JP2013147427A - Pharmaceutical agent for prevention and/or treatment of htlv-i-associated myelopathy - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a therapeutic agent for HTLV-I-associated diseases such as HTLV-I-associated myelopathy and uveitides.SOLUTION: There is provided a pharmaceutical agent for HTLV-I-associated diseases such as HTLV-I-associated myelopathy and uveitides, comprising, as an active ingredient, an RAR agonist represented by formula (I) [wherein Rto Rindependently represent a hydrogen atom, an alkyl group, or an alkyl-substituted silyl group; X represents -CO-NH-, -NH-CO- or -CO-CH=CH-; and A represents a carboxylate-substituted aromatic group or a tropolonyl group].

Description

  The present invention relates to a medicament for the prevention and / or treatment of HTLV-I related myelopathy.

  HTLV-I-related myelopathy (hereinafter sometimes referred to as “HAM” in the present specification) is a viral refractory neurological disorder that presents a pathological picture of chronic myelitis. The virus that causes this disease is HTLV-I (human T-cell leukemia virus type I), which is a type of retrovirus, and is transmitted by vertical infection, particularly lactation infection, blood infection, and sexual infection. HTLV-I carriers are said to be about 1.2 million people nationwide and 10 million to 20 million people worldwide, and many infected people will finish their lives without developing disease, but some infected people In this case, infected cells change to ATL cells, which are leukemia cells, and cause adult T-cell leukemia (hereinafter “ATL”).

  In some other infected individuals, HTLV-I-infected T cells in the peripheral blood infiltrate the spinal cord, causing HAM, and chronic pyramidal tracts that run through the lateral cords of the thoracic spinal cord are affected. Gait disorder, dysuria, etc. progress. HAM is a disease caused by infection with the same causative virus (HTLV-I) as ATL, but leukemia cells (ATL cells) are not involved at all in the onset and progression of HAM. ATL and HAM are clinical It is a disease that is clearly distinguished. There are many HAM patients in the Caribbean, West Africa, Southeast Asia, etc., and in Japan, especially in the Kyushu area. Currently, the number of patients is considered to be around 1500 in Japan and around 5000 worldwide.

The pathological condition of HAM is that the number of HTLV-I-infected cells is extremely high in peripheral blood and cerebrospinal fluid, and an excessive immune response is induced in proportion to the number of HTLV-I-specific cytotoxicity. There is an abnormal increase in sex T lymphocytes. In HAM spinal cord lesions, no viral infection of nerve tissue was observed, but cell infiltration of HTLV-I-infected CD4 ⁺ T cells and the surrounding CD8 ⁺ cytotoxic T lymphocytes and overproduction of inflammatory cytokines were observed. The From these facts, it is considered that the pathological condition of HAM is a neurological tissue disorder caused by an excessive immune response caused by infected cells.

  Treatment strategies for HAM based on these pathological conditions include (1) elimination of HTLV-I-infected cells, (2) calming of the hyperimmune response (spinal cord inflammation), and (3) regeneration of the damaged spinal cord. Conventionally, as a therapeutic method for HAM, in addition to administration of prednisolone and interferon-α, a blood purification method and the like have been used for the purpose of realizing the suppression of the hyperimmune response of (2) (Non-patent Documents 1 to 3). reference). Of these, treatment with steroids is highly effective and many patients are taking long-term steroids, but there is a problem that long-term administration is difficult due to side effects. Interferon alpha is the only drug that is covered by medical insurance for HAM as a supplement to steroids. However, the effect of interferon α is not sufficient, and attention should be paid to side effects.

  In addition, these conventional treatment methods are symptomatic treatments that suppress inflammation with immunosuppressive drugs, and although short-term effects can be expected, side effects and attenuation of therapeutic effects are recognized in the long term, and There is a problem that the progress cannot be sufficiently suppressed. In addition, these treatments are not effective in reducing the number of infected cells, which are the main cause of the disease, and are not HAM root treatments. Against this background, development of a highly effective treatment for HAM is eagerly desired.

