CN101180096A - Method and composition for treating mucosal disorders - Google Patents

Method and composition for treating mucosal disorders Download PDF

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CN101180096A
CN101180096A CNA2006800172054A CN200680017205A CN101180096A CN 101180096 A CN101180096 A CN 101180096A CN A2006800172054 A CNA2006800172054 A CN A2006800172054A CN 200680017205 A CN200680017205 A CN 200680017205A CN 101180096 A CN101180096 A CN 101180096A
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prostaglandin
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compound
disease
prostaglandin compound
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CN101180096B (en
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上野隆司
久能祐子
A·T·布里克斯拉格
A·J·莫伊塞
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NORTH CARLINA STATE UNIVERSITY
Sucampo GmbH
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Sucampo GmbH
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Abstract

Provided is a method and composition for treating mucosal disorders using a specific prostaglandin compound. The prostaglandin compound induces a conformational change in the tight junction that results in recovery of mucosal barrier function. Accordingly, the prostaglandin compound used herein is useful for the treatment of mucosal disorders.

Description

The method and composition that is used for the treatment of membrane disease
Technical field
The present invention relates to be used for the treatment of the method and composition of membrane disease.
Especially, the present invention relates to be used for the treatment of the method and composition of mammalian subject and mucosal barrier function reduction associated conditions.
Technical background
Epithelial tissue is as the barrier of two fluids between at interval, epithelial cell and provide the epithelium barrier function in conjunction with their tight contact (tight junction) (hereinafter to be referred as TJ).TJ is the top component of cell-cell contact complex, plays crucial effects in organizing the polar foundation of inner cell and keeping, and as at macromolecular selectivity barrier, and prevents lipid and protein diffusion between top and the basolateral membrane zone.TJ has also produced variable barrier, and this barrier scalable molecule is organized dynamic equilibrium by parietal cell (paracelluler) motion of epithelial layer thereby keep.Mucous epithelium TJ is a dynamic structure, and reinvent at epithelial tissue, wound repair, inflammation and being transformed into stand between tumor stage to regulate.Show the early stage research of epithelial cancer TJ structure modify, hinted related between unusual TJ function and the epithelioma formation.
A lot of reports about most important relation between mucosa TJ function reduction or loss and the multiple cancer are arranged.
It is reported that helicobacter pylori (working) destroys epithelium barrier function (Infection and Immunity 66 (6): 2943-2950,1998 and Science 300:1430-1434,2003) in gastric cancer forms.Report that in addition closely the proteic downward adjusting of contact is common in late gastric cancer (Oncology Reports 13:193-199,2005).
It is reported that colonic epithelium TJ permeability increases, and the epithelium barrier function that causes thus descend appear at colon cancer form before (Carcinogenesis 20 (8): 1425-1431,1999).
It is reported that the TJ changing function may be important (International Journal of Molecular Medicine 16:3-9,2005) in the formation of bladder inflammation and transitional cell carcinoma.
It is reported, in people's breast carcinoma, observe TJ function and TJ developed by molecule disappearance (AmericanJournal of Pathology 153 (6): 1767-1773,1998 and Journal of MammaryGland Biology and Neoplasia 8 (4): 449-462,2003).
It is reported that closely closely related between structure atypia and the malignant potential thereof in contact disappearance and the people's carcinoma of endometrium process (Human Pathology 35 (2), 159-164:2004).
It is reported that the destruction of TJ (being considered to impel epithelial tumor to take place) sees ovarian cancer cell (The Journal of Biological Chemistry 280 (28): 26233-26240,2005).
It is reported that the TJ variation sees thyroid oxyphil cell tumor (UltrastructuralPathology 22 (6): 413-420,1998).
It is reported that occur the disintegration of tight contact in hepatocarcinoma, these textural anomalies may change the interchange between permeability barrier and restrictive cell, this may promote the propagation behavior (J.Submicrosc.Cytol.15 (3) of regenerative cell; 799-810,1983).
Barrett esophagus (BE) has been represented the most serious consequence of organizing of gastroesophageal reflux disease (GERD), and the incidence rate in suffering from patient GERD is 5 to 10%.The Barrett esophagus is considered to precancerous disease, and the incidence rate of adenocarcinoma in the crowd who suffers from Barrett esophagus disease is far above the general population.
It is reported, parietal cell in the barrett's epithelium (paracellular) barrier is obviously different, compare with normal esophagus, there is significant functional aberrancy (American Journal of Gastroenterology 98 (8): 1901-1903,2003) in the barrier characteristics of barrett's epithelium.
It is reported that the proteic change of TJ probably increases the permeability of epithelium of esophagus in the reflux esophagitis (GERD), thereby weakens the defense mechanism (Joumal ofGastroenterology 40,781-790,2005) of this epithelium.
Intestinal barrier function is meant that intestinal mucosa prevents the ability that potential deleterious chamber composition (for example antibacterial and relevant toxin) passes epithelium and enters body tissue.Multiple pathologic condition comprises ischemia injury, shock, anxiety, infectious disease and inflammatory bowel (IBD), can cause the intestinal barrier function collapse.
Inflammatory bowel (IBD) is defined as agnogenic chronic, recurrent enteritis, and wherein two principal modes are Crohn disease (Crohn ' s disease) and ulcerative colitis.As if two kinds of diseases all comprise the antigenic immunoreation imbalance in gastrointestinal (GI) road (mucosal barrier function destruction), and/or to continuing intestinal infection, collagen diseases, radiotherapy, oral drugs etc. bad inflammatory reaction are arranged.
The feature of Crohn disease is that the gastrointestinal wall zone thickens (inflammation diffuses to all layers), deep ulcer and mucosa crack, and granuloma appears.Involved area can appear at any position of gastrointestinal, often relates to terminal ileum, and they can alternately scatter with the zone of relative normal structure.In ulcerative colitis, disease also appears in colon and the rectum.At involved area, inflammation be the surface but be successive, rare granuloma.
Be apparent that equally more and more many critical patients suffer from the multiple organ failure that the internal organs hypoperfusion causes.Multiple organ failure is the first cause of intensive care unit patient death.
These gastrointestinal mucosa diseases are difficult to cure usually, in some cases, and also with this disease of surgical operation therapy.The active drug treatment that is used for these diseases at present comprises steroid, Salazopyrin (general azulfidine by name), immunosuppressant etc.Yet the long-time heavy dose of steroid medicine has side effect, and owing to have very deleterious side effect, also must careful use immunosuppressant.Therefore, the expectation medicine developing effective treatment intractable gastrointestinal mucosa disease and can long-term safety use.
Prostaglandin (hereinafter to be referred as PG) is the member of organic carboxyl acid class, and it is present in people or other mammiferous tissue or the organ, has a variety of physiologically actives.The PG (former PG) that nature is found has the prostanoic acid skeleton shown in the formula (A) usually:
Figure S2006800172054D00031
According to pentacyclic structure and substituent group, PG is divided into several types, for example,
A series prostaglandin (PGA);
Figure S2006800172054D00032
B series prostaglandin (PGB);
Figure S2006800172054D00041
C series prostaglandin (PGC);
D series prostaglandin (PGD);
Figure S2006800172054D00043
E series prostaglandin (PGE);
Figure S2006800172054D00044
F series prostaglandin (PGF);
Figure S2006800172054D00045
Deng.
In addition, they are divided into contain 13, the PG of the two keys of 14- 1Contain 5, the two keys and 13 of 6-, the PG of the two keys of 14- 2And contain 5, the two keys, 13 of 6-, the two keys and 17 of 14-, the PG of the two keys of 18- 3Known PG has multiple pharmacology and physiologically active, for example vasodilation, inflammation-induced, platelet aggregation, stimulation uterus muscle, the activity of stimulation myenteron meat, antiulcer action etc.The main prostaglandin that people's gastrointestinal (GI) system generates is prostaglandin E, I and F series (Sellin, gastrointestinal and hepatopathy: pathophysiology, diagnosis and processing (Gastrointestinal and Liver Disease:Pathophysiology, Diagnosis, and Management). (WB SaundersCompany, 1998); Robert, gastrointestinal physiology (Physiology of theGastrointestinal Tract) 1407-1434 (Raven, 1981); Rampton, prostaglandin: the biology of prostaglandin and associated class arachic acid and chemistry (Prostaglandins:Biologyand Chemistry of Prostaglandins and Related Eicosanoids) 323-344 (Churchill Livingstone, 1988); People such as Hawkey, gastroenterology (Gastroenterology), 89:1162-1188 (1985); People such as Eberhart, gastroenterology (Gastroenterology), 109:285-301 (1995)).
