WO2003030905A1

WO2003030905A1 - Dihydroorotate dehydrogenase inhibitor

Info

Publication number: WO2003030905A1
Application number: PCT/JP2002/010030
Authority: WO
Inventors: Akinori Arimura; Junji Kishino; Norihiko Tanimoto
Original assignee: Shionogi & Co., Ltd.
Priority date: 2001-10-01
Filing date: 2002-09-27
Publication date: 2003-04-17
Also published as: JPWO2003030905A1

Abstract

A compound represented by the formula (I): wherein R1 and R4 each independently is alkyl or alkoxy; R2 and R3 each independently is hydrogen or alkyl; R5 is hydrogen or halogeno; R6 is hydrogen or hydroxy; and X1 and X2 each independently is -O- or -NH-. The compound was found to have dihydroorotate dehydrogenase inhibitory activity.

Description

Description Jihi-Drorotate-dehi-Drogenase inhibitor Technical field

The present invention relates to dihydrorotate dehydrogenase inhibitors. Background art

Dihydrorotate dehydrogenase is an enzyme that catalyzes the redox step located at the fourth position of pyrimidine biosynthesis (see Non-Patent Document 1). Rapid cell growth requires new pyrimidine biosynthesis for DNA and MA synthesis, protein glycosylation, membrane lipid biosynthesis, and nucleic acid chain repair. The step catalyzed by dihydro-orotate dehydrogenase is the rate-limiting step in pyrimidine biosynthesis.

Dihydrololate dehydrogenase is used for rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, uveitis, myasthenia gravis, bronchial asthma, atopic dermatitis, psoriasis, and viral infections It is known to be associated with bacterial infections, bacterial infections, parasitic infections, cancer, transplant rejection, and graft-versus-host disease. Therefore, dihydrolotate dehydrogenase inhibitors are useful for treating or preventing the above-mentioned diseases (see Non-Patent Documents 2 to 6).

The dihidrolotate dehydrogenase inhibitors include the formula:

(Wherein R is hydrogen, methyl, tert-butyl, trifluoromethyl, etc.) is disclosed (see Non-Patent Document 7). On the other hand, it is disclosed that the compound according to the present invention has an inhibitory action on IgE antibody production and an inhibitory action on Th2 differentiation (see Patent Documents 1 and 2).

Further, Patent Documents 3 to 28, Non-patent Documents 8 and 9, and the like, which have a skeleton similar to the compound of the present invention and have an immunosuppressive effect, an antiallergic effect or an anticancer effect, are disclosed.

Patent Document 1 WO 99/38829 Pamphlet

Patent Document 2 WO 01/07032 pamphlet

Patent Document 3 WO 94/27980 Pamphlet

Patent Document 4 WO 95/13067 pamphlet

Patent Document 4 WO 96/15123 pamphlet

Patent Document 5 WO 95/15318 pamphlet

Patent Document 6 WO 96/40659 Pamphlet

Patent Document 7 WO 96/40143 Pamphlet

Patent Document 8 WO 96/38412 brochure

Patent Document 9 WO 96/10012 Pamphlet

Patent Document 10 WO 97/24356 Pamphlet

Patent Document 11 WO 97/27181 pamphlet

Patent Document 1 2 WO 97/24324 Pamphlet

Patent Document 13 WO 97/39999 pamphlet

Patent Document 14 WO 97/44333 Pamphlet

Patent Document 15 WO 97/46524 Pamphlet

Patent Document 16 WO 98/04508 pamphlet

Patent Document 17 International Publication No. 98/24766 Pamphlet

Patent Document 18 WO 98/24782 pamphlet

Patent Document 19 International Publication No. 98/56785 Pamphlet

Patent Document 20 French Patent Application Publication No. 2301250

Patent Document 2 1 U.S. Pat.No. 5,539,991 Patent Document 2 2 Japanese Patent Publication No. 47-7368

Patent Document 23 JP-A-51-91259

Patent Document 24 JP-A-8-3163

Patent Document 25 JP-A-9-124571

Patent Document 26 JP-A-9-71564

Patent Document 27 JP-A-9-124571

Patent Document 28 JP-A-11-79993 Non-patent Document 1 Structure 2000, Vol. 8, p.25-31 Non-Patent Document 2 Immunopharmacology 2000, Vol. 47, p. .63-83

Non-Patent Document 3 Immntopliarinacology 2000, Vol. 47, p.273-289

Non-Patent Document 4 Cancer Research 1986, Vol. 46,. 5014-5019

Non-Patent Document 5 Biochemistry 1994, Vol. 33, p.5268-5274

Non-Patent Document 6 Biochemical Pharmacology

Pharmacology) 2000, Vol. 60, .339-342)

Non-Patent Document 7 Tetrahedron Letters 2001, Vol. 42, p.547-551

Non-Patent Document 8 Bioorganic & Medicinal Chemistry Letters 1995, Vol. 5, No. 18, p.2143-2146

Non-Patent Document 9 Journal Off 'Medicinal Chemistry

(Journal of Medicinal Chemistry) 1974, Vol. 17, No. 11, p. 1177-1181 0

Disclosure of the invention

The present invention provides a novel dihydrolotate dehydrogenase inhibitor. We have found that formula (I):

