CN101048163A - Prostaglandin derivatives for treating gastrointestinal disorder - Google Patents
Prostaglandin derivatives for treating gastrointestinal disorder Download PDFInfo
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- CN101048163A CN101048163A CN 200580036665 CN200580036665A CN101048163A CN 101048163 A CN101048163 A CN 101048163A CN 200580036665 CN200580036665 CN 200580036665 CN 200580036665 A CN200580036665 A CN 200580036665A CN 101048163 A CN101048163 A CN 101048163A
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Abstract
The present invention relates to a method for the long term treatment of gastrointestinal disorders in a human subject, which comprises administering an effective amount of a halogenated prostaglandin compound and/or its tautomer to the subject. The method induces substantially no electrolyte shifting during the term of the treatment. The compound used in the present invention can improve quality of life in the human subjects with gastrointestinal disorders, are similarly effective in treating male and female human subjects, and also effective in a human subject aged even 65 years and older.
Description
Technical field
The present invention relates to the method and composition of the gastroenteropathy of long-term treatment human patients.
The present invention also relates to treat the method and composition of men and women patient's gastroenteropathy.
The invention still further relates to the method and composition of the gastroenteropathy of treatment over-65s human patients.
In addition, the present invention relates to improve the method and composition of the quality of life of gastroenteropathy human patients.
Background technology
Constipation is normally defined defecation frequency and reaches difficult defecation less.Medical report estimates have 1/50 people to suffer from constipation in the U.S..That is to say, be one of modal disease of American.Compared with the male, constipation more was common in the women, and is common in the old man especially, was Exponential growth later at 65 years old.The actual incidence rate of constipation may be than report higher because many people stay at home and do not seek specialty treatment.
Although constipation can cause by blocking in some cases, but most of constipation are with relevant such as following factor: solubility and insoluble fibre content are low in the meals, do not get enough athletic exercise, use medicine (especially opium analgesic, anticholinergic, antidepressants, antihistaminic and catharanthus alkaloid), intestinal tract disease, neuromuscular disorder, dysbolismus, abdominal pressure deficiency or muscle to lack tension force.
Be difficult to quantity definition is accurately carried out in constipation, because too wide to the sensation scope of " normally " bowl evacuation habit, and the multiformity of constipation symptom and sign.FDA thinks and need carry out predetermined treatment to sporadic constipation.
Prostaglandin (hereinafter being called PG) is a class organic carboxyl acid member of being contained in human body or other mammalian tissues or the organ, and they demonstrate multiple physiologically active.The PG that nature is found (basic PG) has the prostanoic acid skeleton shown in the following formula (A) usually:
(α chain)
(ω chain)
According to the substituent group on structure and the 5 yuan of rings, with PG divide into several classes type, for example,
A type prostaglandin (PGA);
Type B prostaglandin (PGB);
C type prostaglandin (PGC);
D type prostaglandin (PGD);
E type prostaglandin (PGE);
F type prostaglandin (PGF);
Or the like.In addition, PG also can be divided into PG
1, PG
2And PG
3, PG wherein
1Contain 13, the two keys of 14-; PG
2Contain 5, the two keys and 13 of 6-, the two keys of 14-; PG
3Contain 5, the two keys, 13 of 6-, the two keys and 17 of 14-, the two keys of 18-.Known PG has different pharmacologically actives and physiologically active, for example vasodilation, bring out inflammation, platelet aggregation, stimulation uterus muscle, stimulate myenteron meat, antiulcer effect etc.The main prostaglandin that human intestines and stomach (GI) system produces is E type, I type and F type (Sellin, Gastrointestinal and Liver Disease:Pathophysiology, Diagnosis, and Management. (WB Saunders Company, 1998); Robert, Physiology ofthe Gastrointestinal Tract 1407-1434 (Raven, 1981); Rampton, Prostaglandins:Biology and Chemistry of Prostaglandins and RelatedEicosanoids 323-344 (Churchill Livingstone, 1988); Hawkey etc., Gastroenterology, 89:1162-1188 (1985); Eberhart etc., Gastroenterology, 109:285-301 (1995)).
Under normal physiological conditions, the prostaglandin of endogenous generation plays main effect keeping on the GI function, comprises motion and the transhipment of regulating intestinal and regulates feces hardness (fecalconsistency).(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 andRelated Eicosanoids 323-344 (Churchill Livingstone, 1988); Hawkey etc., Gastroenterology, 89:1162-1188 (1985); Eberhart etc., Gastroenterology, 109:285-301 (1995); Robert, Adv Prostaglandin Thromboxane Res, 2:507-520 (1976); Main etc., Postgrad Med J, 64 (supplementary issue 1): 3-6 (1988); Sanders, Am J Physiol, 247:G117 (1984); Pairet etc., Am J Physiol., 250 (3pt 1): G302-G308 (1986); Gaginella, Textbook of Secretory Diarrhea 15-30 (Raven Press, 1990)).When with the pharmacological dose administration, PGE
2And PGF
2 αThe intestinal transhipment be can both stimulate and diarrhoea (Robert, Physiology of the Gastrointestinal Tract1407-1434 (Raven, 1981) caused; Rampton, Prostaglandins:Biology andChemistry of Prostaglandins and Related Eicosanoids 323-344 (ChurchillLivingstone, 1988); Robert, Adv Prostaglandin Thromboxane Res, 2:507-520 (1976)).In addition, (a kind of exploitation is used for the treatment of the PGE of peptic ulcer disease to misoprostol
1Analog) the side effect of normal report is suffered from diarrhoea exactly that (Monk etc., Drugs 33 (1): 1-30 (1997)).
PGE or PGF can stimulate intestinal and cause that intestinal shrinks, but defecation effect (enteropooling effect) is but good inadequately.Therefore, PGE or PGF can not be used as cathartic because of its side effect (stomachache due to for example intestinal shrinks).
Reported and comprised that regulating enteric nervous reacts, changes smooth muscle contraction, stimulation mucous secretion, irritation cell ion (especially living electric Cl
-Transport) and increase the intestinal fluid volume in interior number of mechanisms, all give the credit to GI effect (Robert, the Physiology of theGastrointestinal Tract 1407-1434 (Raven, 1981) of prostaglandin; Rampton, Prostaglandins:Biology and Chemistry of Prostaglandins and Related Eicosanoids 323-344 (Churchill Livingstone, 1988); Hawkey etc., Gastroenterology, 89:1162-1188 (1985); Eberhart etc., Gastroenterology, 109:285-301 (1995); Robert, Adv Prostaglandin Thromboxane Res, 2:507-520 (1976); Main etc., Postgrad Med J, 64 (supplementary issue 1): 3-6 (1988); Sanders, Am J Physiol, 247:G117 (1984); Pairet etc., Am J Physiol, 250 (3 pt 1): G302-G308 (1986); Gaginella, Textbook of Secretory Diarrhea 15-30 (Raven Press, 1990); Federal Register the 50th volume, the 10th phase (GPO, 1985); Pierce etc., Gastroenterology 60 (1): 22-32 (1971); Beubler etc., Gastroenterology, 90:1972 (1986); Clarke etc., Am J Physiol 259:G62 (1990); Hunt etc., J VetPharmacol Ther, 8 (2): 165-173 (1985); Dajani etc., Eur J Pharmacol, 34 (1): 105-113 (1975); Sellin, Gastrointestinal and Liver Disease:Pathophysiology, Diagnosis, and Management 1451-1471 (WB SaundersCompany, 1998)).Prostaglandin also has cell protective effect (Sellin, Gastrointestinal and Liver Disease:Pathophysiology, Diagnosis, andManagement. (WB Saunders Company, 1998); Robert, Physiology of theGastrointestinal Tract 1407-1434 (Raven, 1981); Robert, AdvProstaglandin Thromboxane Res 2:507-520 (1976); Wallace etc., AiimentPharmacol Ther 9:227-235 (1995)).
United States Patent (USP) the 5th, 317, No. 032 (Ueno etc.) have introduced prostaglandin analogue cathartic (comprise and have identical dicyclo tautomer), and United States Patent (USP) the 6th, 414, No. 016 (Ueno) introduced the dicyclo tautomer (having very high activity as anti-emplastic) of prostaglandin analogue.The dicyclo tautomer of prostaglandin analogue (it is replaced by one or more halogen atoms, especially fluorine atom on the C-16 position) can be used for constipation relieving low dose ofly.
U.S. Patent Publication number No. 2003/0130352 (Ueno etc.) has been introduced prostaglandin compound and has been opened and can activate chloride channel, especially ClC passage, more particularly ClC-2 passage.
U.S. Patent Publication number No. 2003/0119898 (Ueno etc.) has been introduced the concrete compositions that is used for the treatment of with the halo prostaglandin analogue of prevent constipation.
U.S. Patent Publication number No. 2004/0138308 (Ueno etc.) has been introduced chloride channel opener, especially prostaglandin compound and can be used for treating abdominal discomfort, and be used for the treatment of functional gastrointestinal disease, for example irritable bowel syndrome and functional dyspepsia.
