WO1998032750A1 - Derives de ms-444 - Google Patents

Derives de ms-444 Download PDF

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Publication number
WO1998032750A1
WO1998032750A1 PCT/JP1998/000265 JP9800265W WO9832750A1 WO 1998032750 A1 WO1998032750 A1 WO 1998032750A1 JP 9800265 W JP9800265 W JP 9800265W WO 9832750 A1 WO9832750 A1 WO 9832750A1
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WIPO (PCT)
Prior art keywords
compound
bond
hydrogen
oxygen
lower alkyl
Prior art date
Application number
PCT/JP1998/000265
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English (en)
Japanese (ja)
Inventor
Kuniaki Tatsuta
Satoshi Nakanishi
Isami Takahashi
Original Assignee
Kyowa Hakko Kogyo Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kyowa Hakko Kogyo Co., Ltd. filed Critical Kyowa Hakko Kogyo Co., Ltd.
Priority to AU55766/98A priority Critical patent/AU5576698A/en
Publication of WO1998032750A1 publication Critical patent/WO1998032750A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/92—Naphthofurans; Hydrogenated naphthofurans

Definitions

  • the present invention relates to a novel MS-444 derivative having an immunosuppressive action and an antipruritic action.
  • the derivative of the present invention is useful for prevention and treatment of autoimmune diseases, allergic diseases, rejection at the time of organ transplantation, and the like. Also pruritic skin disease, pruritus due to visceral diseases, pruritus due to environmental factors or drugs, pruritus seen in late pregnancy, psychiatric pruritus, dry skin, pruritus associated with senile xerosis, etc. It is also useful for the treatment of Background art
  • Naphthoquinones include 5-hydroxy-3-methyl-4 (9H) -naphtho [2,3-c] furanone and 5-hydroxy-3-methyl-4 () isolated as a component of aloe (Aloe ferox). 1H) -Naphtho [2,3-c] furanone and 5-hydroxy-3-methylnaphtho [2,3-c] furan-4,9-dione [Phytochemistry 37, 1147-1148 ( 1994)], and 1,3-diphenylnaphtho [2,3-c] furanones as intermediates for the synthesis of aromatic orthodiketones [Cond'Landue de Sos Dou La Catemya Cyanus, Suri C (Comptes Rendus des Seances de 1 'Academie des Sciences, Serie 0 Vol. 274, pp. 1410-1412 (1972), Journal B-Kemicarille Lisaichi, Synops (Journalof ChemiCal Research,
  • Known immunosuppressants include corticosteroids, antimetabolites, alkylating agents, alkaloids, antibiotics, anti-lymphocyte globulin, anti-CD3 monoclonal antibodies, etc., and are used for autoimmune diseases, allergic diseases, organs, etc. It is used as a therapeutic agent for transplantation and the like.
  • conventional therapeutic agents do not always sufficiently satisfy medical needs in terms of efficacy, sustainability, side effects, and the like, and there is a need for the development of better immunosuppressants.
  • pruritus includes contact dermatitis, atopic dermatitis, pruritic skin diseases accompanied by rashes such as rash and toxic rash, thyroid gland, parathyroid dysfunction, diabetes, bile cholestasis, liver cirrhosis, chronic Skin pruritus associated with internal diseases such as renal failure, uremia, Hodgkin disease, iron deficiency anemia, malignant tumors, parasitic diseases, multiple sclerosis, cerebral infarction, and mechanical irritation, humidity, diet, etc.
  • the pathogenesis is complicated, and there are many parts that have not yet been elucidated.
  • the number of patients with pruritus is rapidly increasing compared to before due to the remarkable changes in life patterns in recent years.
  • its treatment has not been established because the mechanism of its onset is often unclear.
  • the use of antihistamines and steroids is limited. When these drugs are effective, they are very limited, and effective antipruritic drugs are desired.
  • An object of the present invention is to provide a novel MS-444 derivative having an excellent immunosuppressive effect and an excellent antipruritic effect.
  • the present invention provides a compound represented by the general formula (I):
  • R 1 and R 2 represents hydrogen or lower alkyl the same or different, V 1 represents an oxygen becomes represent a hydroxy or lower alkoxy, or V 2 and integrated.
  • V 2 is V 1 and a bond together or W 1 and represents oxygen together.
  • W 1 is either hydrogen, or represents a bond becomes V 2 integrally, or X 2 and together represent a bond.
  • X 1 represents a lower alkyl, or X 2 and.
  • X 2 representing oxygen together represents hydrogen, or represents an oxygen becomes X 1 integral, or the W 1 a bond together.
  • Y represents a bond Te represents hydrogen, or W 2 and integrally summer.
  • W 2 is represents hydrogen, or represents a bond becomes Y integral or I integral, represents a bond becomes.
  • Z represents a binding together or W 2 and hydrogen.
  • R 1 and R 2 water In and, X 1 is methyl, 2 and oxygen together, and a bond becomes W 1 and X 2, and Y and W 2 gar body, when Z is hydrogen are excluded. ).
  • compound (I) the compound represented by the formula (I) is referred to as compound (I).
  • compound (I) the compound represented by the formula (I).
  • the lower alkyl moiety in the lower alkyl and the lower alkoxy is a straight or branched chain having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, Represents sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, etc.
  • V 1 and V 2 are in the form of oxygen
  • W 1 and X 2 are in the form of a bond
  • X 1 is A compound that is a lower alkyl
  • V 1 and V 2 are in the form of oxygen
  • W 1 and X 2 are in the form of a bond
  • X 1 is lower alkyl
  • Y, W 2 and A compound in which Z is hydrogen
  • V 1 is hydroxy
  • V 2 and W 1 are in a bond
  • X 1 is Lower alkyl
  • compound X 2 is hydrogen
  • V 1 is hydroxy
  • X 1 is lower alkyl
  • X 2 is hydrogen
  • V 1 and V 2 are in the form of oxygen
  • W 1 is hydrogen
  • X 1 and X 2 are Compounds that are in the form of oxygen, V 1 and V 2 are in the form of oxygen, W 1 is hydrogen
  • Compound (I) may have stereoisomers such as enantiomers and chemically equivalent tautomers, but the present invention includes all of these possible isomers and mixtures thereof.
  • the mixing ratio includes any ratio.
  • R la and R 2a each represent lower alkyl except hydrogen from R 1 and R 2 , and X la represents lower alkyl.
  • the compound (Ia) is produced by treating the compound (A) obtained in the following steps 2 to 5 with an acid such as p-toluenesulfonic acid or camphorsulfonic acid in a solvent such as benzene, toluene or xylene. be able to.
  • an acid such as p-toluenesulfonic acid or camphorsulfonic acid
  • a solvent such as benzene, toluene or xylene.
  • the acid is used in an amount of 0.01 to 1 equivalent to the compound (A), and the reaction is completed in 50 to 100 times in 1 to 5 hours.
  • Methyl tetrolate is used in an amount of 0.8 to 2 equivalents relative to compound (B), and the reaction is carried out in a sealed autoclave at 150 to 250 times. In 30 hours to 10 days.
  • R 1 and R 2 are lower alkyl, 1 month 2 Toe
  • R la and R 2a are as defined above.
  • Compound (lb) can be produced by reacting compound (C) with crotonolactone in a solvent such as tetrahydrofuran (THF), tetrahydropyran or dioxane in the presence of a base such as lithium diisopropylamide.
  • a solvent such as tetrahydrofuran (THF), tetrahydropyran or dioxane
  • a base such as lithium diisopropylamide.
  • R 1 and R 2 are lower alkyl, V 1 is lower alkoxy, V 2 is bonded to W 1 to form a bond, and X 1 and X 2 are
  • the compound (I c) wherein Y represents oxygen and Y, W 2 and I represent hydrogen can be produced by the following steps.
  • Compound (Ic) can be produced by reacting compound (lb) with a lower trialkyl orthoformate in a solvent such as methanol in the presence of an acid such as P-toluenesulfonic acid or camphorsulfonic acid.
  • the acid is used in an amount of 0.01 to 1 equivalent and the lower trialkyl orthoformate is used in an amount of 1 to 5 equivalents based on the compound (lb), and the reaction is completed at 20 to 80 in 5 to 24 hours.
  • Compound (A) can be produced by reacting compound (Ic) with lower alkyllithium or lower alkylmagnesium bromide in a solvent such as dichloromethane, dichloroethane or THF.
  • the alkyl lithium or alkyl magnesium bromide is used in an amount of 1 to 3 equivalents to the compound (Ic), and the reaction is completed at -50 to -90 in 0.5 to 3 hours.
  • Manufacturing method 4
  • R 1 and R 2 are hydrogen, X 1 is lower alkyl, V 1 is combined with V 2 to represent oxygen, and W 1 is combined with X 2 to be combined And a compound (Id) in which Y, W 2 and I represent hydrogen can be produced by the following steps.
  • the compound (id) can be produced by treating the compound (la) with a Lewis acid such as boron tribromide in a solvent such as dichloromethane or dichloroethane.
  • a Lewis acid such as boron tribromide
  • a solvent such as dichloromethane or dichloroethane.
  • the acid is used in 2 to 4 equivalents to the compound (Ia), and the reaction is completed at -78 to 10 in 0.5 to 3 hours.
  • R 1 is lower alkyl
  • R 2 is hydrogen
  • X 1 is lower alkyl
  • V 1 together with V 2 represents oxygen
  • 1 ⁇ 1 represents 2
  • the compound (Ie), which forms a bond to represent a bond and Y, W 2 and I represent hydrogen, can be produced by the following steps.
  • Compound (Ie) can be obtained by treating compound (Ia) with lithium chloride in a solvent such as toluene or ⁇ ', N-dimethylformamide.
  • Lithium chloride is used in an amount of 2 to 5 equivalents relative to compound (Ia), and the reaction is completed in a sealed autoclave at 120 to 250 ° C for 24 to 100 hours.
  • R 1 and R 2 are hydrogen, X 1 is lower alkyl, V 1 is combined with V 2 to represent oxygen, and W 1 is combined with X 2 to be combined the stands, Y is W 2 and represents a bond together, compound I represents hydrogen (I f) [However, if X 1 is methyl are known MS-444, the compound (I f) , And in compound (I), R 1 and R 2 are hydrogen, V 1 is hydroxy, V 2 and W 1 are a bond, and X 1 is lower alkyl. , X 2 represents hydrogen, Y represents hydrogen, and W 2 and Z form a bond to form a bond (I g), which can be produced by the following steps.
  • the compound (Ig) may exist as a chemically equivalent enedione-type compound (Ig ') [for example, the compound (4) in Example 4 corresponds to the compound (Ig)]. ].
  • Compound (Id) can be prepared from various compounds such as cyclohexene and 10% palladium activated carbon in a solvent such as benzene, toluene, and xylene.
  • the compound (If) and (Ig) or (Ig ') or both can be obtained by treating in the presence of a palladium-carbon catalyst.
  • Cyclohexene is 5-20 equivalents to compound (Id), and palladium activated carbon is
  • R 1 and R 2 are lower alkyls, V 1 is a hydroxy, V 2 and W 1 are a bond, X 1 represents a lower alkyl, X 2 Represents hydrogen, Y represents hydrogen, and W 2 and I form a bond to represent a bond.
  • (Ih) can be produced from compound (Ia) by the following step 9 under the same conditions as in step 8 above.
  • Table 1 shows specific examples of the compound of the present invention.
  • Test Example 1 T cell proliferation inhibition test in mouse lymphocyte mixed reaction
  • spleens were aseptically removed from AKR mice (Nippon S.L.C.I. Co., Ltd.) and converted into single cell suspension using HBSS-FCS.
  • Mitomycin C (MC) [Kyowa Hakko Kogyo Co., Ltd. (Final concentration: 50 g / ml), and cultured at 37 for 30 minutes. After culturing, wash three times with HBSS-FCS, then
  • a single cell suspension (1 ⁇ 10 7 cells / ml) was prepared using (RPMI 1640).
  • BR mice each Ueru of 50 1 (1.5 X 10 5 eel Is contained), spleen cell suspension 50 H 1 of AKR mice (5 X 10 5 cells containing ) and culture 100 1 containing the test compound test concentrations were added and cultured for 72 hours in C0 2 incubator within one 37 ° C.
  • [ 3 H] -thymidine 1.0 Ci was added 18 hours before the completion of the culture.
  • the cells were scavenged on a filter paper in Xel-Ha one base star, after drying toluene-based scintillator Isseki one added, incorporated into the cells in a liquid scintillation counter evening one [3 H] - a radioactivity of thymidine Measured (test group).
  • a culture solution containing no test compound was added, and the cells were cultured in the same manner as above, and the amount of [ 3 H] -thymidine incorporated into the cells was measured.
  • B10. Add 150 ml of the culture solution to the lymph node cell suspension 50 1 (containing 1.5 x 10 5 cells) of the BR mouse or the spleen cell suspension 50 1 of the AKR mouse, and incubate the cells as described above. The radioactivity of [ 3 H] -thymidine incorporated was measured.
  • the T cell proliferation inhibition rate was calculated according to the following equation. In the control group
  • Compound 48/80 was subcutaneously administered at 0.5 mg / kg.
  • the number of drawing actions was measured for 10 to 10 minutes after administration of the compound 48/80.
  • the suppression rate of the number of contact actions was calculated according to the following equation. In addition, 10 animals were used for each group. Sample administration group
  • the MS-444 derivative has excellent immunosuppressive activity, is useful as a therapeutic agent for autoimmune diseases, allergic diseases, organ transplantation, etc. and has excellent antipruritic effect It was confirmed that.
  • Me represents methyl
  • pheno l represents phenol
  • ke to represents keto
  • eno l represents enol
  • gem represents two groups bonded to the same atom. Mean relationship.
  • Table 4 shows the structures of the reference compounds used in the examples.
  • the reference compound (8) (1.42 g, 10.0 mmol) synthesized from 1,4-dimethoxybenzene was weighed into an autoclave according to the method described in Society, Perkin Transactions Part 1), p. Methyl monolate (1.00 m then 10.0 mmol) was added at room temperature. Seal the autoclave and stir at 180 for 1 week, then 200. And stirred for 8 hours.
  • THF anhydrous tetrahydrofuran
  • LDA lithium diisopropylamide
  • the reference compound (9) (705.0 mg, 3.35 mmol) was dissolved in 21 ml of anhydrous THF, cooled to -40 ° C, and the previously prepared 1.0 M LDA-THF solution (10.0 m, 10.0 mmol) was added under a nitrogen atmosphere. It was added dropwise over 20 minutes. After stirring at -40 ° C for 2 hours to lithify, a solution of crotonolatatone (0.47 ml, 6.70 mmol) in anhydrous THF
  • Reference compound (7) (85.6 mg, 0.31 mmol) was dissolved in anhydrous dichloromethane (2.6 ml) and cooled to -78 ° C. A 1.04 M methyllithium ether solution (0.74 ml, 0.77 mmol) was added dropwise, and the mixture was stirred as it was under a nitrogen atmosphere at -78 for 1 hour. After the reaction was completed, saturated aqueous ammonium chloride was added, and the mixture was separated. The aqueous phase was extracted three times with a black hole form, and the combined organic phases were washed with saturated saline, dried over sodium sulfate, and concentrated under reduced pressure.

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  • Organic Chemistry (AREA)
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Abstract

Nouveaux dérivés de MS-444 présentant un excellent effet immunodépresseur et anti-démangeaison, de formule générale (I). Dans ladite formule, R1 et R2 sont identiques ou différents, représentant chacun hydrogène ou alkyle inférieur; V1 est hydroxy, alcoxy inférieur, etc.; V2 représente oxygène avec V1 ou une liaison avec W1; W1 représente hydrogène ou une liaison avec V2 ou X2, etc.; X1 représente alkyle inférieur ou oxygène avec X2; X2 représente hydrogène ou oxygène avec X1, etc.; Y représente hydrogène ou une liaison avec W2; W2 représente hydrogène ou une liaison avec Y, etc.; et Z représente hydrogène ou une liaison avec W2, à condition d'exclure le cas où R1 et R2 représentent chacun hydrogène, X1 représente méthyle, V1 et V2 forment ensemble oxygène, une paire de W1 et X2 et une paire de Y et W2 représentent chacune une liaison, et Z représente hydrogène.
PCT/JP1998/000265 1997-01-23 1998-01-23 Derives de ms-444 WO1998032750A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU55766/98A AU5576698A (en) 1997-01-23 1998-01-23 Ms-444 derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP1062697 1997-01-23
JP9/10626 1997-01-23

Publications (1)

Publication Number Publication Date
WO1998032750A1 true WO1998032750A1 (fr) 1998-07-30

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005007163A1 (fr) * 2003-07-17 2005-01-27 Sumitomo Pharmaceuticals Co., Ltd. Agent antiprurigineux contenant un compose de chromane en tant qu'ingredient actif
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993009109A1 (fr) * 1991-11-07 1993-05-13 Kyowa Hakko Kogyo Co., Ltd. Compose ms-444

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993009109A1 (fr) * 1991-11-07 1993-05-13 Kyowa Hakko Kogyo Co., Ltd. Compose ms-444

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"TOTAL SYNTHESIS OF MS-444, A MYOSIN LIGHT CHAIN KINASE INHIBITOR.", THE JOURNAL OF ANTIBIOTICS, NATURE PUBLISHING GROUP, GB, vol. 50., no. 03., 1 March 1997 (1997-03-01), GB, pages 289/290., XP002914044, ISSN: 0021-8820 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005007163A1 (fr) * 2003-07-17 2005-01-27 Sumitomo Pharmaceuticals Co., Ltd. Agent antiprurigineux contenant un compose de chromane en tant qu'ingredient actif
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection

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AU5576698A (en) 1998-08-18

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