GB2252041A - Use of macrolide compounds in treatment of autoimmune myocarditis - Google Patents
Use of macrolide compounds in treatment of autoimmune myocarditis Download PDFInfo
- Publication number
- GB2252041A GB2252041A GB9101503A GB9101503A GB2252041A GB 2252041 A GB2252041 A GB 2252041A GB 9101503 A GB9101503 A GB 9101503A GB 9101503 A GB9101503 A GB 9101503A GB 2252041 A GB2252041 A GB 2252041A
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- alkyl
- represent
- macrolide compounds
- substituted
- autoimmune myocarditis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
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- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The use of macrolide compounds of the following formula for the prophylactic and/or therapeutic treatment of autoimmune myocarditis:- <IMAGE> wherein [R<1> and R<2>], [R<3> and R<4>], [R<5> and R<6>] independently a) represents two vicinal hydrogen atoms, or b) form a second bond between the vicinal carbon atoms to which @ they are attached; and R<2> may be alkyl; R<7> represents H,OH, protected hydroxy or O-alkyl, or with R<1> may represent =O; R<8> and R<9> are H or OH; R<10> represents H, alkyl alkyl substituted by one or more hydroxyl groups, alkenyl, alkenyl, alkenyl substituted by one or @more hydroxyl groups, or alkyl substituted by =O; X represents O, (H,OH) (H,H) or -CH2O-; Y represents O, (H,OH), (H,H), N-NR<11>R<12> @or N-OR<13>; R<11> and R<12> are H, alkyl aryl or tosyl; R<13>, R<14>, R<15>, R<16>, @R<17>, R<18>, R<19>, R<22> @and R<23> independently represents H or alkyl; R<20> and R<21> are O, or they represent (R<20>a,H) and (R<21>a,H) respectively; @R<20>a and R<21>a are OH, O-alkyl or OCH2OCH2CH2OCH3 or @R<21>a is protected hydroxy; in addition, R<20>a and R<2>1a may together @represent an oxygen atom in an epoxide ring; n is 1, 2 or 3; in addition to their significances above, Y, R<10> @and R<23>, together with the carbon atoms to which they @are attached, are a 5- 6- membered N-, S- or O- containing @heterocyclic ring, saturated or unsaturated, which may be @substituted by one or more groups selected from alkyl, hydroxy, @alkyl substituted by one or more hydroxyl groups, O-alkyl, @benzyl and -CH2Se(CH6H5); or a pharmaceutically acceptable salt thereof.
Description
NEW USE
This invention relates to a new use of macrolide compounds for autoimmune myocarditis.
Accordingly, this invention provides a new use of the macrolide compounds for preventing or treating autoimmune myocarditis.
Further, this invention provides a prophylactic or therapeutic agent for autoimmune myocarditis, which comprises the macrolide compounds.
Still further, this invention provides a method for preventing or treating autoimmune myocarditis, which comprises administering said macrolide compounds to mammals.
Some of the macrolide compounds used in this invention are known and disclosed, for example, in European Patent
Publication No. 0184162 and International Patent-Application WO 89/05304.
Those known macrolide compounds include the fermentation products, FR-900506, FR-900520, FR-900523 and
FR-900525 isolated from microorganisms belonging to genus StreDtomvces and their related compounds prepared from these fermentation products. Further, new macrolide compounds can be prepared from the above known macrolide compounds in a conventional manner.
These macrolide compounds were indicated inter alia for use in the treatment of rejection to transplantation, autoimmune diseases and infectious diseases.
The inventors of this invention have surprisingly found that the macrolide compounds mentioned hereinbelow are useful for preventing or treating autoimmune myocarditis.