MiraLax
TM(Polyethylene Glycol 3350 is used for the NF Powder of solution) is synthesizing polyethylene glycol, and mean molecule quantity is 3350, can be used for treating sporadic constipation.General maximum 2 weeks of use of this product.Long-term frequent or excessive use MiraLax
TM, can cause electrolyte imbalance, laxative is produced dependency (MiraLax
TMPackage insert).MiraLax
TMPlay the effect of penetrating agent, it produces uneven in enteric cavity and permeability for liquids ground is sucked enteric cavity.The softening feces of the fluid level that increases promotes defecation (bowel movement).
Equally, think that above-mentioned ClC-2 chloride channel activator works to the enteric cavity secretion by stimulating chloride ion, such secretion sucks enteric cavity with the mechanism of permeating with moisture, promotes defecation then.Suppose that concrete prostaglandin compound is the ion channel activator, and believe can be to be similar to MiraLax
TMPenetration mode work, expection life-time service described prostaglandin compound also will have MiraLax
TMShortcoming.Therefore in practice, its use resembles MiraLax only for several weeks
TMThe same.
Zelnorm (tegaserod maleate) is applicable to short term therapy women's irritable bowel syndrome (IBS), and this syndromic main intestinal symptom is exactly constipation.At two that have that 288 male participate at random, in the double-blind study of placebo, between placebo and Zelnorm response rate, not significant difference.Do not determine that as yet Zelnorm is to safety and the effectiveness of IBS with the male of constipation.In addition, over-65s patient group is analyzed, show that Zelnorm and placebo all do not have significant curative effect.That is to say, do not determine the effectiveness of Zelnorm as yet the patients with chronic idiopathic constipation of over-65s.In addition, the Zelnorm if the patient stops using, symptom is recovered again in week at 1-2.(Zelnorm package insert).
Summary of the invention
Although have basic osmosis mechanism, the inventor is surprised to find, and when some halo prostaglandin compound is used for human patients for a long time, does not have electrolyte shift.
The inventor also finds, the effectively long-term treatment of halo prostaglandin compound, even after stopping to carry out long-term treatment, do not have rebound effect basically with described chemical compound.
In addition, the inventor finds that the halo prostaglandin compound has improved gastroenteropathy patient's quality of life, and similar to men and women patient's curative effect, even also effective to the patient of over-65s.
In other words, the invention provides the method for the gastroenteropathy of long-term treatment human patients, this method comprises prostaglandin compound and/or its tautomer by following formula (I) expression that the patient of needs effective dose is arranged:
W wherein
1And W
2For
R
3And R
4Be hydrogen; Perhaps in them is OH, and another is a hydrogen;
X
1And X
2Be hydrogen, low alkyl group or halogen, precondition is that at least one is halogen in them;
R
2Be hydrogen or alkyl;
Y is saturated or unsaturated C
2-10Hydrocarbon chain, it is unsubstituted or is replaced by following group: oxo base, halogen, alkyl, hydroxyl or aryl;
A is-CH
2OH ,-COCH
2OH ,-COOH or its functional derivatives;
R
1Be saturated or unsaturated, straight chain, side chain or ring formation lower hydrocarbon, it is unsubstituted or is replaced by following group: halogen, oxo base, hydroxyl, low alkyl group, lower alkoxy, lower alkanoyloxy, low-grade cycloalkyl, rudimentary cycloalkyloxy, aryl or aryloxy group; Low-grade cycloalkyl; Rudimentary cycloalkyloxy; Aryl; Or aryloxy group;
Key between C-13 position and the C-14 position is two keys or singly-bound,
The steric configuration of C-15 position is R, S or its mix-configuration.
The present invention also provides the method for the gastroenteropathy of treatment male patient or over-65s human patients, and this method comprises prostaglandin compound and/or its tautomer by formula (I) expression that the patient of needs effective dose is arranged.
The present invention also provides the method for the quality of life of improving the gastroenteropathy human patients, and this method comprises prostaglandin compound and/or its tautomer by formula (I) expression that the patient of needs effective dose is arranged.
In each embodiment of the inventive method, total daily dose of PG chemical compound is preferably 6-96 μ g.
Method of the present invention can followingly be implemented: the pharmaceutical composition that will comprise above-mentioned prostaglandin compound and/or its tautomer gives patient to be treated.Therefore, in another aspect of this invention, the pharmaceutical composition of the gastroenteropathy of long-term treatment human patients is provided, and said composition comprises prostaglandin compound and/or its tautomer and the (ii) pharmaceutically suitable excipient by formula (I) expression of (i) effective dose.
The present invention also provides the pharmaceutical composition of the gastroenteropathy of treatment men and women patient or over-65s human patients, and said composition comprises prostaglandin compound and/or its tautomer and the (ii) pharmaceutically suitable excipient by formula (I) expression of (i) effective dose.
The present invention also provides the pharmaceutical composition of the quality of life of improving the gastroenteropathy human patients, and said composition comprises prostaglandin compound and/or its tautomer and the (ii) pharmaceutically suitable excipient by formula (I) expression of (i) effective dose.
In another aspect of this invention, provide by the prostaglandin compound of formula (I) expression and/or its tautomer purposes in preparing pharmaceutical composition as defined above.
The accompanying drawing summary
Fig. 1 is a curve chart, is presented at 6 months constipation orders of severity during the treatment.
Fig. 2 is a curve chart, is presented at 12 months constipation orders of severity during the treatment.
Fig. 3 is a curve chart, is presented at 6 months abdominal bloatings during the treatment.
Fig. 4 is a curve chart, is presented at 12 months abdominal bloatings during the treatment.
Fig. 5 is a curve chart, is presented at 6 months abdominal discomforts during the treatment.
Fig. 6 is a curve chart, is presented at 12 months abdominal discomforts during the treatment.
Fig. 7 is a curve chart, shows the influence of defecation weekly.
Fig. 8 is a curve chart, shows the influence to abdominal bloating.
Fig. 9 is a curve chart, shows the influence to abdominal discomfort.
Figure 10 is a curve chart, shows the influence to the constipation order of severity.
Figure 11 is a curve chart, shows the influence to nervous (straining).
Figure 12 is a curve chart, shows the influence to hardness.
Figure 13 is a curve chart, shows the influence to men and women patient's defecation.
Figure 14 is a curve chart, shows the influence to all ages and classes patient defecation.
Detailed Description Of The Invention
In the present invention, " effective dose " can be determined according to factors such as age of patient to be treated, body weight, illness, the curative effect of wanting, method of administration, treatment cycle. According to the present invention, the dosage of prostaglandin compound is 0.001-1000 μ g/kg body weight/day, more preferably 0.01-100 μ g/kg body weight/day, most preferably 0.1-10 μ g/kg body weight/day. To repeatedly, twice of preferred every day is to repeatedly for once a day for administration frequency. Usually give patient's the about 6-96 μ of amount g/ days. According to this specification and claims, dosage or dosage are determined according to the about 60kg patient of body weight.
Term " about " used herein may be defined as+/-30% when with the measurement unit coupling, preferred+/-20%, especially+/-10%. For example, the total about 6-96 μ of daily dose g preferable range is 5.4-105.6 μ g. The preferred about 6-72 μ of dosage range g. In a preferred embodiment, dosage range is about 6-60 μ g. For example the dosage of described halogenated compound is about 8-48 μ g.
(i) prostaglandin compound of formula (I)
The present invention uses the prostaglandin compound by following formula (I) expression:
W wherein1And W2For
R
3And R4Be hydrogen; Perhaps in them is OH, and another is hydrogen;
X
1And X2Be hydrogen, low alkyl group or halogen, precondition is that at least one is halogen in them;
R
2Be hydrogen or alkyl;
Y is saturated or unsaturated C2-10Hydrocarbon chain, it is unsubstituted or is replaced by following group: oxo base, halogen, alkyl, hydroxyl or aryl;
A is-CH2OH、-COCH
2OH ,-COOH or its functional derivatives;
R
1Be saturated or unsaturated, straight chain, side chain or become the ring lower hydrocarbon that it is unsubstituted or is replaced by following group: halogen, oxo base, hydroxyl, low alkyl group, lower alkoxy, lower alkanoyloxy, low-grade cycloalkyl, rudimentary cycloalkyloxy, aryl or aryloxy group; Low-grade cycloalkyl; Rudimentary cycloalkyloxy; Aryl; Or aryloxy group;
Key between C-13 position and the C-14 position is two keys or singly-bound,
The steric configuration of C-15 position is R, S or its mix-configuration.
In following formula, term " halogen " comprises fluorine atom, chlorine atom, bromine atoms and iodine atom. For X1And X2, particularly preferred halogen atom is fluorine atom.
At R1In the definition of Y, term " unsaturated " comprises at least one or a plurality of pairs of keys and/or triple bond, these keys can be separately, separately or continued presence between main chain and/or side chain carbon. According to conventional nomenclature, the unsaturated bond between two continuous positions represents with less positional number in two positions, and the unsaturated bond between two remote locations can be with any represents in two positions.
Except as otherwise noted, otherwise this specification and claims in full used term " rudimentary " comprise the group with 1-6 carbon atom.
Term " ring " refers to low-grade cycloalkyl, rudimentary cycloalkyloxy, aryl or aryloxy group.
Term " low alkyl group " refers to contain the straight or branched saturated hydrocarbyl of 1-6 carbon atom, comprises for example methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, amyl group and hexyl.