  In HAM patients, interstitial pneumonia, alveolitis, Sjogren's syndrome, arthropathy, joint disorders, eye lesions (uveitis, dry keratoconjunctivitis, keratitis, retinal cotton-like vitiligo, retinal vasculitis, reticular Choroidal degeneration etc.) are known to occur at a high frequency, and its relevance to HAM has been pointed out (Toshiki Watanabe et al. “HTLV and disease” Bunkodo published in 2007). Infrequently, diseases associated with HAM include cutaneous erythema, polymyositis, pseudohypoparathyroidism, Behcet's disease, etc. (Hiroshi Namiko “HAM Pathology and Treatment”, 100th Japan General meeting of the Society of Internal Medicine (Fukuoka, April 3, 2003)). Furthermore, it has been found that these diseases can occur without merging with HAM in HTLV-I carriers (for example, many cases of developing uveitis in HTLV-I carriers without HAM, Effectively treating the above-mentioned diseases that develop in HTLV-I carriers (currently called HTLV-I-related uveitis) is also extremely important clinically (interstitial pneumonia, alveoli in this specification) Inflammation, Sjogren's syndrome, arthropathy, arthropathy, uveitis, dry keratoconjunctivitis, keratitis, retinal cotton-like vitiligo, retinal vasculitis, retina choroidal degeneration, erythema, polymyositis, pseudohypoparathyroidism, And Behcet's disease is called HTLV-I related disease).

  On the other hand, the retinoic acid receptor (RAR) belonging to the nuclear receptor superfamily (Evans, RM, Science, 240, p.889, 1988) existing in the cell nucleus proliferates through the binding of ligands. -It has been clarified that it controls differentiation or cell death (Petkovich, M., et al., Nature, 330, pp.444-450, 1987). The ligand naturally present in the living body for this RAR is all-trans / retinoic acid (vitamin A acid) which is an active metabolite of vitamin A.

  Compounds having biological activity like retinoic acid (for example, 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) carbamoyl] benzoic acid, etc.) Is sometimes referred to as Am80 or “Tamivaloten” in the present specification.) Like retinoic acid, it is suggested to bind to RAR and 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 may be useful in animal experiments or clinically for the treatment and prevention of vitamin A deficiency, keratosis of epithelial tissues, rheumatism, delayed allergy, bone disease, and leukemia and certain cancers. Has been found. In addition, retinoids such as all-trans retinoic acid are used for the treatment of ATL, but the purpose of the retinoid is to reduce systemic symptoms associated with ATL by reducing ATL cells.

Ann. Neurol., 21, pp.117-122, 1987 J. Neurol. Sci., 106, pp.186-192, 1991 Lancet, ii, pp.1109-1113, 1988 Toshiki Watanabe et al. “HTLV and Disease” Bunkodo published in 2007 Hiromi Naomi “HAM Pathology and Treatment” Lecture at the 100th Annual Meeting of the Japanese Society of Internal Medicine (Fukuoka, April 3, 2003) http://www5f.biglobe.ne.jp/~osame/kouenn-koukaikouza/ham-kouenn/ 9-other-diseases / 9-other-diseases.html Science, 240, p.889, 1988 Nature, 330, pp.444-450, 1987 Cell Struct. Funct., 16, pp.113-123, 1991 Biochem. Biophys. Res. Commun., 166, pp.1300-1307, 1990 J. Clin. Invest., 115, pp.1361-1368, 2005 PLoS, ONE, 4, e6517, 2009,

  The subject of this invention is providing the pharmaceutical for the prevention and / or treatment of HTLV-I related myelopathy. Another object of the present invention is to provide a medicament for the prevention and / or treatment of HTLV-I-related diseases in HTLV-I carriers.

The present inventor has conducted research focusing on HTLV-I-infected cells in order to find an effective root treatment for HAM. As a result, it was found that HTLV-I was selectively infected with CD4 ⁺ CD25 ⁺ T cells in HAM patients, and that these infected cells excessively stimulated the immune response (see Non-Patent Document 10). ). CD4 ⁺ CD25 ⁺ T cells are known to contain regulatory T cells that suppress the onset of autoimmune diseases. As a result of further research, the present inventor has found that a quantitative and functional decrease of regulatory T cells is observed in CD4 ⁺ CD25 ⁺ T cells of HAM patients, and that regulation is possible by expression of the tax gene of HTLV-I. It was found that the expression of FoxP3, which is a T cell marker transcription factor, is suppressed (see Non-Patent Document 11). This is a different phenotype from ATL caused by the same HTLV-I, and the difference between HTLV-I-infected cells is caused by two completely different diseases caused by the same virus (autoimmune disease (HAM) and leukemia (ATL)). ) Phenotype.

Based on these findings, the present inventors have further studied, and as a result, RAR receptor agonists such as Am80 have the effect of reducing CD4 ⁺ CD25 ⁺ T cells infected with HTLV-I in HAM patients, It was found that radical treatment for HAM can be performed by reducing the HAM-causing cells. In addition, the present inventors have found that RAR receptor agonists exhibit high effectiveness against HTLV-I related diseases that develop in HTLV-I carriers. The present invention has been completed based on the above findings.

That is, according to the present invention, there is provided a medicament for the prevention and / or treatment of HTLV-I-related myelopathy, which has 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 when any two adjacent groups of R ⁵ are lower alkyl groups, they may be taken together to form a 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 —CO—NH—, —NH—CO—, or —CO—CH═CH—, and A has a substituent. A carboxylic acid-substituted aromatic group which may optionally be substituted or a troponyl group which may have a substituent] is provided as an active ingredient.

  From another perspective, Sjogren's syndrome in HTLV-I carriers, arthropathy, joint disorders, uveitis, dry keratoconjunctivitis, keratitis, retinal cotton-like vitiligo, retinal vasculitis, choroidal degeneration, skin erythema, A medicament for the prevention and / or treatment of an HTLV-I related disease selected from the group consisting of polymyositis, pseudohypoparathyroidism, and Behcet's disease, represented by the above general formula (I) Provided is a medicament comprising a retinoic acid receptor agonist or a salt thereof as an active ingredient. According to a preferred embodiment of the present invention, there is provided the aforementioned medicament, wherein the HTLV-I related disease is a complication of HTLV-I related myelopathy.

According to a preferred embodiment of each of the above pharmaceuticals, in the retinoic acid receptor agonist represented by the general formula (I), R ¹ and R ⁵ are hydrogen atoms, and A is a 4-carboxylic acid-substituted phenyl group. Wherein R ² and R ³ are each independently a lower alkyl group (the lower alkyl groups together may form a 6-membered ring with the carbon atom on the benzene ring to which they are attached, 1 or 2 or more alkyl groups), and R ⁴ is a hydrogen atom; R ² and R ⁴ each independently represent a lower alkyl group or a lower alkyl-substituted silyl group; And R ³ is a hydrogen atom.

According to a further preferred embodiment of each of the above pharmaceuticals, in the retinoic acid receptor agonist represented by the general formula (I), R ¹ and R ⁵ are hydrogen atoms, and A is a 4-carboxylic acid-substituted phenyl group. (A) R ² and R ³ are each independently a lower alkyl group, and the lower alkyl group together is a 6-membered ring together with the carbon atom on the benzene ring to which they are bonded (the ring is 1 or 2 Or R ⁴ is a hydrogen atom and X is —NH—CO—, or (b) R ² and R ⁴ are each independently a lower alkyl group. R ³ is a hydrogen atom and X is -CO-CH = CH-, or (c) R ² and R ⁴ are each independently a lower alkyl-substituted silyl group, and R ³ is The above medicament is provided which is a hydrogen atom and X is -CO-NH-. As a particularly preferred embodiment, the retinoic acid receptor agonist represented by the above general formula (I) is 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) carbamoyl. ] Benzoic acid (Am80), 4- [3,5-bis (trimethylsilyl) benzamide] benzoic acid (Tac101), or (E) -4- [3- (3,5-di-tert-butylphenyl) -3 -Oxo-1-propenyl] The above-mentioned medicament which is benzoic acid (Ch55) is provided.

  From another aspect, use of a retinoic acid receptor agonist represented by the above general formula (I) or a salt thereof for the manufacture of the above-mentioned medicament; a method for preventing and / or treating HTLV-I-related myelopathy A method comprising the step of administering an effective amount of a retinoic acid receptor agonist represented by the above general formula (I) or a salt thereof to mammals including humans; prevention and / or treatment of the above-mentioned HTLV-I related diseases; A method comprising the step of administering an effective amount of a retinoic acid receptor agonist represented by the above general formula (I) or a salt thereof to a mammal including humans infected with HTLV-I is provided by the present invention. The

The medicament of the present invention is fundamentally effective in reducing HTLV-I-infected CD4 ⁺ CD25 ⁺ T cells, which are HAM-causing cells, for HTLV-I-related myelopathy for which no effective therapeutic method is known. It is extremely useful as a medicine that enables prevention and / or treatment. In addition, the medicament of the present invention is useful as a medicament exhibiting high effectiveness against HTLV-I-related diseases such as Sjogren's syndrome and uveitis that develop in HTLV-I carriers.

