JP2000159761A - Fluorothalidomide - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound which is a fluorothalidomide derivative prevented from racemization, capable of retaining excellent immunosuppression action of thalidomide and free from teratogenicity by substituting hydrogen at 3 position of thalidomide with fluorine atom. SOLUTION: This 3-fluorothalidomide derivative is represented by formula I [R1 to R4 are each H, a (halogenated)lower alkyl, a lower alkoxy, a halogen, a (substituted)amino, a lower alkylthio or the like; Q and X are each CH2 or C=O; (n) is 15-3], specifically 3-(R)-fluorothalidomide, 3-(S)-fluorothalidomide or the like. The compound of formula I is obtained by treating 3- phthalimidepiperizine-2-one derivative of formula II [R11 to R14 are each same as R1 to R4; R15 is H or a protecting group of amino group; (m) is 1-3] with a fluorinated reagent and a base and deprotecting the derivative when R15 is a protecting group of amino group.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a thalidomide derivative fluorinated at the 3-position and a method for producing the same.

[0002]

2. Description of the Related Art Thalidomide was approved as a hypnotic in 1958 and was taken in 46 countries around the world. Once disappeared from the market. Since then, thalidomide was found to show significant effects on skin diseases such as erythema nodosum of leprosy, and thalidomide has been used in the treatment of skin diseases such as leprosy in 39 countries around the world. The U.S. Food and Drug Administration (FDA) has imposed very strict restrictions on the use of thalidomide as a treatment for erythema nodosum in leprosy ("Salomid", Celgene).

[0003] The immunosuppressive effect of thalidomide is TNF-α.
Is thought to be based on the suppression of the production of
Since NF-α has been shown to be involved in the induction of cachexia and angiogenesis, promotion of HIV replication, acquisition of insulin resistance, etc., acquired immunodeficiency syndrome (AIDS), transplantation to host Anti-T using thalidomide against various autoimmune diseases such as hepatitis (GVHD), diabetic retinitis, senile macular degeneration, Behcet's disease
The usefulness of NF-α therapy is expected (Makonkawkeyo
on, S., et al., Proc. Natl. Acad. Sci., 90, 5974,
1993; Hashimoto, Y., Clinical Immunity, 29, pp.14
03-1408, 1997).

[0004] Under such circumstances, dozens of cases of malformed thalidomide in Brazil were reported in 1990 in Brazil, and thalidomide phytotoxicity has become a social problem again. The teratogenicity of thalidomide is determined by its optical isomer (S
It has been shown that teratogenicity can be avoided by using the other pure optical isomer (R-isomer) (Blaschke, VG, et al., Arznei
m.-Forsch., 29, 1640, 1979). However, because of the high acidity of the proton bonded to the asymmetric carbon at position 3 of thalidomide, even when pure form of R-thalidomide is used as a medicament, R-thalidomide is easily racemized in vivo to form S-thalidomide. Harm can not be avoided (Nishimura, K., et al., Biochem. Bi
ophys. Res. Commun., 199, 455, 1994;
ashimoto, Y., Pharmacia, 30, pp.1276-1280, 199
Four).

For the purpose of providing a thalidomide derivative having no teratogenicity, a thalidomide derivative in which a lower alkyl group is introduced at the 3-position of thalidomide to avoid racemization has been proposed (Hashimoto, Y., Clinical Immunity, 29). , pp.1403-140
8, 1997). Although the above publication suggests replacing the hydrogen at the α-position with a fluorine atom, this compound has not been produced and its biological effects have not been elucidated until now due to technical difficulties. In addition, International Publication WO98 / 3502 states that
Although a thalidomide derivative in which the -position is substituted with halogen is suggested, a halogen-substituted derivative is not specifically disclosed.

[0006]

SUMMARY OF THE INVENTION An object of the present invention is to provide a compound which retains the excellent immunosuppressive action of thalidomide and has no teratogenicity. More specifically, an object of the present invention is to provide a derivative in which racemization is prevented by replacing the 3-position hydrogen of thalidomide with a fluorine atom. The present inventors have conducted intensive studies to solve the above-mentioned problems and succeeded for the first time in producing a derivative in which the 3-position hydrogen of thalidomide has been replaced with a fluorine atom.