Term " lower alkoxy " refers to low alkyl group-O-, and wherein low alkyl group as above defines.
The group that term " lower alkanoyloxy " the formula RCO-O-of referring to represents, wherein RCO-is as defined above low alkyl group oxidation and the acyl group that generates, for example acetyl group.
Term " low-grade cycloalkyl " is meant as defined above but contains the cyclic group that the low alkyl group of 3 above carbon atoms generates through cyclisation, comprises for example cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl.
Term " rudimentary cycloalkyloxy " is meant low-grade cycloalkyl-O-, and wherein low-grade cycloalkyl as above defines.
Term " aryl " is meant aromatic carbocyclic or heterocyclic group (preferred monocyclic groups), for example phenyl that does not replace or replace, naphthyl, tolyl, xylyl, furyl, thienyl, pyrrole radicals, azoles base, different azoles base, thiazolyl, isothiazolyl, imidazole radicals, pyrazolyl, furazan base (furzanyl), pyranose, pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidino, piperazinyl, morpholino, indyl, benzothienyl, quinolyl, isoquinolyl, purine radicals (puryl), quinazolyl, carbazyl, acridinyl, phenanthridinyl (phenathridinyl), benzimidazolyl, the benzimidazoline ketone group, benzothiazolyl and phenothiazinyl.Substituent example is halogen atom and halo (rudimentary) alkyl, and wherein halogen atom and low alkyl group as above define.
The group that term " aryloxy group " the formula ArO-of being meant represents, wherein Ar is aryl as defined above.
" functional derivatives " of term A comprises salt (preferred pharmaceutically acceptable salt), ether, ester and amide.
Suitable " pharmaceutically acceptable salt " comprises nontoxic salts commonly used, for example the salt of inorganic base, for example alkali metal salt (for example sodium salt and potassium salt), alkali salt (for example calcium salt and magnesium salt), ammonium salt; Or the salt of organic base, for example amine salt (for example methylamine salt, dimethylamine salt, cyclohexylamine salt, benzylamine salt, piperidinium salt, ethylenediamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, three (methylol amino) ethane salt, monomethyl-monoethanolamine salt, procaine salt and caffeine salt), alkaline amino acid salt (for example arginine salt and lysinate), tetraalkylammonium salt etc.These salt can prepare according to conventional method, for example prepare from corresponding bronsted lowry acids and bases bronsted lowry, perhaps by salt exchange preparation.
The example of ether comprises alkyl ether, for example lower alkyl ether, for example methyl ether, ethylether, propyl ether, isopropyl ether, butyl ether, isobutyl ether, tertbutyl ether, amyl ether and 1-cyclopropyl ethylether; With middle rank or senior alkyl ether, for example Octyl Ether, diethylhexyl ether, lauryl ether and cetyl ether; Unsaturated ethers, for example oleyl ether and Caulis et Folium Lini base ether; Low-grade alkenyl ether, for example vinyl Ether, allyl ether; Low-grade alkynyl ether, for example acetylene ether and propine ether; Hydroxyl (rudimentary) alkyl ether, for example hydroxyethyl ether and hydroxyl isopropyl ether; Lower alkoxy (rudimentary) alkyl ether, for example methoxy ether and 1-methoxy ethyl ether; The optional aryl ether that replaces, for example phenyl ether, tosyl ether, tert-butyl-phenyl ether, salicyl ether, 3,4-two-methoxyphenyl ether and benzoylamino phenyl ether; And aryl (rudimentary) alkyl ether, for example benzylic ether, trityl ether and dibenzyl ether.
The example of ester comprises aliphatic (acid) ester, for example lower alkyl esters, for example methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, the tert-butyl ester, pentyl ester and 1-cyclopropyl ethyl ester; Low-grade alkenyl ester, for example vinyl acetate and allyl ester; Low-grade alkynyl ester, for example ethynyl ester and propynyl ester; Hydroxyl (rudimentary) Arrcostab, for example hydroxyethyl ester; Lower alkoxy (rudimentary) Arrcostab, for example methoxyl group methyl ester and 1-methoxyl group ethyl ester; With the optional aryl ester that replaces, for example phenyl ester, toluene ester, tert-butyl group phenyl ester, salicyl ester, 3,4-two-methoxyl group phenyl ester and Benzoylamide phenyl ester; And aryl (rudimentary) Arrcostab, for example benzyl ester, trityl ester and benzhydryl ester.
The amide of A the is meant formula-CONR ' R " group of expression; R ' and R " respectively do for oneself hydrogen, low alkyl group, aryl, alkyl sulphonyl, aryl sulfonyl, low-grade alkenyl or low-grade alkynyl wherein, and comprise for example low alkyl group amide, for example Methanamide, acetamide, diformamide and diacetayl amide; Aryl amide, for example N-anilide and N-acyl toluidines; With alkyl sulphonyl amide or aryl sulfonyl amide, for example methyl sulphonyl amide, ethylsulfonyl amide and tolylsulfonyl-base amide.
The example of Y comprises for example 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-C≡C-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-C ≡ C-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 is optional in the aliphatic hydrocarbon of Y is replaced by oxygen, nitrogen or sulfur.
Preferred A is-COOH or its pharmaceutically acceptable salt or ester.
Preferred X
1And X
2All be halogen atom, more preferably fluorine atom.
Preferred W
1For=O.
Preferred Y is the unsubstituted saturated or aliphatic unsaturated hydrocarbon that contains 6-8 carbon atom.
Preferred R
1For the hydrocarbon that contains 1-6 carbon atom, more preferably contain the hydrocarbon of 1-4 carbon atom.R
1Can have one or two side chain, this side chain contains a carbon atom.
R
2Be preferably hydrogen.
The most preferred embodiment is the prostaglandin compound of formula (I), and wherein A is-COOH;
Y is (CH
2)
6W
1For=O; W
2For
R wherein
3And R
4All be hydrogen; R
2Be hydrogen; X
1And X
2Be fluorine; R
1Be (CH
2)
3CH
3Or CH
2CH (CH
3) CH
2CH
3
Activating agent of the present invention is that the PG chemical compound of formula (I) exists with Solid Double cycle compound form, but when being dissolved in solvent, a part of compound formation tautomer.Under anhydrous situation, the represented chemical compound of formula (I) mainly exists with the twin nuclei form.It is believed that in aqueous medium, form hydrogen bond between the ketone part of hydrone and for example C-15 position, form thereby hinder dicyclo.In addition, it is believed that the halogen atom promotion dicyclo formation of C-16 position.As follows, just have 13,14 singly-bounds and have the chemical compound of two fluorine atoms in the C-16 position and opinion, the tautomerism between the ketone part of the hydroxyl of C-11 position and C-15 position is obvious especially.
Therefore, the present invention can comprise the isomers of halo prostaglandin compound.For example, has ketone group and have a monocycle tautomer of halogen atom in the C-16 position as follows in the C-15 position.
Dicyclo form single annular formula
According to conventional prostaglandin nomenclature, but the preferred The compounds of this invention called after 13 of monocycle form, 14-dihydro-15-ketone-16,16-two fluoro-PGE
1
(ii) pharmaceutically suitable excipient
According to the present invention, pharmaceutical composition can be mixed with any form.Therefore, can select pharmaceutically suitable excipient according to the desired form of compositions.According to the present invention, " pharmaceutically suitable excipient " is meant the inert substance that mixes and be suitable for preparing desired form with active component of the present invention.
For example, solid composite for oral use of the present invention can comprise tablet, preparation, granule etc.In such solid composite, one or more active component can with the mixing diluents of at least a non-activity, described diluent is lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline Cellulose, starch, polyvinylpyrrolidone, magnesium aluminate silicate etc. for example.According to working procedure commonly used, compositions can contain the additive except that the non-activity diluent, for example lubricant, for example magnesium stearate; Disintegrating agent, for example fibrous calcium gluconate; Stabilizing agent, cyclodextrin for example, for example alpha-cyclodextrin, beta-schardinger dextrin--or gamma-cyclodextrin; Etherificate cyclodextrin, for example dimethyl-alpha-cyclodextrin, DM-, TM-or HP-; Branched cyclodextrin, for example glucityl-cyclodextrin, malt-base-cyclodextrin; Formylated cyclodextrin, sulfur-containing cyclodextrins; Phospholipid etc.When using above-mentioned cyclodextrin, can form the clathrate that contains cyclodextrin sometimes, to increase stability.Perhaps, can use phospholipid sometimes, cause stability to increase to form liposome.
Can optionally give tablet or coating of pill with being dissolved in the gastrointestinal thin film, described thin film is sugar, gelatin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose phthalate for example.In addition, but can use absorbing material (for example gelatin) preparation capsule.Preferably the liquid substance of compositions with halo prostaglandin compound and MCT Oil is formulated in the soft gelatin capsule.The example of the MCT Oil that the present invention is used comprises the triglyceride that contains 6-14 carbon atom and can have the saturated or unsaturated fatty acid of side chain.Preferred fatty acid is a linear saturated fatty acids, for example caproic acid (C6), sad (C8), capric acid (C10), lauric acid (C12) and myristic acid (C14).In addition, two or more MCT Oil use capable of being combined.More appropriate excipients is disclosed among the PCT application WO 01/27099 that has announced.