Under normal physiological condition, the prostaglandin that endogenous generates plays main effect in keeping GI function (comprise mobility and the transmission of regulating intestinal and regulate the feces consolidation).(Sellin, gastrointestinal and hepatopathy: pathophysiology, diagnosis and processing (Gastrointestinal andLiver Disease:Pathophysiology, Diagnosis, and Management). (WBSaunders Company, 1998); Robert, gastrointestinal physiology (Physiology of theGastrointestinal Tract) 1407-1434 (Raven, 1981); Rampton, prostaglandin: the biology of prostaglandin and associated class arachic acid and chemistry (Prostaglandins:Biologyand Chemistry of Prostaglandins and Related Eicosanoids) 323-344 (Churchill Livingstone, 1988); People such as Hawkey, gastroenterology (Gastroenterology), 89:1162-1188 (1985); People such as Eberhart, gastroenterology (Gastroenterology), 109:285-301 (1995); Robert, Adv ProstaglandinThromboxane Res, 2:507-520 (1976); People such as Main, Postgrad Med J, 64Suppl1:3-6 (1988); Sanders, Am J Physiol, 247:G117 (1984); People such as Pairet, Am J Physiol., 250 (3pt 1): G302-G308 (1986); Gaginella, Textbook of Secretory Diarrhea 15-30 (Raven Press, 1990)).When giving pharmacology dosage, PGE 2And PGF 2 αAll show and promote the intestinal transmission and cause diarrhoea (Robert, gastrointestinal physiology (Physiology of the Gastrointestinal Tract) 1407-1434 (Raven, 1981); Rampton, prostaglandin: the biology of prostaglandin and associated class arachic acid and chemistry (Prostaglandins:Biology and Chemistry of Prostaglandins andRelated Eicosanoids) 323-344 (Churchill Livingstone, 1988); Robert, Adv Prostaglandin Thromboxane Res, 2:507-520 (1976)).In addition, a kind of PGE1 analog misoprostol that is used for treating gastric ulcer, the side effect of normal report is diarrhoea people such as (, medicine (Drugs) 33 (1): 1-30 (1997)) Monk.
PGE or PGF can stimulate intestinal to shrink, and effect is very weak but intestinal mixes (enteropooling).
Accordingly, owing to for example cause the side effect that the intestinal of abdominal pain shrinks, be unpractical as cathartic with PGE or PGF.
It is reported that mechanism and multiple (comprises that the reaction of adjustment enteric nervous, change smooth muscle contraction, stimulating mucosal secretion, irritation cell ion secretion (particularly produce electric Cl -Transmission) and increase the intestinal fluid volume) caused GI effect (Robert, gastrointestinal physiology (the Physiology of the Gastrointestinal Tract) 1407-1434 (Raven, 1981) of prostaglandin; Rampton, prostaglandin: the biology of prostaglandin and associated class arachic acid and chemistry (Prostaglandins:Biology and Chemistry of Prostaglandins and RelatedEicosanoids) 323-344 (Churchill Livingstone, 1988); People such as Hawkey, gastroenterology (Gastroenterology), 89:1162-1188 (1985); People such as Eberhart, gastroenterology (Gastroenterology), 109:285-301 (1995); Robert, Adv ProstaglandinThromboxane Res, 2:507-520 (1976); People such as Main, Postgrad Med J, 64 supplementary issue 1:3-6 (1988); Sanders, Am J Physiol, 247:G117 (1984); People such as Pairet, Am J Physiol, 250 (3pt 1): G302-G308 (1986); Gaginella, secretion diarrhoea textbook (Textbook of Secretory Diarrhea) 15-30 (Raven Press, 1990); Federal Register Vol.50, No.10 (GPO, 1985); People such as Pierce, gastroenterology (Gastroenterology), 60 (1): 22-32 (1971); People such as Beubler, gastroenterology (Gastroenterology), 90:1972 (1986); People such as Clarke, Am J Physiol259:G62 (1990); People such as Hunt, J Vet Pharmacol Ther, 8 (2): 165-173 (1985); People such as Dajani, Europe pharmacology's magazine (EurJ Pharmacol), 34 (1): 105-113 (1975), Sellin, gastrointestinal and hepatopathy: pathophysiology, diagnosis and processing (Gastroint estinaland Liver Disease:Pathophysiology, Diagnosis, and Management) 1451-1471 (WB Saunders Company, 1998)).Prostaglandin also shows cytoprotection (Sellin, gastrointestinal and hepatopathy: pathophysiology, diagnosis and processing (Gastrointestinal andLiver Disease:Pathophysiology, Diagnosis, and Management). (WBSaunders Company, 1998); Robert, gastrointestinal physiology (Physiology of theGastrointestinal Tract), 1407-1434 (Raven, 1981); Robert, AdvProstaglandin Thromboxane Res, 2:507-520 (1976); People such as Wallace, Aiiment Pharmacol Ther 9:227-235 (1995)).
United States Patent (USP) the 5th, 225, No. 439, the 5th, 166, No. 174, the 5th, 284, No. 858, the 5th, 428, No. 062, the 5th, 380, No. 709, the 5th, 876, No. 034 and the 6th, 265, it is effective to have described some prostaglandin E compound treatment ulcer (for example duodenal ulcer and gastric ulcer) for No. 440.
Authorize people's such as Ueno United States Patent (USP) and described the prostaglandin compound cathartic for the 5th, 317, No. 032, it comprises and has the dicyclo tautomer, the United States Patent (USP) of authorizing Ueno has been described the dicyclo tautomer with remarkable activity as anti-emplastic for the 6th, 414, No. 016.The dicyclo tautomer that is replaced by one or more halogen atoms can low dose be used for constipation relieving.On the C-16 position, particularly fluorine atom can low dose be used for constipation relieving.
People's such as Ueno U.S. Patent Application Publication has been described prostaglandin compound No. 2003/0130352 and No. 2003/0166632, and it opens and activate chloride channel, particularly ClC passage, especially ClC-2 passage.
People's such as Ueno U.S. Patent Application Publication has been described the concrete composition that is used for the treatment of with the halogenation prostaglandin compound of prevent constipation for No. 2003/0119898.
The inventor had proved in the external intestinal ischemia model of pig in the past, produced prostaglandin (PG) and related to activated Cl by relating to through Cycloxygenase dependence approach -Excretory mechanism mediates the reparation of intestinal barrier function.(Am J Physiol, 276:G28-36,1999 and Am JPhysiol Gastrointest Liver Physiol, 284:G46-56,2003).
The inventor had also proved in the past, PGE 2And PGI 2In recovering intestinal barrier function, synergism is arranged, however every kind of adding separately, and effect weakens (J.Clin.Invest., 1997.100 (8): 1928-1933).
In addition, show PGE 1The Cl that stimulates -Secretion reduces (J.Clin.Invest.76:1828-1836,1985) in the recovery of intestinal barrier function.
In further studying, show that misoprostol (Misoprostol) is influential to barrier function, although deoxidation-PGE 1And sulprostone (Sulprostone) is to its not influence (Am.J.Physiol.Gastrointest.Liver Physiol.281:G375-81,2001).
Summary of the invention
The object of the invention provides a kind of method and composition for the treatment of the mammalian subject membrane disease.The object of the invention also is to provide the method and composition of protection mammalian subject mucosa.
Do not consider prior art, the inventor finds that special prostaglandin compound has remarkable effect to the conformational change of TJ, thereby causes mucosal barrier function to recover, and finishes the present invention.
