JPH04182429A - Non-aqueous solution pharmaceutical preparation - Google Patents

Abstract

PURPOSE:To obtain the title pharmaceutical preparation useful for the therapies for the rejections to transplanted organs, autoimmune diseases and infectious diseases by dissolving in a non-aqueous solvent a macrolide such as FR-900506 in combination with an oil. CONSTITUTION:The objective pharmaceutical preparation can be obtained by dissolving in a non-aqueous solvent a compound of the formula [R<1> and R<2>, R<3> and R<4>, and R<5> and R<6> form, respectively, linkage together with the two hydrogen atoms adjacent thereto, R<2> is also alkyl; R<7> is H, (protected) OH or alkyloxy; R<8> and R<9> are each H or OH; R<10> is H, (substituted) alkyl or (substituted) alkenyl; X is O, (H, OH), (H, H) or CH2O; Y is O, (H, OH), (H, H), N-NR<11>R<12> or N-OR<13>; R<11> and R<12> are each H, alkyl, aryl, etc.; R<13>-R<19>,R<22> and R<25> are each H or alkyl; R<20> and R<21> are each O or (R, H) and (R, H); R and R are each OH, alkyloxy, etc.] or its salt in combination with an oil such as mineral oil or vegetable oil (pref. olive oil).

Description

DETAILED DESCRIPTION OF THE INVENTION This invention relates to new pharmaceutical formulations containing certain known compounds and their uses.

Yoguchi-7P Patent Application No. 0184162 (Fujisawa Pharmaceutical Co., Ltd.) discloses several macrolides isolated from microorganisms belonging to the genus Streptomyces.
om ces tsukubaensis ) No
9993 (Feikoken Article No. 927), or Streptomyces bigroscopicus subspecies.
Yakushima Ensu (Ei Chu Ei Chu E San Yu 1 set concave 5ub
sp, akushimaansis) No 7
The macrolides isolated from 238 (Feikoken Joyori No. 928) are FR-900506, FR-900520,
They are numbered FR-900523 and FR-900525. International patent application number 089105304 (7
Isons Public Limited Company) also discloses a number of macrocycles. The compounds disclosed in both of the above documents, as well as their pharmaceutically acceptable salts, are said to be useful in the treatment of transplanted organ rejection, autoimmune diseases and infectious diseases, among others.

Here we have found several novel non-aqueous formulations suitable for the administration of these compounds.

That is, according to the present invention, there can be provided a non-aqueous solution preparation containing at least one compound represented by formula I or a pharmaceutically acceptable salt thereof as an active ingredient and dissolved in a non-aqueous solvent together with an oil. .

(wherein each adjacent pair of R1 and R2, R3 and R4, R5 and R6 each independently represents a) two adjacent hydrogen atoms, or b) a bonding carbon '1gw , forming another bond with the child; in addition, R2 may be an alkyl group, and R7 represents a hydrogen atom, a hydroxy group, a protected hydroxy group, or an alkyloxy group. or together with R1 may represent an oxo group, R8 and R9 independently represent a hydrogen atom or a hydroxy group, R10 represents a 1g atom of water, an alkyl group, or an alkyl substituted with one or more hydroxy groups. group, alkenyl group, alkenyl group substituted with one or more hydroxy groups, or alkyl group substituted with oxo group, where X is an oxo group, (hydrogen atom, hydroquine group), (hydrogen atom, hydrogen atom), or the formula A group represented by -CH20-, Y is an oxo group, (hydrogen atom, hydroxy group), (hydrogen atom, hydrogen atom), or a group represented by 2N-NR11R12 or N-0R13, R11 and R12 are independent R, R, R, R, R, R, R, R and R23 independently represent a hydrogen atom or an alkyl group, R and R21 independently represent a hydrogen atom, an alkyl group, an aryl group, or a tosyl group; oxo group, or each independently (R20, hydrogen atom) and (R21, a
a
hydrogen atom), and R20 and R21 are independently a hydroxy group, an alkyloxy group, or a group of formula 0
A group represented by CH20CH2CH2oCH3 or R21 represents a hydroxyl group requiring protection, and R and R21 together represent an epoch a
a may represent an oxygen atom in the cyto ring, and n is 1.2
Or represents 3.