The form of fluid composition for oral use can be Emulsion, solution, suspensoid, syrup or the elixir that comprises non-activity diluent commonly used.This based composition also can contain additive except that the diluent that contains non-activity, for example lubricant, sweeting agent, correctives, antiseptic, solubilizing agent, antioxidant etc.Optional those additives in any common textbook in pharmacy field, introduced of additive.This class I liquid I compositions can directly be wrapped in the soft balsam wafer.Compositions of the present invention can be suppository, enema etc.Their form can be for example sterile aqueous or non-aqueous solution agent, suspensoid, Emulsion etc.Aqueous solution agent, suspensoid, the used excipient example of Emulsion comprise for example distilled water, normal saline and Ringer's solution etc.
The used excipient example of non-aqueous solution agent, suspensoid or Emulsion can comprise for example propylene glycol, Polyethylene Glycol, fatty acid triglycercide, vegetable oil (for example olive oil), alcohols (for example ethanol), Polysorbate etc.This based composition can contain additive, for example antiseptic, wetting agent, emulsifying agent, dispersant, antioxidant etc.
According to the present invention, pharmaceutical composition can be used for parenteral or oral administration, the preferred oral compositions.In an example, active component preferably is dissolved in MCT Oil and is filled in the capsule.
The method according to this invention, compositions of the present invention can be administered systemically by the mode of oral or parenteral or topical, comprises with suppository, enema etc. and carries out parenteral.Compositions of the present invention can give 1 every day extremely repeatedly.
The about 6-96 μ of the total daily dose scope g of preferred prostaglandin compound of the present invention, more preferably from about 6-72 μ g, also more preferably from about 6-60 μ g, especially 8-48 μ g.Can add factors such as patient age and body weight, disease, curative effect, route of administration, treatment cycle according to doctor's handling suggestion, dosage can be changed slightly.
Term used herein " does not have electrolyte shift basically " and is meant that electrolyte imbalance is far smaller than the imbalance that is caused by the uneven derivant of known electrolyte during treating.In addition, term " does not have electrolyte shift basically " and is meant that the serum electrolyte level of being treated the patient is in the clinician in understandable clinical normal range.As mentioned above, the MiraLax that is used for the treatment of constipation
TMCan cause electrolyte imbalance, cause dangerous cardiac problems.On the other hand, prove that the used prostaglandin compound of the present invention can not cause electrolyte shift basically, even also be like this when long-term prescription as following examples.
The following examples also show, after stopping to carry out long-term treatment with pharmaceutical composition of the present invention, pharmaceutical composition of the present invention can not cause constipation of knock-on property or other problem basically.Therefore, compositions of the present invention can be used for long-term treatment.
In addition, the quality of life evaluation to constipation and IBS patient demonstrates the quality of life that The compounds of this invention has improved the patient.
According to the present invention, chemical compound of the present invention can be used for the long-term treatment gastroenteropathy.Effect is similar on treatment men and women patient.In addition, it also can be used for treating the over-65s patient.
" gastroenteropathy " used herein includes but not limited to for example acute or chronic constipation, functional gastrointestinal disease (for example irritable bowel syndrome and functional dyspepsia), gastric ulcer, big intestinal ulcer, small intestinal ulcer and abdominal discomfort.
Although be not specifically limited, the constipation type of being treated comprises functional constipation, for example lusitropic constipation, spastic constipation, proctogenous constipation and postoperative ileus; By intestinal tract disease and postoperative intestinal adhesion and the organ constipation due to narrow; With for example constipation that causes of opiate of medicine.
Compositions of the present invention is except alleviation or prevent constipation, and hernia that anxiety causes when also can be used for preventing the patient because of defecation or cardiovascular disease perhaps are used for the softening feces of anal orifice and rectal intestine patient.In addition, compositions of the present invention can be used for cleaning gastrointestinal tract, to prepare to carry out splanchnoscopy or diagnosis or surgical operation (for example colonoscopy, barium coloclysis X ray and intravenous pyelography) and emergency operation (for example urgent gastrointestinal tract flushing is to get rid of poisonous substance) etc.Therefore, such embodiment is contained in the present invention: compositions wherein of the present invention is used to clean the male patient of needs or the gastrointestinal tract of over-65s human patients.
Term used herein " treatment " comprises any control methods such as prevention, nursing, mitigation symptoms, minimizing symptom and the development of prevention symptom.Term used herein " long-term treatment " is meant and gives chemical compound at least 2 weeks.In whole treatment cycle, but chemical compound give every day, perhaps gave in one day to several days at interval.
But more details reference test embodiment of the present invention, yet these embodiment must not be considered as limitation of the present invention.
(method)
Carry out the research of multicenter, open label, with estimate give every day sporadic constipation patient 48 μ g compd As (13,14-dihydro-15-ketone-16,16-two fluoro-PGE
1) (24 μ g compd As, twice of every day) safety in totally 24 weeks (6 months) or 48 weeks (12 months).Accepted the chronic constipation history for medical treatment at least 3 months (being less than SBM weekly 3 times) and at least one related symptoms (for example excrement matter is stiff, defecation not thoroughly, anxiety) the patient.No medicine was eliminated after date in 14 days, and they accept 48 μ g compd As (24 μ g compd As, twice of every day), and are oral, totally 48 weeks.
In this research, estimated following parameter.
1) electrolyte balance
6 weeks before giving the compd A treatment and after treatment begins, 12 weeks, 18 weeks, 24 weeks, 30 weeks, 36 weeks, 48 week and 50 weeks, measure sodium, potassium, chlorine, calcium, magnesium and phosphate ion concentration in patient (n=299) serum.
Obtain from the conventional term of reference of central laboratory and respectively to organize electrolytical laboratory standard value.2) the constipation order of severity, 3) abdominal bloating and 4) abdominal discomfort
Patient to 6 months (n=246) or 12 months (n=304) treatment estimates each parameter (the constipation order of severity, abdominal bloating or abdominal discomfort) according to following scoring: 0 (not having), 1 (slightly), 2 (moderates), 3 (seriously) and 4 (very serious).
(result)
1) electrolyte balance
Treat with compd A,, see Table 1 the not influence of the sodium among the patients serum, potassium, chlorine, calcium, magnesium and phosphate ion concentration.The result proves that compd A can not cause electrolyte shift basically when long-term prescription.
Table 1. average serum chemical results
Week | Sodium (mmol/L) | Potassium (mmol/L) | Chlorine (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 |
18 | 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 |
30 | 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 |
50 | 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 year 2.5-5.3mg/dL, 〉=20 years old 2.5-4.5mg/dL
Male: 15-19 year 2.5-5.6mg/dL, 〉=20 years old 2.5-4.5mg/dL
2) the constipation order of severity (6 months and 12 months), 3) abdominal bloating (6 months and 12 months) and 4) abdominal discomfort (6 months and 12 months) is seen Fig. 1 to Fig. 6 respectively.
Shown in Fig. 1-6, compd A is effective during treating in 6 months and 12 months.
(method)
In the part of total group, carry out multicenter, double blinding, at random, placebo-controlled study, with estimate 4 all active treatments (the total daily dose of 48 μ g compd As) and 3 weeks at random drug withdrawal week after date the treatment afterreaction.Accepted the chronic constipation history for medical treatment at least 6 months (being less than SBM weekly 3 times) and at least one related symptoms (for example excrement matter is stiff, defecation not thoroughly, anxiety) the patient.No medicine was eliminated after date in 14 days, and they accept oral 48 μ g (total daily dose) compd A, totally 28 days, accepted 0 or 48 μ g (total daily dose) compd A again, totally 21 days.
In this research, estimated following parameter.
1) defecation weekly
2) abdominal bloating
3) abdominal discomfort
4) the constipation order of severity
5) anxiety
6) hardness
Come each parameter (abdominal bloating, abdominal discomfort, the constipation order of severity or anxiety) of evaluate patient according to following scoring: 0 (not having), 1 (slightly), 2 (moderates), 3 (seriously) and 4 (very serious).According to following scoring evaluation hardness: 0 (very soft), 1 (soft), 2 (normally), 3 (stiff) and 4 (very stiff, coccoid).
(result)
1) defecation weekly, 2) abdominal bloating, 3) abdominal discomfort, 4) the constipation order of severity, 5) nervous and 6) hardness sees Fig. 7 to Figure 12 respectively.
Shown in Fig. 7-12, observe and stop not have rebound effect basically, and after stopping treatment, the effect of compd A is still kept with after the compd A treatment.
This result shows that patient's quality of life is improved because of giving compd A.
(method)
Irritable bowel syndrome (IBS) patient treated for 48 weeks with 48 μ g compd As (24 μ g compd As, twice of every day).
In this research, we have estimated following parameter.
1) abdominal discomfort
2) abdominal bloating
3) the constipation order of severity
Abdominal discomfort and abdominal bloating according to following scoring difference evaluate patient: 0 (not having), 1 (slightly), 2 (moderates), 3 (seriously) and 4 (very serious).According to the following scoring evaluate patient constipation order of severity: 0 (very soft), 1 (soft), 2 (normally), 3 (stiff) and 4 (very stiff).
(result)
1) abdominal discomfort, 2) abdominal bloating and 3) the constipation order of severity sees Table 2 respectively to table 4.
