GB2249787A

GB2249787A - Lactone compounds

Info

Publication number: GB2249787A
Application number: GB9025068A
Authority: GB
Inventors: Yoshihiro Namiki; Noriaki Kihara
Original assignee: Fujisawa Pharmaceutical Co Ltd
Current assignee: Fujisawa Pharmaceutical Co Ltd
Priority date: 1990-11-19
Filing date: 1990-11-19
Publication date: 1992-05-20
Also published as: GB9025068D0

Abstract

Compounds of the formula: <IMAGE> in which R<1> and R<2> are independently O, (H, OH), (H, protected hydroxy), or (H, alkoxy), R<3> is hydrogen, hydroxy, alkoxy or protected @@ hydroxy, R<4> is alkyl or alkenyl, n is 1 or 2, and the symbol of a line and a dotted line is a single bond @@ or a double bond, or a pharmaceutically acceptable salt thereof, possess immunosuppressive and antimicrobial activities.

Description

LACTONE COMPOUNDS This invention relates to novel lactone compounds having pharmacological activities, to a process for their production and to a pharmaceutical composition containing the same.

More particularly, it relates to novel lactone compounds, which have pharmacological activities such as immunosuppressive activity, antimicrobial activity, and the like, to a process for their production, to a pharmaceutical composition containing the same and to a use thereof as a medicament.

Accordingly, one object of this invention is to provide novel lactone compounds, which are useful as an immunosuppressant and an antimicrobial agent.

Another object of this invention is to provide a process for production of lactone compounds.

A further object of this invention is to provide a pharmaceutical composition containing, as an active ingredient, lactone compounds.

Still further object of this invention is to provide a use of lactone compounds as a medicament for treating and preventing immune-mediated diseases such as resistance to transplantation, graft-versus-host diseases by medulla ossium transplantation, autoimmune diseases and the like, and further infectious diseases.

The new lactone compounds of this invention can be represented by the following general formula

in which R1 and R2 are independently 0, (H, OH), (H, protected hydroxy), or (H, alkoxy), R3 is hydrogen, hydroxy, alkoxy or protected hydroxy, R4 is alkyl or alkenyl, n is 1 or 2, and the symbol of a line and a dotted line is a single bond or a double bond.

With respect to the lactone compounds (I) of this invention, it is to be understood that there may be one or more stereoisomeric pairs such as optical and geometrical isomers due to asymmetric carbon atom(s) and double bond(s), and such isomers are also included within a scope of this invention.

According to this invention, the object lactone compounds (I) can be prepared by the following process.

Process

or a salt thereof

Photolysis

or a salt thereof in which R1, R2, R3, R4, n and the symbol of a line and a dotted line are each as defined above.

Particulars of the above definitions and the preferred embodiments thereof are explained in detail as follows.

The term "lower" used in the specification is intended to mean 1 to 6, preferably 1 to 4 carbon atoms, unless otherwise indicated.

Suitable "alkyl" may include a straight or branched alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, octyl, nonyl, and the like, in which the preferred one is lower alkyl and the most preferred one is methyl, ethyl and propyl.

Suitable "alkoxy" may include a straight or branched alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, hexyloxy, octyloxy, nonyloxy, and the like, in which the preferred one is lower alkoxy and the most preferred one is methoxy.

Suitable "alkenyl" may include a straight or branched alkenyl such as vinyl, allyl, butenyl, pentenyl, hexenyl, octenyl, nonenyl, and the like, in which the preferred one is lower alkenyl and the most preferred one is allyl.

Suitable hydroxy-protective group in the "protected hydroxy" may include l-(lower alkylthio)(lower)alkyl such as lower alkylthiomethyl (e.g. methylthiomethyl, ethylthiomethyl, propylthiomethyl, isopropylthiomethyl, butylthiomethyl, isobutylthiomethyl, hexylthiomethyl, etc.), and the like, in which the preferred one may be C1-C4alkylthiomethyl and the most preferred one may be methylthiomethyl;; trisubstituted silyl such as tri(lower)alkylsilyl (e.g. trimethylsilyl, triethylsilyl, tributylsilyl, tert-butyl-dimethylsilyl, tri-tert-butylsilyl, etc.), lower alkyl-diarylsilyl (e.g. methyl-diphenylsilyl, ethyl-diphenylsilyl, propyl-diphenylsilyl, tert-butyl-diphenylsilyl, etc.), and the like, in which the preferred one may be tri(C1-C4)alkylsilyl and C1 -C4alkyl-diphenylsilyl, and the most preferred one may be tert-butyl-dimethylsilyl and tert-butyl-diphenylsilyl; acyl such as aliphatic acyl, aromatic acyl and aliphatic acyl substituted with aromatic group, which are derived from carboxylic, sulfonic and carbamic acids; and the like.