It is the figure which showed the growth inhibitory effect by Am80 with respect to HAM patient origin T cell line HCT-4 and HTLV-I non-infected T cell line Jurkat cell. It is the figure which showed the result of having measured the growth inhibitory effect of HAM patient PBMC spontaneous growth response by Am80 and Ch55. In the figure, HD: PBMC derived from healthy subjects; HAM: PBMC derived from HAM patients. It is the figure which showed the result of having measured the number of provirus copies of HAM patient PBMC in presence or absence of Am80.

The medicament of the present invention is a medicament for the prevention and / or treatment of HTLV-I-related myelopathy (HAM), or a medicament for the prevention and / or treatment of an HTLV-I-related disease in an HTLV-I carrier. The retinoic acid receptor agonist represented by the above general formula (I) or a salt thereof is included as an active ingredient. The medicament of the present invention has an action of reducing HTLV-I-infected CD4 ⁺ CD25 ⁺ T cells, which are HAM-causing cells, and provides fundamental prevention and / or treatment for HTLV-I-related myelopathy. to enable.

  HTLV-I-related myelopathy is a disease caused by HTLV-I, a type of retrovirus. The condition and diagnosis of HTLV-I-related myelopathy are specifically described in Toshiki Watanabe et al. “HTLV and disease” published in Bunkodo 2007. Therefore, those skilled in the art can accurately diagnose HTLV-I-related myelopathy to which the medicament of the present invention should be applied based on the teachings of the above publications.

  In this specification, HTLV-I-related diseases in HTLV-I carriers include interstitial pneumonia, alveolitis (T lymphocyte alveolitis), Sjogren's syndrome, arthropathy, joint disorder, uveitis, dry horn Included are diseases selected from the group consisting of conjunctivitis, keratitis, retinal cotton-like vitiligo, retinal vasculitis, choroidal degeneration, erythema, polymyositis, pseudohypoparathyroidism, and Behcet's disease. The medicament of the present invention can be used for the prevention and / or treatment of one or more diseases selected from the above-mentioned HTLV-I-related diseases in an HTLV-I carrier. The medicament of the present invention can be used for prevention and / or treatment of the above-mentioned HTLV-I-related diseases, preferably in an HTLV-I carrier that has already developed HTLV-I-related myelopathy. Among these, a particularly preferred disease as an application target of the medicament of the present invention is uveitis.

  As used herein, the term “prophylaxis and / or treatment” is used to completely prevent the development of HTLV-I-related myelopathy or HTLV-I-related disease, or to HTLV-I-related myelopathy or HTLV- In addition to preventive therapies to prevent progression of clinical symptoms of I-related diseases, therapeutic therapies to reduce or eliminate clinical symptoms of HTLV-I-related myelopathy or HTLV-I-related diseases Include. The effect of prevention and / or treatment should be interpreted in the broadest sense, including improvement of findings based on the judgment of the doctor and improvement of subjective symptoms.

  The compound represented by the general formula (I) which is an active ingredient of the medicament of the present invention is a compound that acts as a retinoic acid receptor (RAR) agonist. Retinoids are all-trans retinoic acid (all-trans retinoic acid (atRA)) or retinoic acid receptor (sometimes also retinoic acid X receptor) which is a receptor necessary for 9-cis-retinoic acid to exert physiological effects. Is a compound that binds to retinoic acid and exerts an action similar to or a part of retinoic acid, and includes at least one kind of retinoid-like action, for example, cell differentiation action, cell growth promoting action, life sustaining action, etc. It means a compound having more than a kind of action. In this specification, the retinoic acid receptor agonist means a physiologically active compound that binds to a retinoic acid receptor and exerts at least one of the above-described actions. Whether or not it is a retinoid can be easily determined by the method described in H. de The, A. Dejean: “Retinoids: 10 years on.”, Basel, Karger, 1991, pp. 2-9. Subtype α and subtype β are known to exist as retinoic acid receptors, but the retinoic acid receptor agonist used as the active ingredient of the medicament of the present invention selectively binds to any subtype or both. It may be bonded to.