Wherein R ¹ and R ⁴ are each independently alkyl or alkoxy; R ² and R ³ are each independently hydrogen or alkyl; R ⁵ is hydrogen or halogen; R ⁶ is hydrogen or hydroxy; X ¹ and X ² are each independently —0— or 1 NH 1), and have found that they have a dihydrorotate dehydrogenase inhibitory action, and have completed the following invention. BEST MODE FOR CARRYING OUT THE INVENTION

The present invention

(1) Formula (I):

Wherein R ¹ and R ⁴ are each independently alkyl or alkoxy; R ² and R ³ are each independently hydrogen or alkyl; R ⁵ is hydrogen or halogen; R ⁶ is hydrogen or hydroxy X ¹ and X ² are each independently 10-or 1 NH 1), a prodrug thereof, a pharmaceutically acceptable salt thereof or a dihydrorotate containing a solvate thereof. Dehydrogenase inhibitors,

(2) R ¹ and R ⁴ are each independently alkyl; R ² and R ³ are hydrogen; R ⁵ is halogen; R ⁶ is hydrogen; X ¹ is 1 NH— ; And the dihydrofluorodehydrogenase inhibitor according to the above (1), wherein X ² is 10—

(3) The dihydrofluorodetohydrogenase inhibitor according to the above (1), wherein alkyl is methyl; alkoxy is methoxy; and halogen is fluorine.

(4) Equation (I):

Wherein R ¹ and R ⁴ are each independently alkyl or alkoxy; R ² and R ³ are each independently hydrogen or alkyl; R ⁵ is hydrogen or halogen; R ⁶ is hydroxy; X ¹ And X ² are each independently 111 or 1 NH—), a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof,

(5) The compound according to (4), wherein R ¹ is alkoxy; R ² is alkyl; R ³ is alkyl; R ⁵ is hydrogen; and X ^{1 is} —0—. Prodrugs, pharmaceutically acceptable salts or solvates thereof,

(6) the compound according to the above (4) or (5), wherein the alkyl is methyl; the alkoxy is methoxy; and the halogen is fluorine, its prodrug, its pharmaceutically acceptable salt or Its solvates,

(7) A pharmaceutical composition comprising the compound according to any of (4) to (6) above,

(8) A dihydrolotate dehydrogenase inhibitor comprising the compound according to any of (4) to (6) above,

(9) the dihydrololate dehydrogenase inhibitor according to any one of the above (1) to (3) and (8), which is an agent for treating or preventing cancer; (10) The dihydrololate dehydrogenase inhibitor according to any of (1) to (3) and (8) above, which is a therapeutic or prophylactic agent for a viral infection.

(11) the dihydrofluorate dehydrogenase inhibitor according to any of (1) to (3) and (8), which is a therapeutic or preventive agent for rheumatoid arthritis; (12) suppression of rejection in transplantation (1) to (3) and

The dihydrorotate dehydrogenase inhibitor according to any of (8).

In addition, the present invention

(13) The compound according to any one of the above (1) to (3) and (8), a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof is administered. A method for treating or preventing a disease associated with the action of drogenase,

(14) Treatment or prevention of cancer by administering the compound according to any one of the above (1) to (3) and (8), a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof. Method,

(15) Treatment of viral infection by administering the compound according to any one of the above (1) to (3) and (8), a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof. Or preventive measures,

(16) Treatment of rheumatoid arthritis administered with the compound according to any of (1) to (3) and (8), a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof. Or preventive measures,

(17) Rejection in transplantation to which the compound according to any one of (1) to (3) and (8) above, a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof is administered. Suppression method,

(18) The compound according to any one of the above (1) to (3) and (8), for producing a therapeutic or prophylactic agent for a disease associated with the action of dihydrofluorodehydrogenase, a prodrug thereof, Use of a pharmaceutically acceptable salt or solvate thereof, (19) The compound according to any one of the above (1) to (3) and (8) for producing an agent for treating or preventing cancer, a prodrug thereof, a pharmaceutically acceptable salt thereof or a salt thereof. Use of solvates,

(20) The compound according to any one of (1) to (3) and (8) for producing a therapeutic or prophylactic agent for a viral infection, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. Use of solvates,

(21) The compound according to any one of (1) to (3) and (8) for producing a therapeutic or prophylactic agent for rheumatoid arthritis, a prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt thereof. Use of solvates,

(22) The compound according to any one of (1) to (3) and (8), a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvent thereof for producing an agent for suppressing rejection in transplantation. Use of Japanese products,

(23) Contacting the compound according to any one of the above (1) to (3) and (8), a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof with dihydrochloride dehydrogenase. A method of inhibiting dihydro-dehydrogenase,

About.

Each term used in this specification is defined below.

"Alkyl" refers to straight or branched alkyl having 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, and most preferably 1 to 3 carbon atoms. Including, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl, n-heptyl, Isoheptyl, n-octyl, isooctyl, n-nonyl, n-decyl and the like. Particularly, methyl is preferred.