In addition to the above meanings, Y, R10 and R23 together with the carbon atom to which they are bonded represent a nitrogen atom, sulfur atom or oxygen atom consisting of a saturated or unsaturated 5- or 6-membered ring. may represent a heterocyclic group containing an alkyl group, a hydroxy group, an alkyl group substituted with one or more hydroxy groups, an alkyloxy group, a benzyl group and a group of the formula -CH2S.
may be substituted with one or more groups selected from the groups represented by e(C6H5)).

"Lower, unless otherwise specified, shall mean groups having from 1 to 6 carbon atoms.

Preferred examples of "alkyl groups" include straight-chain or branched-chain aliphatic hydrocarbon residues, such as methyl,
Examples include lower alkyl groups such as ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, neopentyl, and hexyl.

"Preferred examples of alkenyl groups J include straight-chain or branched-chain aliphatic hydrocarbon residues containing one double bond, such as vinyl, propenyl, futhynyl, methylpropenyl, pentenyl, hexenyl, etc. Examples include lower alkenyl groups.

Preferred examples of the "aryl group" include phenyl, tolyl, xylyl, cumenyl, mesityl, naphthyl, and the like.

Suitable protecting groups for the unprotected hydroxy group include, for example, lower alkylthiomethyl groups such as methylthiomethyl, ethylthiomethyl, propylthiomethyl, isopropylthiomethyl, butylthiomethyl, isobutylthiomethyl, and hexylthiomethyl. 1-(lower alkylthio)(lower)alkyl group, preferably C1-C4 alkylthiomethyl group, most preferably methylthiomethyl group; e.g. triethylsilyl, triethylsilyl, tributylsilyl, tertiary-butyl-dimethylsilyl , tri(lower)alkylsilyl such as tri-tert-butylsilyl, lower alkyl-diarylsilyl such as methyl-diphenylsilyl, nibble-diphenylsilyl, propyl-diphenylsilyl, tert-butyl-diphenylsilyl, etc. silyl groups, preferably tri(C-C)alkylsilyl groups and C1-C4 alkyldiphenylsilyl groups, most preferably tertiary-butyl-dimethylsilyl groups and tertiary-butyl-diphenylsilyl groups; Acyl groups such as aliphatic acyl groups derived from carboxylic acids, sulfonic acids and carbamic acids, aromatic acyl groups, and aliphatic acyl groups substituted with aromatic groups; and the like.

Examples of aliphatic acyl groups include formyl, acetyl,
Lower alkanoyl which may have one or more suitable substituents such as carboxy, such as propionyl, butyryl, imbutyryl, valeryl, invaleryl, pivaloyl, hexanoyl, carboxyacetyl, carboxypropionyl, carboxybutyryl, carboxyhexanoyl, etc. groups, such as lower alkyl, such as cyclopropyloxyacetyl, cyclobutyloxyprobionyl, cyclohebutyloxybutyryl, menthyloxyacetyl, menthyloxypropionyl, menthyloxybutyryl, menthyloxypentanoyl, menthyloxyhexanoyl, etc. cyclo(lower)alkoxy(lower)alkanoyl group which may have one or more suitable substituents, camphorsulfonyl group, such as carboxymethylcarbamoyl, carboxyethylcarbamoyl, carboquinepropylcarbamoylcarbamoyl, carboquinepentylcarbamoyl, Carboxy (lower) such as carboxyhexylcarbamoyl
Alkylcarbamoyl groups, or for example trimethylsilylmethoxycarbonylethylcarhamoyl, trimethylsilylethoxylponylbrobylcarbamoyl, triethylsilylethoxycarbonylpropylcarbamoyl, tertiary butyldimethylsilylethoxylponylbropylcarbamoyl, trimethylsilylpropoxycarbonylbutyl suitable substituents such as carboxy or protected carboxy such as tri(lower)alkylsilyl(lower)alkoxycarbonyl(lower)alkylcarbamoyl group such as carbamoyl group, protected carboxy(lower)alkylcarbamoyl group etc. Examples include lower alkylcarbamoyl groups having one or more of the following.

Examples of aromatic acyl groups include aroyl groups which may have one or more suitable substituents such as nitro, such as benzoyl, toluoyl, xyloyl, naphthoyl, nitrobenzoyl, dinitcobenzoyl, nitronaphthoyl; For example, benzenesulfonyl, toluenesulfonyl, xylenesulfonyl, naphthalenesulfonyl, fluorobenzenesulfonyl, chlorobenzenesulfonyl, bromobenzenesulfonyl, iodobenzenesulfonyl, etc.
Examples include arenesulfonyl groups which may have one or more suitable substituents such as halogen.

Examples of the aliphatic acyl group substituted with an aromatic group include phenylacetyl, phenylpropionyl, phenylbutyryl, 2-trifluoromethyl-2-methquin-2-
Phenylacetyl, 2-ethyl-2-trifluoromethyl-2-phenylacetyl, 2-trifluoromethyl-
Examples include alkanoyl groups which may have one or more suitable substituents such as lower alkoxy and trihalo(lower) alkyl, such as 2-propoxy-2-phenylacetyl.

Among the above acyl groups, preferable acyl groups include 01-C4 alkanoyl group which may have carboxy, and cyclo(05-C6) alkyloxy (05-C6) alkyloxy group having two (01-C) alkyl groups in the cycloalkyl moiety. 01~C
4) Alkanoyl group, camphorsulfonyl group, carboxy(C1-C4)alkylcarbamoyl group, tri(0
1-C4) alkylsilyl (01-C4) alkoxycarboxylic (Cl-C4) alkylcarbamoyl group, pendiyl group which may have 1 or 2 nitro groups, containing halogen Examples include benzenesulfonyl group, phenyl(01-C4)alkanoyl group having C-C alkoxy and trihalo(01-C)alkyl group, among which the most preferred are acetyl, carboxypropionyl, menthyloxyacetyl, Camphorsulfonyl, benzoyl, nitrobenzoyl, dinitrobenzoyl, iodobenzenesulfonyl and 2-trifluoromethyl-2-methoxy-2-phenylacetyl.

Preferred examples of the "heterocyclic group consisting of a 5- or 6-membered ring containing a nitrogen atom, a sulfur atom, or an oxygen atom" include a biyloryl group, a tetrahydrofuryl group, and the like.

Pharmaceutically acceptable salts of the compound (I) include non-toxic, conventional pharmaceutically acceptable salts, such as alkali metal salts such as sodium salts and potassium salts, alkaline earth salts such as calcium salts and magnesium salts. Mention may be made of metal salts, ammonium salts, salts with inorganic or organic bases, such as triethylamine salts, amine salts of N-benzyl-N-methylamine salts.

In compound (I), there may exist one or more pairs of stereoisomers such as optical isomers and geometric isomers due to the Hunhomer or asymmetric carbon atom and double bond, and such Hunhomer or isomer are also included within the scope of this invention.

As oils, mention may be made of certain mineral oils as well as vegetable oils, such as corn oil, peanut oil, sesame oil, castor oil, olive oil, cottonseed oil. However, olive oil and sesame oil are preferred.

The amount of oil that can be used in the formulation is not particularly limited, and the amount that can be used medicinally can be selected as appropriate.

If necessary, the formulation can also contain emulsifiers. Emulsifiers include fatty acids having 6 to 22 carbon atoms, such as caproic acid, octanoic acid, lauric acid, valmitic acid, stearic acid, linoleic acid, lylinic acid, ostearic acid, and oleic acid, and ethylene glycol, Esters or partial esters with aliphatic polyhydric alcohols such as glycerin, erythritol, arabitol, mannitol, sorbitol, hexyletol anhydride derived from sorbitol, or their cyclic anhydrides (the esters of hexitol anhydride are registered as '5PAN') ) and nonionic surfactants such as polyoxyethylene and polyoxypropylene derivatives of these esters. Mixed esters such as mixed or natural glycerides may also be used.

Other nonionic surfactants include oleic acid esters of sorbitan, such as the registered trademark 'Ar1ac
al CJ (sorbitan trioleate), '5p
an 80 J (sorbitan monooleate),'
5pan 85 J (sorbitan trioleate), which is no longer sold. Specific examples of other nonionic surfactants that may be employed include sorbitan monolaurate, polyoxyterensorbitol tetraoleate, polyoxyethylene sorbitol pentaoleate, and polyoxypropylene mannitol dioxyate. . If available, hydrogenated, ethoxylated, polyoxyethylated, or hydrogenated polyoxyethylated derivatives of the above surfactants may be employed.

However, preferred as emulsifier are one or more ethoxylated oleic acid glycerides, such as Labrafil M1944C5®.