In the general formula (I), the lower alkyl group represented by R ¹ , R ² , R ³ , R ⁴ , and R ⁵ is a straight chain having about 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Alternatively, 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 two or more arbitrary substituents may be present on the lower alkyl group. Examples of the substituent include a hydroxyl group, a lower alkoxy group, a halogen atom and the like. 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 one 6-member together with the carbon atom on the benzene ring to which they are attached A ring may be formed. 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 that 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 R ³ are bonded to each other, and a 5,6,7,8-tetrahydronaphthalene ring or 5,5,8,8-tetramethyl-5,6,7,8 together with a benzene ring that they substitute -It is preferable to form a tetrahydronaphthalene ring or the like.

  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. Of these, A is particularly preferably a 4-carboxyphenyl group.

In the general formula (I), R ¹ and R ⁵ are preferably both hydrogen atoms, and in this case, A is more preferably a p-carboxylic acid-substituted phenyl group. In a preferred embodiment in which R ¹ and R ⁵ are both hydrogen atoms and A is a p-carboxylic acid-substituted phenyl group, R ² and R ³ are each independently a lower alkyl group (the lower alkyl groups are And may form a 6-membered ring together with carbon atoms on the benzene ring to which they are bonded, and the ring may have one or more alkyl groups), and R ⁴ is hydrogen. More preferably, it is an atom. In this case, X is preferably —NH—CO— (when X is —NH—CO—, the nitrogen atom of X is bonded to the benzene ring substituted by R ^{1 to} R ⁵ ). . In a preferred embodiment in which R ¹ and R ⁵ are both hydrogen atoms and A is a p-carboxylic acid-substituted phenyl group, R ² and R ⁴ each independently represent a lower alkyl group or a lower alkyl-substituted silyl group. And R ³ is more preferably a hydrogen atom. In this case, X is preferably —CO—NH— or —CO—CH═CH—.

As a particularly preferred embodiment when R ¹ and R ⁵ are both hydrogen atoms and A is a p-carboxylic acid-substituted phenyl group, (a) R ² and R ³ are each independently a lower alkyl group, and Together with a carbon atom on the benzene ring to which they are bonded to form a 6-membered ring (which may have one or more alkyl groups), and R ⁴ is hydrogen And when X is -NH-CO-, (b) R ² and R ⁴ are each independently a lower alkyl group, R ³ is a hydrogen atom, and X is -CO-CH = Or (c) R ² and R ⁴ are each independently a lower alkyl-substituted silyl group, R ³ is a hydrogen atom, and X is —CO—NH—. it can.

  As a particularly preferred retinoic acid receptor agonist, 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) carbamoyl] benzoic acid (Am80: Cell Struct. Funct., 16 , pp. 113-123, 1991), 4- [3,5-bis (trimethylsilyl) benzamido] benzoic acid (Tac101: J. Med. Chem., 33, pp. 1430-1437, 1990: Tac101 "is labeled" Am55S "), or (E) -4- [3- (3,5-di-tert-butylphenyl) -3-oxo-1-propenyl] benzoic acid (Ch55: J Med. Chem., 33, pp.1430-1437, 1990), but is not limited thereto.

  As an active ingredient of the medicament of the present invention, a salt of the above retinoic acid receptor agonist may be used. For example, a physiologically acceptable salt such as a metal salt such as sodium salt, potassium salt, magnesium salt, or calcium salt, ammonium salt, or organic amine salt such as triethylamine salt or ethanolamine salt is 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 retinoic acid receptor agonist may be used. A prodrug refers to a compound or salt thereof that is orally or parenterally administered to a mammal and then undergoes a change such as hydrolysis in vivo, preferably blood, to produce a retinoic acid receptor agonist or a salt thereof. It is. 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 retinoic acid receptor agonist or a salt thereof is not particularly limited. For example, when the retinoic acid receptor agonist 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 retinoic acid receptor agonist may have one or more asymmetric carbons depending on the type of substituent, but any optical isomer based on these asymmetric carbons, any of the optical isomers Any of these mixtures, racemates, diastereoisomers based on two or more asymmetric carbons, any mixture of diastereoisomers, and the like can be used as the active ingredient 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.

