JP2761104B2 - Spinocerebellar degeneration treatment agent - Google Patents

Description

The present invention relates to a compound of formula (I): [Wherein, R ¹ and R ² each represent a hydrogen atom or together represent a single bond, and when R ¹ and R ² represent a hydrogen atom, R ³ represents —CH (OH) _{CH (OH) CH 3, -CH} (O
COCH ₃ ) CH (OCOCH ₃ ) CH ₃ , —CH ₃ , —CH ₂ OH or a phenyl group, and when R ¹ and R ² together represent a single bond, R ³ is —COCH (OH ) Represents CH ₃ ] or a pharmaceutically acceptable salt thereof as an active ingredient.

BACKGROUND ART Spinocerebellar degeneration is a neurodegenerative disease centered on the cerebellar system, which is sporadic and hereditary, in which the cerebellum and spinal cord and their connections, and the basal ganglia show systematic degeneration. Due to the gradual decline of nerve function, cerebellar ataxia such as ataxic gait disorder and trembling of limbs is the main feature, and involuntary movements such as speech disorders, swallowing disorders, respiratory disorders, dystonia, etc. It is an intractable disease that interferes with life, and the cause of the onset of this disease is completely unknown. Regarding treatment, a patient with Machado-Joseph disease, which is one of spinocerebellar degeneration, was administered an antibacterial agent sulfamethoxazole-trimethoprim combination (hereinafter referred to as an ST agent). Report that significant improvement of neurological symptoms was observed (Archives of Neurology, 1988; 45;
210-213), however, the use of this drug as a therapeutic agent for this disease has not been studied because of its severe side effects. Therefore, at present, not only a causative therapeutic drug but also a symptomatic therapeutic drug that can surely alleviate symptoms has not yet been established, and there is a strong demand for a therapeutic drug. The compound of formula (I), which is an active ingredient of the therapeutic agent of the present invention, is a known compound, and is known for use as a therapeutic agent for malignant hyperphenylalaninemia, depression, Parkinson's disease, and the like. For example, see JP-A-59-25323, JP-A-59-76086, JP-A-61-277618, and JP-A-63-267781.

SUMMARY OF THE INVENTION The present invention aims to provide a therapeutic agent that restores the nervous function of the brain in spinocerebellar degeneration, improves symptoms, relieves patients from difficulties in daily life, and provides safe therapeutic agents without side effects. Aim.

In order to solve the above-mentioned problem, the present inventors have improved the neurological symptoms when administering an antibacterial agent (ST) to a patient with Machado-Joseph's disease, which is one of the aforementioned spinocerebellar degenerations (Archives). of Neurology, 1988; 45; 210-213). After intensive studies on the pharmacological mechanism of action of the ST agent, they hypothesized that increasing the brain turnover rate of tetrahydrobiopterin, which is present in a small amount in the living body, might improve neurological symptoms. I was Thus, treatment of patients with Machado-Joseph's disease with tetrahydrobiopterin was attempted. As a result, they found that the neurological symptoms were remarkably improved, and completed the present invention. The present invention relates to a therapeutic agent for Machado-Joseph's disease and other spinocerebellar degeneration having cerebellar lesions and pathology in common therewith.

DETAILED DESCRIPTION OF THE INVENTION Accordingly, the present invention provides a compound of formula (I): [Wherein, R ¹ and R ² each represent a hydrogen atom or together represent a single bond, and when R ¹ and R ² represent a hydrogen atom, R ³ represents —CH (OH) _{CH (OH) CH 3, -CH} (O
COCH ₃ ) CH (OCOCH ₃ ), —CH ₃ , —CH ₂ OH or a phenyl group, and when R ¹ and R ² together represent a single bond, R ³ is —COCH (OH) CH ₃ ] or a salt thereof, as an active ingredient.

The compounds of formula (I) which are the active ingredients of the present invention include the following and salts thereof: (6R) -L-erythro-5,6,7,8-tetrahydrobiopterin "BH4".) (6R, S) -5,6,7,8-tetrahydrobiopritene 1 ', 2'-diacetyl-5,6,7,8-tetrahydrobiopterin Sepiapterin 6-methyl-5,6,7,8-tetrahydropterin 6-phenyl-5,6,7,8-tetrahydropterin Among the above compounds, the preferred compound is 5,6,7,8-tetrahydrobiopterin or a salt thereof, and the most preferred compound is BH4 or a salt thereof.