As show shown in the 2-4, compd A is effective to IBS patient during treatment in 12 months.
The analysis of table 2. abdominal discomfort
Week | Compd A meansigma methods ± SD (N) meta scope | Compd A meansigma methods ± SD (N) meta scope p-value * |
Baseline | 1.95±0.850(183) 2.00 0.00-4.00 | The variation of baseline |
The 12nd week | 1.16±0.836(135) 1.00 0.00-4.00 | -0.79±0.993(135) -1.00 -3.00-2.00 <0.001# |
The 18th week | 0.98±0.874(111) 1.00 0.00-3.00 | -0.97±1.031(111) -1.00 -4.00-3.00 <0.001# |
The 24th week | 1.09±0.917(107) 1.00 0.00-4.00 | -0.82±1.035(107) -1.00 -4.00-3.00 <0.001# |
The 36th week | 0.93±0.799(57) 1.00 0.00-3.00 | -0.77±0.926(57) -1.00 -4.00-2.00 <0.001# |
The 48th week | 0.87±0.929(52) 1.00 0.00-4.00 | -0.81±0.908(52) -1.00 -2.00-2.00 <0.001# |
Treatment finishes | 1.28±1.020(183) 1.00 0.00-4.00 | -0.66±1.112(183) -1.00 -4.00-2.00 <0.001# |
Follow up a case by regular visits to | 1.40±0.996(121) 1.00 0.00-4.00 | -0.55±1.080(121) -1.00 -4.00-2.00 <0.001# |
*The P-value is from the Wilcoxon signed rank test.
The analysis of table 3. abdominal bloating
Week | Compd A meansigma methods ± SD (N) meta scope | Compd A meansigma methods ± SD (N) meta scope p-value * |
Baseline | 2.23±0.927(183) 2.00 0.00-4.00 | The variation of baseline |
The 12nd week | 1.43±0.919(135) 1.00 0.00-4.00 | -0.84±1.045(135) -1.00 -3.00-3.00 <0.001# |
The 18th week | 1.19±0.837(111) 1.00 0.00-3.00 | -1.07±1.068(111) -1.00 -3.00-3.00 <0.001# |
The 24th week | 1.26±0.915(107) 1.00 0.00-4.00 | -0.95±1.102(107) -1.00 -4.00-3.00 <0.001# |
The 36th week | 1.05±0.854(57) 1.00 0.00-3.00 | -1.00±1.134(57) -1.00 -4.00-2.00 <0.001# |
The 48th week | 1.12±0.832(52) 1.00 0.00-4.00 | -0.94±0.802(52) -1.00 -3.00-1.00 <0.001# |
Treatment finishes | 1.50±1.005(183) 1.00 0.00-4.00 | -0.73±1.075(183) -1.00 -4.00-2.00 <0.001# |
Follow up a case by regular visits to | 1.55±0.957(121) 2.00 0.00-4.00 | -0.69±1.109(121) -1.00 -3.00-3.00 <0.001# |
*The P-value is from the Wilcoxon signed rank test.
The analysis of the table 4. constipation order of severity
Week | Compd A meansigma methods ± SD (N) meta scope | Compd A meansigma methods ± SD (N) meta scope p-value * |
Baseline | 2.95±0.751(183) 3.00 1.00-4.00 | The variation of baseline |
The 12nd week | 1.76±1.003(135) 2.00 0.00-4.00 | -1.16±1.099(135) -1.00 -4.00-2.00 <0.001# |
The 18th week | 1.33±0.985(111) 1.00 0.00-4.00 | -1.59±1.148(111) -2.00 -4.00-3.00 <0.001# |
The 24th week | 1.50±0.965(107) 1.00 0.00-4.00 | -1.40±1.036(107) -1.00 -3.00-2.00 <0.001# |
The 36th week | 1.39±0.921(57) 1.00 0.00-4.00 | -1.33±1.123(57) -1.00 -4.00-2.00 <0.001# |
The 48th week | 1.37±0.894(51) 1.00 0.00-3.00 | -1.37±1.095(51) -1.00 -3.00-1.00 <0.001# |
Treatment finishes | 1.84±1.120(183) 2.00 0.00-4.00 | -1.11±1.148(183) -1.00 -4.00-2.00 <0.001# |
Follow up a case by regular visits to | 2.07±0.946(121) 2.00 0.00-4.00 | -0.88±1.122(121) -1.00 -4.00-2.00 <0.001# |
*The P-value is from the Wilcoxon signed rank test.
(method)
Carry out multicenter, parallel grouping, double blinding, placebo-controlled study, with the influence of comparative compound A to men and women patient's spontaneous defecation frequency weekly.Sporadic constipation men and women patient accepts 48 μ g (total daily dose) compd A (24 μ g compd As, twice of every day), totally 4 weeks.The defecation frequency of record patient during treating.
(result)
48 μ g compd As are seen Figure 13 to the influence of the spontaneous defecation frequency weekly of male patient and female patient.
As shown in figure 13, compd A is obviously all effective to men and women patient.There is not significant difference between men and women patient's the effect.
(method)
Carry out multicenter, parallel grouping, double blinding, placebo-controlled study, with the sporadic constipation patient weekly influence of spontaneous defecation frequency of comparative compound A to improving all ages and classes.The patient accepts 48 μ g (total daily dose) compd A (24 μ g compd As, twice of every day), totally 4 weeks.The defecation frequency of record patient during treating.
(result)
The results are shown in Figure 14.As shown in figure 14, compd A is obviously all effective to all age group and over-65s patient.
(method)
Carried out a multicenter study in 48 weeks by a definite date, to estimate safety and the effectiveness of 48 μ g (total daily dose) compd A to sporadic constipation patient.Accepted the constipation history for medical treatment at least 3 months (being less than SBM weekly 3 times) and at least one related symptoms (for example excrement matter is stiff, defecation not thoroughly, anxiety) the patient.No medicine was eliminated after date in 14 days, and they accept oral 48 μ g compd As (24 μ g chemical compounds 1, twice of every day), totally 48 weeks every day.
When (baseline) and treatment finish when the research beginning (the 48th week), (this is a kind of conventional QOL evaluation table that uses for Medical Outcomes Study, the short tables of 36 clauses and subclauses (SF-36) MOS) to allow the patient finish medical effect research.Each clauses and subclauses of MOS SF-36 (Med Care 30 (6), 473-483,2000) are summarized as follows:
Physique aspect: somatic function (Physical Function), body role (Role-Physical), human body pain (Bodily Pain) and general health situation (General Health)
Spirit aspect: vitality (Vitality), social function (Social Function), emotion role (Role-Emotional) and mental health (Mental Health)
Guide (comprising publisher ' s guidelines for imputingmissing variables) according to publisher writes down this 8 clauses and subclauses item by item.When treatment finishes (the 48th week), the baseline that writes down these 8 clauses and subclauses item by item changes and checks with pairing T-to be estimated.
(result)
As shown in table 5, to mark one by one for these 8 clauses and subclauses, average baselining is marked between 47 to 52, shows that patient colony generally is healthy.In the 48th week, the average baselining of each clauses and subclauses scoring changes to demonstrate a little and increases, and shows the improvement of respective entries.In the 48th week, observe in the improvement of somatic function, body role, human body pain, general health situation, vitality, social function and mental health each side obviously non-vanishing.
The result shows that compd A has improved patient's QOL.
Table 5.SF36 result gather
Clauses and subclauses/score | ||||||||
Somatic function | The body role | Human body pain | The general health situation | Vitality | Social function | Emotion role | Mental health | |
Baseline N meansigma methods (Std) | 320 49.04 9.817 | 320 49.75 9.457 | 319 47.53 9.765 | 319 51.52 9.069 | 319 50.61 9.940 | 320 50.12 9.778 | 319 49.52 9.973 | 319 50.60 9.829 |
The 48th week a)The N meansigma methods b)(Std) | 153 2.48 **8.431 | 153 1.95 ** 7.403 | 151 3.38 ** 9.883 | 151 1.47 * 7.827 | 151 2.89 ** 9.163 | 152 2.22 ** 8.973 | 151 1.22 9.560 | 151 1.97 ** 9.201 |
A): the numerical value in these the 48th weeks is variations of baseline.
B):
*P<0.05,
*P<0.01 (pairing T-check).
(method)
Double blinding, the random research in 12 weeks have by a definite date been carried out, to estimate safety and the effectiveness of oral 16 μ g, 32 μ g and 48 μ g (total daily dose) compd A to irritable bowel syndrome (IBS) patient.
According to following IBS QOL user's manual (irritable bowel syndrome patients ' life quality scale (IBS-QOL)), when baseline, the 4th week, the 12nd week and research finish, allow the patient answer IBS QOL questionnaire and to the questionnaire survey result mark (User ' s Manual and ScoringDiskette for United States Version.Seattle, Washington:University ofWashington; 1997).The scoring of record is used for all analyses, and is as described below, counts the score according to user's manual:
Score=([each clauses and subclauses summation of IBS-QOL-minimum possibility score]/possible original score scope)) * 100
When the 4th week, the 12nd week and research finish, estimate the variation of baseline, to estimate average PTS and average each clauses and subclauses score (dysphoria, active interference, body image, healthy worry, food are avoided (food avoidance), social response, property and relation).