The macrolide compounds used in this invention can be represented by the following general formula (I).
wherein each vicinal pair of substituents [R1 and R2), [R3 and R4), [R5 and R6] independently a) represent two vicinal hydrogen atoms, or b) form a second bond between the vicinal carbon atoms to which they are attached;
in addition to its significance above, R2 may represent an alkyl group;
R7 represents H, OH, protected hydroxy or O-alkyl, or in conjunction with R1 it may represent =0; R8 and R9 independently represent H or OH;
R10 represents H, alkyl, alkyl substituted by one or more hydroxyl groups, alkenyl, alkenyl substituted by one or more hydroxyl groups, or alkyl substituted by =O;
X represents 0, (H,OH), (H,H) or -CH2O-; Y represents 0, (H,OH), (H,H), N-NR11R12 or N-OR13;; Rll and R12 independently represent H, alkyl, aryl or tosyl;
R13, R14, R15, R16, R17, R18, R19, R22 and R23 independently represent H or alkyl;
R20 and R21 independently represent 0, or they may independently represent (R20a,H) and (R2la,H) respectively;
R20a and R21a independently represent OH, O-alkyl or
OCH2OCH2CH2OCH3 or R21a is protected hydroxy;
in addition, R20a and R21a may together represent an oxygen atom in an epoxide ring;
n is 1, 2 or 3;;
in addition to their significances above, Y, R10 and
R23, together with the carbon atoms to which they are attached, may represent a 5- or 6- membered N-, S- or O- containing heterocyclic ring, which may be saturated or unsaturated, and which may be substituted by one or more groups selected from alkyl, hydroxy, alkyl substituted by one or more hydroxyl groups, O-alkyl, benzyl and -CH2Se(C6HS); and pharmaceutically acceptable derivatives thereof.
The term "lower" used in the specification is intended to mean 1 to 6 carbon atoms, unless otherwise indicated.
Suitable "alkyl" means straight or branched saturated aliphatic hydrocarbon residue and may include lower alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, neopentyl, hexyl, and the like.
Suitable "alkenyl" means straight or branched unsaturated aliphatic hydrocarbon residue having one double bond and may include lower alkenyl such as vinyl, propenyl, butenyl, methylpropenyl, pentenyl, hexenyl, and the like.
Suitable "aryl" may include phenyl, tolyl, xylyl, cumenyl, mesityl, naphthyl, and the like.
Suitable hydroxy-protective group in the "protected hydroxy" may include 1lower alkylthio)(lower)alkyl, trisubstituted silyl and acyl as exemplified in European
Patent Publication No. 0184162.
Suitable "5- or 6-membered N-, S- or O-containing heterocyclic ring" may include pyrrolyl, tetrahydrofuryl, and the like.
Preferred embodiments of the Symbols R1 to R30, R14 to
R23, X, Y and n are as follows.
R1 and R2 are each hydrogen or combined to form a second bond;
R3 and R4 are combined to form a second bond;
R5 and R6 are combined to form a second bond;
R7 is hydrogen, hydroxy, O-lower alkyl such as methoxy or protected hydroxy;
R8 is hydrogen;
R9 is hydroxy;
R10 is methyl, ethyl, propyl or allyl;
R14, R15, R16, R171 R18 and R19 are each methyl;
R20 is oxo or (R20a,H), wherein R20a is hydroxy or methoxy;
R21 is [R21a,H], wherein R21a is hydroxy or protected hydroxy;
R23 is hydrogen;
X is oxo, (H,OH) or (H,H);
Y is oxo; and
n is 1 or 2.
Particularly, the most interesting compound is
FR-900506 of the following formula.
FR-900506 ( FK506
With respect to the macrolide compounds (I) of this invention, it is to be understood that there may be one or more conformers or stereoisomeric pairs such as optical and geometrical isomers due to asymmetric carbon atoms and double bonds, and such isomers are also included within the scope of the present invention.
Salts of the macrolide compounds of the present invention include all pharmaceutically acceptable salts without limitation.
As example for showing pharmacological activity, the pharmacological test data of the macrolide compounds are illustrated in the following.
Test (materials and methods)
Rats: Lewis rats were purchased from Charles River Japan
Inc.. They were bred and maintained at our animal facilities.
Drug: FK-506 was obtained from Fujisawa Pharmaceutical Co.,
Osaka, Japan.
Purification of cardiac myosin: Cardiac myosin was prepared from the ventricular muscle of human hearts, according to the method of Murakami et al. with some modifications.
Immunization: On day 0, rats (6-7 weeks old) were injected subcutaneously into the footpads with human cardiac myosin in Freund's complete adjuvant supplemented with
Mycobacterium tuberculosis. On day 7, the rats were immunized again using the same protocol.