The compound represented by the formula (I) used as an active ingredient in the present invention is a known compound. For example, JP-A-59-25323
Nos., 59-76086, 61-277618, and 6
See 3-267781. These may be used as suitable salts, and such salts include pharmacologically non-toxic acids such as hydrochloric acid, phosphoric acid, sulfuric acid, mineral acids such as boric acid, and acetic acid, formic acid, maleic acid, and the like. Examples thereof include salts with organic acids such as fumaric acid and mesylic acid.

As used herein, the term “spinal cerebellar degeneration” refers to a neurodegenerative disease centered on the cerebellar system, and shows a pathological condition that develops around cerebellar ataxia. Spinocerebellar degeneration can be either sporadic or hereditary; in both cases, the cerebellum and spinal cord and their connections, as well as the basal ganglia, exhibit systematic degeneration, and these neural functions gradually decline To do so, it is characterized by cerebellar ataxia such as ataxic walking disorder or trembling of the limbs, and causes involuntary movements such as speech disorders, swallowing disorders, respiratory disorders and dystonia.

Spontaneous spinocerebellar degeneration includes Shy-Drager syndrome,
Olive bridge cerebellar atrophy (Dejerine-Thomas type), striatum substantia nigra, and late-onset cerebellar cortical degeneration are included.

Inherited spinocerebellar degeneration includes autosomal dominant inheritance and autosomal recessive inheritance, and the former refers to everything controlled by a dominant gene having a locus on an autosome. A good example is Matach Joseph (Ma
chado-Joseph disease (having its locus on chromosome 14q), SCA1 (having its locus on chromosome 6p), SCA2
(Having its locus on chromosome 12q), hereditary cerebellar cortical atrophy (Holmes type), dendritic nucleus pallidum pallidum atrophy (DRPLA) (having its locus on chromosome 12p), hereditary Spastic paraplegia and the like have been mentioned, and it has been found that most of the cases conventionally referred to as hereditary olive bridge cerebellar atrophy (OPCA) or Menzel-type olive bridge cerebellar atrophy (OPCA) belong to these. The latter refers to anything controlled by a recessive gene having a locus on an autosome, such as Friedreich-type ataxia (chromosome 9q
13-q21).

These diseases are pathologically similar, with the cerebellum and other surrounding sites also degenerate to a greater or lesser extent.

Hereinafter, the present invention will be described as an example of spinocerebellar degeneration with a high frequency of Machado-Joseph's disease in autosomal dominant hereditary spinocerebellar degeneration.
1, having cerebellar lesions and pathology in common with other hereditary and sporadic spinocerebellar degenerations such as SCA2, this example supports the effect of the compound represented by formula (I) on these diseases Things. In addition, Machado-Joseph disease is characterized mainly by cerebellar ataxia and pyramidal tract symptoms.
It is classified into three types, Type 3 (Tetsuo Sakai: Neurology, 30: 246-252, 1989). The diagnostic criteria have also been proposed by Sakai (ibid., 249-251), and these criteria were adopted in the treatment examples of the present invention.

The therapeutic agent of the present invention comprises a compound (active ingredient) represented by the formula (I) and a carrier used in a general pharmaceutical preparation, and is orally, rectally or parenterally (intravenously, into cerebrospinal fluid) by a conventional method. (Including administration).

The carrier used in these pharmaceutical preparations depends on the dosage form used, but generally includes excipients, binders, disintegrants and the like.

Representative examples of excipients include starch, lactose, sucrose, glucose, mannitol, cellulose and the like, and binders include polyvinylpyrrolidone, starch, sucrose, hydroxypropylcellulose, gum arabic and the like. Examples of the disintegrant include starch, agar, gelatin powder, cellulose, CMC and the like, but generally used excipients,
Other binders and disintegrants may be used.

The therapeutic agent of the present invention preferably contains an antioxidant for stabilizing the active ingredient, in addition to the above carrier. The antioxidant is appropriately selected from those commonly used in pharmaceutical preparations, and examples include ascorbic acid, N-acetylcysteine, L-cysteine, dl-α-tocopherol, natural tocopherol and the like. The amount to be used may be an amount which stabilizes the active ingredient (one or more), but is generally 0.2 to 2.0 per weight of the active ingredient 1.
Is preferred.