That is to say, the present invention relates to treat the method for mammalian subject membrane disease, it comprises the prostaglandin of following general formula (I) expression of the patient's effective dose that needs:
Wherein, L, M and N are hydrogen, hydroxyl, halogen, low alkyl group, hydroxyl (rudimentary) alkyl, low-grade alkane acidyl oxygen base or oxo base, and wherein at least one is the group outside the dehydrogenation among L and the M, and five-membered ring can have at least one two key;
A is-CH 3Perhaps-CH 2OH ,-COCH 2OH ,-COOH or its functional derivatives;
B be singly-bound ,-CH 2-CH 2-,-CH=CH-,-C ≡ C-,-CH 2-CH 2-CH 2-,-CH=CH-CH 2-,-CH 2-CH=CH-,-C ≡ C-CH 2-or-CH 2-C ≡ C-;
Z is
Perhaps singly-bound;
Wherein, R 4And R 5Be hydrogen, hydroxyl, halogen, low alkyl group, lower alkoxy or hydroxyl (rudimentary) alkyl, wherein R 4And R 5Be not hydroxyl and lower alkoxy simultaneously;
R 1Be saturated or undersaturated bivalent lower or intermediate aliphatic hydrocarbon residue, it is unsubstituted or is replaced by halogen, alkyl, hydroxyl, oxo base, aryl or heterocyclic radical, and at least one carbon atom is optional in the aliphatic hydrocarbon is replaced by oxygen, nitrogen or sulfur; And
Ra is saturated or undersaturated rudimentary or intermediate aliphatic hydrocarbon residue, and it is unsubstituted or is replaced by following group: halogen, oxo base, hydroxyl, low alkyl group, lower alkoxy, low-grade alkane acidyl oxygen base, ring (rudimentary) alkyl, ring (rudimentary) alkoxyl, aryl, aryloxy group, heterocyclic radical or heterocycle-oxygen base; Lower alkoxy; Low-grade alkane acidyl oxygen base; Ring (rudimentary) alkyl; Ring (rudimentary) alkoxyl; Aryl; Aryloxy group; Heterocyclic radical; Heterocycle-oxygen base, condition are that Ra is replaced by halogen, and perhaps Z is C=O.
Especially, the present invention relates to the method for a kind of treatment disease relevant with the reduction of mammalian subject mucosal barrier function, it comprises formula (I) prostaglandin compound of the patient's effective dose that needs.
The invention still further relates to the method for protection mammalian subject mucosa, it comprises the concrete prostaglandin compound of the patient's effective dose that needs protection.
Another aspect of the present invention provides the compositions of formula (I) prostaglandin compound that comprises effective dose, and said composition is used for the treatment of the mammalian subject membrane disease.The present composition can be used for the invention described above method.
Another aspect of the present invention provides the purposes of formula (I) prostaglandin compound in the Pharmaceutical composition of production for treating mammalian subject membrane disease.
Description of drawings
Fig. 1 is presented in the ischemic injuries pig ileum, and the response compd A (13,14-dihydro-15-ketone-16,16-two fluoro-PGE 1) transepithelial electrical resistance value (TER).This value is represented meansigma methods ± SE; N=6.Containing indomethacin (indomethacin) (5 * 10 -6The ischemic tissue of soaking in the Ringer ' s solution M) proves, in the presence of compd A (0.1 μ M and 1 μ M dosage) that 30 minutes balance period add later, transepithelial cell resistance value (TER) significantly raises.
Fig. 2 A shows the influence of compd A to short circuit current.The short circuit current that Fig. 2 B is presented at response compd A in the ischemic injuries pig ileum changes (Δ Isc).In two figure, this value is represented meansigma methods ± SE; N=6.Ischemic tissue is immersed in contains indomethacin (indomethacin) (5 * 10 -6M) in the Ringer ' s solution.The absolute change of short circuit current (Isc) and short circuit current (Δ Isc) all shows Cl -The secretion remarkable increase (P＜0.05) is arranged, observe this increase corresponding with the treatment of the compd A of cumulative dosage ( *P＜0.05).
Fig. 3 shows that compd A is to mucosa-to-chorion 3The influence of H-mannitol flow.This value is represented meansigma methods ± SE; N=4.Ischemic tissue is immersed in contains indomethacin (indomethacin) (5 * 10 -6M) in the Ringer ' s solution.The pig ileum stands intestinal ischemia, and shows 3H-mannitol mucosa-to-chorion flow increase (comparing) with non-ischemic control.Use the compd A of 1 μ M, reduced 3The level of H-mannitol mucosa-to-chorion flow to non-ischemic control. *P＜0.05。
Fig. 4 has shown the variation of the short circuit current that the response compd A is handled in the ascending colon on the pig of ischemic injuries.
Fig. 5 has shown the transepithelial electrical resistance value (TER) that the response compd A is handled in the ascending colon on the pig of ischemic injuries.
Fig. 6 has shown on the pig of ischemic injuries the chorion that the response compd A is handled in the ascending colon-to-mucosa 3H-mannitol flow.
Detailed Description Of The Invention
Here used prostaglandin compound nomenclature is based on the numbering system of the prostanoic acid of representative in the following formula (A).
Formula (A) shows the basic framework of C-20 carbon atom, but the invention is not restricted to the compound that these have same carbon atoms number. In formula (A), the carbon atoms numbered that forms PG compound basic framework begins (volume is 1) from carboxylic acid, and it is 2 to 7 that the carbon atom on α-chain is compiled towards the five-membered ring direction, and the carbon atom volume is that the carbon atom volume on 8 to 12, the ω-chain is 13 to 20 on the ring. When carbon number on α-chain reduces, sequentially delete numbering since 2; And when carbon number on α-chain increased, the compound called after had the separately substituted compound of substituting group (replacing carboxyl (C-1)) at 2. Similarly, when carbon number on ω-chain reduces, sequentially delete numbering since 20; And when carbon number on ω-chain increased, the carbon atom that surpasses 20 was named as substituting group. The compound spatial chemistry is identical with the situation of following formula (A), except as otherwise noted.
Generally speaking, each term PGD, PGE and PGF representative are at 9 and/or 11 the PG compounds that hydroxyl is arranged, but in this manual, these terms comprise that also those have substituent compound outside the hydroxyl-removal at 9 and/or 11. These compounds refer to that 9-goes hydroxyl-9-replacement-PG compound or 11-to remove hydroxyl-11-replacement-PG compound. With the PG compound of the alternative hydroxyl of hydrogen, simple called after 9-or 11-deoxidation-PG compound.
As mentioned above, the nomenclature of PG compound is based on the prostanoic acid skeleton. Yet, if compound has the similar part-structure such as prostaglandin, can use abbreviation " PG " '. Therefore, the PG compound called after 2-decarboxylation-2-(2-carboxyethyl) of 2 carbon atoms of α-chain elongation (namely, 9 carbon atoms being arranged on α-chain)-PG compound. Similarly, the PG compound called after 2-decarboxylation-2-(4-carboxylic butyl) of 11 carbon atoms-PG compound is arranged on α-chain. In addition, the PG compound called after 20-ethyl of 2 carbon atoms of ω-chain elongation (namely, 10 carbon atoms being arranged on ω-chain)-PG compound. Yet these compounds can also be named according to the IUPAC nomenclature.
The example of analog (derivative that comprises replacement) or derivative comprises the esterified PG compound of α-chain end carboxyl; The compound of α-chain elongation; Acceptable salt on its physiology; Two keys are arranged in the 2-3 position or the compound of triple bond is arranged in the 5-6 position; Compound at 3,5,6,16,17,18,19 and/or 20 substds; And at 9 and/or 11 compounds that low alkyl group or hydroxyl (rudimentary) alkyl (replacement hydroxyl) are arranged.
