents a saturated or unsaturated C _2-10 hydrocarbon chain which is unsubstituted or substituted by an oxo group, halogen, alkyl, hydroxy or aryl;

A represents —CH ₂ OH, —COCH ₂ OH, —COOH, or functional derivatives thereof;

R ₁ represents a saturated or unsaturated, linear-chain, branched-chain or cyclic lower hydrocarbon which is unsubstituted or substituted by halogen, oxo, hydroxy, lower alkyl, lower alkoxy, lower alkanoyloxy, lower cycloalkyl, lower cycloalkyloxy, aryl or aryloxy; lower cycloalkyl; lower cycloalkyloxy; aryl; or aryloxy;

the bond between C-13 and C14 is a double or single bond and

the steric configuration of the C-15 position is an R, S configuration, or a mixture thereof.

In the above formula, the term “halogen” includes fluorine, chlorine, bromine and iodine atoms. Particularly preferred halogen atoms for the substituents X ₁ and X ₂ are fluorine atoms.

The term “unsubstituted”, as used in the definition of substituents R ₁ and Y, includes at least one or more double bonds and / or triple bonds that are located between carbon atoms in the main and / or side chain and which can be separate, separated and located periodically. In accordance with the accepted nomenclature, the unsaturated bond between two consecutive positions is determined by indicating a lower number of two positions, and the unsaturated bond between two remote positions from each other is determined by indicating both positions.

Used in the description and claims, the term "lower" includes a group containing 1-6 carbon atoms, unless otherwise noted.

The term “ring” refers to lower cycloalkyl, lower cycloalkyloxy, aryl or aryloxy.

The term "lower alkyl" refers to a straight or branched chain saturated hydrocarbon group containing 1-6 carbon atoms, and includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl.

The term "lower alkoxy" refers to the group lower alkyl-O-, in which lower alkyl is defined as described above.

The term "lower alkanoyloxy" refers to a group represented by the formula RCO-O-, in which RCO- is an acyl group, for example acetyl, formed by the oxidation of a lower alkyl group, as described above.

The term “lower cycloalkyl” refers to a cyclic group formed by cyclization of the aforementioned lower alkyl group, but containing three or more carbon atoms, and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term "lower cycloalkyloxy" refers to the group lower cycloalkyl-O-, in which lower cycloalkyl is defined as described above.

The term “aryl” refers to unsubstituted or substituted aromatic carbocyclic or heterocyclic groups (preferably monocyclic groups), for example, such as phenyl, naphthyl, tolyl, xylyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazol, furanyl, pyranyl, pyridyl, pyridazyl, pyrimidyl, pyrazyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidino, piperazinyl, morpholino, indolyl, benzothienyl, quinolyl, isoquinolyl, puryl, quinazinyl phenyl, quinazolinyl, nzimidazolyl, benzimidazolonyl, benzothiazolyl and phenothiazinyl. Examples of substituents include a halogen atom and halo (lower) alkyl, where a halogen atom and lower alkyl are defined as described above.

The term “aryloxy” refers to a group represented by the formula ArO—, in which Ar is aryl, as defined above.

The term "functional derivative" A includes salts (preferably pharmaceutically acceptable salts), ethers and esters and amides.

Suitable “pharmaceutically acceptable salts” include conventionally used non-toxic salts, for example, an inorganic base salt, such as an alkali metal salt (eg, sodium and potassium salt), alkaline earth metal salt (eg, calcium and magnesium salt), ammonium salt; or an organic base salt, for example, an amine salt (such as methylamine salt, dimethylamine salt, cyclohexylamine salt, benzylamine salt, piperidine salt, ethylenediamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, tris (hydroxymethylamino) ethane salt, monomethylamine-monoethanolamine salt , procaine salt and caffeine salt), a salt of a basic amino acid (such as an arginine salt and a lysine salt), a tetraalkylammonium salt, and the like. These salts can be obtained by conventional methods, for example, from the corresponding acid and base or by salt exchange.

Examples of ethers include alkyl ethers, for example lower alkyl ethers such as methyl ether, ethyl ether, propyl ether, isopropyl ether, butyl ether, isobutyl ether, tert-butyl ether, pentyl ether and 1-cyclopropylethyl ether; and middle and higher alkyl ethers such as octyl ether, diethylhexyl ether, lauryl ether and cetyl ether; unsaturated esters such as oleyl ether and linolenyl ether; lower alkenyl ethers, such as vinyl ether, allyl ether; lower alkynyl ethers, such as ethynyl ether and propynyl ether; hydroxy (lower alkyl) esters such as hydroxyethyl ether and hydroxyisopropyl ether; lower alkoxy esters (lower alkyl), such as methoxymethyl ether and 1-methoxyethyl ether; optionally substituted aryl ethers such as phenyl ether, tosyl ether, tert-butylphenyl ether, salicylic ether, 3,4-dimethoxyphenyl ether and benzamidophenyl ether; and aryl (lower alkyl) esters such as benzyl ether, trityl ether and benzhydryl ether.

Examples of esters include aliphatic esters, for example lower alkyl esters such as methyl ether, ethyl ether, propyl ether, isopropyl ether, butyl ether, isobutyl ether, tert-butyl ether, pentyl ether and 1-cyclopropylethyl ester; alkenyl ethers such as vinyl ether and allyl ether; alkynyl esters such as ethynyl ether and propynyl ether; hydroxy (lower alkyl) ester such as hydroxyethyl ether; lower alkoxy esters (lower alkyl) esters such as methoxymethyl ether and 1-methoxyethyl ester; and optionally substituted aryl esters such as phenyl ether, tolyl ether, tert-butylphenyl ether, salicylic ether, 3,4-dimethoxyphenyl and benzamidophenyl ether; and also an aryl (lower alkyl) ester such as benzyl ether, trityl ether and benzhydryl ether.

Amide part A denotes a group represented by the formula —CONR′R ″ in which each of R ′ and R ″ represents hydrogen, lower alkyl, aryl, alkyl or arylsulfonyl, lower alkenyl and lower alkynyl, and includes, for example, lower alkylamides such as methylamide, ethylamide, dimethylamide and diethylamide; acrylamides such as anilide and toluidide; as well as alkyl or arylsulfonamides such as methylsulfonylamide, ethylsulfonylamide and tolylsulfonylamide.