Formulations of the present invention suitable for oral administration include tablets, capsules, powders, powders or granules, each containing a predetermined amount of the active ingredient (s), or syrups.
It can be provided as a suspension in a non-aqueous liquid such as an emulsion or a ready-to-use drug.

Granules are provided by uniformly mixing the active ingredient (one or more) and one or more of the above-mentioned carriers, auxiliary ingredients such as antioxidants, granulating, and sieving using a sieve. Is done. A tablet may be made by compression or moulding, the active ingredient (s), optionally with one or more accessory ingredients. Capsules are made by filling a powder or granules of the active ingredient (one or more), optionally with one or more accessory ingredients, into a suitable capsule, using a filler or the like. Formulations for rectal administration can be presented as a suppository using a conventional carrier such as cocoa butter. Formulations for parenteral administration may be provided by sealing the active ingredient (one or more) as a dry solid in a sterile nitrogen purging container. At the time of parenteral administration, the dried solid preparation can be dispersed or dissolved in a predetermined amount of sterile water and administered to a patient.

In the production of these preparations, it is preferable to add the above-mentioned antioxidants in addition to the active ingredient and the usual carriers, and if necessary, buffers, flavoring agents, surfactants, thickeners, lubricants and the like. One or more auxiliary components selected from agents, lubricants and the like may be further contained.

The dosage of the active ingredient, ie the compound of formula (I), will, of course, vary with the route of administration, the condition being treated and the patient being treated, but will ultimately be at the discretion of the physician. You can leave it.

A suitable dose for treating spinocerebellar degeneration is 0.1
It is in the range of / 50 mg / kg (body weight) / day, with a typical preferred dose being 0.5-10 mg / kg (body weight) / day.

The desired dosage may be such that the above-mentioned active ingredient is administered once a day, or may be administered in 2 to 4 divided doses at appropriate intervals throughout the day.

The active ingredient may be administered alone or as it is without being mixed with other ingredients. However, it is preferable to administer the active ingredient as a pharmaceutical preparation for the purpose of facilitating the adjustment of the dose.

The preparation of the present invention comprises at least one compound selected from the group consisting of tryptophan, 5-hydroxytryptophan (5-HTP), tyrosine and L-dopa (L-DOPA) together with a compound represented by the formula (I) as an active ingredient. Species may be included as supplementary active ingredients. By mixing these active ingredients, it can generally be expected that a more excellent therapeutic effect on spinocerebellar degeneration is exhibited as compared with the case of using the compound represented by the formula (I) alone. The ratio of each of the above-mentioned components in the preparation of the present invention is not particularly limited. For example, the ratio of 1 of the compound represented by the formula (I) by weight to the group consisting of tryptophan, 5-HTP, tyrosine and L-DOPA with respect to 1 At least one selected is in the range of 0.1 to 10, preferably
It can be in the range of 0.5 to 2.

An appropriate dose for treating spinocerebellar degeneration with this mixed preparation is 0.1 to 50 mg / kg as the total amount of the active ingredients.
(Body weight) / day, preferably 0.5 to 10 mg / kg
(Weight) / day.

Upon treatment, the selection of a preparation containing the compound represented by the formula (I) alone as an active ingredient and a preparation containing another active ingredient together with the active ingredient is appropriately selected by a doctor according to age, symptoms, and the like.

Active ingredients used in spinocerebellar degeneration of the present invention,
(6R) -L-erythro-5,6,7,8-tetrahydrobiopterin (BH4) and its salts are most preferred, but (6R,
S) -5,6,7,8-Tetrahydrobiopterin, 1 ', 2'-
Diacetyl-5,6,7,8-tetrahydrobiopterin, sepiapterin, 6-methyl-5,6,7,8-tetrahydropterin or 6-phenyl-5,6,7,8-tetrahydropterin and salts thereof May be a similar compound. However, it goes without saying that BH4, which is a natural substance existing in the living body, is preferable. The acute toxicity of this BH4 dihydrochloride to rats is 2 g / kg (body weight) or more by oral administration, and almost no toxicity is found. Also, (6R, S) -5,6,7,8-tetrahydrobiopterin, which is not an optically active substance, has low toxicity as shown in the treatment of Parkinson's disease described in JP-A-59-25323 and spinal cerebellar degeneration. It can be used to treat the disease. Compounds belonging to formula (I) other than these have almost no acute toxicity.