(result)
Lacking the last average baselining of observing the IBS-QOL score of (LOCF, Last observation carried forward) changes to gather and sees Table 6 to table 8.
These data show that the baseline of all groups changes obviously all non-vanishing.Generally speaking, at the concrete zone of each clauses and subclauses of all groups and QOL generally, 16 μ g compd A groups all show maximum baseline improvement.
The baseline variation of table 6. IBS QOL (16 μ g) gathers
Clauses and subclauses/score | |||||||||
QOL is overall | Dysphoria | To active interference | Body image | Healthy worry | Food is avoided | Social response | The property | Relation | |
Baseline N meansigma methods (Std) | 51 55.66 21.165 | 51 53.19 27.333 | 51 65.82 22.544 | 51 41.42 22.877 | 51 37.74 23.113 | 51 46.08 30.016 | 51 63.97 24.546 | 51 64.95 33.913 | 51 67.81 25.387 |
The 4th all N meansigma methodss (Std) | 45 14.7 ** 14.842 | 45 17.85 ** 18.483 | 45 10.87 ** 14.899 | 45 16.39 ** 19.867 | 45 22.41 ** 20.241 | 45 13.89 ** 22.332 | 45 11.94 ** 19.439 | 45 13.33 ** 25.057 | 45 10.74 ** 17.463 |
The 12nd all N meansigma methodss (Std) | 42 18.54 ** 17.698 | 42 23.51 ** 20.949 | 42 13.95 ** 18.392 | 42 22.32 ** 21.701 | 42 23.81 ** 22.129 | 42 15.28 ** 26.792 | 42 14.58 ** 21.548 | 42 16.67 ** 29.82 | 42 15.47 ** 21.897 |
Research finishes N meansigma methods (Std) | 49 16.82 ** 17.145 | 49 21.62 ** 20.451 | 49 11.95 ** 18.348 | 49 20.41 ** 21.491 | 49 21.94 ** 21.562 | 49 13.95 ** 25.762 | 49 13.78 ** 20.57 | 49 14.03 ** 28.485 | 49 14.28 ** 20.692 |
The baseline variation of table 7. IBS QOL (32 μ g) gathers
Clauses and subclauses/score | |||||||||
QOL is overall | Dysphoria | To active interference | Body image | Healthy worry | Food is avoided | Social response | The property | Relation | |
Baseline N meansigma methods (Std) | 49 60.14 22.05 | 49 59.69 24.79 | 49 69.82 23.385 | 49 43.37 24.387 | 49 44.38 24.672 | 49 52.21 32.175 | 49 66.84 28.562 | 49 68.62 31.367 | 49 70.23 23.385 |
The 4th all N meansigma methodss (Std) | 36 11.25 ** 16.277 | 36 14.58 ** 20.39 | 36 7.04 * 17.753 | 36 15.28 ** 18.264 | 36 16.9 ** 17.534 | 36 8.33 * 23.988 | 36 9.9 ** 16.46 | 36 8.68 ** 18.131 | 36 7.64 * 18.831 |
The 12nd all N meansigma methodss (Std) | 33 13.08 ** 13.527 | 33 15.25 ** 15.285 | 33 9.42 ** 18.052 | 33 17.99 ** 15.21 | 33 19.44 ** 21.616 | 33 11.36 ** 23.46 | 33 10.8 ** 14.173 | 33 10.98 ** 18.424 | 33 9.09 * 20.87 |
Research finishes N meansigma methods (Std) | 44 12.58 ** 12.621 | 44 14.77 ** 14.429 | 44 8.2 ** 16.726 | 44 17.47 ** 15.344 | 44 17.61 ** 22.317 | 44 10.79 ** 21.906 | 44 11.08 ** 14.32 | 44 10.23 ** 16.894 | 44 10.79 ** 20.139 |
The baseline variation of table 8. IBS QOL (48 μ g) gathers
Clauses and subclauses/score | |||||||||
QOL is overall | Dysphoria | To active interference | Body image | Healthy worry | Food is avoided | Social response | The property | Relation | |
Baseline N meansigma methods (Std) | 45 59.85 21.664 | 45 56.81 26.802 | 45 68.25 23.396 | 45 45.69 21.396 | 45 44.07 23.274 | 45 50.37 31.927 | 45 66.81 27.074 | 45 71.94 30.404 | 45 75.18 22.365 |
The 4th all N meansigma methodss (Std) | 34 12.43 ** 11.619 | 34 17.28 ** 16.842 | 34 9.14 ** 14.477 | 34 13.24 ** 13.568 | 34 19.61 ** 18.562 | 34 12.01 ** 19.59 | 34 8.82 ** 14.028 | 34 6.46 ** 15.607 | 34 6.87 ** 12.558 |
The 12nd all N meansigma methodss (Std) | 30 14.8 ** 13.65 | 30 20.83 ** 18.863 | 30 10.95 ** 15.091 | 30 17.08 ** 18.419 | 30 23.33 ** 18.098 | 30 11.3 **9 22.153 | 30 14.17 ** 21.143 | 30 5 18.159 | 30 6.95 ** 12.202 |
Research finishes N meansigma methods (Std) | 43 11.54 ** 13.002 | 43 16.28 ** 18.62 | 43 7.97 ** 14.387 | 43 14.24 ** 17.43 | 43 17.05 ** 19.067 | 43 8.33 ** 20.002 | 43 12.06 ** 18.72 | 43 3.49 17.535 | 43 6.01 ** 12.244 |
*P<0.05,
*P<0.01 (pairing T-check)
Claims (63)
1. method that is used for the gastroenteropathy of long-term treatment human patients, this method comprise prostaglandin compound and/or its tautomer by following formula (I) expression that the patient of needs effective dose is arranged:
W wherein
1And W
2For
R
3And R
4Be hydrogen; Perhaps in them is OH, and another is a hydrogen;
X
1And X
2Be hydrogen, low alkyl group or halogen, precondition is that at least one is halogen in them;
R
2Be hydrogen or alkyl;
Y is saturated or unsaturated C
2-10Hydrocarbon chain, it is unsubstituted or is replaced by following group: oxo base, halogen, alkyl, hydroxyl or aryl;
A is-CH
2OH ,-COCH
2OH ,-COOH or its functional derivatives;
R
1Be saturated or unsaturated, straight chain, side chain or ring formation lower hydrocarbon, it is unsubstituted or is replaced by following group: halogen, oxo base, hydroxyl, low alkyl group, lower alkoxy, lower alkanoyloxy, low-grade cycloalkyl, rudimentary cycloalkyloxy, aryl or aryloxy group; Low-grade cycloalkyl; Rudimentary cycloalkyloxy; Aryl; Or aryloxy group;
Key between C-13 position and the C-14 position is two keys or singly-bound,
The steric configuration of C-15 position is R, S or its mix-configuration.
2. the process of claim 1 wherein that described prostaglandin compound is the monocycle tautomer of formula (I).
3. the process of claim 1 wherein that the dosage scope of described prostaglandin compound was about 6-96 μ g/ days.
4. the process of claim 1 wherein that the dosage scope of described prostaglandin compound was about 6-72 μ g/ days.
5. the process of claim 1 wherein that the dosage scope of described prostaglandin compound was about 6-60 μ g/ days.
6. the process of claim 1 wherein that the dosage scope of described prostaglandin compound was about 8-48 μ g/ days.
7. the process of claim 1 wherein the described prostaglandin compound of orally give.
8. the method for claim 7, wherein said prostaglandin compound gives with the oil solvent as excipient.
9. the method for claim 8, wherein said oil solvent is a medium-chain fatty acid.
11. the process of claim 1 wherein that described gastroenteropathy is selected from constipation, irritable bowel syndrome and functional dyspepsia.
12. the process of claim 1 wherein that described prostaglandin compound gave at least 2 weeks.
13. the process of claim 1 wherein that described prostaglandin compound gave at least 3 weeks.
14. the process of claim 1 wherein that described prostaglandin compound gave at least 4 weeks.
15. the process of claim 1 wherein that described prostaglandin compound gives at least 2 months.
16. the process of claim 1 wherein that described prostaglandin compound gives at least 6 months.
17. the process of claim 1 wherein that described prostaglandin compound gives at least 1 year.
18. the process of claim 1 wherein and give described prostaglandin compound for a long time.
19. a method for the treatment of male patient's gastroenteropathy, this method comprise prostaglandin compound and/or its tautomer by following formula (I) expression that the male patient of needs effective dose is arranged:
W wherein
1And W
2For
R
3And R
4Be hydrogen; Perhaps in them is OH, and another is a hydrogen;
X
1And X
2Be hydrogen, low alkyl group or halogen, precondition is that at least one is halogen in them;
R
2Be hydrogen or alkyl;
Y is saturated or unsaturated C
2-10Hydrocarbon chain, it is unsubstituted or is replaced by following group: oxo base, halogen, alkyl, hydroxyl or aryl;
A is-CH
2OH ,-COCH
2OH ,-COOH or its functional derivatives;
R
1Be saturated or unsaturated, straight chain, side chain or ring formation lower hydrocarbon, it is unsubstituted or is replaced by following group: halogen, oxo base, hydroxyl, low alkyl group, lower alkoxy, lower alkanoyloxy, low-grade cycloalkyl, rudimentary cycloalkyloxy, aryl or aryloxy group; Low-grade cycloalkyl; Rudimentary cycloalkyloxy; Aryl; Or aryloxy group;
Key between C-13 position and the C-14 position is two keys or singly-bound,
The steric configuration of C-15 position is R, S or its mix-configuration.
20. a method for the treatment of the gastroenteropathy of over-65s human patients, this method comprise prostaglandin compound and/or its tautomer by following formula (I) expression that the over-65s of needs patient effective dose is arranged:
W wherein
1And W
2For
R
3And R
4Be hydrogen; Perhaps in them is OH, and another is a hydrogen;
X
1And X
2Be hydrogen, low alkyl group or halogen, precondition is that at least one is halogen in them;
R
2Be hydrogen or alkyl;
Y is saturated or unsaturated C
2-10Hydrocarbon chain, it is unsubstituted or is replaced by following group: oxo base, halogen, alkyl, hydroxyl or aryl;
A is-CH
2OH ,-COCH
2OH ,-COOH or its functional derivatives;
R
1Be saturated or unsaturated, straight chain, side chain or ring formation lower hydrocarbon, it is unsubstituted or is replaced by following group: halogen, oxo base, hydroxyl, low alkyl group, lower alkoxy, lower alkanoyloxy, low-grade cycloalkyl, rudimentary cycloalkyloxy, aryl or aryloxy group; Low-grade cycloalkyl; Rudimentary cycloalkyloxy; Aryl; Or aryloxy group;
Key between C-13 position and the C-14 position is two keys or singly-bound,
The steric configuration of C-15 position is R, S or its mix-configuration.
21. a method of improving the quality of life of gastroenteropathy human patients, this method comprise prostaglandin compound and/or its tautomer by following formula (I) expression that gives described patient's effective dose:
W wherein
1And W
2For
R
3And R
4Be hydrogen; Perhaps in them is OH, and another is a hydrogen;
X
1And X
2Be hydrogen, low alkyl group or halogen, precondition is that at least one is halogen in them;
R
2Be hydrogen or alkyl;
Y is saturated or unsaturated C
2-10Hydrocarbon chain, it is unsubstituted or is replaced by following group: oxo base, halogen, alkyl, hydroxyl or aryl;
A is-CH
2OH ,-COCH
2OH ,-COOH or its functional derivatives;
R
1Be saturated or unsaturated, straight chain, side chain or ring formation lower hydrocarbon, it is unsubstituted or is replaced by following group: halogen, oxo base, hydroxyl, low alkyl group, lower alkoxy, lower alkanoyloxy, low-grade cycloalkyl, rudimentary cycloalkyloxy, aryl or aryloxy group; Low-grade cycloalkyl; Rudimentary cycloalkyloxy; Aryl; Or aryloxy group;
Key between C-13 position and the C-14 position is two keys or singly-bound,
The steric configuration of C-15 position is R, S or its mix-configuration.
22. the compositions of the gastroenteropathy of a long-term treatment human patients, said composition comprises
(i) prostaglandin compound and/or its tautomer by following formula (I) expression of effective dose:
W wherein
1And W
2For
R
3And R
4Be hydrogen atom; Perhaps in them is OH, and another is a hydrogen;
X
1And X
2Be hydrogen atom, low alkyl group or halogen atom, precondition is that at least one is halogen atom in them;
R
2Be hydrogen atom or alkyl;
Y is saturated or unsaturated C
2-10Hydrocarbon chain, it is unsubstituted or is replaced by following group: oxo base, halogen, alkyl, hydroxyl or aryl;
A is-CH
2OH ,-COCH
2OH ,-COOH or its functional derivatives;
R
1Be saturated or unsaturated, straight chain, side chain or ring formation lower hydrocarbon, it is unsubstituted or is replaced by following group: halogen, oxo base, hydroxyl, low alkyl group, lower alkoxy, lower alkanoyloxy, low-grade cycloalkyl, rudimentary cycloalkyloxy, aryl or aryloxy group; Low-grade cycloalkyl; Rudimentary cycloalkyloxy; Aryl; Or aryloxy group;
Key between C-13 position and the C-14 position is two keys or singly-bound,
The steric configuration of C-15 position is R, S or its mix-configuration;
(ii) pharmaceutically acceptable excipient.
23. the compositions of claim 22, wherein said prostaglandin compound are the monocycle tautomers of formula (I).
24. the compositions of claim 22, said composition are mixed with g/ days described prostaglandin compound of about 6-96 μ.
25. the compositions of claim 22, said composition are mixed with g/ days described prostaglandin compound of about 6-72 μ.
26. the compositions of claim 22, said composition are mixed with g/ days described prostaglandin compound of about 6-60 μ.
27. the compositions of claim 22, said composition are mixed with g/ days described prostaglandin compound of about 8-48 μ.
28. the compositions of claim 22, the said composition oral administration gives.
29. the compositions of claim 28, wherein said pharmaceutically suitable excipient is an oil solvent.
30. the compositions of claim 29, wherein said oil solvent is a medium-chain fatty acid.
32. the compositions of claim 22, wherein said gastroenteropathy is selected from constipation, irritable bowel syndrome and functional dyspepsia.
33. the compositions of claim 22, said composition gave at least 2 weeks.
34. the compositions of claim 22, said composition gave at least 3 weeks.
35. the compositions of claim 22, said composition gave at least 4 weeks.
36. the compositions of claim 22, said composition gives at least 2 months.
37. the compositions of claim 22, said composition gives at least 6 months.
38. the compositions of claim 22, said composition gives at least 1 year.
39. the compositions of claim 22, said composition gives for a long time.
40. a compositions for the treatment of men and women patient's gastroenteropathy, said composition comprises
(i) prostaglandin compound and/or its tautomer by following formula (I) expression of effective dose:
W wherein
1And W
2For
R
3And R
4Be hydrogen atom; Perhaps in them is OH, and another is a hydrogen;
X
1And X
2Be hydrogen atom, low alkyl group or halogen atom, and at least one is a halogen atom in them;
R
2Be hydrogen atom or alkyl;
Y is saturated or unsaturated C
2-10Hydrocarbon chain, it is unsubstituted or is replaced by following group: oxo base, halogen, alkyl, hydroxyl or aryl;
A is-CH
2OH ,-COCH
2OH ,-COOH or its functional derivatives;
R
1Be saturated or unsaturated, straight chain, side chain or ring formation lower hydrocarbon, it is unsubstituted or is replaced by following group: halogen, oxo base, hydroxyl, low alkyl group, lower alkoxy, lower alkanoyloxy, low-grade cycloalkyl, rudimentary cycloalkyloxy, aryl or aryloxy group; Low-grade cycloalkyl; Rudimentary cycloalkyloxy; Aryl; Or aryloxy group;
Key between C-13 position and the C-14 position is two keys or singly-bound;
The steric configuration of C-15 position is R, S or its mix-configuration;
(ii) pharmaceutically suitable excipient.
41. a compositions for the treatment of the gastroenteropathy of over-65s human patients, said composition comprises
(i) prostaglandin compound and/or its tautomer by following formula (I) expression of effective dose:
W wherein
1And W
2For
R
3And R
4Be hydrogen atom; Perhaps in them is OH, and another is a hydrogen;
X
1And X
2Be hydrogen atom, low alkyl group or halogen atom, precondition is that at least one is halogen atom in them;
R
2Be hydrogen atom or alkyl;
Y is saturated or unsaturated C
2-10Hydrocarbon chain, it is unsubstituted or is replaced by following group: oxo base, halogen, alkyl, hydroxyl or aryl;
A is-CH
2OH ,-COCH
2OH ,-COOH or its functional derivatives;
R
1Be saturated or unsaturated, straight chain, side chain or ring formation lower hydrocarbon, it is unsubstituted or is replaced by following group: halogen, oxo base, hydroxyl, low alkyl group, lower alkoxy, lower alkanoyloxy, low-grade cycloalkyl, rudimentary cycloalkyloxy, aryl or aryloxy group; Low-grade cycloalkyl; Rudimentary cycloalkyloxy; Aryl; Or aryloxy group;
Key between C-13 position and the C-14 position is two keys or singly-bound,
The steric configuration of C-15 position is R, S or its mix-configuration;
(ii) pharmaceutically suitable excipient.
42. a compositions of improving the quality of life of gastroenteropathy human patients, said composition comprises
(i) prostaglandin compound and/or its tautomer by following formula (I) expression of effective dose:
W wherein
1And W
2For
R
3And R
4Be hydrogen atom; Perhaps in them is OH, and another is a hydrogen;
X
1And X
2Be hydrogen atom, low alkyl group or halogen atom, precondition is that at least one is halogen atom in them;
R
2Be hydrogen atom or alkyl;
Y is saturated or unsaturated C
2-10Hydrocarbon chain, it is unsubstituted or is replaced by following group: oxo base, halogen, alkyl, hydroxyl or aryl;
A is-CH
2OH ,-COCH
2OH ,-COOH or its functional derivatives;
R
1Be saturated or unsaturated, straight chain, side chain or ring formation lower hydrocarbon, it is unsubstituted or is replaced by following group: halogen, oxo base, hydroxyl, low alkyl group, lower alkoxy, lower alkanoyloxy, low-grade cycloalkyl, rudimentary cycloalkyloxy, aryl or aryloxy group; Low-grade cycloalkyl; Rudimentary cycloalkyloxy; Aryl; Or aryloxy group;
Key between C-13 position and the C-14 position is two keys or singly-bound,
The steric configuration of C-15 position is R, S or its mix-configuration,
(ii) pharmaceutically suitable excipient.