The alkyl part of “alkoxy” is the same as the above “alkyl”. "Alkoxy" includes linear or branched alkoxy having 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, and most preferably 1 to 3 carbon atoms. Including, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, isohexyloxy, n- Heptoxy, isoheptyloxy, n-octyloxy, isooctyloxy, n-nonyloxy, n-decyloxy and the like. Particularly, methoxy is preferred.

"Halogen" includes fluorine, chlorine, bromine and iodine. Particularly, fluorine and chlorine are preferred, and fluorine is more preferred.

The compound according to the present invention can be produced according to the methods described in Patent Documents 1 and 2 described above. Hereinafter, the method for producing the compound according to the present invention will be described.

_{D E-EtOH-aqNa 2 C0} 3

Ι-Α

(I)

Wherein R ¹ and R ⁴ are each independently alkyl or alkoxy; R ² and R ³ are each independently hydrogen or alkyl; R ⁵ is hydrogen or halogen; R ⁶ is hydrogen or hydroxy; X ¹ and X ² are each independently — 0— or one NH 1; Y ¹ and Y ² are each independently halogen; R ^x is a formula: —Χ ¹ — CH ₂ — CH = C (CH ₃ ) ₂ And R ^Y is a group represented by the formula: 1 X ² —CH ₂ —CH = C (CH ₃ ) ₂ or a group that induces the group. Process

This is a step of reacting a compound represented by the formula (I-A) with a compound represented by the formula (I-B) to obtain a compound represented by the formula (I-C). A compound represented by the formula (I-A) and a compound represented by the formula (I-I: B) are converted into a suitable solvent (for example, benzene, toluene, N-dimethylformamide, dimethyloxetane, tetrahydrofuran, dioxane, ethanol). or a mixed system or anhydrous systems such as methanol) and ice, a palladium catalyst (e.g. _{P d (PP h 3) P} d C 12 (PP h 3) 2, P d C l 2, P d (0 a c) ₂ or _{_{P d C l 2 (CH 3}} CN) 2 etc., preferably P d (PP h ₃₎ the presence of _4), basic conditions (as the base for example _{_{K 3 P 0 4, NaH C0}} 3, Na_〇 _{_{_{C 2 H 5, Na 2 C}}} 0 3, with _{_{_{(C 2 H 5) 3 N}}} , B a (OH) 2, C s 2 C0 3, C s F, NaOH or Ag ₂ C0 _3, etc.), at room temperature to heating The reaction is carried out for several tens of minutes to several tens of hours to obtain a compound represented by the formula (I-C).

Second step

This is a step of reacting a compound represented by the formula (IC) with a compound represented by the formula (ID) to obtain a compound represented by the formula (IE).

This step can be performed in the same manner as in the first step.

3rd step

This is a step of producing a compound represented by the formula (I) from a compound represented by the formula (IE).

In this step, R ^x is derived to a group represented by the formula: — X ¹ — CH ₂ — CH 2 C (CH ₃ ) ₂ , and R ^{Y is represented} by the formula: — X ₂ — CH ₂ — CH = C ( This is a step comprising a step of deriving a group represented by CH ₃ ) ₂ .

When performing the first step, the second step, and the third step, if there is a substituent that affects the reaction, after protecting with a protecting group or the like, the above step ′ is performed, and then the deprotection is performed. Good.

As used herein, the term "prodrug" refers to a group of compounds that can be easily converted in vivo into the active compound of the present invention. The method can also be performed. Methods for selecting and manufacturing suitable prodrug derivatives are described, for example, in the Design of Prodrugs, Elsevier, 0030

Amsterdam 1985. In accordance therewith, a group generally used for prodrug formation may be introduced into hydroxy, amino or the like bonded to any position of the compound of the present invention.

For example, if there is a human de port alkoxy as a substituent, one CO CH ₂ CH ₂ CO_〇_H one CO CH two CH COOH, One C_〇 CH ₂ S 0 ₃ H, one P 0 ₃ H _2, one CO CH ₂ N (CH ₃ ) ₂ , -C 0 -P yr (P yr represents pyridyl) or the like can be introduced. _{C When} amino is a substituent, for example, one C〇 0 CR ^h R i 0 C 0 CH 2 RJ [R ^h and R ¹ are each independently chromium or lower alkyl, and R j is H, -OH, one CO NHR ^K , -OCO NH R ^K ,-(NHCOCR! R ¹¹¹ ) uNHCO CH ₃ , one (NH COC! ¹¹¹ ) U NH COC ₂ H ₅ , -C SNH ₂ , one (0 CH ₂ CH ₂ ) t OH, one O CH ₃ ,-(0 CH ₂ CH ₂ ) t O CH ₃ , -CO CH ₃ , one C〇C ₂ H ₅ , one CO CH ₃ , one OC〇C ₂ H ₅ , one NHOH, one NHC ONH ₂ , one NH CS NH ₂ , -NHS 0 ₂ CH ₃ -N (S〇 ₂ CH ₃ ) ₂ , — S 0 ₂ NH ₂ , — S 0 CH ₃ ,-S 0 a C 2 H ₅ , one O CH ₂ CONH ₂ , one O CH 2 CON (CH ₃ ) ₂ , -SO 2 N (CH ₃ ) ₂ , one PO (O CH ₃ ) ₂ , one NH CS NH C ₂ H _S , — CH = NNH C ONH ₂ , 1 CH 2 NNHCSNH ₂ , 1 CH = NNHS〇 ₂ CH ₃ , triazolyl and tetrazolyl, etc., and R ^k , R ¹ and R ^m are hydrogen or lower alkyl And t is 1 or 2 and u is an integer from 0 to 2],-C 00 CH (CH ₃ ) 〇 C 〇 C (CH ₃ ) ₃ , one C OO CH ₂ 〇 C 0 (CH ₂ ) Introduce ₁₄ CH ₃ , -CO O CH ₂ OC OP yr _s -CH ₂ NH C 0-C ₆ H ₄ — o— O CH ₂ OAc etc. (where Py is pyridyl and Ac is acetyl) I just need.