  The medicament of the present invention contains one or more substances selected from the group consisting of the above retinoic acid receptor agonists and salts thereof, and hydrates and solvates thereof as active ingredients. Preferred efficacy may be obtained by administering two or more different active ingredients in combination. The above-mentioned substance itself may be administered as the medicament of the present invention, but it can be preferably administered as an oral or parenteral pharmaceutical composition that can be produced by methods well known to those skilled in the art.

  Examples of the pharmaceutical composition suitable for oral administration include tablets, capsules, fine granules, granules, liquids, and syrups. Examples of the pharmaceutical composition suitable for parenteral administration include Examples include injections, suppositories, inhalants, eye drops, nasal drops, ointments, creams, patches, and transdermal absorption preparations. As an example of parenteral administration, for example, a mode of local administration in spinal fluid can be mentioned, but the administration method is not limited to this specific mode.

  The above pharmaceutical composition can be produced by adding one or more pharmacologically and pharmaceutically acceptable additives for pharmaceutical preparation. Examples of the additives for preparation include excipients, disintegrants or disintegration aids, binders, lubricants, coating agents, dyes, diluents, bases, solubilizers or solubilizers, isotonic agents, Examples thereof include, but are not limited to, pH adjusters, stabilizers, propellants, and pressure-sensitive adhesives.

  For example, for the production of pharmaceutical compositions for oral administration such as tablets, capsules, granules and powders, excipients such as lactose, crystalline cellulose and starch, lubricants such as magnesium stearate and talc, hydroxypropylcellulose In addition, a binder such as polyvinylpyrrolidone, a strength ruboxymethylcellulose calcium, a disintegrant such as low-substituted hydroxypropylmethylcellulose, a coating agent such as hydroxypropylmethylcellulose, macrogol, and a silicone resin can be used as necessary.

  The dosage of the medicament of the present invention is not particularly limited, and can be appropriately selected according to conditions such as patient symptoms, age, body weight, etc., administration method, type of active ingredient, and the like. For example, in the case of oral administration, 0.01 to 1000 mg per day, preferably 0.05 to 50 mg, more preferably 0.1 to 10 mg may be administered once or divided into several times. However, the above dose is for illustrative purposes and can be increased or decreased as appropriate.

  The timing of administration is not particularly limited, for example, a method in which administration is started immediately after the occurrence of symptoms, preferably after the occurrence of clinical symptoms of HAM and / or HTLV-I-related diseases is recognized subjectively or objectively, or In addition to therapeutic administration in clinically occurring and chronic conditions, clinical manifestations of HAM and / or HTLV-I-related diseases appear in carriers with proven HTLV-I infection It is also possible to administer prophylactic administration to prevent the onset before. For example, it can be administered at two or more of the above periods. Desirably, there can be mentioned a method of continuous administration from immediately after the onset of symptoms to the chronic phase. The medicament of the present invention can be used in combination with other therapeutic methods, for example, anti-inflammatory therapy with steroidal agents or α-interferon.

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: Proliferation inhibitory effect of Am80 on T cell lines derived from HAM patients <Method>
HAM patient-derived HCT-4 was used as the HTLV-I-infected T cell line, and Jurkat cells were used as the HTLV-I-uninfected T cell line. Various cell lines were cultured at a concentration of 2 × 10 ⁵ cells / ml for 24 hours in the presence of various concentrations of Am80, and uptake of Tritium Thymidine was measured.
<Result>
The relative growth inhibitory effect with respect to the value at zero concentration is shown in FIG. Am80 suppressed the growth of HCT-4, a HAM patient-derived T cell line, in a concentration-dependent manner, but did not suppress the growth of Jurkat, an uninfected T cell line.

Example 2: Antiproliferative effect of retinoids on PBMC spontaneous proliferative response in HAM patients <Method>
1． Preparation of PBMCs and cell separation Peripheral blood mononuclear cells (PBMCs) were isolated from the blood of healthy individuals and HAM patients by the Ficoll centrifugal specific gravity method.
2． Cell Culture RPMI medium (5% human serum, 1% penicillin, 1% streptomycin added) was dispensed into each well of a round bottom 96-well microplate. Healthy individuals and HAM patients PBMCs were seeded in 5 × 10 ⁴ wells each dispensed with RPMI medium, then Am80 or Ch55 was added to final concentrations of 10 ⁻⁸ and 10 ⁻⁶ M, respectively. The cells were cultured for 6 days at 5 ° C. in a 5% CO ₂ atmosphere.
3． Measurement of Cell Proliferation Activity For PBMCs after culture, ³ H-thymidine was incorporated for 16 hours, and cell proliferation activity was measured.