According to the present invention, preferred substituting group comprises alkyl, particularly methyl and the ethyl with 1 to 4 carbon atom on 3,17,18 and/or 19. Preferred substituting group comprises low alkyl group (for example methyl and ethyl), hydroxyl, halogen atom (for example chlorine and fluorine) and aryloxy group (for example 4-trifluoromethylphenopendant) on 16. Preferred substituting group comprises low alkyl group (for example methyl and ethyl), hydroxyl, halogen atom (for example chlorine and fluorine), aryloxy group (for example 4-trifluoromethylphenopendant) on 17. Preferred substituting group comprises saturated or unsaturated low alkyl group (for example C1-4 alkyl), lower alkoxy (for example C1-4 alkoxyl) and low-grade alkoxy alkyl (for example, C1-4 alkoxy-C 1-4 alkyl) on 20. Preferred substituting group comprises halogen atom (for example chlorine and fluorine) on 5. Preferred substituting group comprises the oxo base that forms carbonyl on 6. Can be α, β or its mixture 9 and/or 11 spatial chemistry with PG of hydroxyl, low alkyl group or hydroxyl (rudimentary) alkyl substituent.
In addition, above-mentioned analog or derivative can be the compounds that has alkoxyl, cycloalkyl, cycloalkyloxy, phenoxy group or phenyl at ω-chain end, and the chain here is shorter than former PG.
The used concrete prostaglandin compound of the present invention is the compound with formula (I) representative:
Figure S2006800172054D00121
Wherein, L, M, N, A, B, Z, R1With as described above identical of Ra.
The used preferred compound of the present invention is the compound of formula (II) representative:
Figure S2006800172054D00122
Wherein, L and M are hydrogen atom, hydroxyl, halogen, low alkyl group, hydroxyl (rudimentary) alkyl, low-grade alkane acidyl oxygen base or oxo base, and wherein at least one is the group outside the dehydrogenation among L and the M, and five-membered ring can have one or more pairs of keys;
A is-CH3Perhaps-CH2OH、-COCH 2OH ,-COOH or its functional derivatives;
B be singly-bound ,-CH2-CH 2-、-CH＝CH-、-C≡C-、-CH 2-CH 2-CH 2-、- CH＝CH-CH 2-、-CH 2-CH＝CH-、-C≡C-CH 2-or-CH2-C≡C-；
Z is
Figure S2006800172054D00123
Perhaps singly-bound;
Wherein, R 4And R 5Be hydrogen, hydroxyl, halogen, low alkyl group, lower alkoxy or hydroxyl (rudimentary) alkyl, wherein R 4And R 5Be not hydroxyl and lower alkoxy simultaneously;
X 1And X 2Be hydrogen, low alkyl group or halogen;
R 1Be saturated or unsaturated bivalent lower or intermediate aliphatic hydrocarbon residue, it is unsubstituted or is replaced by halogen, alkyl, hydroxyl, oxo base, aryl or heterocyclic group, and at least one carbon atom is optional in the aliphatic hydrocarbon is replaced by oxygen, nitrogen or sulfur;
R 2Be singly-bound or low-grade alkylidene; And
R 3Be low alkyl group, lower alkoxy, low-grade alkane acidyl oxygen base, ring (rudimentary) alkyl, ring (rudimentary) alkoxyl, aryl, aryloxy group, heterocyclic radical or heterocycle-oxygen base; Condition is X 1And X 2One of replaced by halogen, perhaps Z is C=O.
In following formula, R 1Mean with term " unsaturated " in the Ra definition and to comprise at least one or a plurality of pairs of keys and/or triple bond, isolated, separately or continued presence between the carbon atom of main chain and/or side chain.According to conventional nomenclature, the unsaturated bond between two continuous positions represents by the low numbering that indicates these two positions, and the unsaturated bond between two terminal positions is represented by indicating these two positions.
Term " rudimentary or intermediate aliphatic hydrocarbon " is meant have 1 to 14 carbon atom (for side chain, preferred 1 to 3 carbon atom), preferred 1 to 10 carbon atom, particularly the straight or branched alkyl of 1 to 8 carbon atom.
Term " halogen atom " comprises fluorine, chlorine, bromine and iodine.
Term in the whole description " rudimentary " comprises the group with l to 6 carbon atom, except as otherwise noted.
Term " low alkyl group " is meant the straight or branched saturated hydrocarbyl that contains 1 to 6 carbon atom, and comprises for example methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, amyl group and hexyl.
Term " low-grade alkylidene " is meant the straight or branched divalent saturated hydrocarbon base that contains 1 to 6 carbon atom, and comprises for example methylene, ethylidene, propylidene, isopropylidene, butylidene, isobutylidene, the inferior tert-butyl group, pentylidene and hexylidene.
Term " lower alkoxy " is meant low alkyl group-O-group, wherein as above defined of low alkyl group.
Term " hydroxyl (rudimentary) alkyl " is meant the low alkyl group of the as above defined that is replaced by at least one hydroxyl, for example methylol, 1-ethoxy, 2-ethoxy and 1-methyl isophthalic acid-ethoxy.
The group that term " low-grade alkane acidyl oxygen base " the formula RCO-O-of being meant represents, wherein RCO-is the low alkyl group oxidation of as above defined and the acyl group that forms, for example acetyl group.
Term " ring (rudimentary) alkyl " is meant by the as above low alkyl group of the defined annular group that (comprising 3 or a plurality of carbon atom), cyclisation formed, comprises for example cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl.
Term " ring (rudimentary) alkoxyl " is finger ring (rudimentary) alkyl-O-group, and its medium ring (rudimentary) alkyl is defined as above.
Term " aryl " can comprise the aromatic hydrocarbon ring (preferred monocyclic groups) that does not replace or replace, for example, and phenyl, tolyl, xylyl.Substituent example is halogen atom and halo (rudimentary) alkyl, wherein as above defined of halogen atom and low alkyl group.
The group that term " aryloxy group " the formula ArO-of being meant represents, wherein Ar is the as above aryl of defined.
Term " heterocyclic group " can comprise 5 to 14 yuan, monocycle to three ring of preferred 5 to 10 yuan of rings, preferred monocyclic heterocyclic group, described ring have the optional carbon atom that replaces and 1 to 4, preferred 1 to 3 a kind or 2 kinds of hetero atom that are selected from nitrogen-atoms, oxygen atom and sulphur atom.The example of heterocyclic radical comprises furyl, thienyl, pyrrole radicals,  azoles base, different  azoles base, thiazolyl, isothiazolyl, imidazole radicals, pyrazolyl, furazan base (furazanyl), pyranose, pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl, the 2-pyrrolinyl, pyrrolidinyl, the 2-imidazolinyl, imidazolidinyl, the 2-pyrazolinyl, pyrazolidinyl, piperidino (piperidino), piperazinyl, morpholino, indyl, benzothienyl, quinolyl, isoquinolyl, purine radicals, quinazolyl, carbazyl, acridinyl, phenanthridinyl, benzimidazolyl, the benzimidazoline base, benzothiazolyl, phenothiazinyl.Substituent in this case example comprises the low alkyl group that halogen and halogen replace, and wherein halogen atom and low alkyl group are as mentioned above.
The group that term " heterocycle-oxygen base " the formula HcO-of being meant represents, wherein Hc-is aforesaid heterocyclic group.
" functional derivatives " of term A comprises salt (preferred pharmaceutically acceptable salt), ether, ester and amide.
Suitable " pharmaceutically acceptable salt " comprises habitual non-toxic salt class, 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; The perhaps salt of organic base, for example amine salt (for example methylamine salt, dimethyl amine salt, cyclohexylamine salt, benzylamine salt, piperidinium salt, ethylenediamine salt, ethanolamine salt, diethylate, 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 with conventional method, for example exchange from corresponding bronsted lowry acids and bases bronsted lowry or by salt to prepare.
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); And 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 (linolenyl) ether; Light alkene base ether, for example vinyl ethers, allyl ether; Low-grade alkynyl ether, for example acetenyl ether and propinyl 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 benzyl ether, trityl ether and dibenzyl ether.
The example of ester comprises aliphatic ester, for example lower alkyl esters (for example methyl ester, ethyl ester, propyl diester, isopropyl esters, butyl ester, isobutyl, tertiary butyl ester, amyl group ester and 1-cyclopropyl ethyl ester); Low-grade alkenyl ester, for example vinyl esters and allyl ester; Low-grade alkynyl ester, for example acetenyl ester and propinyl ester; Hydroxyl (rudimentary) Arrcostab, for example hydroxyethyl ester; Lower alkoxy (rudimentary) Arrcostab, for example methoxymethyl ester and 1-methoxy ethyl ester; And the optional aryl ester that replaces, for example phenylester, tolyl ester, 1-butyl phenyl ester, salicyl ester, 3,4-two-methoxyphenyl ester and benzoylamino phenyl ester; And aryl (rudimentary) Arrcostab, for example benzyl esters, trityl ester and benzhydryl ester.
