CN1336824A - Use of anti-inflammatory steriods for the treatment of chronic iniflammatory intestinal diseases - Google Patents

Use of anti-inflammatory steriods for the treatment of chronic iniflammatory intestinal diseases Download PDF

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Publication number
CN1336824A
CN1336824A CN98805806A CN98805806A CN1336824A CN 1336824 A CN1336824 A CN 1336824A CN 98805806 A CN98805806 A CN 98805806A CN 98805806 A CN98805806 A CN 98805806A CN 1336824 A CN1336824 A CN 1336824A
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rimexolone
medicine
application
treatment
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J·H·梅杰林克
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Akzo Nobel NV
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Akzo Nobel NV
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Abstract

The invention relates to the use of inflammatory compounds having general formula (I) wherein X is a member of the group consisting of H and halogen; Y is a member of the group consisting of H2, H(OH), H(O(C1-6)Acyl) and O; R1 is a member of the group consisting of H, CH3 and halogen; R2 is (C1-4)Alkyl; R3 is a member of the group consisting of H, O((C1-6)Acyl), O((C1-6)Alkyl) and CH3; R4 is a member of the group consisting of H and (C1-4)Alkyl, and C1-C2 and C6-C7 are saturated or unsaturated bonds, for the manufacture of a medicament for chronic inflammatory colon diseases.