Treatment: Twenty rats were divided into four groups each of which included five rats. Each group was injected intramuscularly FK-506 on days 11-20 after the first immunization as follows: control (saline), group 1 (FK-506, 0.1 mg/kg/day), group 2 (FK-506, 0.32 mg/kg/day), group 3 (FK506, 1.0 mg/kg/day).
Histopathology: Rats were sacrificed on day 24 and examined for the appearance of myocarditis. Then the body and heart were the appearance of myocarditis. Then the body and heart were weighed. The speciments of the hearts were examined with a microscope under x 400 magnification. Myocarditis was scored by histologic extent as follows: 0 (no lesion), 1 (the lesion did not exceed a half of the field), 2 (the lesion exceeded a half of the field), 3 (there was no normal area in the field). All fields of the specimen were examined without exception and the scores were averaged.
Anti-myosin antibodies: Anti-myosin antibodies in sera from rats on day 24 were measured using an enzyme-linded immunosorbent assay.
(results)
Activity of the immunized rats: The rats in control and group 1 became ill from the second week but those of group 2 and group 3 were active until sacrifice.
Histopathology: Histologic scores were as follows: control (2.76), group 1 (0.99), group 2 (0.17), group 3 (0). Rats with high dose of FK506 had lower histologic scores. In group 3 (1.0 mg/kg/day), there were no inflammatory lesions in the myocardium.
Heart weight / Body weight: Heart weight / Body weight were as follows: control (0.77%), group 1 (0.44%), group 2 (0.38%), group 3 (0.36%). This ratio was significantly high in only the control group.
The macrolide compounds of the present invention may be administered as pure compounds or mixtures of compounds or preferably, in a pharmaceutical vehicle or carrier.
The pharmaceutical compositions of this invention can be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains the macrolide compounds of the present invention, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral, intravenous, intramuscular, 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 (saline, for example), emulsion, suspensions (olive oil, for example), 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 and coloring agents and perfumes may be used. The active object compound is included in the pharmaceutical composition in an effective amount sufficient to produce the desired effect upon the process or condition of the disease.
Mammals which may be treated using the method of the present invention include livestock mammals such as cows, horses, etc., domestic animals such as dogs, cats, rats, etc. and humans.
For applying this composition to a human, it is preferable to apply it by oral, parenteral, external, enteral, intravenous, or intramuscular administration.
While the dosage of therapeutically effective amount of the macrolide compounds 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 0.2-0.5 mg, 1 mg, 5 mg, 10 mg, 50 mg, 100 mg, 250 mg and 500 mg is generally administered.
Daily doses for chronic administration in humans will be in the range of about 0.3 mg/kg/day.
The following examples are given for the purpose of illustrating the present invention.
Example 1
FK 506 ig Hydroxypropyl methylcellulose 2910 (TC-SR) 1 g
Lactose 2g
Croscarmellose sodium (Ac-Di-Sol) 1 g
The FK 506 (1 g) was dissolved in ethanol (10 ml), and thereto was added hydroxypropyl methylcellulose 2910 (TC-SR) (1 g) to prepare a suspension. To this suspension was added dichloromethane (5 ml) to prepare a homogeneous solution.
Lactose (2 g) and croscarmellose sodium (Trade Mark:
Ac-Di-Sol, maker: Asahi Chemical Industry) were homogeneously suspended to this solution, and then the organic solvent was removed by evaporation. The residual product was dried under reduced pressure for 10 hours by vacuum dryer, milled for 2 minutes by coffee mill and then passed through a sieve (32 mesh) to give the solid dispersion composition of FK 506 (5 g). This composition was capsulated by a conventional manner to provide capsules containing 1 mg or 5 mg of FK 506 per each capsule.