The amide of A is meant formula-CONR ' R " expression group; wherein R ' and R " respectively are hydrogen, low alkyl group, aryl, alkyl-sulfonyl or aryl-sulfonyl, low-grade alkenyl and low-grade alkynyl, 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; And alkyl-or aryl-sulfonamide, for example sulfonyloxy methyl amine, ethyl sulfonamide and toluenesulfonamide.
The preferred example of L and M comprises hydrogen, hydroxyl and oxo base, and especially, M is a hydroxyl, and L is the oxo base, and it has so-called PGE type five-membered ring structure.
The preferred example of A is-COOH, its pharmaceutically acceptable salt, ester or amide.
X 1And X 2Preferred example be all to be halogen atom, fluorine atom more preferably, so-called 16,16-difluoro type.
Preferred R 1Be to contain 1 to 10 carbon atom, the hydrocarbon residue of preferred 6 to 10 carbon atoms.In addition, at least one carbon atom is optional in the aliphatic hydrocarbon is replaced by oxygen, nitrogen or sulfur.R 1Example comprise for example following group:
-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-。
Preferred Ra contains 1 to 10 carbon atom, the more preferably hydrocarbon of 1 to 8 carbon atom.Ra can have one to two side chain with 1 carbon atom.
The most preferred embodiment of prostaglandin compound is 13,14-dihydro-15-ketone-16,16-two fluoro-prostaglandin E 1Perhaps 13,14-dihydro-15-ketone-16,16-two fluoro-18-methyl-prostaglandin E 1
Ring among following formula (I) and (II) and α-and/or the conformation of ω-chain can be identical with the conformation of former PG or different.Yet the present invention also comprises the chemical compound with prototype conformation and the mixture of non-prototype conformation chemical compound.
In the present invention, be to be that (=O) PG chemical compound forms hemiacetal between can be by the ketone 11 hydroxyl and 15 to ketone, is in the keto-hemiacetal equilibrium on dihydro and 15 between 13 and 14.
For example, have been found that and work as X 1And X 2All be halogen atom, particularly during fluorine atom, this chemical compound comprises tautomer, dicyclic compound.
If above-mentioned tautomer exists, the ratio of two kinds of tautomers changes along with the structure of molecule other parts or existing substituent kind.Sometimes, can there be a kind of main isomer (for another kind of isomer).Yet, it should be understood that to the present invention includes two kinds of isomers.
In addition, the used 15-ketone-PG chemical compound of the present invention comprises dicyclic compound and analog or its derivant.
Dicyclic compound is represented by formula (III):
Figure S2006800172054D00171
Wherein, A is-CH 3Perhaps-CH 2OH ,-COCH 2OH ,-COOH or its functional derivatives;
X 1' and X 2' be hydrogen, low alkyl group or halogen;
Y is
Or
Figure S2006800172054D00182
Wherein, R 4' and R 5' be hydrogen, hydroxyl, halogen, low alkyl group, lower alkoxy or hydroxyl (rudimentary) alkyl, wherein R 4' and R 5' be not hydroxyl and lower alkoxy simultaneously.
R 1Be saturated or undersaturated bivalent lower or intermediate aliphatic hydrocarbon residue, it is unsubstituted or is replaced by halogen, alkyl, hydroxyl, oxo base, aryl or heterocyclic group, and at least one carbon atom is optional in the aliphatic hydrocarbon is replaced by oxygen, nitrogen or sulfur; And
R 2' be saturated or unsaturated rudimentary or intermediate aliphatic hydrocarbon residue, this aliphatic hydrocarbon residue is unsubstituted or is replaced by halogen, oxo base, hydroxyl, low alkyl group, lower alkoxy, low-grade alkane acidyl oxygen base, ring (rudimentary) alkyl, ring (rudimentary) alkoxyl, aryl, aryloxy group, heterocyclic group or heterocycle-oxygen base; Lower alkoxy; Low-grade alkane acidyl oxygen base; Ring (rudimentary) alkyl; Ring (rudimentary) alkoxyl; Aryl; Aryloxy group; Heterocyclic group; Heterocycle-oxygen base.
R 3' be hydrogen, low alkyl group, ring (rudimentary) alkyl, aryl or heterocyclic group.
In addition, although compound used therefor of the present invention can represent by formula or title based on the ketone type, and, it is to be noted that this structure or title are not to get rid of hemiacetal type chemical compound no matter whether have isomer.
In the present invention, can use any isomer, for example independent tautomer and composition thereof or optical isomer and composition thereof, racemic mixture, and other steric isomer for same purpose.
Some used chemical compounds of the present invention can pass through United States Patent (USP) the 5th, 073, No. 569, the 5th, 166, No. 174, the 5th, 221, No. 763, the 5th, 212, No. 324, the 5th, 739, No. 161 and the 6th, the preparation of method described in 242, No. 485 (these lists of references of quoting are incorporated this paper by reference into).
According to the present invention, can give the above-mentioned prostaglandin compound of patient and treat the mammalian subject membrane disease.This patient can be any mammalian subject that comprises the people.This chemical compound can whole body or topical application.Usually, this chemical compound can give by modes such as oral administration, intravenous injection (comprise and inculcating), subcutaneous injection, drop rectum with drug, intravaginal administration, transdermal administrations.
Dosage can change along with type of animal, age, body weight, the symptom of receiving treatment, expection therapeutic effect, route of administration, treatment phase etc.By with 0.001 to 1000 microgram, more preferably the dosage whole body in 0.01 to 100 microgram active component/kg body weight/sky gives active component 1 to 4 time/day or gives active component continuously, can obtain satisfied effect.
The Pharmaceutical composition that can preferably give with suitable usual manner is made into preparation with prostaglandin compound.Said composition can be those suitable oral administrations, injection or dabbling compositions, can also be external preparation, suppository or vaginal suppository.
The present composition can also comprise the physiology and go up acceptable additive.Described additive can comprise excipient, diluent, filler, solvent, lubricant, adjuvant, binding agent, disintegrating agent, coating agent, encapsulation agents (cupsulating agent), ointment substrate, suppository base, propellant (aerozoling agent), emulsifying agent, dispersant, suspending agent, thickening agent, tonicity agent, buffer agent, smoothing preparation, antiseptic, antioxidant, correctives, aromatic, coloring agent, functional materials (for example cyclodextrin and Biodegradable polymeric and stabilizing agent).These additives are known for the present technique field, and can be selected from the additive described in the pharmacy handbook usually.
The amount of above-mentioned prostaglandin compound can change along with the prescription of compositions in the present composition, can be 0.000001 to 10.0% usually, and more preferably 0.00001 to 5.0%, most preferably 0.0001 to 1%.
The example of oral administration solid composite comprises tablet, lozenge, sublingual tablet, capsule, pill, powder, granule etc.Solid composite can prepare by one or more active component are mixed with at least a non-activated thinner.Said composition can also comprise the additive except that non-activated thinner, for example, and lubricant, disintegrating agent and stabilizing agent.If necessary, tablet and pill can carry out coating with intestinal or gastrointestinal thin film, and they can cover two-layer or multilamellar.They can also comprise lasting material, the perhaps microencapsulation of discharging.In addition, said composition can be wrapped in the capsule with the material (as gel) of degraded easily.They can also be dissolved in appropriate solvent, for example fatty acid or its are single, double or triglyceride to make soft capsule.When sublingual tablet needing can be used for quick acting character.
The example of oral administration fluid composition comprises Emulsion, solution, suspension, syrup and elixir etc.Described compositions can also comprise habitual non-activated thinner, for example purified water or ethanol.Said composition can comprise the additive except that non-activated thinner, for example adjuvant (as wetting agent and floatation agent), sweeting agent, spice, aromatic and antiseptic.