Examples Y include, for example, the following groups:

-CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ -,

-CH ₂ -CH = CH-CH ₂ -CH ₂ -CH ₂ -,

-CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH = CH-,

-CH ₂ -C≡C-CH ₂ -CH ₂ -CH ₂ -,

-CH ₂ -CH ₂ -CH ₂ -CH ₂ -O-CH ₂ -,

—CH ₂ —CH = CH — CH ₂ —O — CH ₂ -,

-CH ₂ -C≡C-CH ₂ -O-CH ₂ -,

- CH ₂ - CH ₂ - CH ₂ - CH ₂ - CH ₂ - CH ₂ - CH ₂ ,

—CH ₂ —CH = CH — CH ₂ —CH ₂ —CH ₂ —CH ₂ ,

-CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH = CH-,

—CH ₂ —CH — CH ₂ —CH ₂ —CH ₂ —CH ₂ ,

-CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH (CH ₃ ) -CH ₂ -,

-CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH (CH ₃ ) -CH ₂ -,

- CH ₂ - CH ₂ - CH ₂ - CH ₂ - CH ₂ - CH ₂ - CH ₂ - CH ₂ ,

—CH ₂ —CH = CH — CH ₂ —CH ₂ —CH ₂ —CH ₂ —CH ₂ ,

-CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH = CH-,

—CH ₂ —CH — CH ₂ —CH ₂ —CH ₂ —CH ₂ —CH ₂ -, and

-CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH (CH ₃ ) -CH ₂ -.

In addition, at least one carbon atom in the aliphatic hydrocarbon fragment Y is optionally substituted with oxygen, nitrogen, or sulfur.

Preferred A is —COOH or a pharmaceutically acceptable salt or ester thereof.

Preferred radicals X ₁ and X ₂ can simultaneously be halogen atoms, and more preferably fluorine atoms.

Preferred W ₁ is = O.

Preferred W ₂ is

или

(a),

or

(a)

where both radicals R ₃ and R ₄ are hydrogen atoms.

Preferred Y is an unsubstituted, saturated or unsaturated hydrocarbon chain containing 6-8 carbon atoms.

Preferred R ₁ is a hydrocarbon residue containing 1-6 carbon atoms, more preferably 1-4 carbon atoms. In R ₁ at one carbon atom, one or two side chains may be present.

R _{2 is} preferably hydrogen.

The most preferred embodiment of the invention is a prostaglandin compound having the formula (I) in which A is —COOH; Y represents (CH ₂ ) ₆ ; W ₁ represents = O; W ₂ represents

или

(a),

or

(a)

where both radicals R ₃ and R ₄ are hydrogen; R ₂ represents hydrogen; X ₁ and X ₂ are fluorine; and R ₁ represents (CH ₂ ) ₂ CH ₃ or CH ₂ CH (CH ₃ ) CH ₂ CH ₃ .

The active compound of this invention or the PG compound having the formula (I) exists as a bicyclic compound in the solid state, but when dissolved in a solvent, part of the compound forms a tautomeric form. In the absence of water, the compound represented by formula (I) is advantageously in the form of a bicyclic structure. It is believed that in an aqueous medium a hydrogen bond arises between a water molecule and, for example, a ketone group at position C-15, which complicates the formation of a bicyclic ring. In addition, it is believed that halogen atoms at position C-16 contribute to the formation of a bicyclic ring. As shown below, the tautomerism between the hydroxy group at position C-11 and the keto group at position C-15 plays a particularly important role in the case of compounds containing a 13, 14 single bond and two fluorine atoms at position C-16.

Thus, the present invention may include isomers of halogenated prostaglandin compounds. Below, as an example, monocyclic tautomers are shown containing a keto group at position C-15 and halogen atoms at position C-16.

In accordance with the generally accepted nomenclature of prostaglandins, the monocyclic form of a preferred compound of the present invention may be referred to as 13,14-dihydro-15-keto-16,16-difluoro-PGE ₁ .

(ii) Pharmaceutically acceptable excipient

In accordance with the present invention, the pharmaceutical composition may be formulated in any form. Therefore, a pharmaceutically acceptable excipient may be selected depending on the desired form of the composition. In accordance with the invention, the term "pharmaceutically acceptable excipient" means an inert substance that is used in conjunction with the active ingredient of the invention and is suitable for obtaining the desired form.

For example, a solid oral composition of the present invention may include tablets, preparations, granules, and the like. In such a solid composition, one or more active ingredients can be mixed with at least one inert diluent, for example, lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium aluminate metasilicate and the like. In accordance with normal practice, the composition, in addition to an inert diluent, may contain additives, for example, a lubricant such as magnesium stearate; a disintegrant such as calcium fibrous gluconate; a stabilizer such as cyclodextrin, for example α, β or γ-cyclodextrin; an esterified cyclodextrin such as dimethyl-α-, dimethyl-β-, trimethyl-β- or hydroxypropyl-β-cyclodextrin; branched cyclodextrin, such as glucosyl, maltosylcyclodextrin; formylated cyclodextrin; cyclodextrin containing sulfur; phospholipid and the like When using the above cyclodextrins, sometimes the formation of inclusion compounds can occur, which increases the stability of the product. Alternatively, a phospholipid can sometimes be used to form a liposome, which also contributes to stability.

If necessary, the tablets or pills may be coated with a film soluble in the stomach or intestines, such as sugar, gelatin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose phthalate. In addition, they can be obtained in the form of capsules with absorbable substances, for example gelatins. Preferably, the composition is in the form of a soft gelatin capsule with liquid contents of a halogenated prostaglandin compound and a medium chain fatty acid triglyceride. Examples of medium chain fatty acid triglyceride used in the present invention include a saturated or unsaturated fatty acid triglyceride containing 6-14 carbon atoms, which may have a branched structure. A preferred fatty acid is a linear saturated fatty acid, for example caproic acid (C6), caprylic acid (C8), capric acid (C10), lauric acid (C12) and myristic acid (C14). In addition, a mixture of two or more triglycerides with medium chain fatty acids can be used. Other suitable excipients are described in published PCT application WO 01/27099.