That is, the present invention provides the following formula (I):

Embedded image (In the formula, R ¹ , R ² , R ³ , and R ⁴ are each independently a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, a halogenated lower alkyl group, an amino which may have a substituent. A lower alkylthio group, a lower alkoxycarbonyl group, a carbamoyl group which may have a substituent, a cyano group, a lower alkenyl group, or a lower alkynyl group, and R ¹ , R ² , R ³ , and R ⁴ Two adjacent groups may together form a 5- to 7-membered ring which may have a substituent; Q represents CH ₂ or C ＝ O;
Represents CH ₂ or C ＝ O; n represents an integer of 1 to 3)
And an optically pure form of a 3- (R) -fluorothalidomide derivative or a 3- (S) -fluorothalidomide derivative. According to a preferred embodiment of the present invention,
The above-mentioned 3-fluorothalidomide derivatives, wherein R ¹ , R ² , R ³ and R ⁴ are hydrogen atoms; and R ¹ , R ² , R ³ and R ⁴
Is a hydrogen atom, and Q is C = O. The above-mentioned 3-fluorothalidomide derivative is provided.

From another viewpoint, there is provided a medicament comprising as an active ingredient the above-mentioned 3-fluorothalidomide derivative, preferably the above-mentioned 3-fluorothalidomide derivative wherein R ¹ , R ² , R ³ and R ⁴ are hydrogen atoms. Is done. This medicament is used as an immunosuppressant having an anti-TNF-α action as a therapeutic agent for erythema nodosum of leprosy, AIDS, graft-versus-host disease (GVHD), diabetic retinitis, senile macular degeneration, It can be used as a therapeutic agent for various autoimmune diseases such as Behcet's disease.

[0009] The above-mentioned 3-
Fluorothalidomide derivatives, preferably R ¹ , R ² , R
^Use of the above-mentioned 3-fluorothalidomide derivative wherein R ³ and R ⁴ are hydrogen atoms; and a method for treating and / or preventing a disease associated with TNF-α, wherein the above-mentioned 3-fluorothalidomide derivative, preferably R ¹ The present invention provides a method comprising administering a therapeutically and / or prophylactically effective amount of the above-mentioned 3-fluorothalidomide derivative, wherein R, R ² , R ³ , and R ⁴ are hydrogen atoms, to mammals including humans. Examples of the disease involving TNF-α include erythema nodosum of leprosy, AIDS, and graft versus host disease (G
VHD), diabetic retinitis, senile macular degeneration, autoimmune diseases such as Behcet's disease.

From a further viewpoint, the following formula (Ia):

Embedded imageA 3-fluorothalidomide derivative represented by the formula:
¹, R^Two, R^Three, And R^FourAre each independently a hydrogen atom, lower
Alkyl group, lower alkoxy group, halogen atom, halogen
Lower alkyl group, amino optionally having substituent (s)
Group, lower alkylthio group, lower alkoxycarbonyl
Group, carbamoyl group which may have a substituent, cyano
Group, a lower alkenyl group, or a lower alkynyl group,
R¹, R^Two, R ^Three, And R^FourTwo adjacent groups are the same
To form a 5- to 7-membered ring which may have a substituent
Q is CH_TwoOr C = O; X is CH_TwoShows
N is an integer of 1 to 3), wherein
Formula (II):

Embedded image (Wherein, R ¹¹ , R ¹² , R ¹³ , and R ¹⁴ each independently represent a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, a halogenated lower alkyl group, or an amino which may have a substituent. A lower alkylthio group, a lower alkoxycarbonyl group, a carbamoyl group which may have a substituent, a cyano group, a lower alkenyl group, or a lower alkynyl group; and R ¹¹ , R ¹² , R ¹³ , and R ¹⁴ Two adjacent groups may have a substituent together.
R ¹⁵ represents a hydrogen atom or a protecting group for an amino group; Q represents CH ₂ or CＯO; and m represents an integer of 1 to 3). A step of treating the 3-phthalimidopiperidin-2-one derivative with a fluorinating reagent (preferably perchloryl fluoride) and a base, and when R ¹⁵ is a protecting group for an amino group, deprotecting the amino group Are provided.

Further, the following formula (Ib):

Embedded imageA 3-fluorothalidomide derivative represented by the formula:
¹, R^Two, R^Three, And R^FourAre each independently a hydrogen atom, lower
Alkyl group, lower alkoxy group, halogen atom, halogen
Lower alkyl group, amino optionally having substituent (s)
Group, lower alkylthio group, lower alkoxycarbonyl
Group, carbamoyl group which may have a substituent, cyano
Group, a lower alkenyl group, or a lower alkynyl group,
R¹, R^Two, R ^Three, And R^FourTwo adjacent groups are the same
To form a 5- to 7-membered ring which may have a substituent
Q is CH_TwoOr C = O; X represents C = O
N is an integer of 1 to 3),
The following steps: (1) 3-phthalimidopiperidine represented by the above formula (II)
A 2-fluorinated reagent (preferably a fluorinated reagent)
Perchloryl) and a base followed by R¹⁵Is an amino group
Deprotecting the amino group if it is a protecting group;
And (2) treating the compound obtained in the above step (1) with an oxidizing agent.
A method comprising the steps of:

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION In the present specification, an alkyl group or a substituent containing an alkyl moiety (for example, an alkoxy group,
The alkyl moiety of the alkylthio group and the alkoxycarbonyl group may be linear, branched, cyclic, or a combination thereof. As the lower alkyl group represented by R ¹ , R ² , R ³ , or R ⁴ , for example, an alkyl group having about 1 to 6 carbon atoms can be used. More specifically, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopropylmethyl, n-pentyl group, n-
A hexyl group, a cyclohexyl group, or the like can be used.