Description

The application of antiinflammatory steroid in treatment chronic infection intestinal tract disease
The present invention relates to the application of therapeutic agent in the medicine of the infectious intestinal tract disease of preparation treatment.
Ulcerative colitis (UC) and Crohn disease are that the inflammation of failing to understand with etiology is the chronic intestinal tract disease of feature, are also referred to as infectious intestinal tract disease (IBD).Environment, heredity and immunology factor are considered to relevant with the etiology of these diseases.Crohn disease is owing to often involve terminal ileum thereby be also referred to as regional enteritis.The most normal descending colon and the sigmoid colon of involving of UC.
These diseases to be worsening and alleviation is characteristics, and it is wall that be interrupted, saturating that the inflammation in the Crohn disease is not involved between zone and the affected areas at normal intestinal, and described wall is meant the holostrome that relates to the intestinal tissue from the mucosa to the serous coat.Because inflammatory process is wall, thus non-adjacent intestinal loop mutually adhesion with develop in bulk, fistula or block.Inflammatory infiltration in the intestinal wall that thickens comprises lymphocyte, macrophage, neutrophilic granulocyte and is approximately containing rheumatic granulomas in the half case.The epithelium of UC is invaded profit and inflammation-inhibiting diffusion by neutrophilic granulocyte usually.The danger that the patient who suffers from ulcerative colitis suffers from colon cancer increases, its initial performance be hemorrhage of rectum, diarrhoea, urgent, generate heat, lose weight and stomachache sometimes.
Existing treatment comprises that use can cause steroid, immunosuppressant and the aminosallcylic acid class of extensive side effect.So far, steroid not only has best whole body (spreading all over) effect at taking in sail property aspect of inflammation, and has significant side effects.
The beneficial effect of glucocorticoid mainly is the antiinflammatory activity that helps them, this antiinflammatory active performance is releasing and activity of inflammatory cytokines and activity before reducing, reduce the generation of A2 phospholipase, 5-lipoxygenase and epoxidase, therefore suppressed the generation of arachidonic acid cascade reaction and prevention Prostaglandins and Leukotrienes.In addition, glucocorticoid has some non-specific antiinflammatory actions.
Yet the application of antiinflammatory steroid is not to be safe from danger.These chemical compounds of life-time service usually cause systemic side effects.One of major side effects is to suppress the hypothalamus pituitary adrenal axis, thereby causes the stress incapability.Therefore, the lesion portion that preferably it is used for the topical therapeutic colon.Like this, just need the developing drugs compositions to avoid systemic side effects.
Main purpose of the present invention provides and is used for topical therapeutic IBD and the pharmaceutical composition of the danger of being free from side effects.
Therefore, the present invention relates to the chemical compound of general formula I:
Figure A9880580600041
Wherein, X is one of H and halogen;
Y is H (OH), H (O (C 1-6One of) acyl group) and O;
R 1Be H, CH 3With one of halogen;
R 2Be (C 1-4) alkyl;
R 3Be H, O ((C 1-6) acyl group), O ((C 1-6) alkyl) and CH 3One of;
R 4Be H or (C 1-4) alkyl and C 1-C 2And C 6-C 7It is saturated or unsaturated bond.
Be used to prepare the medicine of treatment chronic infection intestinal tract disease.
The term acyl group is meant by the deutero-carboxyl groups of the organic carboxyl acid that contains the 1-6 carbon atom, as subscript (C 1-6) indicated.The number of carbon atom is by subscript (C in alkyl group 1-4) or (C 1-6) indication.
United States Patent (USP) 3,947,478 disclose alkylating 3,20-diketone-δ-4 steroid.This patent has been described the preparation method of these chemical compounds, at this its full content is introduced reference.These chemical compounds are described has anti-infection property dermatosis effectiveness.In addition, United States Patent (USP) 4,686,214 have described the ophthalmic applications of same chemical compound.
Special preferred formula I chemical compound, wherein X is H, Y is H (OH), R 1Be H, R 2, R 3And R 4Be CH 3, C 1-C 2Be two keys and C 6-C 7It is singly-bound.This chemical compound is called rimexolone.
Rimexolone is a kind of non-halogenated glucocorticoid, shown in the inductive rabbit simple joint of fibrin arthritis, its suppress arthroncus and behind topical, seldom have system's side effect (clinical pharmacology magazine (J.Clin.Pharm.) (1990) 30,476-679).In case appear in the blood flow, it is by tachymetabolism and drainage.
This chemical compound dissolubility in aqueous medium is extremely low.Oral toxicological experiment shows, the few absorption in the oral back of this chemical compound, and the steroid that does not have in a large number to change is discharged with feces.
Moreover, this chemical compound is comparable to dexamethasone to the effect in intestinal tract disease zone.
Depend on route of administration and formulations employed, this chemical compound has long mean residence time.They have the antiinflammatory action of highly significant and the beneficial effect of long duration.
The compounds of this invention can be used as the medicine that improves mammalian infections intestinal tract disease inflammation.The compounds of this invention is more preferably used in the treatment ulcerative colitis, and mammal more preferably is human.