The liquid composition for oral administration may be in the form of an emulsion, solution, suspension, syrup or elixir, and includes a commonly used inert diluent. In addition to an inert diluent, such a composition may contain additives such as lubricants, sweeteners, flavorings, preservatives, solubilizers, antioxidants, and the like. Supplements can be selected from those described in any general pharmaceutical guide. Liquid compositions can be directly placed in soft capsules. The composition of the present invention can be used in the form of a suppository, enema, etc. They may be in the form of sterile aqueous or non-aqueous solutions, suspensions, emulsions, and the like. Examples of excipients for an aqueous solution, suspension or emulsion may include distilled water, saline and Ringer's solution.

Examples of excipients for a non-aqueous solution, suspension or emulsion may include propylene glycol, polyethylene glycol, triglyceride with fatty acids, vegetable oil, for example olive oil, alcohols such as ethanol, polysorbate and the like. Such a composition may contain additives, for example, preservatives, a moisturizer, an emulsifier, a dispersant, antioxidants, and the like.

According to the present invention, the pharmaceutical composition may be intended for parenteral or oral administration, and an oral composition is preferred. In an example, the active ingredient is preferably dissolved in medium chain fatty acid triglyceride and capsules are filled into the solution.

In accordance with the method of the invention, the composition of the present invention can be administered systemically or locally by means of oral or parenteral administration, including parenteral administration by suppository, enema, etc. The composition of the present invention can be entered from one to several times a day.

Preferably, the total daily dose of the prostaglandin compound of the present invention is about 6-96 μg, more preferably about 6-72 μg, even more preferably about 6-60 μg, and particularly preferably 8-48 μg. The dose may vary at the discretion of the therapist depending on the age and body weight of the patient, his condition, therapeutic effect, route of administration, treatment period, etc.

Used in the text, the term "without a significant electrolyte shift" means that the electrolyte imbalance during treatment is expressed to a much lesser extent than under the action of the known means of inducing electrolyte imbalance. In addition, the term “without significant electrolyte shift” refers to the level of serum electrolyte in a patient undergoing treatment, which, as clinicians should understand, is in the range of normal clinical values. As noted above, MiraLax ™, used to treat constipation, can cause electrolyte imbalances, which, among other things, can lead to dangerous cardiac problems. On the other hand, as shown in the following example, the prostaglandin compound used in the present invention practically does not cause electrolyte shift, even with prolonged use of the drug.

The following examples also demonstrate the fact that the pharmaceutical composition of the present invention practically does not cause the onset of symptoms of constipation or other undesirable conditions after termination of long-term treatment with the composition. Thus, as a result of this, the composition of the present invention may be useful in long-term treatment.

Moreover, an assessment of the quality of life of patients suffering from constipation and IBS led to the conclusion that the presented compounds improved the quality of life of patients.

In accordance with the present invention, the present compounds may be useful in the long-term treatment of gastrointestinal disorders. They are equally effective in treating both male and female patients. In addition, they are useful in treating a patient aged 65 years or older.

As used herein, the term “gastrointestinal disturbances” includes, but is not limited to, acute or chronic constipation, functional gastrointestinal disorders such as irritable bowel syndrome and functional dyspepsia, gastric ulcer, colon and small intestine ulcer, and abdominal discomfort .

Various types of constipation to be treated include, but are not limited to, functional constipation, for example, relaxing constipation, spastic constipation, rectal constipation, and postoperative intestinal obstruction; organic constipation caused by bowel disease and stenosis due to postoperative adhesions; as well as constipation caused by drugs, such as an opioid.

In addition to alleviating or preventing constipation, the composition of the present invention can be used to prevent straining during bowel movements in a patient suffering from a hernia or cardiovascular disease, or to soften feces in a patient with anorectal diseases. In addition, the present composition can be used to cleanse the gastrointestinal tract in preparation for endoscopic examination or for diagnostic or surgical procedures, such as colonoscopy, barium enema during x-ray studies and intravenous pyelography, or in case of urgent procedures such as emergency gastrointestinal lavage intestinal tract to remove poisons, etc. Thus, the invention encompasses embodiments in which the composition of the present invention is used to cleanse the gastrointestinal tract in men or people aged 65 years or older.

The term “treatment” as used in the text includes any means of control, such as prevention, patient care, relieving symptoms, alleviating symptoms, and stopping the development of the disease. As used herein, the term “long-term treatment” refers to the administration of a compound for at least two weeks. The compound can be taken daily during the entire treatment period or with an interval of one or more days.

The details of the present invention described below will be followed by reference to experimental examples, which, however, do not limit the scope of the present invention.

Information confirming the possibility of carrying out the invention

Example 1

Method

A multicenter open-label study was performed to evaluate the safety of taking 48 μg of compound A (13.14-dihydro-15-keto-1b, 16-difluoro PGE ₁ ) (24 μg of compound A bid) when taken daily for 24 weeks (6 months) or 48 weeks (12 months) by patients suffering from intermittent constipation. Patients who have had chronic constipation in the past for at least 3 months (less than 3 SBMs per week) and at least one concomitant symptom such as hard stools, incomplete emptying, straining were registered. After a 14-day washout period in the absence of drugs, patients received 48 μg of compound A (24 μg of compound A bid) orally for 48 weeks.

In this study, the following parameters were evaluated.

1. Electrolyte balance

The concentrations of sodium, potassium, chlorine, calcium, magnesium, and phosphorus ions in the serum of patients (n = 299) were measured before treatment and 6, 12, 18, 24, 30, 48, and 50 weeks after the start of treatment with compound A.

Laboratory standard values of the electrolyte set were taken from the normal range of values of the central laboratory.

2) The severity of constipation, 3) bloating and 4) discomfort in the abdomen.

Each parameter (severity of constipation, bloating and discomfort in the abdomen) was evaluated in patients during the 6-month (n = 246) or 12-month (n = 304) treatment according to the following scale: 0 (absence), 1 (weak), 2 (moderate), 3 (heavy) and 4 (very heavy).

results

1. Electrolyte balance

As follows from Table 1, treatment with compound A did not affect the concentration of sodium, potassium, chlorine, calcium, magnesium and phosphorus ions in the blood serum of patients. The results show that compound A does not cause a significant shift in electrolytes during prolonged administration of the drug.