As the lower alkoxy group represented by R ¹ , R ² , R ³ or R ⁴ , for example, an alkoxy group having about 1 to 6 carbon atoms can be used. More specifically, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-
Butoxy, cyclopropylmethyloxy, n-pentoxy, n-hexoxy and the like. The halogen atom represented by R ¹ , R ² , R ³ , or R ⁴ may be any of a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. The halogenated lower alkyl group represented by R ¹ , R ² , R ³ , or R ⁴ includes the above-described alkyl group having about 1 to 6 carbon atoms including a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Examples thereof include a group substituted by one or more halogen atoms selected from the group. When two or more halogen atoms are substituted, they may be the same or different.

When the amino group represented by R ¹ , R ² , R ³ , or R ⁴ has a substituent, the substituent may be, for example, an alkyl group having about 1 to 6 carbon atoms or a halogenated alkyl group described above. Etc. may be provided. More specifically, a monoalkylamino group substituted with an alkyl group having about 1 to 6 carbon atoms, or a dialkylamino group substituted with two alkyl groups having about 1 to 6 carbon atoms (two alkyl groups May be the same or different).
Examples of the alkylthio group represented by R ¹ , R ² , R ³ or R ⁴ include a methylthio group and an ethylthio group. The ^{R 1, R 2, R 3} , or an alkoxycarbonyl group R ⁴ represents, there can be mentioned a methoxycarbonyl group, an ethoxycarbonyl group.

When the carbamoyl group represented by R ¹ , R ² , R ³ or R ⁴ has a substituent, the substituent may be, for example, an alkyl group having about 1 to 6 carbon atoms or a halogenated alkyl group described above. Etc. may be provided. When the carbamoyl group has two substituents, they may be the same or different. For example, a dialkylcarbamoyl group or the like can be preferably used. The number of unsaturated bonds contained in the alkenyl group or alkynyl group represented by R ¹ , R ² , R ³ , or R ⁴ is not particularly limited, but is preferably 1 to
About two. The alkenyl group or alkynyl group is
It may be linear or branched.

R ¹ , R ² , R ³ , or R ⁴ each independently represents any of the substituents defined above, but all may be the same substituent. Further, two adjacent groups among R ¹ , R ² , R ³ , or R ⁴ together form 5 to 7
The ring may form a membered ring, and the ring may be a hydrocarbon ring or a heterocyclic ring. The ring may have a substituent. The type, number, and substitution position of the substituent are not particularly limited, but, for example, an alkyl group having about 1 to 6 carbon atoms can be suitably used as the substituent. For example, the ring may be a single alkyl group or two identical or different
It may have up to 4 alkyl groups. Note that R ¹ ,
A compound in which R ² , R ³ , and R ⁴ are all hydrogen atoms is a preferred embodiment of the present invention. X represents a methylene group (CH ₂ ) or a carbonyl group (C = O), and preferably X is a carbonyl group. Q represents CH ₂ or C ＝ O, and preferably Q is a carbonyl group. n represents an integer of 1 to 3, and n is preferably 2.

The 3-fluorothalidomide derivative of the present invention has one asymmetric carbon to which a fluorine atom is bonded, and may further have one or more asymmetric carbons depending on the type of the substituent. is there. The asymmetric carbon present in the compounds of the invention may be in either (S) or (R) configuration;
All stereoisomers such as optical isomers and diastereoisomers are included in the scope of the present invention. Optically pure forms of the isomers are a preferred embodiment of the present invention. In addition, any mixture of stereoisomers, racemates and the like are also included in the scope of the present invention. The 3-fluorothalidomide derivative of the present invention may form a salt depending on the type of the substituent, or may exist as a hydrate or a solvate, and these substances are all within the scope of the present invention. Is included.