43. be used for the purposes of the pharmaceutical composition of long-term treatment human patients gastroenteropathy by the prostaglandin compound of following formula (I) expression and/or its tautomer in preparation, wherein described compositions had the patient who needs:
W wherein
1And W
2For
R
3And R
4Be hydrogen atom; Perhaps in them is OH, and another is a hydrogen;
X
1And X
2Be hydrogen atom, low alkyl group or halogen atom, precondition is that at least one is halogen atom in them;
R
2Be hydrogen atom or alkyl;
Y is saturated or unsaturated C
2-10Hydrocarbon chain, it is unsubstituted or is replaced by following group: oxo base, halogen, alkyl, hydroxyl or aryl;
A is-CH
2OH ,-COCH
2OH ,-COOH or its functional derivatives;
R
1Be saturated or unsaturated, straight chain, side chain or ring formation lower hydrocarbon, it is unsubstituted or is replaced by following group: halogen, oxo base, hydroxyl, low alkyl group, lower alkoxy, lower alkanoyloxy, low-grade cycloalkyl, rudimentary cycloalkyloxy, aryl or aryloxy group; Low-grade cycloalkyl; Rudimentary cycloalkyloxy; Aryl; Or aryloxy group;
Key between C-13 position and the C-14 position is two keys or singly-bound,
The steric configuration of C-15 position is R, S or its mix-configuration.
44. the purposes of claim 43, wherein said prostaglandin compound are the monocycle tautomers of formula (I).
45. the purposes of claim 43, wherein said compositions are mixed with g/ days described prostaglandin compound of about 6-96 μ.
46. the purposes of claim 43, wherein said compositions are mixed with g/ days described prostaglandin compound of about 6-72 μ.
47. the purposes of claim 43, wherein said compositions are mixed with g/ days described prostaglandin compound of about 6-60 μ.
48. the purposes of claim 43, wherein said compositions are mixed with g/ days described prostaglandin compound of about 8-48 μ.
49. the purposes of claim 43, wherein said compositions oral administration gives.
50. the compositions of claim 49, wherein said compositions also comprises the oil solvent as excipient.
51. the purposes of claim 50, wherein said oil solvent is a medium-chain fatty acid.
53. the purposes of claim 43, wherein said gastroenteropathy is selected from constipation, irritable bowel syndrome and functional dyspepsia.
54. the purposes of claim 43, wherein said compositions gave at least 2 weeks.
55. the purposes of claim 43, wherein said compositions gave at least 3 weeks.
56. the purposes of claim 43, wherein said compositions gave at least 4 weeks.
57. the purposes of claim 43, wherein said compositions gives at least 2 months.
58. the purposes of claim 43, wherein said compositions gives at least 6 months.
59. the purposes of claim 43, wherein said compositions gives at least 1 year.
60. the purposes of claim 43, its midium or long term gives described compositions.
61. be used for the treatment of purposes in the pharmaceutical composition of men and women's patient's gastrointestinal tract disease by the prostaglandin compound of following formula (I) expression and/or its tautomer in preparation, wherein described compositions had the patient who needs:
W wherein
1And W
2For
R
3And R
4Be hydrogen atom; Perhaps in them is OH, and another is a hydrogen;
X
1And X
2Be hydrogen atom, low alkyl group or halogen atom, and at least one is a halogen atom in them;
R
2Be hydrogen atom or alkyl;
Y is saturated or unsaturated C
2-10Hydrocarbon chain, it is unsubstituted or is replaced by following group: oxo base, halogen, alkyl, hydroxyl or aryl;
A is-CH
2OH ,-COCH
2OH ,-COOH or its functional derivatives;
R
1Be saturated or unsaturated, straight chain, side chain or ring formation lower hydrocarbon, it is unsubstituted or is replaced by following group: halogen, oxo base, hydroxyl, low alkyl group, lower alkoxy, lower alkanoyloxy, low-grade cycloalkyl, rudimentary cycloalkyloxy, aryl or aryloxy group; Low-grade cycloalkyl; Rudimentary cycloalkyloxy; Aryl; Or aryloxy group;
Key between C-13 position and the C-14 position is two keys or singly-bound,
The steric configuration of C-15 position is R, S or its mix-configuration.
62. be used for the treatment of purposes in the pharmaceutical composition of gastroenteropathy of over-65s human patients by the prostaglandin compound of following formula (I) expression and/or its tautomer in preparation, wherein described compositions had the patient who needs:
W wherein
1And W
2For
R
3And R
4Be hydrogen atom; Perhaps in them is OH, and another is a hydrogen;
X
1And X
2Be hydrogen atom, low alkyl group or halogen atom, precondition is that at least one is halogen atom in them;
R
2Be hydrogen atom or alkyl;
Y is saturated or unsaturated C
2-10Hydrocarbon chain, it is unsubstituted or is replaced by following group: oxo base, halogen, alkyl, hydroxyl or aryl;
A is-CH
2OH ,-COCH
2OH ,-COOH or its functional derivatives;
R
1Be saturated or unsaturated, straight chain, side chain or ring formation lower hydrocarbon, it is unsubstituted or is replaced by following group: halogen, oxo base, hydroxyl, low alkyl group, lower alkoxy, lower alkanoyloxy, low-grade cycloalkyl, rudimentary cycloalkyloxy, aryl or aryloxy group; Low-grade cycloalkyl; Rudimentary cycloalkyloxy; Aryl; Or aryloxy group;
Key between C-13 position and the C-14 position is two keys or singly-bound,
The steric configuration of C-15 position is R, S or its mix-configuration.
63. be used for improving the purposes of pharmaceutical composition of the quality of life of gastroenteropathy human patients by the prostaglandin compound of following formula (I) expression and/or its tautomer in preparation, wherein described compositions had the patient who needs:
W wherein
1And W
2For
R
3And R
4Be hydrogen atom; Perhaps in them is OH, and another is a hydrogen;
X
1And X
2Be hydrogen atom, low alkyl group or halogen atom, precondition is that at least one is halogen atom in them;
R
2Be hydrogen atom or alkyl;
Y is saturated or unsaturated C
2-10Hydrocarbon chain, it is unsubstituted or is replaced by following group: oxo base, halogen, alkyl, hydroxyl or aryl;
A is-CH
2OH ,-COCH
2OH ,-COOH or its functional derivatives;
R
1Be saturated or unsaturated, straight chain, side chain or ring formation lower hydrocarbon, it is unsubstituted or is replaced by following group: halogen, oxo base, hydroxyl, low alkyl group, lower alkoxy, lower alkanoyloxy, low-grade cycloalkyl, rudimentary cycloalkyloxy, aryl or aryloxy group; Low-grade cycloalkyl; Rudimentary cycloalkyloxy; Aryl; Or aryloxy group;
Key between C-13 position and the C-14 position is two keys or singly-bound,
The steric configuration of C-15 position is R, S or its mix-configuration.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US60652104P | 2004-09-02 | 2004-09-02 | |
US60/606,521 | 2004-09-02 | ||
US60/666,317 | 2005-03-30 | ||
US60/666,593 | 2005-03-31 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2012103704021A Division CN102885821A (en) | 2004-09-02 | 2005-09-01 | Prostaglandin derivatives for treating gastrointestinal disorder |
Publications (1)
Publication Number | Publication Date |
---|---|
CN101048163A true CN101048163A (en) | 2007-10-03 |
Family
ID=38772171
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN 200580036665 Pending CN101048163A (en) | 2004-09-02 | 2005-09-01 | Prostaglandin derivatives for treating gastrointestinal disorder |
Country Status (4)
Country | Link |
---|---|
CN (1) | CN101048163A (en) |
AR (1) | AR107905A2 (en) |
RU (1) | RU2392941C2 (en) |
ZA (1) | ZA200702625B (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101466407B (en) * | 2006-01-24 | 2013-05-15 | 株式会社·R-技术上野 | Pharmaceutical composition comprising a bi-cyclic compound and method for stabilizing the bi-cyclic compound |
-
2005
- 2005-09-01 CN CN 200580036665 patent/CN101048163A/en active Pending
- 2005-09-01 RU RU2007111908/14A patent/RU2392941C2/en not_active IP Right Cessation
-
2007
- 2007-03-29 ZA ZA200702625A patent/ZA200702625B/en unknown
-
2017
- 2017-03-17 AR ARP170100663A patent/AR107905A2/en not_active Application Discontinuation
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101466407B (en) * | 2006-01-24 | 2013-05-15 | 株式会社·R-技术上野 | Pharmaceutical composition comprising a bi-cyclic compound and method for stabilizing the bi-cyclic compound |
Also Published As
Publication number | Publication date |
---|---|
RU2007111908A (en) | 2008-10-10 |
AR107905A2 (en) | 2018-06-28 |
RU2392941C2 (en) | 2010-06-27 |
ZA200702625B (en) | 2008-08-27 |
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