Table 1 The average results of a chemical analysis of blood serum A week Sodium (mmol / L) Potassium (mmol / L) Chloride (mmol / L) Calcium (mg / dl) Magnesium (mg / dl) Phosphorus (mg / dl) 0 141.00 4.28 103.08 9.61 2.18 3.65 6 142.25 4.28 103.00 9.90 2.23 3.20 12 139.78 4.20 103.08 9.71 2.24 3.57 eighteen 141.50 4.40 105.50 9.30 2,35 3,55 24 139.21 4.19 102.56 9.77 2.21 3.61 thirty 136.00 4.30 100.00 9.10 2,30 2,50 36 138.94 4.18 102.51 9.67 2.19 3,58 48 139.59 4.20 102.88 9.66 2.14 3,50 fifty 139.11 4.49 102.67 9.47 2,31 3,54 Laboratory standard 135-148 3,5-5,5 96-109 8.5-10.6 1.6-2.6 * * Women: 15-19 years old 2.5-5.3 mg / dl, ≥ 20 years old 2.5-4.5 mg / dl Men: 15-19 years old 2.5-5.6 mg / dl, ≥ 20 years old 2.5-4.5 mg / dl

2) the severity of constipation (6 and 12 months), 3) bloating (6 and 12 months) and 4) discomfort in the abdomen (6 and 12 months) are shown in figures 1-6, respectively.

As shown in figures 1-6, compound A is effective in treatment for 6 and 12 months.

Example 2

Method

A multi-purpose, double-blind, randomized, placebo-controlled study was performed to evaluate the response after treatment in some patients, after four (4) weeks of active treatment (total daily dose of compound A was 48 μg) and three (3) weeks of a randomized treatment withdrawal period. Patients who have had chronic constipation in the past for at least 6 months (less than 3 SBMs per week) and at least one concomitant symptom such as hard stools, incomplete emptying, straining were registered. After a 14-day washout period in the absence of drugs, patients received 48 μg of compound A (total daily dose) orally for 28 days, and then 0 or 48 μg of compound A (total daily dose) for 21 days.

In this study, the following parameters were evaluated:

1) the number of bowel movements per week;

2) bloating;

3) discomfort in the abdomen;

4) the severity of constipation;

5) straining;

6) consistency.

Each parameter (bloating, abdominal discomfort, severity of constipation or straining) was evaluated in patients on the following scale: 0 (absence), 1 (weak), 2 (moderate), 3 (severe) and 4 (very severe). The consistency was evaluated on a scale of 0 (very loose), 1 (loose), 2 (normal), 3 (dense) and 4 (very dense, small balls).

results

1) the number of bowel movements during the week, 2) bloating, 3) discomfort in the abdomen, 4) the severity of constipation, 5) straining and 6) the consistency shown in figures 7-12, respectively.

As shown in figures 7-12, after the termination of treatment with compound A, there was practically no renewal of symptoms, and the effectiveness of the compound A continued even after the termination of treatment.

This result indicates that the administration of Compound A improves the quality of life of patients.

Example 3

Method

Patients with irritable bowel syndrome (IBS) took 48 μg of compound A (24 μg of compound A b.i.d.) for 48 weeks.

In this study, the following parameters were evaluated:

1) discomfort in the abdomen;

2) bloating;

3) the severity of constipation.

Both discomfort in the abdomen and bloating in patients were evaluated on a scale of 0 (absence), 1 (weak), 2 (moderate), 3 (severe) and 4 (very severe). The severity of constipation in patients was evaluated on a scale of 0 (very weak). 1 (weak), 2 (normal), 3 (heavy), 4 (very heavy).

results

1) discomfort in the abdomen, 2) bloating and 3) the severity of constipation are presented in tables 2-4, respectively.

As shown in tables 2-4, compound A is effective for a 12-month treatment of patients suffering from IBS.

table 2 Abdominal Discomfort Analysis A week Compound A Mean ± SD (N) Compound A Mean ± SD (N) Median Median Interval Interval P value Baseline 1.95 ± 0.850 (183) Deviation from the baseline 2.00 0.00-4.00 12th week 1.16 ± 0.836 (135) -0.79 ± 0.993 (135) 1.00 -1.00 0.00-4.00 -3.00-2.00 <0.001 # 18th week 0.98 ± 0.874 (111) -0.97 ± 1.031 (111) 1.00 -1.00 0.00-3.00 -4.00-3.00 <0.001 # 24th week 1.09 ± 0.917 (107) -0.82 ± 1.035 (107) 1.00 -1.00 0.00-4.00 -4.00-3.00 <0.001 # 36th week 0.93 ± 0.799 (57) -0.77 ± 0.926 (57) 1.00 -1.00 0.00-3.00 -4.00-2.00 <0.001 # 48th week 0.87 ± 0.929 (52) -0.81 ± 0.908 (52) 1.00 -1.00 0.00-4.00 -2.00-2.00 <0.001 # End of treatment 1.28 ± 1.020 (183) -0.66 ± 1.112 (183) 1.00 -1.00 0.00-4.00 -4.00-2.00 <0.001 # Follow-up 1.40 ± 0.996 (121) -0.55 ± 1.080 (121) 1.00 -1.00 0.00-4.00 -4.00-2.00 <0.001 # * p value from the Wilcoxon sign-rank test

Table 3 Bloating analysis A week Compound A Mean ± SD (N) Compound A Median Mean ± SD (N) Median Interval Interval P value Baseline 2.23 ± 0.927 (183) Deviation from the baseline 2.00 0.00-4.00 12th week 1.43 ± 0.919 (135) -0.84 ± 1.045 (135) 1.00 -1.00 0.00-4.00 -3.00-3.00 <0.001 # 18th week 1.19 ± 0.837 (111) -1.07 ± 1.068 (111) 1.00 -1.00 0.00-3.00 -3.00-3.00 <0.001 # 24th week 1.26 ± 0.915 (107) -0.95 ± 1.102 (107) 1.00 -1.00 0.00-4.00 -4.00-3.00 <0.001 # 36th week 1.05 ± 0.854 (57) -1.00 ± 1.134 (57) 1.00 -1.00 0.00-3.00 -4.00-2.00 <0.001 # 48th week 1.12 ± 0.832 (52) -0.94 ± 0.802 (52) 1.00 -1.00 0.00-4.00 -3.00-1.00 <0.001 # End of treatment 1.50 ± 1.005 (183) -0.73 ± 1.075 (183) 1.00 -1.00 0.00-4.00 -4.00-2.00 <0.001 # Follow-up 1.55 ± 0.957 (121) -0.69 ± 1.109 (121) 2.00 -1.00 0.00-4.00 -3.00-3.00 <0.001 # * p value from the Wilcoxon sign-rank test