The method for producing the 3-fluorothalidomide derivative of the present invention is not particularly limited. For example, a known or commercially available substituted phthalic anhydride derivative is used as a raw material, and this is reacted with L-ornithine to obtain the compound of the above formula (II) ), The compound of the formula (II) is treated with perchloryl fluoride and a base, and the amino-protecting group is removed, if necessary, to give the compound of the formula (Ia) ( X is C
H ₂ ) can be produced. The compound of formula (Ia) (the compound where X is CO) can be produced by oxidizing the compound of formula (Ia) obtained by the above reaction, for example, using a ruthenium compound as an oxidizing agent. . Further, by oxidizing in the presence of an appropriate co-oxidizing agent, the amount of the ruthenium compound used can be reduced to the catalytic amount. Further, after introducing an alkoxy group or a carboxy group by electrolytic oxidation or enzymatic oxidation, the compound of the formula (Ib) can be produced by further oxidizing.

In the formula (II), R ¹¹ , R ¹² , R ¹³ and R ¹⁴ correspond to R ¹ , R ² , R ³ and R ⁴ described for the above formula (I), respectively. Preferred examples are also the same. m shows the integer of 1-3. The type of the amino-protecting group represented by R ¹⁵ is not particularly limited as long as it is inactive in the fluorination reaction using perchloryl fluoride and can be easily removed by an appropriate deprotection reaction. Such a protecting group can be appropriately selected by those skilled in the art, and for example, a tert-butoxycarbonyl group or the like can be preferably used.

As the fluorinating reagent, perchloryl fluoride,
Examples thereof include molecular fluorine, N-fluorobenzenesulfonimides, and fluoropyridinium salts represented by Umemoto's reagent. Perchloryl fluoride is most preferred. Perchloryl fluoride can be prepared before use using potassium perchlorate and fluorosulfuric acid. The amount of perchloryl fluoride to be used is generally about 2 to 10 equivalents, preferably about 3 to 6 equivalents, relative to the compound of the formula (II). The reaction is usually
Under cooling in an inert solvent in the presence of a base, for example -78
It can be performed at a temperature of 0 ° C. Although the type of the solvent is not particularly limited, for example, ether solvents such as diethyl ether and tetrahydrofuran can be used.
Examples of the base include lithium bistrimethylsilylamide, lithium diisopropylamide (LDA), 1,1,
1,3,3,3-hexamethyldisilazane (HMDS), sodium hydride, potassium bistrimethylsilylamide, sodium bistrimethylsilylamide, and the like can be used.

The oxidation reaction can be carried out usually at room temperature to about 60 ° C. using a suitable oxidizing agent in a solvent. Although the type of the solvent is not particularly limited, for example, an ester solvent such as ethyl acetate, a halogenated hydrocarbon solvent such as methylene chloride, acetone, acetonitrile, or a mixture thereof can be used. When a co-oxidizing agent is used, it is desirable to add water in addition to these solvents. As the oxidizing agent, ruthenium tetroxide, ruthenium dioxide, ruthenium trichloride and hydrates thereof, ruthenium-phosphine complex, ruthenium-
Ruthenium compounds such as carbon monoxide complexes are preferred. Further, a permanganate such as potassium permanganate, a manganese salt such as manganese acetylacetonate, m-chloroperbenzoic acid, and the like can be used.

Examples of the co-oxidizing agent include periodates such as sodium periodate, perchlorates such as periodate and sodium perchlorate, bromates such as sodium bromate, and the like.
Hypochlorites such as sodium hypochlorite, persulfates such as potassium persulfate, potassium ferricyanide, lead tetraacetate, peroxides such as hydrogen peroxide and tert-butyl hydroperoxide, peracetic acid, m-chloro High valence iodine compounds such as perbenzoic acid and iodosylbenzene, amine N
Oxides, oxygen and the like can be used, and high-valent chlorine species generated by an electrochemical method can also be used. The optically active 3-fluorothalidomide derivative can be produced from the racemic 3-fluorothalidomide derivative obtained by the above method according to a usual optical resolution method. For example, the optically active substance can be easily separated by using a high performance liquid chromatography method using a column for separating the optically active substance.

The 3-fluorothalidomide derivative of the present invention represented by the above formula (I) is useful as an active ingredient of a medicine. The medicament provided by the present invention comprises an anti-TNF-α
It can be used as an immunosuppressant having an effect, for example, various autologous diseases such as erythema nodosum of leprosy, AIDS, graft-versus-host disease (GVHD), diabetic retinitis, senile macular degeneration, and Behcet's disease It can be used as a therapeutic agent for immune diseases. A substance selected from the group consisting of a 3-fluorothalidomide derivative, a physiologically acceptable salt thereof, and a hydrate thereof may be used as it is. It may be desirable to produce and administer a pharmaceutical composition comprising the additive and the excipient.

The route of administration of the medicament of the present invention is not particularly limited, and it can be administered either orally or parenterally. Also, the form of the pharmaceutical composition is not particularly limited, and a form suitable for the administration route can be appropriately selected. For example, compositions for oral administration such as tablets, capsules, powders, granules, syrups, injections, drops, suppositories, transdermal absorbents, transmucosal absorbents, creams, ointments, nasal drops And parenteral administration compositions such as eye drops, ear drops, patches and the like. As the pharmaceutical additive, for example, an excipient, a binder, a disintegrant, a solubilizer, and the like can be used, and two or more pharmaceutical additives may be used in combination.

However, the form of the pharmaceutical composition and the additives for the preparation are not limited to those exemplified above, and it goes without saying that those skilled in the art can appropriately select them. Also,
These pharmaceutical compositions can be manufactured by a method commonly used in the art. Incidentally, the dose of the medicament of the present invention,
The type of target disease, the purpose of treatment or prevention, the age and weight of the patient, can be appropriately selected depending on conditions such as the severity of the disease, but generally, thalidomide already used as a medicine The dose may be determined with reference to the dose. For example, in the case of oral administration,
About 50-500 mg can be administered.

[0026]

EXAMPLES The present invention will be described more specifically with reference to the following examples, but the scope of the present invention is not limited to the following examples. Example 1: 3-Phthalimidopiperidin-2-one 5 g of L-ornithine dihydrochloride was dissolved in as little water as possible, 2.15 g of sodium hydroxide was added, and 30 ml of toluene was further added. After adding 25 g of alumina, Dean-S
The mixture was refluxed all day long while distilling off water with a tark. After removing insolubles, the solvent was distilled off. The resulting residue is treated with 1,4-dioxane
After dissolving in 100 ml, 3.4 g of phthalic anhydride was added and refluxed for one day. After evaporating the solvent, the residue was recrystallized from ether to obtain 1.7 g (23.8%) of the title compound. ¹ H-NMR (270 MHz, CDCl ₃ ) 2.03 (3H, m), 2.41 (1H, m), 3.40 (1H, dddd, J = 2.
0, 3.5, 5.0, 12.0 Hz), 3.55 (1H, dt, J = 4.5, 12.0
Hz), 4.78 (1H, dd, J = 6.0, 12.0 Hz), 6.04 (1H, s),
7.79 (4H, m) mp 235-237 ° C

1-tert-butoxycarbonyl-3-phthalimidopiperidin-2-one 1 g of 3-phthalimidopiperidin-2-one was dissolved in 30 ml of acetonitrile, and then dissolved in 30 ml of acetonitrile.
g and di-tert-butyl dicarbonate (1 g) were added, followed by stirring for one day. After adding a 3% aqueous citric acid solution, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was recrystallized from ethanol to obtain 910 mg (92.2%) of the title compound. ¹ H-NMR (270 MHz, CDCl ₃ ) 1.51 (9H, s), 2.06 (3H, m), 2.33 (1H, m), 3.75 (1
H, ddt, J = 4.0, 11.0, 13.0 Hz), 3.89 (1H, ddt, J =
2.0, 4.5, 13.0 Hz), 4.89 (1H, dd, J = 7.0,12.0 H
z), 7.79 (4H, m) mp 204-207 ℃

1-tert-butoxycarbonyl-3-fluoro-3
-Phthalimidopiperidin-2-one 1-tert-butoxycarbonyl-3-phthalimidopiperidine
To a solution of 1 g of 2-one in 20 ml of tetrahydrofuran was added -78 ° C
Then, 3.5 ml of a 1 molar solution of lithium bistrimethylsilylamide in tetrahydrofuran was added dropwise over 20 minutes.
The temperature was raised to 0 ° C. Perchloryl fluoride generated from 2 g of potassium perchlorate and 8 ml of fluorosulfuric acid was blown into the solution at -10 ° C to 0 ° C over 2 hours. After adding a saturated aqueous ammonium chloride solution, the mixture was extracted with ethyl acetate.
The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was recrystallized from ethanol to obtain 750 mg (71.3%) of the title compound. ¹ H-NMR (270 MHz, CDCl ₃ ) 1.58 (9H, s), 1.87 (1H, m), 2.10 (1H, m), 2.40 (1
H, dddd, J = 6.0, 9.0, 11.0, 15.0 Hz), 3.27 (1H, dd
t, J = 6.5, 15.0, 16.0 Hz), 3.58 (1H, ddd, J = 6.0,
8.0, 13.5 Hz), 3.99 (1H, dt, J = 6.5, 13.5 Hz),
7.84 (4H, m) mp 203-205 ℃