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

Examples Example 1 (granules, fine granules) 1 part (parts by weight) of polyvinylpyrrolidone (Korydone 30)
Was dissolved in sterile purified water, and 10 parts of ascorbic acid and 5 parts of L-cysteine hydrochloride were added to make a uniform solution. Then, 10 parts of BH4.2 dihydrochloride was added to make a uniform solution.

This solution was added to 59 parts of an excipient (mannitol or lactose) and 15 parts of a disintegrant [corn starch or hydroxypropylcellulose (LH-22)], kneaded, granulated, dried and then sieved.

Example 2 (tablets) After 58 parts of lactose and 15 parts of microcrystalline cellulose were mixed with the homogeneous solution of the active ingredient prepared in Example 1, 1 part of magnesium stearate was further added and mixed, followed by tableting.

Example 3 (Capsules) The capsules prepared in Example 1 were filled in capsules. However, 0.2% magnesium stearate as a lubricant
%.

Example 4 (injection) 1.5 g of BH4 dihydrochloride 1.5 g of ascorbic acid L-cysteine hydrochloride 0.5 g of mannitol 6.5 g The above components were dissolved in sterilized purified water, made 100 ml, and sterilized, 1 ml or 2 ml Each was placed in a vial or ampoule and lyophilized and sealed.

Example 5 (Injection) Dissolve 2.0 g of BH4.2 dihydrochloride in sterile purified water without oxygen,
The solution, made up to 00 ml, was sterilized and sealed as in Example 4.

Example 6 (suppository) 150 parts of BH4 · dihydrochloride 150 parts of ascorbic acid 50 parts of L-cysteine · hydrochloride
Dispersed in 50 parts.

Example 7 (Granules) BH4 dihydrochloride 5 parts Ascorbic acid 5 parts L-cysteine hydrochloride 2 parts A homogeneous solution was prepared using the above components.

On the other hand, 55 parts of mannitol, 1 part of polyvinylpyrrolidone,
The above solution was added to a mixture obtained by uniformly mixing 14 parts of hydroxypropylcellulose and 5 parts of 5-HTP, kneading, granulating,
After drying, it was sieved.

Example 8 (granules) BH4.2 dihydrochloride 5 parts Ascorbic acid 5 parts L-cysteine hydrochloride 5 parts Mannitol 52 parts Polyvinylpyrrolidone (Korydone 30) 1 part Hydroxypropylcellulose (LH-22) 12 parts L-DOPA 10 parts Granulated and sieved in the same manner as in Example 7 using the above components.
However, 10 parts of L-DOPA was used instead of 5 parts of 5HTP.

Example 9 (Granules) BH4 dihydrochloride 5 parts Ascorbic acid 5 parts L-cysteine hydrochloride 2 parts A homogeneous solution was prepared using the above components.

On the other hand, 5-HTP 5 parts, L-DOPA 10 parts, mannitol 50
Parts, 1 part of polyvinylpyrrolidone (Kolidone 30) and 9 parts of hydroxypropylcellulose (LH-22) were uniformly mixed, kneaded, granulated, dried and then sieved.

Without being bound by theory, the relevance of treatment with a compound of formula (I) based on biochemical considerations is explained as follows.

Sulfamethoxazole for patients with Machado-Joseph disease
Administration of Trimethoprim (hereinafter referred to as ST) significantly improved neurological symptoms (Arch)
ives of Neurology, 1988; 45: 210-213), the present inventors have found that the enzyme on which sulfamethoxazole acts is not present in the human body, and that trimethoprim has the enzyme on which it acts in the human body. And competitively antagonize dihydrofolate with dihydrofolate reductase (DHFR) to inhibit its activity. DHFR and dihydropteridine reductase (DHPR) have homology, and trimethoprim is DHFR In addition to the possibility of inhibiting DHPR, the following hypothesis was made.

"Before the administration of the ST agent, not only BH4-containing nigrostriatal neurons, but also BH4-containing cerebellar neurons, etc., are degenerated, so that BH4 in the patient's brain is significantly reduced. As a result, the activities of phenylalanine hydroxylase, tyrosine hydroxylase and tryptophan hydroxylase are reduced, and the concentrations of various catecholamines and serotonin generated by these hydroxylation reactions are reduced.