Formula I chemical compound and based on its pharmaceutical formulations for mucosal inflammation medium such as PGE 2, LTB 4And TXB 2Accumulate and have good result.Therefore The compounds of this invention is suitable for the treatment application of treatment colitis.The present invention provides the method that reduces intestinal chronic inflammatory disease process thus, and described method comprises the chemical compound (more preferably rimexolone) of mammal (more preferably people) being bestowed the general formula I of effective dose.
Every day, dosage can be bestowed by for example oral, rectum or injecting pathway by list or multiple dose unit.Preferably, bestow single dosage unit every day by the rectum approach, perhaps available controlled release preparation discharges required total amount every day.
The pharmaceutical preparation that the present invention uses can according to as standard technique preparation described in the canonical reference book, volumes such as Gennaro, the RemmintonShi pharmaceutical science (Remminton ' sPharmaceutical Sciences), (the 18th edition, Mark publishing company, 1990, as the 8th part: pharmaceutical formulations and manufacturing).(18 thed.Mack?Publishing?Company，1990，e.g.：Part?8：Parmaceutical?Preparations?And?TheirManufacture)。In order to make the purpose of pharmaceutical preparation of the present invention, compound of Formula I, rimexolone, or its officinal salt mixes with pharmaceutically suitable carrier or is dissolved in pharmaceutically suitable carrier, and this examples of formulations is tablet, pill, suppository, (little) capsule, powder, Emulsion, cream, ointment, suspension, solution.
The example of pharmaceutically suitable carrier is: starch (as Rhizoma Solani tuber osi or corn starch), sugar (as lactose), lubricant (as the magnesium stearate), binding agent (as amylopectin or polyvinyl pyrrolidone), water, alcohol, glycerol and derivant thereof, vegetable oil, animal oil and mineral oil and fat, aliphatic alcohol, silicone, poly alkylene glycol, cellulose derivative, silicon dioxide, dispersant, emulsifying agent, surfactant, antioxidant, coloring agent and antiseptic.In fact, the conventional medicine carrier of any not interferon activity composition performance can be used for preparation of the present invention.
Enema agent comprises about 100ml water, buffer agent (as phosphate buffer) and salt (as sodium chloride) usually to obtain neutrality and isosmotic solution.Just in case the dissolubility of this reactive compound is too low so that can not dissolve fully, can a kind of thickening agent (as the cellulose of methylcellulose or as polyvinylpyrrolidone) adds in the suspension and limit sedimentation and degree of agglomeration.Detergent (as polysorbate20) can be used for increasing the availability of tissue to active substance.At last, add antiseptic (oxybenzene formic acid methyl and propyl diester).
The anti-inflammatory property of rimexolone is described in early days, and Rabbit Model has disclosed relevant anti-inflammatory property related to the present invention.
The present invention is illustrated by the following example:
Marginal data:
Fig. 1: the rimexolone in the rabbit colitis model.
Low and the high low and high concentration (as shown in the embodiment 1) that is meant rimexolone.Dex refers to dexamethasone.PGE 2It is prostaglandin E 2TXB 2Be thromboxane B 2
Embodiment 1
Induce colitis
(Janssen Belgium) with body weight 2.5-3kg male New Zealand rabbit (SPF) anesthesia, inserts auricular vein with the 22G sleeve pipe to intramuscular injection 0.4mg/kg hypnotic then.Instill the formalin (0.65% volume/volume) () of 4 milliliters of dilutions at 0 o'clock by the 10Fr feeding tube per rectum of a long 15cm, then (after 2 hours) are through the accumulative rabbit immunoglobulin (10mg/ml of vein (ear vein) infusion 0.85ml heat, in 63 ℃ 20 minutes) (Dako, Denmark).
After inducing colitis 24 hours, after the Hypnorm premedication by intravenous injection 150mg/kg sodium phenobarbital with all sacrifice of animal.Put to death and carried out the rectum dialysis in preceding 2 hours.With diameter 6.3mm, (Medicell Int., London), the Visking Dialysis tubing that fills Rheomacrodex (NBPI, Holland) inserts 18cm and also was detained in position 2 hours long 6cm.After shifting out Dialysis tubing, measure the volume of dialysis solution, and store in-20 ℃, within 24 hours, handle.
Therapeutic scheme
48 rabbits are divided into 4 groups at random.The treatment group: induce preceding 1 hour of colitis and induced back 4 hours and 8 hours, the per rectum application dosage be 10mg/kg (low dose group, N=12) or 40mg/kg (high dose group, rimexolone N=12).Control animal: rectal perfusion 0.9% saline (n=12) or 40mg/kg dexamethasone (n=12).
Collection of specimens and processing
The excision DC is opened and in ice-cold phosphate buffered saline (PBS) the feces cleaning down is fallen.Pass through AmprepC 2And C 8(Amersham, Britain) solid phase column is extracted the thromboxane B in the dialysis solution respectively 2(TXB 2) and prostaglandin E 2(PGE 2).The vacuum drying eluent suspends again, and dilution is also analyzed with Biotrak enzyme-linked immunosorbent assay (Amersham).The lowest detectable limit of these analyses is: TXB 210pg/mg, PGE 220pg/mg.Plate reads with Thermomax plate reader that (Molecular devices USA), uses Softmax software analysis result (Molecular Devices).
The result
Studied the antiinflammatory action of rimexolone during 24 hours.Fig. 1 has shown dialysis solution PGE 2And TXB 2Level.Can draw such conclusion: compare with matched group, the rimexolone treatment has reduced animal PGE 2And TXB 2Level.In addition, effect is dose dependent.Effectiveness during high dose is almost similar to the effectiveness of dexamethasone.
Example 2
Enema is formed:
Rimexolone 10-100mg phosphate buffer transfers to pH7 sodium chloride and oozes methylcellulose 1-2%* polysorbate20 1% MOB 0.15% water 100ml to waiting
*) depend on viscosity grade