3-fluoro-3-phthalimidopiperidine-2-
On 1-tert-butoxycarbonyl-3-fluoro-3-phthalimidopiperidin-2-one To a solution of 700 mg of methylene chloride in 100 ml of methylene chloride was added 3 ml of trifluoroacetic acid. After stirring for 1 hour, the solvent was distilled off, and toluene was added until trifluoroacetic acid was completely distilled off, followed by azeotropic distillation. The residue was recrystallized from ethanol to obtain 424 mg of the title compound. ¹ H-NMR (270 MHz, CDCl ₃ ) 1.89 (1H, m), 2.10 (1H, m), 2.51 (1H, dddd, J = 3.
5, 9.0, 12.5, 14.0 Hz), 2.87 (1H, dddd, J = 3.5,
9.0, 14.0, 19.5 Hz), 3.48 (2H, m), 6.29 (1H, br),
7.82 (4H, m) mp 156-159 ℃

3-fluorothalidomide 3-fluoro-3-phthalimidopiperidin-2-one 350 mg
A solution of 20 ml of ethyl acetate and a small amount of methylene chloride, and 90 mg of ruthenium dioxide in 10% aqueous sodium periodate solution.
The solution was added dropwise to a solution dissolved in a 30 ml solution, and the mixture was stirred at 40 ° C for 24 hours. After adding a small amount of 2-propanol, insolubles were removed. After adding water, the mixture was extracted with ethyl acetate. The organic layer was washed with a 10% aqueous sodium thiosulfate solution and saturated saline, and then dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue was recrystallized from ethanol to give 330 mg of the title compound (8
9.5%). ¹ H-NMR (270 MHz, CDCl ₃ ) 2.55 (2H, m), 2.90 (1H, m), 3.59 (1H, m), 7.89 (4
H, m), 8.05 (1H, br) mp 229-232 ° C C ₁₃ H ₉ O ₄ N ₂ F calc.C 56.53, H 3.28, N 10.14; found C
56.42, H 3.19, N 9.91

Example 2: Production of optically active 3-fluorothalidomide The obtained racemic 3-fluorothalidomide was separated by HPLC (Daicel CHIRALPAKAD 2 × 25 cm, EtOH, 4 ml / min) and recrystallized from ethanol. Thus, optically active 3-fluorothalidomide was obtained. Isomer A (retention time 40 min) [α] _D 257.4 ° (c = 1.11, T = 26.7, DMF) mp 231-246 ° C θλ 1.2 × 10 ^-1 [θ] λ 648.6 (0.0185 mol / l, CH ₂ Cl
₂ ) Isomer B (retention time 70 min) [α] _D -263.0 ° (c = 1.18, T = 26.7, DMF) mp 237-240 ° C θλ 5 × 10 ^-2 [θ] λ 230.41 (0.0217 mol / l , CH ₂ C
l ₂ )

Example 3: Determination of absolute configuration of optically active 3-fluorothalidomide (1) 1-tert-butoxycarbonylmethyl-3-fluorothalidomide 36.8 mg of 3-fluorothalidomide (isomer B) at room temperature
To a solution of (0.206 mmol) in 1 ml of dimethylformamide, 41 mg (0.3 mmol) of potassium carbonate and 44 μl (0.3 mmol) of tert-butyl bromoacetate were sequentially added, followed by stirring for 4 hours. After adding 1N hydrochloric acid, the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography (n-Hexane: AcOEt = 2: 1) to give the title compound (84.8 mg) as a mixture with impurities. ¹ H-NMR (CDCl ₃ , 270 MHz) 1.46 (9H, s), 2.44-2.57
(1H, m), 2.62 to 2.69 (1H, m), 2.92 to 3.03 (1H, m),
3.56 to 3.66 (1H, m), 4.41 (1H, d, J = 16.5Hz), 4.56 (1
(H, d, J = 16.5Hz), 7.78 to 7.91 (4H, m)

(2) 1-carboxymethyl-3-fluorothalidomide To a solution of 84.8 mg of 1-tert-butoxycarbonylmethyl-3-fluorothalidomide in 1 ml of dichloromethane was added 1 ml of trifluoroacetic acid at room temperature. Stirred for hours.
The reaction solution was concentrated to give the title compound (76.4 mg) as a mixture with impurities. ¹ H-NMR (CDCl ₃ , 270 MHz) 2.44 to 2.60 (1H, m), 2.64 to
2.71 (1H, m), 2.94 to 3.05 (1H, m), 3.59 to 3.68 (1H,
m), 4.57 (1H, d, J = 17.5 Hz), 4.73 (1H, d, J = 17.5 H
z), 7.79-7.91 (4H, m)

(3) 1- (1,6-dibromo-2-naphthoxy) carbonylmethyl-3-fluorothalidomide 76.4 mg of 1-carboxymethyl-3-fluorothalidomide in dichloromethane
In a 3 ml solution, 1,6-dibromo-2-naphthol 91 m at room temperature
g (0.3 mmol), 4 mg of 4-dimethylaminopyridine and 62 mg (0.3 mmol) of dicyclohexylcarbodiimide were sequentially added. After stirring for 12 hours, acetonitrile was added to remove precipitated crystals. After the solvent was distilled off, the residue was subjected to silica gel column chromatography (n-Hexane: AcOEt = 3: 1 to 1:
Purified in 1). The obtained title compound was further purified with ethyl acetate.
Recrystallized from -n-hexane-ethanol to give the title compound X
A crystal that could be measured by line crystal analysis was obtained. ¹ H-NMR (CDCl ₃ , 270 MHz) 2.46 to 2.64 (1H, m), 2.68 to
2.75 (1H, m), 2.97 to 3.09 (1H, m), 3.61 to 3.72 (1H,
m), 4.89 (1H, d, J = 17.0 Hz), 5.08 (1H, d, J = 17.0 H
z), 7.33 (1H, d, J = 9.0 Hz), 7.66 (1H, dd, J = 2.0,
9.5 Hz), 7.80 to 7.93 (4H, m), 8.00 (1H, d, J = 9.5 H
z), 8.14 (1H, d, J = 8.0 Hz) [α] _D = -148.6 ° (c = 0.3
5, T = 25.7, CH ₂ Cl ₂ ) mp 183-185 ℃

A 0.2 × 0.08 × 0.03 mm crystal of the obtained compound was mounted on a 4-axis diffractometer AFC-7R and irradiated with copper Kα ray to collect diffraction data. 10 for absolute positioning
Bijvoet pair intensity collections were performed for each reflection. The initial phase was determined by the direct method, and the structure was extended by the difference Fourier method. After the phase refinement by the least squares method, the absolute configuration analysis using the anomalous dispersion difference of Br atoms was performed. Finally, we applied the determined correct absolute configuration, performed phase refinement including the anomalous dispersion term, and completed the analysis. As a result of absolute configuration analysis performed on two possible optical isomers, Fobs
The magnitude relation between (H) and Fobs (-H) was consistent with that when the (S) isomer was assumed. Therefore, it was concluded that the absolute configuration of one asymmetric carbon of the above optically active 3-fluorothalidomide was the S configuration.

Example 4: Effect of optically active 3-fluorothalidomide on TNF production In order to examine the effect of the 3-fluorothalidomide of the present invention on TNF production, evaluation was performed using peripheral blood mononuclear cells. As test compounds, thalidomide (Thal) (racemic), optically active 3-fluorothalidomide (R-form (3RF-Thal) and S-form (3SF-Thal)) obtained in Example 2, and dexamethasone (DEX) were used. . Blood was collected from four healthy individuals using heparin as an anticoagulant, a mononuclear cell fraction was separated using a specific gravity separation solution for human leukocyte separation, and cultured under the conditions of 1 × 10 ⁶ cells / ml. 1 μg / ml LPS (E. Coli, O111: B4) and a test compound (10 and 100 mg / ml) were added, and after 6 hours, the culture supernatant was collected. The amount of TNF in the culture was determined by ELISA (Genzym
e) was detected. Thalidomide did not inhibit TNF production at 10 μg / ml, but TNF at 100 μg / ml
An acid suppression effect was observed. The optically active 3-fluorothalidomide of the present invention also has a TNF production inhibitory effect,
S-fluorothalidomide had a stronger effect than thalidomide.

[Brief description of the drawings]

FIG. 1 is a view showing the TNF acid suppression effect of the optically active 3-fluorothalidomide of the present invention. In the figure, THAL represents racemic thalidomide, and 3RF-THAL and 3SF-THAL represent optically active 3-fluorothalidomide (R-form (3RF-T
hal) and S-form (3SF-Thal)), and DEX indicates dexamethasone.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification code FI Theme coat ゛ (Reference) A61P 43/00 A61K 31/00 643D A61K 31/4025 643 31/403 31/40 604 31/454 605 31 / 55 31/445 614 C07D 403/04 207 31/55 209 C07D 403/04 207 209 (72) Inventor Tomoki Shirakami 674-1 Furusawa, Toyama City, Toyama Prefecture Plaza 94 Furusawa 111 F-term (reference) 4C063 AA01 BB02 CC07 CC11 CC19 DD04 DD07 EE01 4C086 AA01 AA02 AA03 AA04 BC08 BC10 BC11 BC21 BC31 GA07 GA16 MA01 MA04 NA14 ZA33 ZA89 ZB02 ZB08 ZC55

Claims (10)