Table 4 Analysis of the severity of constipation A week Compound A Compound A
Mean ± SD (N) Mean ± SD (N) Median Median Interval Interval P value Baseline 2.95 ± 0.751 (183) Baseline Change 3.00 1.00-4.00 12th week 1.76 ± 1.003 (135) -1.16 ± 1.099 (135) 2.00 -1.00 0.00-4.00 -4.00-2.00 <0.001 # 18th week 1.33 ± 0.985 (111) -1.59 ± 1.148 (111) 1.00 -2.00 0.00-4.00 -4.00-3.00 <0.001 # 24th week 1.50 ± 0.965 (107) -1.40 ± 1.036 (107) 1.00 -1.00 0.00-4.00 -3.00-2.00 <0.001 # 36th week 1.39 ± 0.921 (57) -1.33 ± 1.123 (57) 1.00 -1.00 0.00-4.00 -4.00-2.00 <0.001 # 48th week 1.37 ± 0.894 (51) -1.37 ± 1.095 (51) 1.00 -1.00 0.00-3.00 -3.00-1.00 <0.001 # End of treatment 1.84 ± 1.120 (183) -1.11 ± 1.148 (183) 2.00 -1.00 0.00-4.00 -4.00-2.00 <0.001 # Follow-up 2.07 ± 0.946 (121) -0.88 ± 1.122 (121) 2.00 -1.00 0.00-4.00 -4.00-2.00 <0.001 # * p value from the Wilcoxon sign-rank test

Example 4

Method

A multi-purpose, parallel-group, double-blind, placebo-controlled study was performed to compare the effects of compound A on the weekly number of spontaneous bowel movements in male and female patients. Patients of both sexes suffering from intermittent constipation took 48 μg (total daily dose) of compound A (24 μg of compound A b.i.d.) for 4 weeks. During treatment, patients reported bowel movements.

results

Data on the comparative effect of 48 μg of compound A on the weekly number of spontaneous bowel movements in male and female patients is shown in FIG. 13.

As shown in figure 13, compound A was significantly effective when used by both men and women. No significant differences were found between the effects of the drug on men and women.

Example 5

Method

A multi-purpose, parallel-group, double-blind, placebo-controlled study was performed to compare the effect of compound A on improving (increasing) the weekly number of spontaneous bowel movements in patients of different ages suffering from periodic constipation. Patients received 48 μg (total daily dose) of compound A (24 μg of compound A b.i.d.) for 4 weeks. During treatment, patients reported bowel movements.

results

The results are presented in figure 14. As shown in figure 14, compound A was significantly effective in all age groups, even among patients aged 65 years and older.

Example 6

Method

A 48-week multi-purpose study was performed to evaluate the safety and efficacy of 48 μg (total daily dose) of Compound A in patients with intermittent constipation. Patients who have had chronic constipation in the past for at least 3 months (less than 3 SBMs per week) and at least one concomitant symptom such as hard stools, incomplete emptying, straining were registered. After a 14-day washout period in the absence of drugs, patients received 48 μg of compound A per day (24 μg of compound A, b.i.d.) for 48 days.

Patients completed the 36-point short form (SF-36) of the final medical study (MOS), i.e. the traditional evaluation form of QOL, at registration (baseline) and at the end of treatment (48th week). The components of the MOS SF-36 form (Med Care 30 (6), 473-483, 2000) are listed below.

Physical component: physical function, role physical component, somatic pain, and general health.

Mental component: vitality, social function, role-playing emotional component and mental health

Each of the 8 components was evaluated according to publisher guidelines, including guidelines for the use of missing variables. Deviation from the baseline in each of the 8 components at the end of treatment (48th week) was recorded and evaluated using paired t-criteria.

results

As shown in table 5, for the assessment of each of the 8 components, the average value of the baseline is 47-52, which indicates that the studied population was mostly healthy. The average deviation from the baseline for evaluating each component at week 48 is characterized by a slight increase, indicating an improvement in the respective categories. Improvements significantly different from the zero value were observed by the 48th week for physical function, role physical component, somatic pain, general health, vitality, social function, and mental health.

The results show that compound A improves the QOL of patients.

Table 5 Final Results SF36 Component / Scale Rating Physical function Role physical component Somatic pain General health Viability Role-based emotional component Mental health Social function Basic line N 320 320 319 319 319 320 319 319 Average 49.04 49.75 47.53 51.52 50.61 50.12 49.52 50.60 (std) 9,817 9,457 9,765 9,069 9,940 9,778 9,973 9,829 48th week ^a) N 153 153 151 151 151 152 151 151 Mean ^b) 2.48 ** 1.95 ** 3.38 ** 1.47 * 2.89 ** 2.22 ** 1.22 1.97 ** (Std) 8,431 7.403 9,883 7,827 9,163 8,973 9,560 9,201 a) The values presented at week 48 illustrate the deviation from the baseline. b) * p <0.05, ** p <0.01 (paired T-test)

Example 7

Method

A 12-week, double-blind, randomized study was performed to evaluate the safety and efficacy of oral administration of 16 μg, 32 μg and 48 μg (total daily dose) of compound A in patients with irritable bowel syndrome (IBS).

Patients answered the IBS QOL questionnaire at the beginning of treatment, at the 4th week of treatment, at the 12th week of treatment and at the end of treatment, and the questionnaire results were evaluated in accordance with IBS QOL User's manual (A Quality of Life Measure for Persons with Irritable Bowel Syndrome (IBS-QOL): User's Manual and Scoring Diskette for United States Version. Seattle, Washington: University of Washington; 1997). All analyzes used a rating on a scale, and ratings were calculated in accordance with the user manual according to the following formula:

Score on a scale = {[Sum of IBS QOL positions - the smallest possible score] / possible interval of the initial reference} x 100.