Claims (9)

1. compound of Formula I is wherein:
X is one of H and halogen group;
Y is H (OH), H (O (C 1-6One of) acyl group) and the O group;
R 1Be H, CH 3With one of halogen group;
R 2Be (C 1-4) alkyl;
R 3Be H, O ((C 1-6) acyl group), O ((C 1-6) alkyl) and CH 3One of group;
R 4Be H and (C 1-4One of) alkyl, C 1-C 2And C 6-C 7Be saturated or unsaturated bond,
Application in the medicine of preparation treatment chronic infection intestinal tract disease.
2. the application of compound of Formula I in the medicine of preparation treatment Crohn disease.
3. the application of compound of Formula I in the medicine of preparation treatment ulcerative colitis.
4. the application of rimexolone in the medicine of preparation treatment chronic infection intestinal tract disease.
5. the application of rimexolone in the medicine of preparation treatment Crohn disease.
6. the application of rimexolone in the medicine of preparation treatment ulcerative colitis.
7. improve the method for colitis, comprise the compound of Formula I of bestowing the mammal effective dose.
8. improve the method for colitis, comprise the rimexolone of bestowing the mammal effective dose.
9. according to the described method of claim 7-8, wherein mammal is the people.
CN98805806A 1997-06-04 1998-06-02 Use of anti-inflammatory steriods for the treatment of chronic iniflammatory intestinal diseases Pending CN1336824A (en)

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EP97201690 1997-06-04

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AU (1) AU740005B2 (en)
BR (1) BR9809551A (en)
CA (1) CA2290775A1 (en)
HU (1) HUP0003354A3 (en)
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100388919C (en) * 2002-12-24 2008-05-21 爱尔康公司 Use of rimexolone in the treatment of dry eye

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3947478A (en) * 1972-01-12 1976-03-30 Akzona Incorporated Alkylated 3,20-diketo-Δ4 -steroids of the pregnane series
GB1416427A (en) * 1972-01-12 1975-12-03 Akzo Nv Alkylated pregnanes and process for obtaining same
DE3064460D1 (en) * 1979-01-24 1983-09-08 Akzo Nv Novel alkylated pregnanes, processes for their preparation and pharmaceutical compositions containing same
FR2747680B1 (en) * 1996-04-18 1998-07-03 Roussel Uclaf NOVEL STEROIDS, THEIR APPLICATION AS MEDICAMENTS, THEIR PREPARATION PROCESS, THE INTERMEDIATES THEREOF AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100388919C (en) * 2002-12-24 2008-05-21 爱尔康公司 Use of rimexolone in the treatment of dry eye

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HUP0003354A3 (en) 2001-09-28
AU740005B2 (en) 2001-10-25
PL337458A1 (en) 2000-08-14
TR199902812T2 (en) 2000-06-21
CA2290775A1 (en) 1998-12-10
JP2002502409A (en) 2002-01-22
NO995936D0 (en) 1999-12-03
EP0984782A2 (en) 2000-03-15
AU8625298A (en) 1998-12-21
BR9809551A (en) 2000-06-20
WO1998055126A3 (en) 1999-03-11
WO1998055126A2 (en) 1998-12-10
NO995936L (en) 1999-12-03
HUP0003354A2 (en) 2001-03-28

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