The present composition can be the form of spray composite, and it comprises one or more active component, and can prepare according to known method.
The example of the Injectable composition of the present invention of parenteral comprises sterile aqueous or non-aqueous solution, suspension and Emulsion.The diluent that is used for aqueous solution or suspension can comprise, for example, and distilled water for injection, normal saline and Ringer ' s solution.
The non-aqueous diluent that is used for solution and suspension can comprise, for example, and the vegetable oil of propylene glycol, Polyethylene Glycol, for example olive oil, for example alcoholic acid alcohols and polysorbate.Said composition can also comprise additive, for example antiseptic, wetting agent, emulsifying agent, dispersant etc.They can perhaps pass through gas or radiosiotope radiation sterilization by through for example antibacterial-reservation filter filtration sterilization.Injectable composition can also provide as the sterilized powder compositions, is dissolved in the Injectable sterile solvent before use.
This external preparation comprise the external preparation of the dermatology that is useful on and otolaryngology, it comprises ointment, cream, lotion and spraying.
Another kind of form of the present invention is suppository or vaginal suppository, they can be by with active component and conventional substrate (for example, remollescent cacao butter under body temperature) mixing prepares, and non-ionic surface active agent (having suitable softening temperature) can be used for improving absorbability.
Terminology used here " treatment " or " processing " comprise any control methods, for example prevent, nursing, mitigate the disease, weaken the state of an illness and control development.
According to the present invention, formula (I) prostaglandin compound causes the conformational change at tight contact place, thereby recovers mucosal barrier function.Therefore, used here prostaglandin compound is used for the treatment of membrane disease.
Used here term " membrane disease ' ' be meant with mucosal barrier function and reduce relevant disease.This disease relevant with the mucosal barrier function reduction can be any mucosa injury that any pathological factor causes.This factor including, but not limited to, for example inflammation, ischemia injury, shock, pressure, to antigenic immunoreation disorders, infectious disease, intestinal diseases, collagen diseases, radiation, medicine etc.Preferred example comprises the gastrointestinal mucosa disease.
The gastrointestinal mucosa disease including, but not limited to, for example, ischemia injury (strangulated intestinal obstruction for example, as intestinal twisted (vovulus)), acute or chronic mesenteric ischemia damage, intestinal ischemia, the intestinal barrier injury, mucosa injury (for example mucosa injury of suffering a shock and causing), inflammatory bowel (for example Crohn ' s disease), colitis comprises ulcerative colitis, ischemic colitis, proctitis ulcerosa, the ulcer proctosigmoiditis, lymphocyte colitis, intractable DC inflammation, ileocolitis, collagenous colitis, microscope colitis, capsulitis (pouchitis), radiation colitis, antibiotic dependency colitis and diverticulitis, and Behcet disease (Behcet disease).
Here used chemical compound also is used for the treatment of the multiple organ failure that the internal organs hypoperfusion causes, and the forfeiture of the intestinal barrier characteristics that causes thus.
As mentioned above, mucosa tight contact function reduction or forfeiture and many cancers have crucial relation, and therefore, the disease that mucosal barrier function reduces comprises cancer or premalignant disease on the other hand.
Here used cancer or premalignant disease including, but not limited to, esophageal carcinoma, gastroesophageal reflux disease, Barrett esophagus, gastric cancer, duodenal carcinoma, carcinoma of small intestine, vermiform appendix cancer, colorectal cancer, colon cancer, rectal cancer, anus cancer, cancer of pancreas, hepatocarcinoma, carcinoma of gallbladder, spleen cancer, renal carcinoma, bladder cancer, carcinoma of prostate, carcinoma of testis, uterus carcinoma, ovarian cancer, breast carcinoma, pulmonary carcinoma and thyroid carcinoma.
Here used chemical compound also be used for the treatment of based on or with the infection of above-mentioned membrane disease of giving an example.
Pharmaceutical composition of the present invention also can comprise other pharmaceutical component, and condition is that they do not contradict with the object of the invention.
Further details of the present invention will be described with following embodiment, yet, do not want to limit the present invention with this.
Embodiment 1
(method)
The laboratory animal surgical operation
With the stable breedings separately of big Yorkshire cross-bred pigs (regardless of sex) of 6 to 8 weeks, and with commercially available ball shape forage feed.The experiment operation was not taken food to pig in preceding 24 hours.With xylazine (1.5 mg/kg, IM), ketamine (11 mg/kg, IM) and thiopental (15 mg/kg IV) cause general anesthesia, and keep and intermittently import thiopental (6 to 8 mg/kg/hour).Pig is placed on the heating cushion, and leads to 100% oxygen through tracheotomy with time circulation aeration equipment.Conduit is inserted jugular vein and carotid artery, and the promoting the circulation of blood liquid gas analysis of going forward side by side is to prove conclusively the dividing potential drop of normal pH and carbon dioxide and oxygen.Vein gives lactate Ringer ' s solution, keep 15 ml/kg/hour speed.Through the ventrimeson otch near ileum.With 10 centimetres of interval ligation small intestinals, be separated out ileal segment, inaccessible local mesentery blood supply caused ischemia in 45 minutes.
You Si chamber (Ussing chamber) research
45 minutes ischemias are collected the tissue of pig after the period, and at the Ringer ' s solution (mmol/l:Na that leads to oxygen (95% oxygen/5% carbon dioxide) +, 154; K +, 6.3; Cl -, 137; HCO 3 -, 24; PH 7.4) in, mucosa to be peeled off from serous coat sarolemma layer, Ringer ' s solution comprises 5 * 10 -6The M indomethacin is in case produce endogenous PG during the strip step.Then, tissue is contained in the You Si chamber in 3.14 square centimeters of holes.For the test of You Si chamber, will be contained in from the ileum tissue of a pig on a plurality of You Si chamber, and experience different extracorporeal treatment.Soak tissue with 10 milliliters of Ringer ' s solution in serosa side and mucosa side.The serous coat soaking solution comprises the glucose of 10mM, and carries out Osmotic balance with 10mM mannitol in mucosa one side.Soaking solution is handled with oxygen (95% oxygen/5% carbon dioxide), and circulates in water jacket storage storehouse.Measure self power generation potential difference (PD) with the Ringer-agar bridge that is connected on the calomel electrode, use the gauged voltage folder of fluid resistance, make the PD short circuit by the Ag-AgCl electrode.By self power generation potential difference and short circuit current (I Sc) calculating transepithelial electrical resistance (ω .cm 2).If the self power generation potential difference is-1.0 to 1.0 millivolts, organize electric current to press from both sides for 5 seconds so with ± 100 microamperes, and the record potential difference.In 4 hours experiment, first short circuit electric current and potential difference were write down in the interval in per 15 minutes.
Experiment is handled
Tissue is contained in after the You Si chamber, makes it adapt to 30 minutes to obtain stable base line measurement.By chemical compound being added the mucosa soaking solution, handle tissue (t=30 minute) then with the compd A (13,14-dihydro-15-ketone-16,16-two fluoro-PGE1) (0.01 μ M, 0.1 μ M and 1 μ M) of various dose.
3The research of H-mannitol flow
Carry out these researchs in the time of record electrical measurement result.In order to estimate mucosa-to-serous coat flow, will 3H-mannitol adds mucosa solution.After 15 minutes balance period, take standard substance from soaking the storage storehouse.Add to handle back 30 minutes, and added the offside of a side, from soak the storage storehouse, take a sample, carry out three flow phases of successive 60 minutes (experiment the 30th to 210 minute) and measure at isotope.With liquid scintillation counter to sample 3H-mannitol counting.Measure unidirectional mucosa-with normal equation to-serous coat (Jms) flow.
Histological examination
In the time of 0,60 and 180 minute, take to organize the Histological assessment that carries out routine.With tissue slice (5 microns), and with the dyeing of hematoxylin (hematoxylin) and eosin.For each tissue, assess 3 parts of sections.In each section, identify the fine hair and the crypts of 4 good orientations.Under the optical microphotograph eye-lens of the eyepiece, record villus length with micrometer.In addition, measure the height of the epithelium cover part of each fine hair.Calculate the surface area of fine hair with the long-pending formula of periphery.By deducting the area of fine hair bottom, and multiply by, this formula has been carried out revising (gastroenterology (Gastroenterology) 1993 because of the different factors that cause of each fine hair cross-section location; 104:440-471).By the total surface area of fine hair and the fine hair surface area that is covered with epithelium, calculate the percent of the fine hair surface area that keeps exposed.The index that exposed fine hair surface area percent recovers as epithelium.