Deviations from the baseline at week 4, week 12, and at the end of the study were evaluated in relation to the average generalized score and average domain scores (dysphoria, impaired activity, body pattern, health concerns, refusal to eat, social reaction, sexual reaction and addiction).

results

Tables 6-8 show the result of the average deviation of IBS-QOL estimates from the baseline, analyzed without LOCF (method of accounting for the data of the last observation).

The data obtained showed that the deviation from the baseline significantly differ from the zero level in all groups. In the general case, the group receiving 16 μg of compound A was characterized by the most pronounced improvement with respect to the baseline in all groups in each special area and absolutely for all QOLs.

Table 6 Summary of Baseline Deviation in IBS QOL (16 mcg) Component / Scale Rating Total QOL Dysphoria Impaired activity Body outline Health Concern Refusal of food Social reaction Sexual reaction Dependence Baseline N 51 51 51 51 51 51 51 51 51 average 55.66 53.19 65.82 41.42 37.74 46.08 63.97 64.95 67.81 (Std) 21,165 27,333 22,544 22,877 23,113 30,016 24,546 33,913 25,367 4th week N 45 45 45 45 45 45 45 45 45 average 14.7 ** 17.85 ** 10.87 ** 10.39 ** 22.41 ** 13.89 ** 11.94 ** 13.33 ** 10.74 ** (Std) 14,842 18,483 14,899 19,867 20,241 22,332 19,439 25,057 17,463 12th week N 42 42 42 42 42 42 42 42 42 average 18.54 ** 23.51 ** 13.95 ** 22.32 ** 23.81 ** 15.28 ** 14.58 ** 16.67 ** 15.47 ** (Std) 17,698 20.949 18,392 21,701 22,129 26,792 21,548 29.62 21,897 End of study N 49 49 49 49 49 49 49 49 49 Average 16.82 ** 21.62 ** 11.95 ** 20.41 ** 21.94 ** 13.95 ** 13.78 ** 14.03 ** 14.28 ** (Std) 17,145 20,451 18,349 21,491 21,562 25,762 20.57 28,495 20,692

Table 7 Summary of Baseline Deviation in IBS QOL (32 mcg) Component / Scale Rating Total QOL Dysphoria Impaired activity Body outline Health Concern Refusal of food Social reaction Sexual reaction Dependence Baseline N 49 49 49 49 49 49 49 49 49 average 60.14 59.69 69.82 43.37 44.38 52.21 66.84 68.62 70.23 (Std) 22.05 24.79 23,385 24,387 24,672 32,175 28,562 31,367 23,385 4th week N 36 36 36 36 36 36 36 36 36 average 11.25 ** 14.58 ** 7.04 ** 15.28 ** 16.9 ** 8.33 ** 9.9 ** 8.68 ** 7.64 ** (Std) 16,277 20.39 17,753 18,264 17,534 23,998 16.46 18,131 18,831 12th week N 33 33 33 33 33 33 33 33 33 average 13.08 ** 15.25 ** 9.42 ** 17,99 ** 19.44 ** 11.36 ** 10.8 ** 10.98 ** 9.09 ** (Std) 13,527 15,285 18,052 15.21 21,615 23.46 14,173 18,424 20.87 End of study N 44 44 44 44 44 44 44 44 44 average 12.58 ** 14.77 ** 8.2 ** 17.47 ** 17.61 ** 10.79 ** 11.08 ** 10.23 ** 10.79 ** (Std) 12,621 14,429 16,726 15,344 22,317 21,906 14.32 16,894 20,139

Table 8 Summary of Baseline Deviation in IBS QOL (48 mcg) Component / Scale Rating Total QOL Dysphoria Impaired activity Body outline Health Concern Refusal of food Social reaction Sexual reaction Dependence Baseline N 45 45 45 45 45 45 45 45 45 average 59.85 55.81 68.25 45.69 44.07 50.37 66.81 71.94 75.18 (Std) 21,664 26,802 23,396 21,396 23,274 31,927 27,074 30,404 22,365 4th week N 34 34 34 34 34 34 34 34 34 average 12.43 ** 17.28 ** 9.14 ** 13.24 ** 19.61 ** 12.01 ** 8.82 ** 8.46 ** 6.87 ** (Std) 11,619 16,842 14,477 13,568 18,562 19.59 14,028 15,607 12,558 12th week N thirty thirty thirty thirty thirty thirty thirty thirty thirty average 14.8 ** 20.83 ** 10.95 ** 17.08 ** 23.33 ** 11.3 ** 9 14.17 ** 5** 6.95 ** (Std) 13.65 18,863 15,091 18,419 18,098 22,153 21,143 18,159 12,202 End of study N 43 43 43 43 43 43 43 43 43 average 11.54 ** 16.28 ** 7.97 ** 14.24 ** 17.05 ** 8.33 ** 12.06 ** 3.49 ** 6.01 ** (Std) 13,002 18.62 14,387 17.43 19,067 20,002 18.72 17,535 12,244 * P <0.05, ** P <0.01 (paired T-criteria)

Claims (54)

1. A method for the long-term treatment of gastrointestinal disorders in humans, comprising administering to a subject in need of treatment an effective amount of a prostaglandin compound of formula (I) and / or its tautomer:

where W ₁ and W ₂ represent:

,

or

; (a)
R ₃ and R ₄ are hydrogen; or one of the radicals is OH and the other is hydrogen;
X ₁ and X ₂ represent hydrogen, lower alkyl or halogen, provided that at least one of them is halogen;
R ₂ represents hydrogen or alkyl;
Y represents a saturated or unsaturated C _2-10 hydrocarbon chain which is unsubstituted or substituted by oxo, halogen, alkyl, hydroxy or aryl;
A represents —CH ₂ OH, —COCH ₂ OH, —COOH, or functional derivatives thereof;
R ₁ represents a saturated or unsaturated, linear chain, branched chain or cyclic lower hydrocarbon, which may be unsubstituted or substituted with halogen, oxo, hydroxy, lower alkyl, lower alkoxy, lower alkanoyloxy, lower cycloalkyl, lower cycloalkyloxy, aryl or aryl ; lower cycloalkyl; lower cycloalkyloxy; aryl or aryloxy;
the bond between the C-13 and C-14 positions is a double or single bond and the steric configuration of the substituents at the C-15 position is an R, S configuration or a mixture thereof, where the prostaglandin compound is driven for at least 4 weeks. 2. The method according to claim 1, wherein said prostaglandin compound is a monocyclic tautomer of formula (I). 3. The method according to claim 1, wherein the administered amount of said prostaglandin compound is in the range of about 6-96 μg per day. 4. The method according to claim 1, wherein the administered amount of said prostaglandin compound is in the range of about 6-72 μg per day. 5. The method according to claim 1, wherein the administered amount of said prostaglandin compound is in the range of about 6-60 μg per day. 6. The method according to claim 1, wherein the administered amount of said prostaglandin compound is in the range of about 8-48 μg per day. 7. The method according to claim 1, in which the prostaglandin compound is administered orally. 8. The method according to claim 7, in which the specified prostaglandin compound is administered with an oily solvent as a filler. 9. The method of claim 8, wherein said oily solvent is a medium chain fatty acid. 10. The method according to claim 1, in which A represents —COOH, Y represents (CH ₂ ) ₆ ; W ₁ represents = O; W ₂ represents

or

(a)
where R ₃ and R ₄ are hydrogen atoms; R ₂ represents a hydrogen atom, X ₁ and X ₂ represent fluorine atoms, and R ₁ represents (CH ₂ ) ₃ CH ₃ . 11. The method according to claim 1, wherein said gastrointestinal disturbance is selected from the group consisting of constipation, irritable bowel syndrome, and functional dyspepsia. 12. The method according to claim 1, wherein said prostaglandin compound should be administered for at least 2 months. 13. The method according to claim 1, in which the specified prostaglandin compound is administered for at least 6 months. 14. The method according to claim 1, wherein said prostaglandin compound is administered for at least 1 year. 15. The method according to claim 1, wherein said prostaglandin compound is administered continuously. 16. The method according to claim 1, in which the specified subject, the person is a male person. 17. The method according to claim 1, in which the specified subject, the person is a person aged 65 years or older. 18. A method of improving the quality of life in a person with a gastrointestinal disturbance, which comprises administering to the person an effective amount of a prostaglandin compound having the formula (I) and / or its tautomer:

where W ₁ and W ₂ represent:

,

or

; (a)
R ₃ and R ₄ are hydrogen; or one of the radicals is OH and the other is hydrogen;
X ₁ and X ₂ represent hydrogen, lower alkyl or halogen, provided that at least one of them is halogen;
R ₂ represents hydrogen or alkyl;
Y represents a saturated or unsaturated C _2-10 hydrocarbon chain which is unsubstituted or substituted by oxo, halogen, alkyl, hydroxy or aryl;
A represents —CH ₂ OH, —COCH ₂ OH, —COOH, or functional derivatives thereof;
R ₁ represents a saturated or unsaturated, linear chain, branched chain or cyclic lower hydrocarbon, which may be unsubstituted or substituted with halogen, oxo, hydroxy, lower alkyl, lower alkoxy, lower alkanoyloxy, lower cycloalkyl, lower cycloalkyloxy, aryl or aryl ; lower cycloalkyl; lower cycloalkyloxy; aryl or aryloxy;
the bond between positions C-13 and C-14 is a double or single bond, and the steric configuration of the substituents at position C-15 is an R, S configuration or a mixture thereof. 19. A composition for the long-term treatment of gastrointestinal disorders in humans, which includes (1) an effective amount of a prostaglandin compound of formula (I) and / or its tautomer:

where W ₁ and W ₂ represent:

,

or

; (a)
R ₃ and R ₄ are hydrogen; or one of the radicals is OH and the other is hydrogen;
X ₁ and X ₂ represent hydrogen, lower alkyl or halogen, provided that at least one of them is halogen;
R ₂ represents hydrogen or alkyl;
Y represents a saturated or unsaturated C _2-10 hydrocarbon chain which is unsubstituted or substituted by oxo, halogen, alkyl, hydroxy or aryl;
A represents —CH ₂ OH, —COCH ₂ OH, —COOH, or functional derivatives thereof;
R ₁ represents a saturated or unsaturated, linear or branched chain or cyclic lower hydrocarbon which is unsubstituted or substituted by halogen, oxo, hydroxy, lower alkyl, lower alkoxy, lower alkanoyloxy, lower cycloalkyl, lower cycloalkyloxy, aryl or aryloxy, cycloalkyl, lower cycloalkyloxy, aryl or aryloxy;
the bond between positions C-13 and C-14 is a double or single bond and the steric configuration of the substituents at position C-15 is an R, S configuration or a mixture thereof, and (2) a pharmaceutically acceptable excipient, where the composition should be administered over a period of at least four weeks. 20. The composition of claim 19, wherein said prostaglandin compound is a monocyclic tautomer. 21. The composition according to claim 19, which is structured so that about 6-96 μg per day of said prostaglandin compound is administered to a patient. 22. The composition according to claim 19, which is structured as follows, about 6-72 μg per day of said prostaglandin compound is administered to a patient. 23. The composition according to claim 19, which is structured so that about 6-60 μg per day of said prostaglandin compound is administered to a patient. 24. The composition according to claim 19, which is structured so that about 8-48 μg per day of said prostaglandin compound is administered to a patient. 25. The composition according to claim 19, which should be administered orally. 26. The composition according A.25, in which the pharmaceutically acceptable excipient is an oily solvent. 27. The composition according to p. 26, in which the specified oil solvent is a medium chain fatty acid. 28. The composition of claim 19, wherein A is —COOH; Y represents (CH ₂ ) ₆ ; W ₁ represents = O; W ₂ represents

or

(a)
where both radicals R ₃ and R ₄ represent hydrogen atoms; R ₂ represents a hydrogen atom; X ₁ and X ₂ are fluorine atoms; a R ₁ represents (CH ₂ ) ₃ CH ₃ . 29. The composition of claim 19, wherein said gastrointestinal disorder is selected from the group consisting of constipation, irritable bowel syndrome, and functional dyspepsia. 30. The composition according to claim 19, which should be administered for at least 2 months. 31. The composition according to claim 19, which should be administered for at least 6 months. 32. The composition according to claim 19, which should be administered for at least 1 year. 33. The composition according to claim 19, which should be entered continuously. 34. The composition according to claim 19, when the specified subject, the person is a male or female. 35. The composition according to claim 19, when the specified subject, the person is a person aged 65 years or older. 36. A composition for improving the quality of life of a person suffering from a gastrointestinal disturbance, which comprises (1) an effective amount of a prostaglandin compound represented by the formula (I) and / or its tautomer:

where W ₁ and W ₂ represent:

,

or

; (a)
R ₃ and R ₄ are hydrogen; or one of the radicals is OH and the other is hydrogen;
X ₁ and X ₂ represent hydrogen, lower alkyl or halogen, provided that at least one of them is halogen;
R ₂ represents hydrogen or alkyl;
Y represents a saturated or unsaturated C _2-10 hydrocarbon chain which is unsubstituted or substituted by oxo, halogen, alkyl, hydroxy or aryl;
A represents —CH ₂ OH, —COCH ₂ OH, —COOH, or a functional derivative thereof;
R ₁ represents a saturated or unsaturated, linear or branched chain or cyclic lower hydrocarbon which is unsubstituted or substituted by halogen, oxo, hydroxy, lower alkyl, lower alkoxy, lower alkanoyloxy, lower cycloalkyl, lower cycloalkyloxy, aryl or aryloxy; lower cycloalkyl; lower cycloalkyloxy; aryl or aryloxy; the relationship between positions C-13 and C-14 is a double or single bond and the steric configuration of the position at position C-15 is an R, S configuration or a mixture thereof; and
(2) a pharmaceutically acceptable excipient. 37. The use of a prostaglandin compound of the formula (I) and / or its tautomer:

where W ₁ and W ₂ represent:

,

or

; (a)
R ₃ and R ₄ are hydrogen; or one of the radicals is OH and the other is hydrogen;
X ₁ and X ₂ represent hydrogen, lower alkyl or halogen, provided that at least one of them is halogen;
R ₂ represents hydrogen or alkyl;
Y represents a saturated or unsaturated C _2-10 hydrocarbon chain which is unsubstituted or substituted by oxo, halogen, alkyl, hydroxy or aryl;
A represents —CH ₂ OH, —COCH ₂ OH, —COOH or a functional derivative thereof;
R ₁ represents a saturated or unsaturated, linear or branched chain or cyclic lower hydrocarbon which is unsubstituted or substituted by halogen, oxo, hydroxy, lower alkyl, lower alkoxy, lower alkanoyloxy, lower cycloalkyl, lower cycloalkyloxy, aryl or aryloxy; lower cycloalkyl; lower cycloalkyloxy; aryl or aryloxy;
the relationship between the positions C-13 and C-14 is a double or single bond and the steric configuration of the position at position C-15 is an R, S configuration, or a mixture thereof, for the manufacture of a pharmaceutical composition for the long-term treatment of gastrointestinal disorders in humans, where the composition should be administered to a patient in need of treatment, where the specified composition should be administered for at least four months. 38. The use according to clause 37, wherein said prostaglandin compound is a monocyclic tautomer having the formula (I). 39. The application of clause 37, wherein the composition is such that about 6-96 μg per day of said prostaglandin compound is administered to a patient. 40. The use of claim 37, wherein the composition is such that about 6-72 μg per day of said prostaglandin compound is administered to a patient. 41. The application of clause 37, wherein the composition is such that about 6-60 μg per day of said prostaglandin compound is administered to a patient. 42. The application of clause 37, wherein the composition is such that about 8-48 μg per day of said prostaglandin compound is administered to a patient. 43. The application of clause 37, wherein the composition is administered orally. 44. The application of item 43, wherein the composition further includes an oily solvent as a filler. 45. The use of claim 44, wherein said oil solvent is a medium chain fatty acid. 46. The use of claim 37, wherein A is —COOH; Y represents (CH ₂ ) ₆ ; W ₁ represents = O; W ₂ represents

or

(a)
where both radicals R ₃ and R ₄ represent hydrogen atoms; R ₂ represents a hydrogen atom; X ₁ and X ₂ are fluorine atoms; a R ₁ represents (CH ₂ ) ₃ CH ₃ . 47. The application of clause 37, wherein said gastrointestinal disturbance is selected from the group consisting of constipation, irritable bowel syndrome and functional dyspepsia. 48. The application of clause 37, wherein the composition is administered for at least 2 months. 49. The use according to clause 37, wherein the composition is administered for at least 6 months. 50. The application of clause 37, wherein the composition is administered for at least 1 year. 51. The application of clause 37, wherein the composition is administered continuously. 52. The application of clause 37, wherein said subject is a male or female person. 53. The application of clause 37, wherein said subject is a person aged 65 years or older. 54. The use of a prostaglandin compound of the formula (I) and / or its tautomer:

where W ₁ and W ₂ represent:

,

or

; (a)
R ₃ and R ₄ are hydrogen; or one of the radicals is OH and the other is hydrogen;
X ₁ and X ₂ represent hydrogen, lower alkyl or halogen, provided that at least one of them is halogen;
R ₂ represents hydrogen or alkyl;
Y represents a saturated or unsaturated C _2-10 hydrocarbon chain which is unsubstituted or substituted by oxo, halogen, alkyl, hydroxy or aryl;
A represents —CH ₂ OH, —COCH ₂ OH, —COOH, or a functional derivative thereof;
R ₁ represents a saturated or unsaturated, linear or branched chain or cyclic lower hydrocarbon which is unsubstituted or substituted by halogen, oxo, hydroxy, lower alkyl, lower alkoxy, lower alkanoyloxy, lower cycloalkyl, lower cycloalkyloxy, aryl or aryloxy; lower cycloalkyl; lower cycloalkyloxy; aryl or aryloxy;
the relationship between positions C-13 and C-14 is a double or single bond and the steric configuration of the position at position C-15 is an R, S configuration or a mixture thereof, for the manufacture of a pharmaceutical composition, to improve the quality of life of a person suffering from gastrointestinal disorders where the composition should be administered to a subject in need of treatment.

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