WO2009101684A1 - Drug for preventing and/or treating visceral fusion - Google Patents

Abstract

A drug to be systemically administered for preventing and/or treating visceral fusion which contains a compound represented by the following general formula (I) or its salt as the active ingredient: wherein R1 to R5 each represents a hydrogen atom, an alkyl group or an alkylated silyl group; X represents -CONH- or -NHCO-; and A represents a carboxylated aromatic group which may have a substituent or a tropolonyl group which may have a substituent.

Description

Medicament for prevention and / or treatment of visceral adhesions

The present invention relates to a medicament for prevention and / or treatment of visceral adhesion in peritoneal dialysis therapy or adhesive ileus (intestinal obstruction) after surgery.

Adhesion is a biological phenomenon in which tissues or organs that are originally separated medically are joined together to form scar tissue between them. For example, gastroenterology, cardiology, orthopedics, gynecology, or ophthalmology May occur after surgery in each department, or may occur in the form of adhesion between the intestinal walls or adhesion between the intestinal wall and the abdominal wall at the onset of inflammatory bowel disease. Adhesion occurs due to an inflammatory reaction, trauma, surgery, or the like, but is originally considered one of the wound healing processes. However, excessive adhesions cause disorders such as pain, bowel obstruction (ileus), or infertility. In addition, severe adhesions are a factor that complicates re-opening surgery, which is an important medical problem.

As a case different from post-surgical tissue adhesion, intraperitoneal adhesion may be a problem even in patients with peritoneal dialysis (CAPD). This CAPD therapy is a treatment method for patients with renal failure, and its advantage is recognized as one of home medical care. However, when intra-abdominal tissue adhesions, that is, adhesions to the intestinal tract and the abdominal wall, occur as complications, they exhibit advanced passage obstruction in the intestinal tract and further reduce the dialysis effect, so it is unavoidable to discontinue CAPD therapy.

As an approach to avoiding the seriousness of adhesion, an anti-adhesion film (trade name Sepra film) based on polysaccharides (such as hyaluronic acid) has been put into practical use. However, there is a problem that the anti-adhesion film and the polymer polysaccharide solution are expensive. In addition, as pharmacological approaches, methods with the action point of suppression of inflammatory reaction, prevention of blood coagulation, promotion of fibrinolysis, or suppression of fibroblast proliferation are envisaged. The current situation is not applied. Therefore, some kind of pharmacotherapy is strongly desired for an adhesion site such as a serious adhesion or intestinal lumen side, but an inexpensive and effective drug for preventing or treating the adhesion has not been developed. In particular, there is no known drug that can prevent or treat adhesion easily and efficiently by systemically administering the drug orally or parenterally without requiring open surgery or open treatment.

On the other hand, retinoic acid (vitamin A acid) is an active metabolite of vitamin A, and has the effect of differentiating developing immature cells into mature cells with specific functions, cell growth promotion and life support. It has extremely important physiological actions such as. Various vitamin A derivatives synthesized so far, for example, benzoic acid derivatives described in JP-A-61-22047 and JP-A-61-76440, and Journal of Medicinal Chemistry (Journal of Medicinal Chemistry) , 1988, Vol. 31, No. 11, p. 2182) have been shown to have similar physiological effects. The above compounds having retinoic acid and retinoic acid-like biological activity are collectively referred to as “retinoids”.

The above compounds having a retinoic acid-like biological activity (for example, 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) carbamoyl] benzoic acid: tamibarotene) Is also suggested to bind to RAR as well as retinoic acid to exert physiological activity (Hashimoto, Y., Cell struct. Funct., 16, pp.113-123, 1991; Hashimoto, Y., et al., Biochem. Biophys. Res. Commun., 166, pp. 1300-1307, 1990. These compounds have been found clinically useful for the treatment and prevention of vitamin A deficiency, epithelial keratosis, rheumatism, delayed allergy, bone disease, and leukemia and certain cancers. ing.