Statistical analysis
With meansigma methods ± standard error report data.For repeated measure, (ANOVA) analyzes all data with variance analysis, but (San Rafael CA) analyzes peak response for Sigmastat, Jandel Scientific with the one way analysis of variance (one-wayANOVA) of standard.After the variance analysis, use the next difference of determining between the processing of Tukey ' s check.
(result)
To the short circuit current that passes ischemic injuries pig ileum and the influence of transepithelial electrical resistance
The mesentery ischemia that the pig ileum was stood 45 minutes is contained on the You Si chamber then, to its short circuit current (I Sc) (be Cl -Excretory indication) and transepithelial electrical resistance (TER) (being the indication of mucosal barrier function) estimate.Intestinal ischemia caused transepithelial electrical resistance (TER) decline 40% (comparing with non-ischemic control tissue) in 45 minutes, showed that the barrier function of ischemic tissue is weakened.Add the compd A (Fig. 1) of 0.01 μ M, 0.1 μ M and 1 μ M to mucosa one side of ischemic injuries mucosa, causing TER to be dose dependent increases, and the compd A of 1 μ M stimulates TER to produce twice and increases (Δ TER=26 Ω .cm 2, P＜0.01).
Compd A to ischemia mucosal use 0.1 μ M and 1 μ M impels short circuit current (I Sc) peak sharp-pointed and remarkable (P＜0.05) appears, be dose dependent, show the Cl that has promoted to produce in these tissues electricity -Secretion.Assessing compd A to short circuit current (I Sc) absolute change is (for the compd A of 1 μ M, 0.1 μ M and 0.01 μ M, Δ I ScDuring influencing=29 ± 5.1,16 ± 4.5 and 2 ± 0.8), observe similar dose response.I ScRising increases prior to TER.
For the influence of the mucosa of mannitol in the pig ileum of ischemic injuries to the serous coat flow
Because show 3The mucosa of H-mannitol to serous coat flow is the sensitive indicator of mucosal barrier function, so the ischemic injuries mucosa is passed in our measurement 3H-mannitol flow is to determine the TER value.Ischemic injuries causes the mannitol flow significantly to increase (comparing with non-damage control tissue (Fig. 3)), shows the barrier function damage of ischemic tissue.The compd A of using 1 μ M causes 3H-mannitol flow turns back to non-ischemic control level.
The Histological evaluation of the ischemic tissue that handles with compd A
The acute recovery of damage mucosal barrier function comprises 3 kinds of synergistic mechanisms: (1) fine hair shrinks, and reduces total exposed surface area of repairing, (2) recover or cell migration with the basement membrane of seal exposed, and other space of (3) cell and tight closing of contact.Whether part is recovered owing to enhanced epithelium for the improvement of determining the barrier function that the response compd A is handled, we convalescent period several time points the ischemic tissue between convalescent period has been carried out Histological evaluation.The histologic analysis of damaged tissue shows that the enteric epithelium at fine hair top 1/3 comes off with wrinkling.This has this result of 30% exposed surface area to be associated with the epithelium that shows with morphometric analysis (table 1).In 60 minutes, tissue is contained on the You Si chamber, intestinal villus has experienced fast and has recovered completely.
The somatometry of physique assessment that the pig ileal mucous membrane epithelium of table 1. ischemic injuries recovers
Handle Recovery time (minute) Exposed epithelial surface long-pending (%) Height of naps (millimeter)
Non-ischemic control 0 0±0 ?0.16±0.02 *
Ischemia 0 30.2±4.7 ?0.10±0.01
Ischemia/indomethacin 60 ?6.6±2.6 * 0.16±0.01 *
Ischemia/indomethacin/compd A 60 ?4.2±2.5 * 0.21±0.02#
Ischemia/indomethacin 180 ?0±0 ** 0.14±0.03 *
Ischemia/indomethacin/compd A 180 ?0±0 ** 0.20±0.01#
In the table 1, exposed fine hair surface area % and height of naps value are represented with meansigma methods ± standard error; N=3.Tissue is mammiferous ileum, and it is contained in them then in the You Si chamber and recovers response with monitoring through ischemia in 45 minutes bodies.Behind the ischemia in external recovery stage, obtained tissue in 0 minute, 60 minutes and 180 minutes, fixing in 10% buffered formalin, and according to the standard scheme processing, for histological examination.Give the indomethacin (Indo) of 5 μ M to selected tissue, and add the compd A of 1 μ M.Lack common subscript ( *, numerical value #) there are differences, P＜0.05.
Embodiment 2
According to embodiment 1 described same step, use colon rather than ileum, after having studied compd A and handling, the recovery of mucosal barrier function under the ischemia condition.
Fig. 4 to 6 has shown A respectively) the ischemic injuries pig goes up in the ascending colon variation corresponding to the short circuit current of compd A, B) the ischemic injuries pig goes up in the ascending colon transepithelial electrical resistance (TER) corresponding to compd A, and C) the ischemic injuries pig goes up in the ascending colon serous coat corresponding to compd A to mucosa 3H-mannitol flow.
Compd A is applied to the ischemia pig goes up ascending colon, increased Isc (Fig. 4) and TER, and reduced 3H-mannitol serous coat is to mucosa flow (Fig. 5 and Fig. 6).
Conclusion
These data show that ClC-2 agonist (compd A) stimulates Cl -Secretion, thereby the mucosal barrier function of recovery ischemic injuries pig ileum and colon.In addition, compd A is to the beneficial effect of mucosal barrier function, demonstrates to reduce by the other permeability of cell to mediate, and do not rely on epithelium and recovers.These observed results show that ClC-2 agonist (compd A) causes tight contact conformational change, thereby recover barrier function.The selective agonist of ClC-2 can provide new pharmacology mode, promotes the recovery of acute injury intestinal.
Embodiment 3
Female CrI:CD (SD) IGS BR VAF/Plus rat is divided into 4 seminar (65 every group).Group 2 to group 4 gives 20,100 or the compd A of 400 micrograms/kg/day respectively, oral raising by force for 104 weeks.Matched group (group 1) gives excipient (aqueous solution of 1% polysorbate80).The dose volume of all groups is 5 ml/kg/skies.When the irregular death of animal takes place during the research, animal is dissected.After handling in 104 weeks, put to death all surviving animals and dissection.Whether every Mus breast carcinoma occurs with microscopy.
As shown in table 2, compd A has reduced the sickness rate of breast carcinoma.
The sickness rate of table 2. breast carcinoma
Group Dosage microgram/kg/day The size of animal of checking The size of animal that suffers from breast cancer
1. contrast (excipient) ?0 ?65 ?12
2. compd A ?20 ?65 ?6
3. compd A ?100 ?65 ?5
4. compd A ?400 ?63 ?4
Though with reference to its specific embodiment the present invention has been made detailed description,, can carry out various changes and modification to the present invention and do not break away from the spirit and scope of the present invention, this is apparent for those skilled in the art.

Claims (27)

1. the prostaglandin compound of following general formula (I) expression is used for the purposes of the Pharmaceutical composition of production for treating mammalian subject membrane disease:
Figure S2006800172054C00011
Wherein L, M and N are hydrogen atom, hydroxyl, halogen atom, low alkyl group, hydroxyl (rudimentary) alkyl, low-grade alkane acidyl oxygen base or oxo base, and wherein at least one is the group outside the dehydrogenation among L and the M, and five-membered ring can have at least one two key;
A is-CH 3Perhaps-CH 2OH ,-COCH 2OH ,-COOH or its functional derivatives;
B be singly-bound ,-CH 2-CH 2-,-CH=CH-,-C ≡ C-,-CH 2-CH 2-CH 2-,-CH=CH-CH 2-,-CH 2-CH=CH-,-C ≡ C-CH 2-or-CH 2-C ≡ C-;
Z is
Figure S2006800172054C00012
Perhaps singly-bound;
Wherein, R 4And R 5Be hydrogen, hydroxyl, halogen, low alkyl group, lower alkoxy or hydroxyl (rudimentary) alkyl, wherein R 4And R 5Be not hydroxyl and lower alkoxy simultaneously;
R 1Be saturated or undersaturated bivalent lower or intermediate aliphatic hydrocarbon residue, it is unsubstituted or is replaced by halogen, alkyl, hydroxyl, oxo base, aryl or heterocyclic radical, and at least one carbon atom is optional in the aliphatic hydrocarbon is replaced by oxygen, nitrogen or sulfur; And
Ra is saturated or undersaturated rudimentary or intermediate aliphatic hydrocarbon residue, and this aliphatic hydrocarbon residue is unsubstituted or is replaced by following group: halogen, oxo base, hydroxyl, low alkyl group, lower alkoxy, low-grade alkane acidyl oxygen base, ring (rudimentary) alkyl, ring (rudimentary) alkoxyl, aryl, aryloxy group, heterocyclic radical or heterocycle-oxygen base; Lower alkoxy; Low-grade alkane acidyl oxygen base; Ring (rudimentary) alkyl; Ring (rudimentary) alkoxyl; Aryl; Aryloxy group; Heterocyclic radical; Heterocycle-oxygen base, condition are that Ra is replaced by halogen, and perhaps Z is C=O.
2. the purposes of claim 1, wherein said prostaglandin compound are the single or two halogens-prostaglandin compounds of 16-.
3. the purposes of claim 1, wherein said prostaglandin compound is 15-ketone-prostaglandin compound.
4. the purposes of claim 1, wherein said prostaglandin compound is 13, the single or two halogens-prostaglandin compound of 14-dihydro-16-.
5. the purposes of claim 1, wherein said prostaglandin compound is 13,14-dihydro-15-ketone-prostaglandin compound.
6. the purposes of claim 1, wherein said prostaglandin compound is 13, the single or two halogens-prostaglandin compound of 14-dihydro-15-ketone-16-.
7. the purposes of claim 1, wherein said prostaglandin compound is 13, the single or two fluoro-prostaglandin compounds of 14-dihydro-16-.
8. the purposes of claim 1, wherein said prostaglandin compound are the single or two fluoro-prostaglandin compounds of 15-ketone-16-.
9. the purposes of claim 1, wherein said prostaglandin compound is 13, the single or two fluoro-prostaglandin compounds of 14-dihydro-15-ketone-16-.
10. the purposes of claim 1, wherein said prostaglandin compound is 13, the single or two halogens-prostaglandin E compound of 14-dihydro-16-.
11. the purposes of claim 1, wherein said prostaglandin compound are 15-ketone-16-list or two halogens-prostaglandin E compounds.
12. the purposes of claim 1, wherein said prostaglandin compound is 13, the single or two halogens-prostaglandin E compound of 14-dihydro-15-ketone-16-.
13. the purposes of claim 1, wherein said prostaglandin compound is 13,14-dihydro-16,16-two fluoro-prostaglandin E 1Chemical compound.
14. the purposes of claim 1, wherein said prostaglandin compound is 13,14-dihydro-15-ketone-prostaglandin E 1Chemical compound.
15. the purposes of claim 1, wherein said prostaglandin compound is 13,14-dihydro-15-ketone-16,16-two fluoro-prostaglandin E 1Chemical compound or 13,14-dihydro-15-ketone-16,16-two fluoro-18-methyl-prostaglandin E 1Chemical compound.
16. each purposes in the claim 1 to 15, wherein said membrane disease are to reduce relevant disease with mucosal barrier function.
17. the purposes of claim 16, the wherein said disease relevant with the mucosal barrier function reduction is gastrointestinal tract mucous disease.
18. the purposes of claim 17, wherein said gastrointestinal tract mucous disease is an inflammatory bowel.
19. the purposes of claim 18, wherein said inflammatory bowel are Crohn disease, colitis or Behcet disease.
20. the purposes of claim 19, wherein said colitis are selected from ulcerative colitis, ischemic colitis, proctitis ulcerosa, ulcer proctosigmoiditis, lymphocyte colitis, intractable DC inflammation, ileocolitis, collagenous colitis, microscope colitis, capsulitis, radiation colitis, antibiotic dependency colitis and diverticulitis.
21. the purposes of claim 16, the wherein said disease relevant with the mucosal barrier function reduction is cancer or worsens preceding disease.
22. the purposes of claim 16, disease is selected from esophageal carcinoma, gastroesophageal reflux disease, Barrett esophagus, gastric cancer, duodenal carcinoma, carcinoma of small intestine, vermiform appendix cancer, colorectal cancer, colon cancer, rectal cancer, anus cancer, cancer of pancreas, hepatocarcinoma, carcinoma of gallbladder, spleen cancer, renal carcinoma, bladder cancer, carcinoma of prostate, carcinoma of testis, uterus carcinoma, ovarian cancer, breast carcinoma, pulmonary carcinoma and thyroid carcinoma before wherein said cancer or the deterioration.
23. the purposes that the prostaglandin compound of following general formula (I) expression is used to produce the Pharmaceutical composition of protecting the mammalian subject mucosa:
Figure S2006800172054C00031
Wherein, L, M, N, A, B, Z, R 1Described in Ra such as claim 1.
24. a method for the treatment of the mammalian subject membrane disease, this method comprise the prostaglandin compound of following general formula (I) expression of the patient's effective dose that needs:
Figure S2006800172054C00041
Wherein, L, M, N, A, B, Z, R 1Described in Ra such as claim 1.
25. a method of protecting the mammalian subject mucosa, this method comprise the prostaglandin compound of following general formula (I) expression of the patient's effective dose that needs:
Figure S2006800172054C00042
Wherein, L, M, N, A, B, Z, R 1Described in Ra such as claim 1.
26. a compositions for the treatment of the mammalian subject membrane disease, said composition comprise the prostaglandin compound of following general formula (I) expression of effective dose:
Figure S2006800172054C00043
Wherein, L, M, N, A, B, Z, R 1Described in Ra such as claim 1.
27. a compositions of protecting the mammalian subject mucosa, said composition comprise the prostaglandin compound of following general formula (I) expression of effective dose:
Figure S2006800172054C00051
Wherein, L, M, N, A, B, Z, R 1Described in Ra such as claim 1.
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CN102448463A (en) * 2009-05-27 2012-05-09 苏坎波公司 Pharmaceutical compositions comprising prostaglandin derivatives for modulating claudin-mediated functions and treating skin disorders
CN102481302A (en) * 2009-09-16 2012-05-30 苏坎波公司 pharmaceutical combination for treating tumors
CN103781482A (en) * 2011-04-19 2014-05-07 苏坎波公司 Method for modulating cytokine activity

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US5380709A (en) * 1987-01-28 1995-01-10 K.K. Ueno Seiyaku Oyo Kenkyujo Prostaglandins E and anti ulcers containing same
US6492417B1 (en) * 1997-12-22 2002-12-10 Alcon Manufacturing, Ltd. 11-deoxy-16-fluoro-PGF2α analogs as FP receptor antagonists
KR20120045051A (en) * 2002-12-27 2012-05-08 수캄포 아게 Derivatives of prostaglandins for treating abdominal discomfort

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Publication number Priority date Publication date Assignee Title
CN102448463A (en) * 2009-05-27 2012-05-09 苏坎波公司 Pharmaceutical compositions comprising prostaglandin derivatives for modulating claudin-mediated functions and treating skin disorders
CN102481302A (en) * 2009-09-16 2012-05-30 苏坎波公司 pharmaceutical combination for treating tumors
CN107050458A (en) * 2009-09-16 2017-08-18 苏坎波公司 Pharmaceutical combination preparations for treating tumour
CN103781482A (en) * 2011-04-19 2014-05-07 苏坎波公司 Method for modulating cytokine activity
CN107028952A (en) * 2011-04-19 2017-08-11 苏坎波公司 Method for adjusting cytokine activity

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