In the state after administration of the ST agent, DHPR activity in the brain is suppressed. Then, the regeneration of BH4 is decreased, and this stimulates the BH4 biosynthesis metabolism system, and the turnover rate of BH4 biosynthesis in the brain is increased, so that the activities of the above three amino acid hydroxylases are increased, and catecholamines are increased. And the concentration of serotonin increases. In addition, it has been recently revealed that BH4 is also important as a coenzyme for the activity of nitric oxide synthase present in high concentrations in the cerebellum. It is also expected to contribute to increased nitric oxide synthesis in neurons. These effects can explain the improvement of cerebellar symptoms, psychiatric symptoms, dystonia, etc. observed in Machado-Joseph's disease. Next, the following preliminary experiment was performed.

(Preliminary test) An ST drug and a placebo (lactose) were administered to eight patients with Machado-Joseph's disease, and in each of the administration periods (4 weeks each, with a 2-week washout period between each administration period) Neurological examination was performed [Double-blind, placebo control (pla
cebo-controlled), crossover design (crosso)
ver design). ]. Then, it was observed whether the neurological symptoms were improved by the ST agent, and at the same time, the ST agent was improved.
The blood and cerebrospinal fluid total biopterin, oxidized and reduced biopterin, homovanillin (HVA), and 5-hydroxyindoleacetic acid (HIAA) were measured immediately before and on the last day of the drug and placebo treatments. I got the result like this.

1. Clinical research: Clinically, the following eight tests showed statistically significant improvement during the ST drug administration period.

Gait disturbance (p <0.05) Finger-nose test (right hand; p <002) Finger tapping test (left hand; p <0.05) Repetitive test of both hands (right hand; p <0.01, left hand; p <0.0)
5) Tapping test of heel knee (right foot; p <0.02, left foot p <0.
05) Patter repetition test (p <0.05) Phone dialing (p <0.05) Piggy bank coining (p <0.01) 2. Biochemical study to elucidate pharmacological action mechanism: (1) ST agent Before administration: Total biopterin, oxidized and reduced biopterin concentrations in the cerebrospinal fluid were measured in the control disease group (progressive muscular dystrophy 7).
Case, Sjogren syndrome (1 case, total of 8 cases). On the other hand, the HVA concentration in the cerebrospinal fluid was also reduced to less than half of the control group.

(2) After administration of ST agent: The concentrations of total biopterin and oxidized biopterin in the cerebrospinal fluid showed a significant increase (total biopterin was 133% before administration of the ST agent, and oxidized biopterin was S- 172% before administration of the T agent), and the concentration of reduced biopterin did not show a significant increase. Such alteration of biopterin in the cerebrospinal fluid is a unique pattern observed only in dihydropteridine reductase (DHPR) deficiency among three diseases known as BH4 metabolic disorders. According to their hypothesis, it was indirectly demonstrated that ST agents would inhibit DHPR activity in the brain of patients with Machado-Joseph's disease. At the same time, the relative value of HVA in the cerebrospinal fluid and H
Since the relative value of IAA was also significantly increased by the administration of the ST agent, the suppression of DHPR activity induced by the ST agent was
It is considered that stimulated feedback to the BH4 biosynthetic metabolic pathway led to an increase in the turnover rate of BH4 biosynthesis in the brain, resulting in an increase in the synthesis of catecholamines and serotonin in the brain.

This preliminary study hypothesized that the mechanism by which ST agents alleviated the neurological symptoms of Machado-Joseph's disease could be due to the increased turnover rate of BH4, which trimethoprim would have significantly reduced in the brain. You. Therefore,
Based on the idea that it is reasonable to administer BH4 itself, BH4 treatment was applied to patients with Machado-Joseph's disease, and an excellent therapeutic effect was obtained.

(Example of treatment) Five patients with Machado-Joseph's disease shown in Table 1 below,
Placebo (ascorbic acid) and BH
4 was administered in a double-blind fashion.

<Target patients and methods> 1. Target patients According to Sakai's diagnostic criteria (Sakai, supra), “Clinically
3 cases from 3 families diagnosed as "definite family", "P
A total of 5 cases from 2 families diagnosed as "robable family"
A case was selected. Table 1 shows the neurological findings of each patient.

2. Administration period Each of BH4 and ascorbic acid as a placebo was administered for 10 days, with a 9-day drug holiday between them. Total 29 days.

3. Dosage 1 mg / kg (body weight) of a capsule containing BH4 or ascorbic acid was administered once after every lunch. Cases 1-3 and 5
Was administered BH4 dihydrochloride, and Case 4 was administered (6R, S) -L-erythro-5,6,7,8-tetrahydrobiopterin dihydrochloride.

4. Evaluation method Evaluation was performed by the following three methods.

a. Subjective improvement A total of six items: dysarthria, dysphagia, dexterous movements of the hand, impaired resting balance when standing up, impaired walking, and overall impression.

b. Neurological examination Limb muscle tonus, deep reflex, degree of dystonia, balance disorder at standing up, finger nose test, finger tapping test, repetitive test of both hands, heel knee tapping test, dysarthria.

c.Timed test Finger nose test, Finger tapping test, Antagonist repetition test of both hands, Heel knee tapping test, Repeated repetition test of pa / patter, 10m
Measurement of the time required for walking, telephone dialing, and savings box coining.

5. Design A double-blind, placebo-controlled, crossover design was employed.

6. Statistical processing Paired t-test.

<Results> 1. Subjective symptoms: No subjective symptoms showing statistically significant improvement were observed, but dysphagia tended to improve on the first day of BH4 administration (p <0.10).

2. Objective findings: (1) Neurological examination: No findings showing statistically significant improvement were observed, but the increase in patella tendon reflex showed a tendency to improve on day 10 of BH4 administration (P <0.10).

(2) Timed Test: A statistically significant improvement in the following test items was observed during the BH4 administration period.

Finger-nose test (right hand); Day 3 (p <0.02), day 4 (p <0.05), 10
Day (p <0.05) Finger tapping test (left hand); Day 8 of administration (p <0.02) Repetitive test of both hands (right hand); Day 5 of administration (p <0.05) Phone dialing; Day 4 of administration (p <0.05) In addition to the above, the following items also showed an improvement tendency.

Repeated test of both hands (left hand); Day 4 of administration (p <0.10) Coin movement of piggy bank; Day 5 of administration (p <0.10) <Conclusion> From the results of the above subjective symptoms and objective findings, BH4 Was effective in improving neurological symptoms in Machado-Joseph disease.

As described above, the present invention provides a therapeutic agent that effectively improves neurological symptoms of spinal cerebellar degeneration, which is an intractable disease.

──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int. Cl. ⁶ , DB name) A61K 31/505 C07D 475/04 CA (STN) REGISTRY (STN) WPIDS (STN)

Claims (6)

(57) [Claims] 1. The formula: [Wherein, R ¹ and R ² each represent a hydrogen atom or together represent a single bond, and when R ¹ and R ² represent a hydrogen atom, R ³ represents —CH (OH) _{CH (OH) CH 3, -CH} (O
COCH ₃ ) CH (OCOCH ₃ ) CH ₃ , —CH ₃ , —CH ₂ OH or a phenyl group, and when R ¹ and R ² together represent a single bond, R ³ is —COCH (OH ) compound or spinocerebellar degeneration therapeutic agent a salt thereof as an active ingredient represented by represents a CH _3]. (2) R ³ is L-erythro-CH (OH) CH (OH) CH ₃
The therapeutic agent for spinocerebellar degeneration according to claim 1, which is: 3. The therapeutic agent according to claim 1, which improves neurological symptoms of spinocerebellar degeneration. 4. The therapeutic agent according to claim 1, wherein the spinocerebellar degeneration is an autosomal dominant gene spinocerebellar degeneration. 5. The therapeutic agent according to claim 1, wherein the spinocerebellar degeneration is Machado-Joseph's disease. 6. A method for producing a therapeutic agent for spinocerebellar degeneration,
formula: [Wherein, R ¹ and R ² each represent a hydrogen atom or together represent a single bond, and when R ¹ and R ² represent a hydrogen atom, R ³ represents —CH (OH) _{CH (OH) CH 3, -CH} (O
COCH ₃ ) CH (OCOCH ₃ ) CH ₃ , —CH ₃ , —CH ₂ OH or a phenyl group, and when R ¹ and R ² together represent a single bond, R ³ is —COCH (OH ) a compound represented by represents a CH _3] or a salt thereof.