As an effect on the adhesion of these retinoids, US Pat. No. 5,534,261 discloses that all-trans retinoic acid can be locally administered to the surgical site using a solution, microcapsule, etc. to prevent postoperative adhesion formation. It is shown. However, this publication does not describe an embodiment in which all-trans retinoic acid is administered systemically, and there is no suggestion or explanation of an adhesion preventing action when administered systemically. In addition, in visceral adhesions, the local area is often ischemic, so it is generally considered difficult to prevent local adhesions by systemic administration, and there are few drugs that are effective in systemic administration such as oral administration. (Dig. Surg., 18, pp.260-273, 2001). Regarding retinoids, there are no reports of achieving adhesion prevention or treatment effects by systemic administration.

An object of the present invention is to provide a medicine capable of exerting a preventive and / or therapeutic effect on visceral adhesion by systemic administration. In particular, the present invention provides a medicament capable of achieving an excellent preventive and / or therapeutic effect by systemic administration for post-surgical adhesion, intraperitoneal adhesion by peritoneal dialysis, adhesive ileus (intestinal obstruction), and Usherman syndrome. It is a problem.

As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that the following specific retinoids have extremely excellent preventive and / or therapeutic effects on visceral adhesion by systemic administration. The present invention has been completed.

That is, according to the present invention, a medicament for systemic administration for the prevention and / or treatment of visceral adhesion, the following general formula (I):

[Wherein, R ¹ , R ² , R ³ , R ⁴ , and R ⁵ each independently represent a hydrogen atom, a lower alkyl group, or a lower alkyl-substituted silyl group, and R ¹ , R ² , R ³ , R ⁴ And any two adjacent groups of R ⁵ are lower alkyl groups, they together form a 5- or 6-membered ring with the carbon atom on the benzene ring to which they are attached. (The ring may have one or more alkyl groups), X represents —CONH— or —NHCO—, and A represents an optionally substituted carboxylic acid-substituted fragrance. A troponyl group which may have a group or a substituent]] or a salt thereof as an active ingredient.

According to a preferred embodiment of the above invention, there is provided the above medicament wherein the visceral adhesion is post-surgical adhesion, intraperitoneal adhesion by peritoneal dialysis, adhesive ileus, or Asherman syndrome, and the above-mentioned medicament in which systemic administration is oral administration. Provided.

Another aspect is the use of a compound represented by the above general formula (I) or a salt thereof for the manufacture of the above-mentioned medicament; and a method for preventing and / or treating visceral adhesion, There is provided by the present invention a method comprising the step of systemic administration, preferably oral administration, of an effective amount of the compound represented by I) or a salt thereof to a mammal including human.

The medicament of the present invention is useful as a medicament for prevention and / or treatment of visceral adhesion such as postoperative adhesion, intraperitoneal adhesion by peritoneal dialysis, adhesive ileus, or Asherman syndrome, and systemic administration, preferably oral It has the feature that an extremely high prophylactic and / or therapeutic effect can be exhibited by administration.

It is the figure which showed the adhesion preventing effect of the pharmaceutical of this invention.

In the compound represented by the general formula (I), the lower alkyl group represented by R ¹ , R ² , R ³ , R ⁴ , and R ⁵ has about 1 to 6 carbon atoms, preferably 1 to 1 carbon atoms. Four linear or branched alkyl groups can be used. For example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, or a tert-butyl group can be used. One or more arbitrary substituents may be present on the lower alkyl group. Examples of the substituent include a hydroxyl group, a lower alkoxy group, and a halogen atom. Examples of the lower alkyl-substituted silyl group represented by R ¹ , R ² , R ³ , R ⁴ , and R ⁵ include a trimethylsilyl group.

Two adjacent lower alkyl groups selected from the group consisting of R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are joined together to form a 5-membered ring or 6 together with the carbon atom on the benzene ring to which they are bonded. One or two member rings may be formed, preferably one. The ring thus formed may be saturated, partially saturated, or aromatic, and may have one or more alkyl groups on the ring. As the alkyl group which can be substituted on the ring, a linear or branched alkyl group having about 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, can be used. For example, a methyl group, an ethyl group or the like can be used, and preferably 2 to 4 methyl groups, more preferably 4 methyl groups may be substituted. For example, R ² and the benzene ring and R ² and R ³ wherein R ³ is substituted, 5,6,7,8-tetrahydronaphthalene ring or 5,5,8,8-tetramethyl--5,6,7, An 8-tetrahydronaphthalene ring or the like is preferably formed.

As the carboxylic acid-substituted aromatic group represented by A, a carboxylic acid-substituted phenyl group or a carboxylic acid-substituted heterocyclic group can be used, but a carboxylic acid-substituted phenyl group is preferable, and a 4-carboxyphenyl group is more preferable. Examples of the heterocyclic carboxylic acid constituting the carboxylic acid substituted heterocyclic group represented by A include pyrimidine-5-carboxylic acid. Further, the tropolonyl group represented by A is preferably a tropolon-5-yl group. One or more other substituents may be present on the ring of these carboxylic acid-substituted aromatic groups or troponyl groups. Although the kind of substituent is not specifically limited, For example, a hydroxyl group, a halogen atom, an amino group etc. can be illustrated.

As a preferable compound, for example, a compound having a phenyl-substituted carbamoylbenzoic acid or a phenyl-substituted carboxamide benzoic acid as a basic skeleton can be used. 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) carbamoyl] benzoic acid (Hashimoto) is a typical example of a compound having a phenyl-substituted carbamoylbenzoic acid as a basic skeleton. , Y., Cell struct. Funct., 16, pp.113-123, 1991; Hashimoto, Y., et al., Biochem. Biophys. Res. Commun., 166, pp.1300-1307, 1990) 4-[(3,5-bistrimethylsilylphenyl) carboxamide] benzoic acid (J. Med. Chem., 33, pp.1430-1437, 1990) as a representative example of a compound having phenyl-substituted carboxamidebenzoic acid as a basic skeleton Can be mentioned. In the present specification, the term “basic skeleton” means a main chemical structure for bonding one or more arbitrary substituents. Particularly preferred compounds include 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) carbamoyl] benzoic acid.

As the active ingredient of the medicament of the present invention, a salt of the above compound may be used. For example, physiologically acceptable salts such as metal salts such as sodium salt, potassium salt, magnesium salt, or calcium salt, ammonium salts, or organic amine salts such as triethylamine salt or ethanolamine salt are effective for the pharmaceutical of the present invention. It can be used as a component. As an active ingredient of the medicament of the present invention, a prodrug of the above compound may be used. A prodrug is a compound or salt thereof that undergoes a change such as hydrolysis in vivo, preferably in blood, after systemic administration to a mammal orally or parenterally to produce a compound or salt thereof. . For example, many means for converting a drug having a carboxyl group, an amino group, or a hydroxyl group into a prodrug are known, and those skilled in the art can select an appropriate means. The type of prodrug of the compound or a salt thereof is not particularly limited. For example, when the compound has a carboxyl group, a prodrug obtained by converting the carboxyl group to an alkoxycarbonyl group is exemplified. Preferable examples include ester compounds such as methoxycarbonyl group or ethoxycarbonyl group.

The above compounds may have one or more asymmetric carbons depending on the type of substituent, and any optical isomer based on these asymmetric carbons, any mixture of optical isomers, Racemates, diastereoisomers based on two or more asymmetric carbons, any mixture of diastereoisomers, and the like can be used as the active ingredients of the medicament of the present invention. Furthermore, geometric isomers based on cis or trans bonds of double bonds, and any mixtures of geometric isomers, and any hydrates or solvates of compounds in the form of free compounds or salts are also included in the medicament of the present invention. It can be used as an active ingredient.

Visceral adhesions to which the pharmaceutical of the present invention is applied include adhesions that develop after surgery, inflammatory bowel disease, irritable bowel syndrome, duodenal ulcers, acute enterocolitis, protein-losing enteropathy, colon cancer, appendicitis, Examples include, but are not limited to, adhesive ileus (intestinal obstruction) caused by hemorrhagic colitis, intestinal tuberculosis, intestinal Behcet, or colonic diverticulosis, intraperitoneal adhesion by peritoneal dialysis, or uterine adhesion by Asherman syndrome There is no.

The medicament of the present invention contains one or more substances selected from the group consisting of the above retinoids and salts thereof, and hydrates and solvates thereof as active ingredients. The above-mentioned substance itself may be administered as the medicament of the present invention, but it is preferably administered as an oral or parenteral pharmaceutical composition for systemic administration that can be produced by methods well known to those skilled in the art. Can do. Examples of the pharmaceutical composition suitable for oral administration include tablets, capsules, powders, fine granules, granules, liquids, and syrups. The pharmaceutical composition suitable for parenteral administration includes For example, injections, suppositories, inhalants, transdermal absorbents, and the like can be mentioned. In addition to the preventive and / or therapeutic method for systemic administration of the medicament of the present invention, the above-mentioned retinoid solution is locally sprayed or applied to the internal organs and surrounding tissues as needed during surgery, or locally applied to organs and tissues. It is also possible to employ local administration means such as injection.

The above pharmaceutical composition can be produced by adding pharmacologically and pharmaceutically acceptable additives. Examples of pharmacologically and pharmaceutically acceptable additives include, for example, excipients, disintegrants or disintegration aids, binders, lubricants, coating agents, dyes, diluents, bases, and dissolution. Examples include agents or solubilizers, isotonic agents, pH adjusters, stabilizers, propellants, and pressure-sensitive adhesives.

The dosage of the pharmaceutical agent of the present invention is not particularly limited, and can be appropriately increased or decreased according to various factors that should normally be considered, such as patient weight and age, disease type and symptoms, and administration route. Generally, in the case of oral administration, it can be used in the range of about 0.01 to 1,000 mg per day for an adult. Preferably, it can be used in the range of 0.1 mg to 10 mg per adult day. The above dose can be increased or decreased as appropriate.

Hereinafter, the present invention will be described more specifically with reference to examples. However, the scope of the present invention is not limited to the following examples.
Example 1 Evaluation of Tamibarotene in Rat Adhesive Ileus Model Adhesive ileus was prepared using male or female Wistar rats (about 200 g). After fasting for 24 hours, DNBS (2,4-dinitorobenzenesulfonic acid, 30 mg in 0.5 ml ethanol 30%) was enema injected from the anus. As a medicament of the present invention, 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) carbamoyl] benzoic acid (generic name “Tamivaloten”) 0.3 mg each group / kg, 1 mg / kg, 3 mg / kg, as a comparative example (positive control drug), salazosulfapyridine (SASP), a commercially available ulcerative colitis treatment drug, was adjusted to 300 mg / kg respectively. Administration was performed once a day for 5 days, 24 hours before and 2 hours before enema, and 24 hours after enema. Tamibarotene and SASP were suspended orally in 0.5% carboxymethylcellulose (Carboxymethylcellulose). In the control group, the solvent was administered once a day for 5 days 24 hours before and 2 hours before DNBS enema and 24 hours after enema. Necropsy was performed 24 hours after the last administration and the presence or absence of intestinal adhesion was observed. One group of 5 rats was used for each of the tamibarotene administration group, the SASP administration group, the normal group, and the control group.

As shown in Fig. 1, adhesion was observed in 4 out of 5 animals in the control group, whereas any group in the tamibarotene administration group (0.3 mg / kg, 1 mg / kg, 3 mg / kg administration group) Also, no adhesion was observed. It has been clarified that tamibarotene has an extremely excellent effect in preventing adhesions by systemic administration.

Claims (4)

1. A medicament for systemic administration for the prevention and / or treatment of visceral adhesions, the following general formula (I):
   

   

   [Wherein, R ¹ , R ² , R ³ , R ⁴ , and R ⁵ each independently represent a hydrogen atom, a lower alkyl group, or a lower alkyl-substituted silyl group, and R ¹ , R ² , R ³ , R ⁴ And any two adjacent groups of R ⁵ are lower alkyl groups, they together form a 5- or 6-membered ring with the carbon atom on the benzene ring to which they are attached. (The ring may have one or more alkyl groups), X represents —CONH— or —NHCO—, and A represents an optionally substituted carboxylic acid-substituted fragrance. A troponyl group which may have a group or a substituent] or a salt thereof as an active ingredient.
2. 2. The medicine according to claim 1, wherein the visceral adhesion is postoperative adhesion, intraperitoneal adhesion by peritoneal dialysis, adhesive ileus, or Asherman syndrome.
3. The pharmaceutical according to claim 1 or 2, wherein the systemic administration is oral administration.
4. 4. The retinoid according to any one of claims 1 to 3, wherein the retinoid is 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) carbamoyl] benzoic acid. Medicine.

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