<Result>
FIG. 2 shows the effect of Am80 and Ch55 on the proliferation ability of healthy PBMCs and PBMCs of HAM patients. Peripheral blood mononuclear cells of healthy individuals rarely proliferate in vitro without stimulation, but peripheral blood mononuclear cells of HAM patients are spontaneous in vitro even without stimulation. It is known to proliferate. This spontaneous growth is thought to reflect the growth of HTLV-I-infected cells (pathogenic cells) in HAM patients and the hyperimmune response caused by the pathogenic cells. Am80 and Ch55 suppressed the spontaneous proliferation of peripheral blood mononuclear cells in this HAM, and it was proved to have a specific action of specifically inhibiting the proliferation of only the pathogenic cells of HAM.

Example 3: Change in viral load in HAM patient PBMC by Am80 <Method>
1． Preparation of PBMCs and cell isolation
PBMCs were isolated from the blood of HAM patients by Ficoll centrifugal specific gravity method.
2． Cell Culture RPMI medium (5% human serum, 1% penicillin, 1% streptomycin added) was dispensed into each well of a round bottom 96-well microplate. 5 × 10 ⁴ PBMCs are seeded in wells with RPMI medium dispensed and cultured with or without Am80 at a final concentration of 5 μM for 7 days at 37 ° C. in a 5% CO ₂ atmosphere. did.
3． Measurement of HTLV-I viral load The provirus copy number per 100 cells was measured for each cell population by real-time PCR.

<Result>
FIG. 3 is a graph (n = 8) showing the results of measuring the provirus copy number for each cell population. As shown in this graph, the viral load was significantly reduced by administration of Am80 compared to the non-administration group. This result indicates that Am80 can be used to reduce HTLV-I-infected PBMC and, as a result, the amount of HTLV-1 virus in the body can be reduced.

Claims (5)

A medicament for the prevention and / or treatment of HTLV-I-related myelopathy, 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 when any two adjacent groups of R ⁵ are lower alkyl groups, they may be taken together to form a 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 —CO—NH—, —NH—CO—, or —CO—CH═CH—, and A has a substituent. A carboxylic acid-substituted aromatic group which may be substituted or a troponyl group which may have a substituent]], or a salt thereof as an active ingredient. Sjogren's syndrome, arthropathy, arthropathy, uveitis, dry keratoconjunctivitis, keratitis, retinal cotton-like vitiligo, retinal vasculitis, erythema degeneration, cutaneous erythema, polymyositis, pseudoparathyroidism in HTLV-I carriers A retinoic acid receptor agonist represented by the general formula (I) according to claim 1, which is a medicament for the prevention and / or treatment of HTLV-I related diseases selected from the group consisting of hypotension and Behcet's disease Or the pharmaceutical which contains the salt as an active ingredient. The medicament according to claim 2, wherein the HTLV-I-related disease is a complication of HTLV-I-related myelopathy. R ¹ and R ⁵ are hydrogen atoms, A is a 4-carboxylic acid-substituted phenyl group, (a) R ² and R ³ are each independently a lower alkyl group, and these lower alkyl groups are combined together Together with a carbon atom on the benzene ring to which they are bonded to form a 6-membered ring (which may have one or more alkyl groups), R ⁴ is a hydrogen atom, and X is — NH-CO-, (b) R ² and R ⁴ are each independently a lower alkyl group, R ³ is a hydrogen atom, and X is -CO-CH = CH-, or ( c) R ² and R ⁴ are each independently a lower alkyl-substituted silyl group, R ³ is a hydrogen atom, and X is —CO—NH—. Medicine. The retinoic acid receptor agonist is 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) carbamoyl] benzoic acid (Am80), 4- [3,5-bis (Trimethylsilyl) benzamide] benzoic acid (Tac101) or (E) -4- [3- (3,5-di-tert-butylphenyl) -3-oxo-1-propenyl] benzoic acid (Ch55) Item 5. The medicine according to Item 4.