[Claims] 1. The following formula (I): (In the formula, R ¹ , R ² , R ³ , and R ⁴ are each independently a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, a halogenated lower alkyl group, an amino which may have a substituent. A lower alkylthio group, a lower alkoxycarbonyl group, a carbamoyl group which may have a substituent, a cyano group, a lower alkenyl group, or a lower alkynyl group, and R ¹ , R ² , R ³ , and R ⁴ Two adjacent groups may together form a 5- to 7-membered ring which may have a substituent; Q represents CH ₂ or C ＝ O;
Represents CH ₂ or C ＝ O; n represents an integer of 1 to 3)
A 3-fluorothalidomide derivative represented by the formula: 2. The fluorothalidomide derivative according to claim 1, which is an optically pure form of the 3- (R) -isomer or an optically pure form of the 3- (S) -isomer. 3. The 3-fluorothalidomide derivative according to claim ¹ , wherein R ¹ , R ² , R ³ , and R ⁴ are hydrogen atoms, and Q is C ＝ O. 4. A medicament comprising the 3-fluorothalidomide derivative according to any one of claims 1 to 3. 5. The medicament according to claim 4, which is an immunosuppressant. 6. Prevention of a disease associated with TNF-α and / or
6. The medicament according to claim 4 or 5, which is a therapeutic agent. 7. The medicament according to claim 6, wherein the disease is leprosy, AIDS, graft-versus-host disease (GVHD), diabetic retinitis, senile macular degeneration, or Behcet's disease. 8. The following formula (Ia):A 3-fluorothalidomide derivative represented by the formula:
¹, R^Two, R^Three, And R^FourAre each independently a hydrogen atom, lower
Alkyl group, lower alkoxy group, halogen atom, halogen
Lower alkyl group, amino optionally having substituent (s)
Group, lower alkylthio group, lower alkoxycarbonyl
Group, carbamoyl group which may have a substituent, cyano
Group, a lower alkenyl group, or a lower alkynyl group,
R¹, R^Two, R ^Three, And R^FourTwo adjacent groups are the same
To form a 5- to 7-membered ring which may have a substituent
Q is CH_TwoOr C = O; X is CH_TwoShows
N is an integer of 1 to 3), wherein
Formula (II) above:(Where R¹¹, R¹², R¹³, And R¹⁴Are independently
Hydrogen atom, lower alkyl group, lower alkoxy group, halogen
Atom, halogenated lower alkyl group, or substituent.
Amino group, lower alkylthio group, lower alkoxy
Sicarbonyl group, carbamoy optionally having substituent (s)
Group, cyano group, lower alkenyl group, or lower alkynyl
And R represents¹¹, R¹², R¹³, And R¹⁴Adjacent to
Two groups may have a substituent together.
A 7-membered ring; R¹⁵Is a hydrogen atom or amino
Represents a protecting group for the group; Q is CH_TwoOr C = O; m is
3-phthalimidopipe represented by an integer of 1 to 3)
Treatment of lysine-2-one derivative with fluorinating reagent and base
After that, R¹⁵When is a protecting group for an amino group,
A method comprising the step of deprotecting a thio group. 9. The following formula (Ib):A 3-fluorothalidomide derivative represented by the formula:
¹, R^Two, R^Three, And R^FourAre each independently a hydrogen atom, lower
Alkyl group, lower alkoxy group, halogen atom, halogen
Lower alkyl group, amino optionally having substituent (s)
Group, lower alkylthio group, lower alkoxycarbonyl
Group, carbamoyl group which may have a substituent, cyano
Group, a lower alkenyl group, or a lower alkynyl group,
R¹, R^Two, R ^Three, And R^FourTwo adjacent groups are the same
To form a 5- to 7-membered ring which may have a substituent
Q is CH_TwoOr C = O; X represents CO
N is an integer of 1 to 3), wherein
The following steps: (1) The following formula (II):(Where R¹¹, R¹², R¹³, And R¹⁴Are independently
Hydrogen atom, lower alkyl group, lower alkoxy group, halogen
Atom, halogenated lower alkyl group, or substituent.
Amino group, lower alkylthio group, lower alkoxy
Sicarbonyl group, carbamoy optionally having substituent (s)
Group, cyano group, lower alkenyl group, or lower alkynyl
And R represents¹¹, R¹², R¹³, And R¹⁴Adjacent to
Two groups may have a substituent together.
A 7-membered ring; R¹⁵Is a hydrogen atom or amino
Represents a protecting group for the group; Q is CH_TwoOr C = O; m is
3-phthalimidopipe represented by an integer of 1 to 3)
Treatment of lysine-2-one derivative with fluorinating reagent and base
After that, R¹⁵When is a protecting group for an amino group,
Deprotection of the amino group; and (2) obtained in the above step (1).
Treating the compound with an oxidizing agent. 10. The method according to claim 8, wherein the fluorinating reagent is perchloryl fluoride.