The aliphatic acyl may include lower alkanoyl which may have one or more suitable substituent(s) such as carboxy (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, carboxyacetyl, carboxypropionyl, carboxybutyryl, carboxyhexanoyl, etc.), cyclo(lower)alkyloxy(lower)alkanoyl which may have one or more suitable substituent(s) such as lower alkyl (e.g.

cyclopropyloxyacetyl, cyclobutyloxypropionyl, cycloheptyloxybutyryl, menthyloxyacetyl, menthyloxypropionyl, menthyloxybutyryl, menthyloxyheptanoyl, menthyloxyhexanoyl, etc.), camphorsulfonyl, lower alkylcarbamoyl having one or more suitable substituent(s) such as carboxy and a protected carboxy, for example, carboxy (lower) alkylcarbamoyl (e.g. carboxymethylcarbomoyl, carboxyethylcarbamoyl, carboxypropylcarbamoyl, carboxybutylcarbamoyl, carboxypentylcarbamoyl, carboxyhexylcarbamoyl, etc.), protected carboxy ( lower) alkylcarbamoyl such as tri(lower)alkylsilyl (lower) alkoxycarbonyl (lower) alkylcarbamoyl (e.g.

trimethylsilylmethoxycarbonylethylcarbamoyl, tr imethylsi lylethoxycarbonylpropylcarbamyl, triethylsilylethoxycarbonylpropylcarbamoyl, tert-butyldimethylsilylethoxycarbonylpropylcarbamoyl, trimethylsilylpropoxycarbonylbutylcarbamoyl, etc.), and the like.

The aromatic acyl may include aroyl which may have one or more suitable substituent(s) such as nitro (e.g.

benzoyl, toluoyl, xyloyl, naphthoyl, nitrobenzoyl, dinitrobenzoyl, nitronaphthoyl, etc), arenesulfonyl which may have one or more suitable substituent(s) such as halogen (e.g. benzenesulfonyl, toluenesulfonyl, xylenesulfonyl, naphthalenesulfonyl, fluorobenzenesulfonyl, chlorobenzenesulfonyl, bromobenzenesulfonyl, iodobenzenesulfonyl, etc.), and the like.

The aliphatic acyl substituted with aromatic group may include ar(lower)alkanoyl which may have one or more suitable substituent(s) such as lower alkoxy and trihalo(lower)alkyl (e.g. phenylacetyl, phenylpropionyl, phenylbutyryl, 2-trifluoromethyl-2-methoxy-2-phenylacetyl, 2-ethoxy-2-trifluoromethyl-2-phenylacetyl, 2-trifluoromethyl-2-propoxy-2-phenylacetyl, etc.), and the like.

The more preferred acyl group thus defined may be C1- C4alkanoyl which may have carboxy, cyclo(C5-C)alkyloxy- (C1-C4)alkanoyl having two (C1-C4)alkyl groups on the cycloalkyl moiety, camphorsulfonyl, carboxy(C1-C4)- alkylcarbamoyl, tri(C1-C4)alkylsilyl(C1-C4)alkoxyearbonyl- (C1-C4)alkylcarbamoyl, benzoyl which may have one or two nitro, benzenesulfonyl having halogen, phenyl(C1-C4)alkanoyl having C1-C4alkoxy and trihalo(C1-C4)alkyl, and the most preferred one may be acetyl, carboxypropionyl, menthyloxyacetyl, camphorsulfonyl, benzoyl, nitrobenzoyl, dinitrobenzoyl, iodobenzenesulfonyl and 2-trifluoromethyl-2-methoxy-2-phenylacetyl.

The process for production of the lactone compounds (I) of this invention are explained in detail in the following.

The compounds (I) or a salt thereof can be prepared by subjecting the compounds (II) or a salt thereof to photolysis.

The starting compounds (II) used in this process are known and described, for example, European Patent Publication Nos. 0 184 162 and 0 323 042. Among these compounds, the FR-900506 and FR-900525 substances can be produced by fermentation of Streptomyces tsukubaensis No.