Preferred non-aqueous solvents include alcohols such as ethanol.

The method of administering the formulation of the present invention is not particularly limited, and may be administered externally, orally, or parenterally.

The dosage for the above therapeutic uses will, of course, vary depending on the compound used, the method of administration, the treatment desired (eg, parenteral or oral), and the disease indicated.

When treating rejection of a transplanted organ, such as a transplanted liver, a suitable administration regimen is to administer 0.01 to 1 mg, preferably 0.075 to 0.5 mg, of the active ingredient per kg of body weight to the patient intramuscularly every 12 hours after surgery. It will probably be a targeted administration.

Following this, when the patient is able to absorb the drug from the gastrointestinal tract (usually 3 days after surgery), 0% of the active ingredient per kg of body weight is
．． 1-10 mg, preferably 0.15-5 mg, may be administered orally initially every 12 hours and then gradually increasing to every 3 days for as long as treatment is needed.

The above administration mode forms the second aspect of the invention.

The present invention will be explained below with reference to examples, but the present invention is not limited by these examples.

Todorobayu FR-90050612,5q Ethoxylated oleic acid glycerides (Labrafil M1944C5)
420.0 mg.

Ethanol 180.0 ■ Olive oil Amount to make 1 mQ First mix ethanol and FR-900506, then add L
Add abrafil M1944C5 followed by olive oil. The formulation may be administered as a liquid or may be filled into soft gelatin capsules.

Additionally, this formulation is suitable for intramuscular injection.

Claims (1)

[Claims] 1. General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R^1 and R^2, R^3 and R^4, R
Each adjacent pair of ^5 and R^6 each independently a) represents two adjacent hydrogen atoms, or b) forms another bond with the carbon atom to which it is attached. However, in addition, R^2 may be an alkyl group, and R^2 may be an alkyl group.
7 represents a hydrogen atom, a hydroxy group, a protected hydroxy group, or an alkyloxy group, or R^1
Together, they may represent an oxo group, R^8 and R^9 independently represent a hydrogen atom or a hydroxy group, and R^1^0 is substituted with a hydrogen atom, an alkyl group, or one or more hydroxy groups. alkyl group, alkenyl group, 1
an alkenyl group substituted with the above hydroxy group,
or an alkyl group substituted with an oxo group, X is an oxo group, (hydrogen atom, hydroxy group), (hydrogen atom, hydrogen atom), or a group represented by the formula -CH_2O-, Y is an oxo group, , hydroxy group), (hydrogen atom, hydrogen atom), or the formula N-NR^1^1R^1^2
Or the group represented by N-OR^1^3, R^1^
1 and R^1^2 are independently a hydrogen atom, an alkyl group,
Aryl group or tosyl group, R^1^3, R^1^4, R^1^5, R^1^6, R
^1^7, R^1^8, R^1^9, R^2^2 and R^2^3 independently represent a hydrogen atom or an alkyl group, R^2^0 and R^2^1 may be independently an oxo group, or each may independently be (R_a^2^0, hydrogen atom) and (R_a^2^1, hydrogen atom), and R_a
^2^0 and R_a^2^1 are independently a hydroxy group, an alkyloxy group, or the formula OCH_2OCH_
A group represented by 2CH_2OCH_3, or R_a^
2^1 represents a protected hydroxy group, and R_
a^2^0 and R_a^2^1 may together represent an oxygen atom in the epoxide ring, and n represents 1, 2 or 3. In addition to the above meanings, Y, R^1^0 and R^2
^3 may represent a heterocyclic group containing a nitrogen atom, sulfur atom, or oxygen atom consisting of a saturated or unsaturated 5- or 6-membered ring together with the carbon atom to which they are bonded. , the heterocyclic group includes an alkyl group, a hydroxy group, an alkyl group substituted by one or more hydroxy groups, an alkyloxy group, a benzyl group and a group of the formula -
A non-aqueous solution containing a compound (I) or a pharmaceutically acceptable salt thereof, which may be substituted with one or more groups selected from the groups represented by CH_2Se (C_6H_5), and an oil. formulation. 2. The compound is 17-allyl-1,14-dihydroxy-
12-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,2
8-Dioxa-4-azatricyclo[22.3.1.0
^4^,^9]Octacos-18-en-2,3,10
, 16-tetraone. The non-aqueous preparation according to claim 1.