When a prodrug is introduced by introducing the above-mentioned substituted acyloxycarbonyl (1-C〇O CR hR i〇CO CH ₂ R j) into an amino present at any position of the compound of the present invention, for example, any of the compounds of the present invention The prodrug compound can be obtained by α-haloalkoxycarbonylation of the amino present at that position and then reacting it with an appropriate carboxylic acid under appropriate conditions. Such an acyloxyalkyl carbamate can be synthesized according to a known method described in WO96 / 18605 and the like.

Specifically, first, the compound of the present invention having an amino and an α-haloalkyl chloroformate are mixed with a base (pyridine, pyridine, or tetrahydrofuran, 1,4-dioxane, ethyl acetate or toluene, etc.) in an inert solvent. The reaction is carried out at 0 ° C to room temperature in the presence of triethylamine or ホ -methylmorpholine to obtain a haloalkoxycarbamate compound. Then, the obtained compound is dissolved in a solvent (N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, sulfolane, etc.) in a salt of a substituted carboxylic acid compound (eg, an alkali metal salt, an alkali metal salt). A prodrug compound can be obtained by reacting with an earth metal salt, silver salt, mercury salt, etc.) at room temperature to under heating for several hours to several days.

If there is a substituent that hinders the formation of the prodrug, the substituent may be protected with an appropriate protecting group in advance, and may be removed by an ordinary method at an appropriate stage. .

In the present specification, the “pharmaceutically acceptable salt” includes a pharmaceutically acceptable salt of the compound represented by the formula (I) or a prodrug thereof. Pharmaceutically acceptable salts include, for example, salts of mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid and hydrobromic acid; formic acid, acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, Salts of organic acids such as maleic acid and succinic acid; salts of organic bases such as ammonium, trimethylammonium and triethylammonium; salts of alkali metals such as sodium and potassium or salts of calcium and magnesium Salts of alkaline earth metals can be mentioned.

In the present specification, the “solvate” includes a solvate (preferably a hydrate) of the compound represented by the formula (I), a prodrug thereof or a pharmaceutically acceptable salt thereof. Solvates include solvates with organic solvents and / or water. When forming a hydrate, it may be coordinated with any number of water molecules.

The compounds according to the present invention include all stereoisomers (for example, atrob isomers). As used herein, the term "dihydrolotate dehydrogenase inhibitor" refers to a pharmaceutical composition having dihydrorotate dehydrogenase inhibitory activity, i.e., a medicament for treating or preventing a disease associated with the action of dihydrorotate dehydrogenase. Means a composition.

A disease associated with the action of dihydrolotate dehydrogenase means a disease that can be treated or prevented by inhibiting the action of dihydrolotate dehydrogenase. For example, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, uveitis, myasthenia gravis, bronchial asthma, atopic dermatitis, psoriasis, viral infection, bacterial infection, bacterial infection Disease, parasite infection, cancer, transplant rejection, and graft-versus-host disease.In addition to the diseases listed here, it is clear that the disease is related to the action of dihydrodrote-to-dehydrogenase. Also included are those diseases.

For example, Non-Patent Documents 2 and 3 described above describe the usefulness of a dihydrorotate dehydrogenase inhibitor for autoimmune diseases, allergic diseases, transplant rejection, and the like.

In addition, Non-Patent Document 3 describes the application of a dihydrololate dehydrogenase inhibitor as an anticancer agent, and Non-Patent Document 4 describes its usefulness.

In addition, Non-Patent Documents 5 and 6 described above describe the usefulness of a dihydrololate dehydrogenase inhibitor for bacterial infections, bacterial infections, parasitic infections, and the like.

The present invention also includes a method for treating or preventing a disease associated with the action of dihydrololate dehydrogenase by administering the compound of the present invention.Also, a disease associated with the action of dihydrolotrate dehydrogenase is also included. The use of the compound of the formula (I) for the manufacture of a therapeutic or prophylactic agent for is also included.

The present invention also provides a method for inhibiting dihydrolotate dehydrogenase by contacting the compound of the present invention with dihydrorotate dehydrogenase. Are also included.

As the dihydrolotate dehydrogenase inhibitor, in particular, an agent for treating or preventing cancer, an agent for treating or preventing a viral infection, an agent for treating or preventing rheumatoid arthritis, and an agent for suppressing rejection in transplantation are preferable. .

Dihydrorotate dehydrogenase inhibitor can function as a kind of nucleic acid metabolizing enzyme inhibitor because it can inhibit pyrimidine biosynthesis by inhibiting dihydrorotate dehydrogenase. Can be. Therefore, a dihydrolotate dehydrogenase inhibitor can inhibit the growth of pathogens based on pyrimidine biosynthesis, and can treat diseases caused by those pathogens. In particular, it is useful as an agent for treating or preventing cancer, or an agent for treating or preventing viral infections, bacterial infections, bacterial infections, and parasitic infections. That is, dihydrorotate dehydrogenase inhibitors can inhibit the nucleic acid synthesis of cells that are active in de novo synthesis (cancer cells, cells in fetal stage), and myeloma (myeloma, for example, multiple myeloma) It can also be used as a remedy for reformers (lymphoma) and leukemia (leukemia).

It is difficult to treat or prevent these diseases with the inhibitory action of IgE antibody production or Th2 differentiation possessed by the compound according to the present invention, and it is necessary to inhibit dihydrorotate dehydrogenase. Thus, these diseases can be treated or prevented.

When administering the dihydrorotate dehydrogenase inhibitor of the present invention, it can be administered either orally or parenterally. Oral administration may be carried out in a usual dosage form such as tablets, granules, powders, capsules, pills, solutions, syrups, buccals, or sublinguals according to a conventional method. For parenteral administration, any commonly used dosage form can be suitably administered, for example, injections such as intramuscular administration and intravenous administration, suppositories, transdermal absorbents, and inhalants. In particular, oral administration is preferred. An effective amount of the compound according to the present invention is mixed with various pharmaceutical additives such as excipients, binders, wetting agents, disintegrating agents, lubricants, and diluents, which are suitable for the dosage form, if necessary. Pharmaceutical preparations and can do. In the case of injections, the preparation may be prepared by sterilizing with an appropriate carrier.

Specifically, as an excipient, lactose, sucrose, pudose, starch, calcium carbonate or crystalline cellulose, etc., as a binder, methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, gelatin or polyvinylpyrrolidone, etc. Examples of the disintegrant include carboxymethyl cellulose, sodium carboxymethyl cellulose, starch, sodium alginate, powdered agar or sodium lauryl sulfate, and examples of the lubricant include talc, magnesium stearate, and macrogol. As a suppository base, cocoa butter, macrogol, methyl cellulose or the like can be used. In addition, when preparing a liquid formulation or an emulsion or suspension injection, commonly used solubilizers, suspending agents, emulsifiers, stabilizers, preservatives, isotonic agents, etc. are appropriately added. In the case of oral administration, a flavoring agent, a fragrance and the like may be added.

The dihydrorotate dehydrogenase inhibitor of the present invention may be administered alone, or may be used in combination with other agents as needed.

The dose of the dihydrorotate dehydrogenase inhibitor of the present invention is desirably determined in consideration of the patient's age, body weight, type and degree of disease, administration route, and the like. It is usually from 0.05 to 100 mg / kg / day, preferably from 0.1 to 10 mg / kg / day. In the case of parenteral administration, it varies greatly depending on the route of administration, but is usually 0.000 ll Omg / kg g / day, preferably within the range of 0.001 to 1 mg / kg / day. . It may be administered once or several times a day. Example

The method for producing the compound according to the present invention will be illustrated below, but it does not mean that the compound according to the present invention is limited to the compounds in the following examples.

Example 1 Synthesis of Compound (I-11)

(First step)

To a solution of compound (1) (23.7 g 0.1 ml) in dimethoxetane (300 ml) -ethanol (150 ml) was added boronic acid (2) (22.88 g, 0.1 An aqueous solution (150 ml) of m 01) and sodium carbonate (31.8 g, 0.3 m 01) was added, and the reaction solution was degassed. Tetrakis (1, rifenylphosphine) palladium (3.47 g, 3 mm 01) was added, and the mixture was heated under reflux for 2 hours under a nitrogen atmosphere, and the reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated saline, dried and concentrated, and the obtained residue was crystallized from hexane to obtain Compound (3) (24.92 g; yield: 84%).

(2nd step)

After reacting compound (3) (20.0 g, 68.0 mm 01) and polonic acid (4) (14.94 g, 88.3 mmol) in the same manner as in the first step for 18 hours The extraction residue was purified by silica gel chromatography (hexane: ethyl acetate 2: 1) to obtain compound (5) (19.24 g; yield: 84%).

(3rd step)

To a solution of compound (5) (2.1.15 g, 62.5 mmol) in dichloromethane (200 ml) was added pyridine (6.6 ml, 81.2 mmol) under ice cooling, followed by anhydrous toluene. Rifluoroacetic acid (10.6 ml, 75.0 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed successively with water, lmol / L hydrochloric acid, 5% aqueous sodium hydrogen carbonate solution and saturated saline, dried and concentrated to give compound (6) (22.80 g; Yield 84%).

(4th step)

A solution of compound (6) (14.0 g, 32.2111) 1101) in dichloromethane (3001111) was added to a solution of peroxybenzoic acid (1.46 g, 83.8 mm 0 1) was added, and the mixture was stirred at room temperature for 3 hours. An aqueous sodium thiosulfate solution was added to the reaction solution, extracted with ethyl acetate, washed twice with a saturated aqueous sodium hydrogen carbonate solution, dried and concentrated. The residue was washed with hexane to obtain a compound (7) (1.297 g; yield: 86%).

(Fifth step)

Compound (7) (15.0 g, 32.2 mmol) in N, N-dimethylformamide (65 ml) was added to a solution of potassium carbonate (6.67 g, 48.2 mm). o 1) and subsequently prenyl bromide (4.81 ml, 41.8 mmol) were added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated saline, dried and concentrated, and the residue was dissolved in tetrahydrofuran (150 ml). To a solution of prenol (9.8 ml, 96.5 mm o 1) in tetrahydrofuran (150 ml) was added sodium hydride (60% mineral oil, 3.85: 96.5 mm o 1). The prepared reaction solution was added under ice cooling, and the mixture was further stirred at the same temperature for 2 hours. The reaction solution was diluted with ethyl acetate, washed successively with water and saturated saline, dried and concentrated. The residue was purified by silica gel chromatography (hexane: ethyl acetate 7: 1) to obtain a compound (I-1) (12.5 g; yield: 87%).

mp 87-88 ° C

1H NMR (CDC13) δ HI.74 (s, 3H), 1.78 (s, 3H), 1.79 (s, 3H), 1.80 (s, 3H), 2.22 (s, 3H), 2.26 (s, 3H), 3.71 (d, J = 6.9Hz, 2H), 4.87 (d, J = 7.2Hz, 2H), 5.32-5.37 (m, 1H), 5.55-5.60 (m, 1H), 6.35-6.47 (m, 2H) , 6.81 (dd, J2 0.6, 8.4Hz, 1H), 7.02-7.13 (m, 3H), 7.59 (dd, J = 2.4, 8.4Hz, 1H), 8.16 (dd, J = 0,9, 5.7Hz, 1H) ppm.

IR (Nujol): 3330, 2923, 2853, 1627, 1606, 1564, 1527, 1481, 1471, 1395, 1376: 1357, 1337, 1284, 1240, 1178, 1116, 990 cm-1

The following compounds were similarly synthesized.

table

R ¹ R ² R ³ R ⁴ R ⁵ R ⁶ X ¹ X ² Compound (I-1) MeO Me Me MeO H OH-0--0-Compound (I-1) Meo Me Me Me H OH-0-- 0-Compound (I-4) Meo Me Me Me H OH-0- -NH-

(In the table, Me indicates methyl)

The physical properties data of the above compound are shown below.

Compound (I-II)

NMR-NMR δ 1.57 (s, 3H), 1.77 (s, 3H), 1.80 (s, 3H), 1.83 (s, 3H), 2.04 (s, 3H), 2.06 (s, 3H), 3.34 (s, 3H), 3.37 (s, 3H), 4.63 (d, J = 6.9 Hz, 2H), 4.88 (d, J = 6.9 Hz, 2H), 5.51-5.63 (m, 2H), 5.72 (s, 1H), 6.76 (dd, J = 2.1, 8.1 Hz, 1H), 6.84 (d, J = 8.7 Hz, 1H), 6.89 (d, J = 2.1 Hz, 1H), 6.94 (d, J 8.1 Hz, 1H), 7.56 (dd, J = 2.1, 8.7 Hz, 1H), 8.12 (d, J = 2.1 Hz, 1H) Compound (I-13)

NMR-NMR δ 1.77 (s, 3H), 1.80 (s, 3H), 1.83 (s, 6H), 1.98 (s, 6H), 2.05 (s, 3H), 3.33 (s, 3H), 4.63 (d, J = 6.6 Hz, 2H), 4.89 (d, J = 6.9 Hz, 2H), 5.52-5.61 (m, 2H), 5.73 (s, 1H), 6.61 (br d, J = 7.2 Hz, 1H), 6.75 (br s, 1H), 6.83 (d, J = 8.4 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 7.56 (dd, J = 2.1, 8.4 Hz, 1H), 8.12 (d, J = 2.1 Hz, 1H)

Compound (I-IV)

mp 163.5-164.5 ° C; Ή-NMR δ 1.75 (s, 3H), 1.78 (s, 6H), 1.83 (s, 3H), 1.98 (s, 6H), 2.08 (s, 3H), 3.35 (s, 3H), 4.45 (t, J = 6.0 Hz, 2H), 4.45 (t, J = 6.0 Hz, 1H), 4.62 (d, J = 6.9 Hz, 2H), 5.38 (, 1H), 5.55 (m, 1H ), 5.78 (br s, 1H), 6.48 (d, J = 8.4, 1H), 6.61 (br d, J = 7.8, 1H), 6.75 (br s, 1H), 6.93 (d, J = 7.8, 1H), 7.43 (dd, J = 2.4, 8.4, 1H), 8.06 (d, J = 2.4, 1H) A method for producing a prodrug of the compound according to the present invention will be exemplified below. .

Production example of prodrug of compound (I-1)

8

(Step 1) Synthesis of Compound (8)

The compound (I-1) (444 mg, lmmo 1) obtained in Example 1 was dissolved in anhydrous ether (4 OmL), cooled with ice, and stirred under a nitrogen stream while stirring chloromethyl chloroformate (194 mg, lmmol) and triethylamine (210 mL, lmmol) were sequentially added, and the ice bath was removed and stirring was continued for 4 hours. The precipitate in the reaction product was filtered off, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 540 mg of compound (8) as an oil.

Anal Calcd for C31H34N203FC1: C, 69.33; H, 6.38; N, 5.22; F, 3.54; CI, 6.60. Found: C, 68.85; H, 6.42; N, 5.21; F, 3.58; CI, 7.06.

(Step 2) Synthesis of prodrug of compound (I-1)

A mixture of glycolic acid (38 mg, 0.5 mmol), potassium carbonate (35 mg, 0.25 mmol), N, N-dimethylformamide (1 mL) was added at room temperature under reduced pressure. Stir for 10 minutes, then add a solution of compound (8) (54 mg, 0.1 mmol) in N, N-dimethylformamide (0.5 mL) and add potassium bromide (12 mg, 0.1 mg). lmmol) was added and stirred vigorously in an argon atmosphere for 20 hours. Reaction mixing The product was diluted with ether (5 mL), the solid was filtered off, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The remaining crude product was subjected to silica gel column chromatography (eluent; eluent). Purification with hexane: ethyl acetate 2: 1) gave 27 mg of the prodrug of compound (I-11) as an oil.

1H Marauder R (CDC13): δ 1.58 (3Η, s), 1.73 (3H, s), 1.80 (3H, s), 1.82 (3H, s), 2.20 (3H, s), 2.28 (3H, s), 2.33 (1H, bs), 4.25 (2H, bs), 4.30 (2H, d, J = 6.9Hz), 4.88 (2H, d, J = 6.9Hz), 5.30 (1H, bt, J = 6.9Hz), 5.58 (2H, bt, J = 6.9Hz), 5.90 (2H, bs), 6.83 (1H, d, J-8.4Hz), 6.95-7.30 (3H), 7.13 (2H, bs), 7.60 (1H, dd , J = 8.4Hz, 2.4Hz), 8.18 (1H, d, J = 2.4Hz) ppm.

Anal Calcd for C33H37N206F: C, 68.73; H, 6.47; N, 4.86; F, 3.29.

Found: C, 68.59; H, 6.68; N, 4.98; F, 3.25.

It was confirmed by the following test that the compound according to the present invention had a dihydrolotate dehydrogenase inhibitory action.

Test example

Test method for inhibition of dihidrolotate dehydrogenase

Human ϋ-937 cells (human histiocytic lymphoma cell line) した After homogenizing in a homogenizing buffer (20 mM Tris-HCl, pH 7.4, containing 2 mM EDTA and protease inhibitor cocktail), sonicate at 1,200 xg for 15 minutes The cell debris was removed by centrifugation. Further, ultracentrifugation was performed twice at 120,000 X g for 60 minutes to prepare a mitochondrial / microsomal fraction. The obtained fraction was subjected to protein quantification, adjusted to 10 mg / inl, and stored frozen at −40 ° C. until measurement. Reaction mixture (50 mM Tris-HC1, pH 7.4, containing 0.1 ¾ Triton X-100, 1 mM KCN, 100 μ, coenzyme Q10, 200 ^ MDCIP) Compound dilution sequence 10 列 1 in 150 jl and mitochondrial / microsomal fraction 0.2 mg was added and pre-incubated at 37 ° C for 30 minutes. Next, 20 μl of a 5 mM DH0 solution (final concentration: 500 μM) as a substrate was added, and the mixture was incubated at 37 ° C. for 90 minutes. Then, the absorbance at a measurement wavelength of 620 nm was measured. The inhibition rate of the compound at each concentration against the change in absorbance due to the enzyme reaction was determined, and the concentration ( _ICse value) showing 50% inhibition was calculated. The inhibitory activity of the compounds was evaluated.

The activity of the compound is shown below.

Table 2

Compound ICeo iik (ng / mL)

I one 1 45

1-2 51

I one 3 45

1-417 Formulation Examples of the compound of the present invention are described below, but are not limited to the following formulation examples.

Formulation Example 1 Tablet

Compound (I-1) 15 mg

1 5 mg

Breast fe 1 a m g

Crystalline cellulose 19 mg

Polyvinyl alcohol 3 mg

30 ml of distilled water

Calcium stearate 3 mg

Components other than calcium stearate were uniformly mixed, crushed and granulated, and dried to obtain granules of an appropriate size. Next, calcium stearate was added and compression-molded into tablets.

Formulation Example 2 Granules

Compound (I-II) 30 g

Lactose 2 6 5 g

Magnesium stearate 5 g

After mixing well, compression molding, pulverized, sized, and sieved to obtain granules of appropriate size. Formulation Example 3 Capsules

Compound (I-3) 10 g

Heavy magnesium oxide 20 g

Lactose 70 g

Was uniformly mixed to obtain a powdery or fine-grained powder, which was filled in a capsule container to obtain a forcepsel. Industrial applicability

The compound represented by the formula (I) has a dihydrofluorate dehydrogenase inhibitory activity, and is used for chronic rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, uveitis, severe disease For the treatment or prevention of myasthenia, bronchial asthma, atopic dermatitis, psoriasis, viral infections, bacterial infections, bacterial infections, parasitic infections, cancer, transplant rejection, graft-versus-host disease Can be used.

Claims

The scope of the claims

1 · Equation (I)

Wherein R ¹ and R ⁴ are each independently alkyl or alkoxy; R ² and R ³ are each independently hydrogen or alkyl; R ⁵ is hydrogen or halogen; R ⁶ is hydrogen or hydroxy; And X ¹ and X ² are each independently 10— or 1 NH—), a prodrug thereof, a pharmaceutically acceptable salt thereof, or a dihydrololate containing the solvate thereof. Todehydrogenase inhibitor (

2. R ¹ and R ⁴ are each independently alkyl; R ² and R ³ are hydrogen; R ⁵ is halogen; R ⁶ is hydrogen; X ¹ is mono-NH—; ^2. The dihydrolotrate dehydrogenase inhibitor according to claim 1, wherein X ² is —0—.

3. The dihydrolotrate dehydrogenase inhibitor according to claim 1, wherein alkyl is methyl; alkoxy is methoxy; and halogen is fluorine.

4. Formula (I):

(Wherein R ¹ and R ⁴ are each independently alkyl or alkoxy; R ² and R ³ are each independently hydrogen or alkyl; R ⁵ is hydrogen or halogen; R ⁶ is hydroxy; X ¹ and X ² is each independently 0— or 1 NH—) Or a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

5. The compound according to claim 4, wherein R ¹ is alkoxy; R ² is alkyl; R ³ is alkyl; R ⁵ is hydrogen; and X ¹ is —◦ one. A prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

6. The compound according to claim 4 or 5, wherein the alkyl is methyl; the alkoxy is methoxy; and the halogen is fluorine, a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof. object.

7. A pharmaceutical composition comprising the compound according to any one of claims 4 to 6.

8. A dihydrofluorate dehydrogenase inhibitor comprising the compound according to any one of claims 4 to 6.

9. The dihydrololate dehydrogenase inhibitor according to any one of claims 1 to 3, which is an agent for treating or preventing cancer.

10. The dihydrorotate dehydrogenase inhibitor according to any one of claims 1 to 3 and 8, which is an agent for treating or preventing a viral infection.

11. The dihydrololate dehydrogenase inhibitor according to any one of claims 1 to 3, and 8, which is an agent for treating or preventing rheumatoid arthritis.

12. The dihydrolotrate dehydrogenase inhibitor according to any one of claims 1 to 3, which is an inhibitor of rejection in transplantation.

13. The effect of dihydroro- tetodehydrogenase upon administration of the compound according to any one of claims 1 to 3 and 8, its prodrug, its pharmaceutically acceptable salt or its solvate. A method for treating or preventing a related disorder.

14. A method for treating or preventing cancer, which comprises administering the compound according to any one of claims 1 to 3 and 8, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

15. A viral infection which administers the compound according to any one of claims 1 to 3 and 8, a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof. How to treat or prevent the disease.

16. Treatment or prevention of rheumatoid arthritis by administering the compound according to any one of claims 1 to 3 and 8, a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof. Method.

17. A method for suppressing rejection in transplantation, which comprises administering the compound according to any one of claims 1 to 3 and 8, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

18. The compound according to any one of claims 1 to 3 and 8 for producing a therapeutic or prophylactic agent for a disease associated with the action of dihydrofluorodehydrogenase, a prodrug thereof, or a pharmaceutical thereof. Use of the above acceptable salts or solvates thereof.

19. The compound according to any one of claims 1 to 3 and 8 for producing a therapeutic or prophylactic agent for cancer, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. Use of things.

20. The compound according to any one of claims 1 to 3 and 8 for producing a therapeutic or prophylactic agent for a viral infection, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvent thereof. Use of Japanese products.

21. The compound according to any one of claims 1 to 3 and 8 for producing a therapeutic or prophylactic agent for rheumatoid arthritis, a prodrug thereof, a pharmaceutically acceptable salt thereof or a salt thereof. Use of solvates.

22. The compound according to any one of claims 1 to 3, and 8 for producing an agent for suppressing rejection in transplantation, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. Use of things.

23. The compound according to any one of claims 1 to 3 and claim 8, a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof, and contacted with dihydrofluorate dehydrogenase. Method for inhibiting droolotate dehydrogenase.