9993 (FERM BP-927), and the FR-900523 substance can be produced by fermentation of Streptomyces hyqroscopicus subsp. yakushimaensis No. 7238 (FERM BP-928), and further the FR-900520 substance can be produced by fermentation of both microorganisms.

The photolysis can be carried out by a conventional manner, for example, exposure to light, preferably intense light such as 30,000 luxes.

This photolysis can be carried out in the absence or presence of a solvent which does not adversely influence the reaction. Further, this reaction can also be carried out in a suspension, for example, in water.

The reaction temperature is not restrictive, and the reaction is usually carried out at ambient temperature.

In this reaction, the following compounds (III) and (IV) can also be produced, both of which possess the similar pharmacological activities to those of the lactone compounds (I).

or a salt thereof

or a salt thereof in which R1, R, R3, R41 n and the symbol of a line and a dotted line are each as defined above.

The lactone compounds (I) possess pharmacological activities such as immunosuppressive activity, antimicrobial activity, and the like, and therefore are useful for the treatment and. prevention of immune-mediated diseases controlled. by a immunosuppressant such as the resistance to transplantation of organs or tissue such as heart, kidney, liver, medulla osmium, skin, cornea etc., graft-versus-host diseases by medulla ossium transplantation, autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia. gravis., type I diabetes, uveitis such as Behcet's disease, etc., vernal keratoconjunctivitis, and the like, and further infectious diseases caused by pathogenic microorganisras.

And further, the lactone compounds (I) are also useful in the topical administration for the treatment and the prophylaxis of inflammatory and hyperproliferative skin diseases and cutaneous manifestations of immunologically-mediated illnesses, such as psoriasis, atopical dermatitis, contact dermatitis and further eczematous dermatitises, seborrhoeis dermatitis, Lichen planus, Pemphigus, bullous Pemphigoid, Epidermolysis bullosa, urticaria, angioedemas, vasculitides, erythemas, cutaneous eosinophilias, Lupus erythematosus and Alopecia areata.

As an example for showing such pharmacological activities, the pharmacological test data of the lactone compounds (I) are illustrated in the following.

Test 1 Suppression of in vitro Mixed Lymphocyte Reaction (MLR) The MLR test was performed in microtiter plates, with each well containing 5 x 10 C57BL/6 responder cells tH-2b), 5 x 105 mitomycin C treated (25 pg/ml mitomycin C at 37"C for 30 minutes and washed three times with RPMI 1640 medium) BALB/C stimulator cells (H-2d) in 0.2 ml RPMI 1640 medium supplemented with 10% fetal calf serum, 2 mM sodium bicarbonate, penicillin (50 unit/ml) and streptomycin (50 pg/ml). The cells were incubated at 37"C in humidified atmosphere of 5% carbon dioxide and 95% of air for 68 hours and pulsed with 3H-thymidine (0.5 VCi) 4 hours before the cells were collected.The object compound of this invention were dissolved in ethanol and further diluted in RPMI 1640 medium and added to the cultures to give final concentrations of 100 nM or less.

The IC50 value (mol concentration to suppress 50% of MLR) was calculated by a conventional method.

The pharmaceutical composition of this invention can be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains the lactone compounds (I), as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external (topical), enteral or parenteral applications. The active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, injections, ointments, liniments, eye drops lotion, gel, cream and any other form suitable for use.

The carriers which can be used are water, glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato, starch, urea and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form, and in addition auxiliary, stabilizing, thickening, solubilizing an coloring agents and perfumes may be used. Particularly, as a solubilizing agent, there may be exemplified water-soluble cellulose polymer (i.e. hydroxypropyl methylcellulose, etc.), water-soluble glycol (i.e. propylene glycol, etc.), etc.

The active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of diseases.

For applying this composition to human, it is preferable to apply it by parenteral, enternal or external administration. While the dosage of therapeutically effective amount of the lactone compounds (I) varies from and also depends upon the age and condition of each individual patient to be treated, a daily dose of about 0.01-1000 mg, preferably 0.1-500 mg and more preferably 0.5-100 mg, of the active ingredient is generally given for treating diseases, and an average single dose of about 0.5 mg, 1 mg, 5 mg, 10 mg, 50 mg; 100 mg, 250 mg and 500 mg is generally administered.

The following examples are given for the purpose of illustrating the present invention.

Example 1 5 g of l7-Allyl-1,l4-dihydroxy-l2-(2-(4-hydroxy-3- methoxycyclohexyl) -1-methylvinyll -23, 25-dimethoxy- 13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo- [22.3.1.04,91octacos-18-ene-2,3,10,16-tetraone (FR-900506 Substance) was suspended in 500 ml of water, and exposed to light (30000 Luxes) with stirring for 30 days. The aged suspension was lyophilized and subsequently isolated by preparative high-pressure liquid chromatography (HPLC).

The first preparative HPLC procedure used a COSMOSIL 5C18 column 20 mm i.d. x 15 cm, NACALAI TESQUE INC.) with water:isopropanol:isopropyl ether (20:12:1) as an eluent.

The products mixture was dissolved in methanol and injected onto the column. The each fraction which contained each desired product was combined and lyophilized.

The second preparative HPLC step was used to be further purified each product. In this step, each product in chloroform was injected onto a TSKgel 120-OH (4.6 mm i.d. x 25 cm, TOSOH Co., Ltd.) with n-hexane:isopropanol:ethanol (18:1:1) as a mobile phase.

The fraction which contained each product was combined and the solvent was removed on a rotary evaporator to yield each chromatographycally pure material. By these operations, the following four degradation products were obtained.

Degradation Product (1)

(one of two diastereomers at the carbon atom marked by 3C-NMR : 9.04, 12.38, 15.61, 16.51, 19.74, 21.51, 25.55, 26.42, 27.12, 30.30, 30.97, 31.24, 32.01, 34.43, 35.00, 35.36, 35.56, 38.97, 44.08, 45.91, 48.06, 50.74, 52.57, 56.39, 56.54, 57.76, 67.21, 73.29, 73.46, 77.37, 80.08, 82.14, 84.17, 116.64, 123.74, 130.91, 133.73, 135.51, 138.52, 161.86, 169.58, 175.34, 211.29 FAB Mass : m/z 908 (M + Cs)+ Degradation Product (2)

(the other of two diastereomers at the carbon atom marked by "*") 13C-NMR : 8.96, 12.28, 16.46, 17.04, 19.60, 21.51, 25.56, 26.44, 26.91, 30.29, 31.23, 32.26, 33.35, 34.42, 34.81, 35.01, 35.30, 38.83, 44.09, 45.94, 48.48, 50.75, 52.55, 56.41, 56.81, 57.55, 67.08, 73.47, 73.65, 77.00, 82.42, 82.55, 84.17, 116.57, 123.72, 130.90, 133.91, 135.57, 138.64, 161.87, 169.57, 173.69, 211.15 FAB Mass : m/z 908 (M + Cs)+ Degradation Product (3)

13C-NMR : 10.47, 11.64, 16.67, 20.48, 20.98, 25.86, 25.91, 26.00, 26.42, 29.57, 30.34, 31.31, 33.14, 34.13, 34.43, 34.97, 38.45, 44.78, 45.40, 47.13, 50.19, 52.05,:52.71, 56.34, 56.70, 57.49, 66.27, 70.45, 72.37, 73.49, 76.69, 79.65, 84.29, 85.04, 116.23, 124.68, 130.83, 133.90, 135.84, 138.18, 169.53, 174.63, 171.75, 211.02 FAB Mass : m/z 936 (M + Cs)+ Degradation Product (4)

3C-NMR : 9.74, 13.67, 14.75, 15.77, 20.10, 21.07, 25.59, 25.66, 28.45, 30.54, 31.19, 32.27, 32.93, 34.73, 34.91, 35.71, 37.11, 41.98, 42.11, 47.66, 49.28, 51.93, 55.89, 56.52, 56.90, 57.89, 69.91, 73.10, 73.44, 73.53, 75.92, 78.02, 84.16, 97.63, 116.36, 123.30, 130.45, 132.49, 135.83, 139.31, 169.71, 169.80, 213.12 FAB Mass : m/z 908 (M + Cs) Example 2 The FR-900506 Substance in solid state was exposed to light under similar conditions to Example 1, and the same Degradation Products (1) to (4) could be obtained.

Claims

What is claimed is

1. A compound of the formula

in which R1 and R2 are independently 0, (H, OH), (H, protected hydroxy), or (H, alkoxy), R is hydrogen, hydroxy, alkoxy or protected hydroxy, R4 is alkyl or alkenyl, n is 1 or 2, and the symbol of a line and a dotted line is a single bond or a double bond, or a pharmaceutically acceptable salt thereof.

2. A process for production of a compound of the formula (I) as defined in claim 1 or a salt thereof, which comprises subjecting a compound of the formula

or a salt thereof to photolysis.