Claims (7)
1. A use of macrolide compounds of the formula:
wherein each vicinal pair of substituents [R1 and R2), (R3 and R4), [R5 and R6] independently
a) represent two vicinal hydrogen atoms, or
b) form a second bond between the vicinal
carbon atoms to which they are attached;
in addition to its significance above, R2 may
represent an alkyl group;
R7 represents H, OH, protected hydroxy or
O-alkyl, or in conjunction with R1 it may
represent =0; R8 and R9 independently represent H or OH;
R10 represents H, alkyl, alkyl substituted by
one or more hydroxyl groups, alkenyl,
alkenyl substituted by one or more hydroxyl
groups, or alkyl substituted by =O;
X represents 0, (H,OH), (H,H) or -CH2O-;;
Y represents 0, (H,OH), (H,H), N-NR11R12 or
N-OR13; R11 and R12 independently represent H, alkyl,
aryl or tosyl;
R13, R14, R151 R16, R171 R18, R19, R22 and R23
independently represent H or alkyl;
R20 and R21 independently represent 0, or they
may independently represent (R20a,H) and
(R21a,H) respectively;R20a and R21a
independently represent OH, O-alkyl or
OCH2OCH2CH2OCH3 or R21a is protected
hydroxy;
in addition, R20a and R21a may together
represent an oxygen atom in an epoxide ring;
n is 1, 2 or 3;
in addition to their significances above, Y, R10
and R23, together with the carbon atoms to which
they are attached, may represent a 5- or 6
membered N-, S- or 0- containing heterocyclic
ring, which may be saturated or unsaturated, and
which may be substituted by one or more groups
selected from alkyl, hydroxy, alkyl substituted
by one or more hydroxyl groups, O-alkyl, benzyl
and -CH2Se(C6Hs);
or a pharmaceutically acceptable salt thereof, for
preventing or treating autoimmune myocarditis.
2. A use of the macrolide compounds (I) defined in Claim 1
as a prophylactic or therapeutic agent for autoimmune
myocarditis.
3 A prophylactic or therapeutic agent for autoimmune
myocarditis, which comprises the macrolide compounds (I)
defined in Claim 1.
4. A method for preventing or treating autoimmune
myocarditis, which comprises administering the macrolide
compounds (I) defined in claim 1 to mammals.
5. A use of the macrolide compounds (I) defined in claim 1
for manufacturing a medicament for preventing or treating
autoimmune myocarditis.
6. A pharmaceutical composition for autoimmune myocarditis,
which comprises the macrolide compounds (I) defined in
Claim 1 in admixture with a carrier or excipient.
7. A process for preparing the pharmaceutical composition of
Claim 6, which is characterized by admixing the macrolide
compounds (I) with a carrier or excipient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9101503A GB2252041A (en) | 1991-01-23 | 1991-01-23 | Use of macrolide compounds in treatment of autoimmune myocarditis |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9101503A GB2252041A (en) | 1991-01-23 | 1991-01-23 | Use of macrolide compounds in treatment of autoimmune myocarditis |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB9101503D0 GB9101503D0 (en) | 1991-03-06 |
| GB2252041A true GB2252041A (en) | 1992-07-29 |
Family
ID=10688908
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB9101503A Withdrawn GB2252041A (en) | 1991-01-23 | 1991-01-23 | Use of macrolide compounds in treatment of autoimmune myocarditis |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2252041A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003035068A1 (en) * | 2001-10-23 | 2003-05-01 | Novartis Ag | Macrolides containing pharmaceutical compositions |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1989005304A1 (en) * | 1987-12-09 | 1989-06-15 | Fisons Plc | Macrocyclic compounds |
| WO1990004398A1 (en) * | 1988-10-28 | 1990-05-03 | Klaus Bendtzen | A new pharmaceutical use of fusidic acid and derivatives thereof |
-
1991
- 1991-01-23 GB GB9101503A patent/GB2252041A/en not_active Withdrawn
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1989005304A1 (en) * | 1987-12-09 | 1989-06-15 | Fisons Plc | Macrocyclic compounds |
| WO1990004398A1 (en) * | 1988-10-28 | 1990-05-03 | Klaus Bendtzen | A new pharmaceutical use of fusidic acid and derivatives thereof |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003035068A1 (en) * | 2001-10-23 | 2003-05-01 | Novartis Ag | Macrolides containing pharmaceutical compositions |
| JP2005509634A (en) * | 2001-10-23 | 2005-04-14 | ノバルティス アクチエンゲゼルシャフト | Pharmaceutical composition comprising macrolide |
| US7259170B2 (en) | 2001-10-23 | 2007-08-21 | Novartis Ag | Macrolides containing pharmaceutical compositions |
Also Published As
| Publication number | Publication date |
|---|---|
| GB9101503D0 (en) | 1991-03-06 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |