CA2023485A1 - Macrocyclic compounds - Google Patents
Macrocyclic compoundsInfo
- Publication number
- CA2023485A1 CA2023485A1 CA002023485A CA2023485A CA2023485A1 CA 2023485 A1 CA2023485 A1 CA 2023485A1 CA 002023485 A CA002023485 A CA 002023485A CA 2023485 A CA2023485 A CA 2023485A CA 2023485 A1 CA2023485 A1 CA 2023485A1
- Authority
- CA
- Canada
- Prior art keywords
- formula
- compound
- carbon
- hydroxy
- ethyl
- Prior art date
- Legal status (The legal status 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 status listed.)
- Abandoned
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/01—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing oxygen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
Abstract
ABSTRACT
MACROCYCLIC COMPOUNDS
There are described compounds of formula I, I
wherein R1 represents H or OH; R2 represents H; in addition, R1 and R2 may together represent a second carbon-carbon bond between the carbon atoms to which they are attached; R3 represents OH or OCH3; X represents O
or (H,OH); and Y represents O or N-OR4, in which R4 represents H or alkyl C1-6; provided that when R1 is OH, R2 is H and X is O, then Y does not represent O.
Processes for their production and compositions containing them, eg for use as immunosuppressive agents, are also described.
MACROCYCLIC COMPOUNDS
There are described compounds of formula I, I
wherein R1 represents H or OH; R2 represents H; in addition, R1 and R2 may together represent a second carbon-carbon bond between the carbon atoms to which they are attached; R3 represents OH or OCH3; X represents O
or (H,OH); and Y represents O or N-OR4, in which R4 represents H or alkyl C1-6; provided that when R1 is OH, R2 is H and X is O, then Y does not represent O.
Processes for their production and compositions containing them, eg for use as immunosuppressive agents, are also described.
Description
20~g5 MACROCYCLIC COMPOUNDS
This invention relates to novel macrocycli~ compounds, more particularly to novel macrocyclic immunosuppressive compounds, processes for their preparation, their use as 5 medicaments, and compositions containing th~m.
European Patent Application 184162 (to Fujisawa Pharmaceuticals Co Ltd) discloses a number of macrocyclic compounds isolated from microorganisms belonging to the genus Streptomyces. The macrolides are numbered FR-900506, 10 FR-900520, FR-900523 and FR-900525, and the preparation of some of their derivatives is also described.
International Patent Application WO 89/05304 (to Fisons plc), European Patent Application 353678 (to Fujisawa Pharmaceuticals Co Ltd), European Patent 15 Applications 349049 and 349061 (to Merck & Co Inc) and European Patent Application 356399 (to Sandoz AG) also disclose a number of macrocyclic immunosuppressant compounds.
We have now found a novel group of compounds which 20 possess certain advantageous properties over those disclosed previously.
Thus, according to the invention, we provide a compound of formula I, ~o~
C~3~y ~ ~ I
~ O~ C~3 C~3 ~ c~3 wherein R1 represents H or OH;
R2 represents H;
15 in addition, Rl and R2 may together represent a second carbon-carbon bond between the carbon atoms to which they are attached;
R3 represents OH or OCH3;
X represents O or (H,OH); and Y represents O or N-oR4~ in which R4 represents H
or alkYl Cl-6;
provided that when R1 is OH, R2 is H and X is O, then Y
does not represent O.
According to the invention, we also provide a process 25 for the production of a compound of formula I, which comprises:
a) dehydration of a compound of formula I as defined above, but without proviso, in which R1 represents OH and ~23`~
R2 rPpresents H, to give a corresponding compound o~
formula I in which Rl and R2 together represent a second carbon-carbon bond between the carbon atoms to which they are attached;
5 b) reduction of a compound of formula I as defined above in which R1 and R2 togethPr represent a second carbon-carbon bond between the carbon atoms to which they are attached, to give a corresponding compound of formula I
in which Rl and R2 each represent hydrogen;
10 c) reacting a compound of formula NH2-oR4, where R4 is as defined above, or a derivative thereof, with a compound of formula I as defined above, but without proviso, in which Y represents O, to give a corresponding compound of formula I in which Y represents N-oR4; or 15 d) reduction of a compound of formula I as defined above, but without proviso, in which X represents O, to give a corresponding compound of formula I in which X represents (H,OH) In process (a), the dehydration may be carrisd out in 20 a solvent which does not adversely affect the reaction (eg toluene), in the presence of a trace amount of acid (eg p-toluenesulphonic acid), at a kemperature o~ from 50 to 100 C.
In process (b), the reduction may be carried out 25 catalytically using hydrogen. Suitable catalysts include platinum catalysts (eg platinum black, platinum oxides), palladium catalysts (eg palladium oxides, palladium on charcoal), nickel cataly ts (eg nickel oxide, Raney 2~3~
Nickel), and rhodium catalysts (eg rhodium on alumina).
Suitable solvents are those which do not adversely affect the reaction, and include methanol, ethanol, ethyl acetate, dichloromethane and dimethylformamide. The reduction may 5 be carried out at or around room temperature.
In process (c), derivatives of NH2-oR4 which may be mentioned include acid addition salts (eg hydrochlorides). Suitable solvents are those which do not adversely affect the reaction, and include methanol and 10 ethanol. The reaction may be carried out at a temperature of from 50 to 100C, eg the reflux temperature of the solvent employed, and preferably in the presence of pyridine .
In process (d), suitable reagents for the reduction 15 include tri-nbutyltin hydride in a solvent which does not adversely affect the reaction (eg toluene) at a temperature of from 50 to 100C, sodium borohydride, zinc in acetic acid at or around room temperature, sodium triacetoxyborohydride in acetic acid, L-Selectride 20 (Re~istered Trade Mark) in tetrahydrofuran~ or borane/tbutylamine complex in a solvent such as methanol or ethanol.
FR-900520 from EP 184162 and the compound of EP 349061 are useful starting materials for production of compounds 25 f the present invention. Alternatively, the compound of the present invention, or s~arting materials therefor, may be produced by total synthssis (eg by modi~ication of the method disclosed in European Patent Application 378318 to ~3~8~
Merck & co Inc).
The teaching of all the documents mentioned above is herein incorporated by reference.
The compounds of formula I may be isolated from their 5 reaction mixtures using conventional techniques.
The compounds of formula I are useful because they possess pharmacological activity in animals; in particular they are useful because they possess immunosuppressive activity, eg in the tests set out in Tests A, B and C.
10 Thus the compounds are indicated for use in the treatment or prevention of resistance to transplanted organs or tissues, such as kidney, heart, lung, bone marrow, skin, cornea, etc; and of autoimmune, inflammatory, proliferative and hyperproli~erative diseases, and of cutaneous 15 manifestations of immunologically-mediated diseases: for example rheumatoid arthritis, lupus erythematosus, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type 1 diabetes, uveitis, nephrotic syndrome, psoriasis, atopical dermatitis, contact 20 dermatitis and further eczematous dermatitides, seborrheic dermatitis, Lichen planus, Pemphi~us, bullous Pemphigoid, Epidermolysis bullosa, urticaria, angioedemas, vasc~litides, erythemas, cutaneous eosinophiliast Alopecia arsata, etc.
25The compounds o~ the invention are also indicated in the treatment of reversible ob~tructive airways disease.
Further, the cQmpounds o~ the invention are indicated in the treatment of a disease selected ~rom intestinal 2~3~8~
inflammations/allergies such as Coeliac disease, proctitis,eosinophilic gastroenteritis, mastocytosis, Crohn's disease and ulcerative colitis: and food related allergic diseases which have symptomatic manifestation remote from the 5 gastro-intestinal tract, for example migraine, rhinitis and eczema.
The compounds of the invention are also indicated for use as antimicrobial agents, and thus may be used in the treatment of diseases caused by pathogenic microorganisms 10 and the like.
We therefore provide the use of compounds of formula I
as pharmaceuticals.
Further, we provide the use of a compound of formula I
in the manufacture of a medicament for use as an 15 immunosuppressive agent.
For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired (e~ topical, parenteral or oral) and the disease 20 indicated. However, in general, satisfactory results are obtained when the compounds are administered at a daily dosage of from 0.001 to 20mg per kg of animal body weight.
For man the indicated total daily dosage is in the range of from O.Olmg to lOOOmg and preferably from 0.5mg to 25 lOOmg, which may be administered, for example twice weekly, or in divided doses from 1 to 6 times a day or in sustained release form. Thus unit dosage forms suitable for administration, eg oesophageally, comprise from O.Olmg to 2~23~
500mg, and preferably 0.5mg to lOOmg of the compound preferably admixed with a solid or liquid pharmaceutically acceptable diluent, carrier or adjuvant.
According to our invention we also provide a 5 pharmaceutical composition comprising preferably less than 80~, and more preferably less than 50% by weight, of a compound of fomula I in combination with a pharmaceutically acceptable adjuvant, diluent or carrier. Examples of suitable adjuvants, diluents or carriers are: for tablets, 10 capsules and dragees - microcrystalline cellulose, calcium phosphate, diatomaceous earth, a sugar such as lactose, dextrose or mannitol, talc, stearic acid, starch, sodium bicarbonate and/or gelatin; for suppositories - natural or hardened oils or waxes; and for inhalation compositions -15 coarse lactose. The compound of formula I preferably is ina form having a mass median diameter of from 0.01 to lO~m. The compositions may also contain suitable preserving, stabilising and wetting agents, solubilisers (eg a water-soluble cellulose polymer such as hydroxypropyl 20 methylcellulose, or a water-soluble glycol such as propylene glycol), sweetening and colouring agents and flavourings. The compositions may, if desired, be formulated in sustained release form.
For the treatment of reversible obstructive airways 25 disease, we prefer the compound of formula I to be administered by inhalation to the lung, especially in the form of a powderO
According to a further aspect of the invention, there 8 ~
is provided a method of effecting immunosuppression which comprises administering a therapeutically effective amount of a compound of formula I, as defined above, to a patient.
The compounds of formula I have the advantage that 5 they are less toxic, more e~ficacious, are longer acting, have a broader range of activity, are more potent~ are more stable, produce fewer side e~fects, are more easily absorbed or have other useful pharmacological properties, than compounds previously used in the therapeutic fields 10 mentioned above.
The compounds of formula I have a number of chiral centres and may exist in a variety of stereoisomers. The invention provides all optical and stereoisomers, as well as racemic mixtures. The isomers may be resolved or 15 separated by conventional techniques.
However, the preferred stereochemistry of various chiral carbon atoms are shown in formula Ia, HO.~
N~ ~ ~C~a~ Ia O~X ~ ~
This invention relates to novel macrocycli~ compounds, more particularly to novel macrocyclic immunosuppressive compounds, processes for their preparation, their use as 5 medicaments, and compositions containing th~m.
European Patent Application 184162 (to Fujisawa Pharmaceuticals Co Ltd) discloses a number of macrocyclic compounds isolated from microorganisms belonging to the genus Streptomyces. The macrolides are numbered FR-900506, 10 FR-900520, FR-900523 and FR-900525, and the preparation of some of their derivatives is also described.
International Patent Application WO 89/05304 (to Fisons plc), European Patent Application 353678 (to Fujisawa Pharmaceuticals Co Ltd), European Patent 15 Applications 349049 and 349061 (to Merck & Co Inc) and European Patent Application 356399 (to Sandoz AG) also disclose a number of macrocyclic immunosuppressant compounds.
We have now found a novel group of compounds which 20 possess certain advantageous properties over those disclosed previously.
Thus, according to the invention, we provide a compound of formula I, ~o~
C~3~y ~ ~ I
~ O~ C~3 C~3 ~ c~3 wherein R1 represents H or OH;
R2 represents H;
15 in addition, Rl and R2 may together represent a second carbon-carbon bond between the carbon atoms to which they are attached;
R3 represents OH or OCH3;
X represents O or (H,OH); and Y represents O or N-oR4~ in which R4 represents H
or alkYl Cl-6;
provided that when R1 is OH, R2 is H and X is O, then Y
does not represent O.
According to the invention, we also provide a process 25 for the production of a compound of formula I, which comprises:
a) dehydration of a compound of formula I as defined above, but without proviso, in which R1 represents OH and ~23`~
R2 rPpresents H, to give a corresponding compound o~
formula I in which Rl and R2 together represent a second carbon-carbon bond between the carbon atoms to which they are attached;
5 b) reduction of a compound of formula I as defined above in which R1 and R2 togethPr represent a second carbon-carbon bond between the carbon atoms to which they are attached, to give a corresponding compound of formula I
in which Rl and R2 each represent hydrogen;
10 c) reacting a compound of formula NH2-oR4, where R4 is as defined above, or a derivative thereof, with a compound of formula I as defined above, but without proviso, in which Y represents O, to give a corresponding compound of formula I in which Y represents N-oR4; or 15 d) reduction of a compound of formula I as defined above, but without proviso, in which X represents O, to give a corresponding compound of formula I in which X represents (H,OH) In process (a), the dehydration may be carrisd out in 20 a solvent which does not adversely affect the reaction (eg toluene), in the presence of a trace amount of acid (eg p-toluenesulphonic acid), at a kemperature o~ from 50 to 100 C.
In process (b), the reduction may be carried out 25 catalytically using hydrogen. Suitable catalysts include platinum catalysts (eg platinum black, platinum oxides), palladium catalysts (eg palladium oxides, palladium on charcoal), nickel cataly ts (eg nickel oxide, Raney 2~3~
Nickel), and rhodium catalysts (eg rhodium on alumina).
Suitable solvents are those which do not adversely affect the reaction, and include methanol, ethanol, ethyl acetate, dichloromethane and dimethylformamide. The reduction may 5 be carried out at or around room temperature.
In process (c), derivatives of NH2-oR4 which may be mentioned include acid addition salts (eg hydrochlorides). Suitable solvents are those which do not adversely affect the reaction, and include methanol and 10 ethanol. The reaction may be carried out at a temperature of from 50 to 100C, eg the reflux temperature of the solvent employed, and preferably in the presence of pyridine .
In process (d), suitable reagents for the reduction 15 include tri-nbutyltin hydride in a solvent which does not adversely affect the reaction (eg toluene) at a temperature of from 50 to 100C, sodium borohydride, zinc in acetic acid at or around room temperature, sodium triacetoxyborohydride in acetic acid, L-Selectride 20 (Re~istered Trade Mark) in tetrahydrofuran~ or borane/tbutylamine complex in a solvent such as methanol or ethanol.
FR-900520 from EP 184162 and the compound of EP 349061 are useful starting materials for production of compounds 25 f the present invention. Alternatively, the compound of the present invention, or s~arting materials therefor, may be produced by total synthssis (eg by modi~ication of the method disclosed in European Patent Application 378318 to ~3~8~
Merck & co Inc).
The teaching of all the documents mentioned above is herein incorporated by reference.
The compounds of formula I may be isolated from their 5 reaction mixtures using conventional techniques.
The compounds of formula I are useful because they possess pharmacological activity in animals; in particular they are useful because they possess immunosuppressive activity, eg in the tests set out in Tests A, B and C.
10 Thus the compounds are indicated for use in the treatment or prevention of resistance to transplanted organs or tissues, such as kidney, heart, lung, bone marrow, skin, cornea, etc; and of autoimmune, inflammatory, proliferative and hyperproli~erative diseases, and of cutaneous 15 manifestations of immunologically-mediated diseases: for example rheumatoid arthritis, lupus erythematosus, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type 1 diabetes, uveitis, nephrotic syndrome, psoriasis, atopical dermatitis, contact 20 dermatitis and further eczematous dermatitides, seborrheic dermatitis, Lichen planus, Pemphi~us, bullous Pemphigoid, Epidermolysis bullosa, urticaria, angioedemas, vasc~litides, erythemas, cutaneous eosinophiliast Alopecia arsata, etc.
25The compounds o~ the invention are also indicated in the treatment of reversible ob~tructive airways disease.
Further, the cQmpounds o~ the invention are indicated in the treatment of a disease selected ~rom intestinal 2~3~8~
inflammations/allergies such as Coeliac disease, proctitis,eosinophilic gastroenteritis, mastocytosis, Crohn's disease and ulcerative colitis: and food related allergic diseases which have symptomatic manifestation remote from the 5 gastro-intestinal tract, for example migraine, rhinitis and eczema.
The compounds of the invention are also indicated for use as antimicrobial agents, and thus may be used in the treatment of diseases caused by pathogenic microorganisms 10 and the like.
We therefore provide the use of compounds of formula I
as pharmaceuticals.
Further, we provide the use of a compound of formula I
in the manufacture of a medicament for use as an 15 immunosuppressive agent.
For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired (e~ topical, parenteral or oral) and the disease 20 indicated. However, in general, satisfactory results are obtained when the compounds are administered at a daily dosage of from 0.001 to 20mg per kg of animal body weight.
For man the indicated total daily dosage is in the range of from O.Olmg to lOOOmg and preferably from 0.5mg to 25 lOOmg, which may be administered, for example twice weekly, or in divided doses from 1 to 6 times a day or in sustained release form. Thus unit dosage forms suitable for administration, eg oesophageally, comprise from O.Olmg to 2~23~
500mg, and preferably 0.5mg to lOOmg of the compound preferably admixed with a solid or liquid pharmaceutically acceptable diluent, carrier or adjuvant.
According to our invention we also provide a 5 pharmaceutical composition comprising preferably less than 80~, and more preferably less than 50% by weight, of a compound of fomula I in combination with a pharmaceutically acceptable adjuvant, diluent or carrier. Examples of suitable adjuvants, diluents or carriers are: for tablets, 10 capsules and dragees - microcrystalline cellulose, calcium phosphate, diatomaceous earth, a sugar such as lactose, dextrose or mannitol, talc, stearic acid, starch, sodium bicarbonate and/or gelatin; for suppositories - natural or hardened oils or waxes; and for inhalation compositions -15 coarse lactose. The compound of formula I preferably is ina form having a mass median diameter of from 0.01 to lO~m. The compositions may also contain suitable preserving, stabilising and wetting agents, solubilisers (eg a water-soluble cellulose polymer such as hydroxypropyl 20 methylcellulose, or a water-soluble glycol such as propylene glycol), sweetening and colouring agents and flavourings. The compositions may, if desired, be formulated in sustained release form.
For the treatment of reversible obstructive airways 25 disease, we prefer the compound of formula I to be administered by inhalation to the lung, especially in the form of a powderO
According to a further aspect of the invention, there 8 ~
is provided a method of effecting immunosuppression which comprises administering a therapeutically effective amount of a compound of formula I, as defined above, to a patient.
The compounds of formula I have the advantage that 5 they are less toxic, more e~ficacious, are longer acting, have a broader range of activity, are more potent~ are more stable, produce fewer side e~fects, are more easily absorbed or have other useful pharmacological properties, than compounds previously used in the therapeutic fields 10 mentioned above.
The compounds of formula I have a number of chiral centres and may exist in a variety of stereoisomers. The invention provides all optical and stereoisomers, as well as racemic mixtures. The isomers may be resolved or 15 separated by conventional techniques.
However, the preferred stereochemistry of various chiral carbon atoms are shown in formula Ia, HO.~
N~ ~ ~C~a~ Ia O~X ~ ~
3 ~ ~ ) "
OCt~3 OC~1 3 20Z~8~
wherein Rl to R3, X and Y are as first defined above.
Test A
Mixed Lymphocyte Reaction fMLR~ I
The MhR test was performed in microtitre plates, with 5 each well containing 5 x 105 C57BL/6 responder cells (H-2b), 5 x 105 mitomycin C treated (25~g/ml mitomycin C at 37C for 30 minutes and washed three times with RPMI 1640 medium) BALB/C stimulator cells (H-2d) in 0.2ml RPMI 1640 medium supplemented with 10% fetal calf l~ serum, 2mM sodium Aydrogen carbonate, penicillin (50~g/ml) and streptomycin (50~g/ml). The cells were incubated at 37C in a humidified atmosphere of 5% carbon dioxide and 95% of air for 68 hours and pulsed with 3H-thymidine (0.5~Ci) 4 hours before the cells were 15 collected~ The object compound of this invention was dissolved in ethanol and further diluted in RPMI 1640 medium and added to the cultures to give final concentrations of O.l~g/ml or l~ss.
Test B
20 Mixed Lymphocyte Reaction fMLR~ II
The MLR test was performed in 96-well microtitre plates with each well containing 3 x 105 cells from each of two responding donors in a final volume of 0.2ml RPMI
1640 medium supplemented with lO~ human serum, L-glutamine 25 and penicillin/streptomycin. The compound under test was dissolved at lOmg/ml in ethanol and further diluted in RPMI
1640. The cells were incubated at 37C in a humidified 202~8~
atmosphere at 5~ carbon dioxide for 96 hours.
3H-thymidine (0.5~Ci) was added for the final 24 hours of the incubation to provide a measure of proliferation.
Test C
5 Graft versus Host Assav (GVH) Spleen cells from DA and DAxLewis Fl hybrid rats were prepared at approximately 108 cells/ml. O.lml of these suspensions were injected into the rear footpads of DAxLewis Fl rats (left and right respectively). Recipient 10 animals aere dosed with the compound under test, either orally or subcutaneously, on days 0-4. The assay is t~rminated on day 7 when the popliteal lymph nodes of the animals are removed and weighed. The increase in weight of the left node relative to the wieght of the right is a 15 measure of the GVH response.
The invention is illustrated, but in no way limited by, the following Examples.
Example 1 1 2,14-Trihydroxy-12- r 2-(4-hydroxY-3-methoxYcy~lohexyl) 1-20 methylvinvll-23.2$-dimethoxv-17-ethyl-13 19.21.27-tetramethyl;11,28-dioxa-4-azatricyç~1O~22.3.1.04~91 octacQS
18-ene-3 10,16-trione A solution of 1,14-dihydroxy-12 [2-(4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy-17-ethyl-25 13,19,21,27-tetramethyl 11,28-dioxa-4~azatricyclo [22.3.1.04~9]octacos-18-ene-2,3,10,16-tetraone (FR-900520, EP 184162) (80mg) and tri-~butyltin hydride (0.2ml) in toluene (5ml) was heated at 70C for 2 hours.
~3~g~
The cooled reaction mixture was then evaporated in vacuo and the residue purified by column chromatogragphy on silica eluting with ethyl acetate to give the title compound as a foam (50mg).
5 MS (FAB): 878 [M+Rb]+; 816 [M+Na]+; 794 [M+H]+; 776 [M-OH]+
3C NMR (CDC13~ ~: 214.5 (C16); 173.7 (C10); 169.5 (C3); 138.8 (Cl9); 131.9 (C29); 128.8 (C31); 122.8 (C18);
g7.7 (C1); 84.2 (C34) 10 The title compound was also produced in the following manner:
A solution of 1,14-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl~-l-methylvinyl]-23,25-dimethoxy-17-ethyl-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo 15 [22.3.1.04/930ctacos-18-ene-2,3,10,16-tetraone (FR-90052Q, EP 184162) (80mg) in acetic acid (lOml) was treated with excess zinc dust (lg) over 1 hour at room temperature. The reaction mixture was then ~iltered and evaporated in vacuo to a colourless oil. Chromatograghy on 2~ silica eluting with ethyl acetate then gave the diastereoi~omers of the title compound (51mg and llmg).
The minor product was found to be identical to the product of the tri-nbutyltin hydride reduction described above.
MS ~FAB): (major product) 878 [M+Rb~+; 816 [M+Na3+; 794 25 [M+H] ; 776 [M-OH]~
3C NMR (CDC13) ~: (major product) 212.6 ~C16); 173 (Cl~); 170.3 (C3); 140.2 (Cl9); 132.5 ~C29), 130 (C31);
123.2 (C18); 99.3 (1); 84.2 ~C34) .
~23~
Exam~le 21.14-Dihydroxy-12 r 2-(4-hvdroxy-3-methoxycyclohex~l)-1-methylvinyl~-23.25-dimethoxy-17-ethyl-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04~9~octacos-5 18-ene-2,3,10,16-tetraone Cl6-oxime A solution of 1,14-dihydroxy-12-~2-(4-hydroxy-3-methoxycyclohexyl)-l-methylvinyl]-23,25-dimethoxy-17-ethyl-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.04~9]octacos-18-ene-2,3,10,16-tetraone 10 (FR-900520, EP 184162) (71mg), hydroxylamine hydrochloride (80mg) and pyridine (0.2ml) in dry ethanol (5ml) was refluxed under an atmosphere of nitrogen for 2 hours. The reaction mixtur~ was then cooled and poured into a mixture of dilute aqueous hydrochloric acid ~lN~ and ethyl 15 acetate. The ethyl acetate extract was washed with saturated aqueous sodium hydrogen carbonate solution, dried (MgSO4), filtered and e~aporated in vacuo to an oil.
Chromatograghy on silica eluting with hexane/ace~one [2:1]
then gave the Z-oxime (7mg) followed by the E-oxime (10mg).
20 MS (FAB): (E- and Z-oximes~ 891 [M+Rb3~; 829 [M~NaJ+;
807 [M+H~+; 789 [M-OH~+
3C NMR (CDC13) ~:
oxi~ 197.1 (C2); 169.3 (C10); 165.3 (C3); 162 (C16);
138.1 ~C19); 132.7 (C29); ~28 (C31): 125.8 (C18); 97.3 25 (Cl); 84.2 (C34); 39.7 (C13~; 39.1 (C5); 24.~ (C8); 21~4 (C6); 21 (C7); 12 (C44); 9.9 (C39) Z-o~im~ 169.5 (C2); 169 (C10); 165.3 (C3); 161.7 (C16);
138 (Cl9); 132.6 ~C29); 128 (C31); 125.8 (C18); 97.3 (Cl);
2~3~
84.2 (C34); 9.5 (C3~) Example 3 l-Hydroxy-l2- r 2-(4-hydroxy-3-methoxycyclohexyl~-1-methylvinyll-23,2~-dimethoxv-17-ethyl-13 19 21 27-5 tetramethyl-11.28-dioxa-4-azatricyclo r 22.3.1~Q4'9~octacosa -14 18-diene-2 3~10 16-tetraone 1,14-Dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl~-23,25-dimethoxy-17-ethyl-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricy~10[22.3.1.04'9]octacos-10 14-ene-2,3,10,16-tetraone (FR-900520, EP 184162) (lOOmg) and p-toluenesulphonic acid (2mg) were dissolved in dry toluene (20ml) and heated for 2 hours at 100C under an atmosphere of nitrogen. Removal of solvent in vacuo and chromatography on silica eluting with hexane/acetone [2:1 15 gave the title compound as a foam (80mg).
MS (FAB): 774.8 [M+H]+; 796.85 [M+Na~+; 858.71 [M+Rb]
3C NMR ~: (major rotamer) 201.15 (C16)~ 196.0 (C2);
16g.2 (C10); 165.1 (C3); 147.8 (C15); 138.0 (Cl9); 123.82 20 ~C18): 97.88 (C1); 84.0S (C34) Example 4 l-Hvdroxy-12- r 2-(4-hydroxv-3-methoxyc~clohex~l-1-methylvinyl~-23 25-dimethoxy-17-ethyl-13~1g.21~27-tetramethYl-11,28-dioxa-4-azatricyclo[~2.3.1.04~91sctacos 25 -18-ene~2 3,10 16-t~traone A sample sf the title cvmpound of Example 3 was dissolved in mPthanol (20ml) and 10% Pd-on-carbon (lOmg) was added.
The mixture was stirred in an atmosphere of hydrogen ~or 2(~23~
1.5 hours at room temperature and pressure, and was then filtered through celite and evaporated to an oil in vacuo.
Column chromatography on silica eluting with hexane/acetone [2:1] gave the title compound as a foam (50mg).
5 MS (FAB): 776 [M~H]+, 798 [M+Na]+; 860 [M+Rb]+
13C NMR ~: (major rotamer) 212.34 (C16); 196.42 ~C2);
169.3~ (C10); 165.16 tC3~; 138.9 (Cl9); 124.16 (C18); 97.41 (Cl); 84.19 (C34)
OCt~3 OC~1 3 20Z~8~
wherein Rl to R3, X and Y are as first defined above.
Test A
Mixed Lymphocyte Reaction fMLR~ I
The MhR test was performed in microtitre plates, with 5 each well containing 5 x 105 C57BL/6 responder cells (H-2b), 5 x 105 mitomycin C treated (25~g/ml mitomycin C at 37C for 30 minutes and washed three times with RPMI 1640 medium) BALB/C stimulator cells (H-2d) in 0.2ml RPMI 1640 medium supplemented with 10% fetal calf l~ serum, 2mM sodium Aydrogen carbonate, penicillin (50~g/ml) and streptomycin (50~g/ml). The cells were incubated at 37C in a humidified atmosphere of 5% carbon dioxide and 95% of air for 68 hours and pulsed with 3H-thymidine (0.5~Ci) 4 hours before the cells were 15 collected~ The object compound of this invention was dissolved in ethanol and further diluted in RPMI 1640 medium and added to the cultures to give final concentrations of O.l~g/ml or l~ss.
Test B
20 Mixed Lymphocyte Reaction fMLR~ II
The MLR test was performed in 96-well microtitre plates with each well containing 3 x 105 cells from each of two responding donors in a final volume of 0.2ml RPMI
1640 medium supplemented with lO~ human serum, L-glutamine 25 and penicillin/streptomycin. The compound under test was dissolved at lOmg/ml in ethanol and further diluted in RPMI
1640. The cells were incubated at 37C in a humidified 202~8~
atmosphere at 5~ carbon dioxide for 96 hours.
3H-thymidine (0.5~Ci) was added for the final 24 hours of the incubation to provide a measure of proliferation.
Test C
5 Graft versus Host Assav (GVH) Spleen cells from DA and DAxLewis Fl hybrid rats were prepared at approximately 108 cells/ml. O.lml of these suspensions were injected into the rear footpads of DAxLewis Fl rats (left and right respectively). Recipient 10 animals aere dosed with the compound under test, either orally or subcutaneously, on days 0-4. The assay is t~rminated on day 7 when the popliteal lymph nodes of the animals are removed and weighed. The increase in weight of the left node relative to the wieght of the right is a 15 measure of the GVH response.
The invention is illustrated, but in no way limited by, the following Examples.
Example 1 1 2,14-Trihydroxy-12- r 2-(4-hydroxY-3-methoxYcy~lohexyl) 1-20 methylvinvll-23.2$-dimethoxv-17-ethyl-13 19.21.27-tetramethyl;11,28-dioxa-4-azatricyç~1O~22.3.1.04~91 octacQS
18-ene-3 10,16-trione A solution of 1,14-dihydroxy-12 [2-(4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy-17-ethyl-25 13,19,21,27-tetramethyl 11,28-dioxa-4~azatricyclo [22.3.1.04~9]octacos-18-ene-2,3,10,16-tetraone (FR-900520, EP 184162) (80mg) and tri-~butyltin hydride (0.2ml) in toluene (5ml) was heated at 70C for 2 hours.
~3~g~
The cooled reaction mixture was then evaporated in vacuo and the residue purified by column chromatogragphy on silica eluting with ethyl acetate to give the title compound as a foam (50mg).
5 MS (FAB): 878 [M+Rb]+; 816 [M+Na]+; 794 [M+H]+; 776 [M-OH]+
3C NMR (CDC13~ ~: 214.5 (C16); 173.7 (C10); 169.5 (C3); 138.8 (Cl9); 131.9 (C29); 128.8 (C31); 122.8 (C18);
g7.7 (C1); 84.2 (C34) 10 The title compound was also produced in the following manner:
A solution of 1,14-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl~-l-methylvinyl]-23,25-dimethoxy-17-ethyl-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo 15 [22.3.1.04/930ctacos-18-ene-2,3,10,16-tetraone (FR-90052Q, EP 184162) (80mg) in acetic acid (lOml) was treated with excess zinc dust (lg) over 1 hour at room temperature. The reaction mixture was then ~iltered and evaporated in vacuo to a colourless oil. Chromatograghy on 2~ silica eluting with ethyl acetate then gave the diastereoi~omers of the title compound (51mg and llmg).
The minor product was found to be identical to the product of the tri-nbutyltin hydride reduction described above.
MS ~FAB): (major product) 878 [M+Rb~+; 816 [M+Na3+; 794 25 [M+H] ; 776 [M-OH]~
3C NMR (CDC13) ~: (major product) 212.6 ~C16); 173 (Cl~); 170.3 (C3); 140.2 (Cl9); 132.5 ~C29), 130 (C31);
123.2 (C18); 99.3 (1); 84.2 ~C34) .
~23~
Exam~le 21.14-Dihydroxy-12 r 2-(4-hvdroxy-3-methoxycyclohex~l)-1-methylvinyl~-23.25-dimethoxy-17-ethyl-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04~9~octacos-5 18-ene-2,3,10,16-tetraone Cl6-oxime A solution of 1,14-dihydroxy-12-~2-(4-hydroxy-3-methoxycyclohexyl)-l-methylvinyl]-23,25-dimethoxy-17-ethyl-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.04~9]octacos-18-ene-2,3,10,16-tetraone 10 (FR-900520, EP 184162) (71mg), hydroxylamine hydrochloride (80mg) and pyridine (0.2ml) in dry ethanol (5ml) was refluxed under an atmosphere of nitrogen for 2 hours. The reaction mixtur~ was then cooled and poured into a mixture of dilute aqueous hydrochloric acid ~lN~ and ethyl 15 acetate. The ethyl acetate extract was washed with saturated aqueous sodium hydrogen carbonate solution, dried (MgSO4), filtered and e~aporated in vacuo to an oil.
Chromatograghy on silica eluting with hexane/ace~one [2:1]
then gave the Z-oxime (7mg) followed by the E-oxime (10mg).
20 MS (FAB): (E- and Z-oximes~ 891 [M+Rb3~; 829 [M~NaJ+;
807 [M+H~+; 789 [M-OH~+
3C NMR (CDC13) ~:
oxi~ 197.1 (C2); 169.3 (C10); 165.3 (C3); 162 (C16);
138.1 ~C19); 132.7 (C29); ~28 (C31): 125.8 (C18); 97.3 25 (Cl); 84.2 (C34); 39.7 (C13~; 39.1 (C5); 24.~ (C8); 21~4 (C6); 21 (C7); 12 (C44); 9.9 (C39) Z-o~im~ 169.5 (C2); 169 (C10); 165.3 (C3); 161.7 (C16);
138 (Cl9); 132.6 ~C29); 128 (C31); 125.8 (C18); 97.3 (Cl);
2~3~
84.2 (C34); 9.5 (C3~) Example 3 l-Hydroxy-l2- r 2-(4-hydroxy-3-methoxycyclohexyl~-1-methylvinyll-23,2~-dimethoxv-17-ethyl-13 19 21 27-5 tetramethyl-11.28-dioxa-4-azatricyclo r 22.3.1~Q4'9~octacosa -14 18-diene-2 3~10 16-tetraone 1,14-Dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl~-23,25-dimethoxy-17-ethyl-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricy~10[22.3.1.04'9]octacos-10 14-ene-2,3,10,16-tetraone (FR-900520, EP 184162) (lOOmg) and p-toluenesulphonic acid (2mg) were dissolved in dry toluene (20ml) and heated for 2 hours at 100C under an atmosphere of nitrogen. Removal of solvent in vacuo and chromatography on silica eluting with hexane/acetone [2:1 15 gave the title compound as a foam (80mg).
MS (FAB): 774.8 [M+H]+; 796.85 [M+Na~+; 858.71 [M+Rb]
3C NMR ~: (major rotamer) 201.15 (C16)~ 196.0 (C2);
16g.2 (C10); 165.1 (C3); 147.8 (C15); 138.0 (Cl9); 123.82 20 ~C18): 97.88 (C1); 84.0S (C34) Example 4 l-Hvdroxy-12- r 2-(4-hydroxv-3-methoxyc~clohex~l-1-methylvinyl~-23 25-dimethoxy-17-ethyl-13~1g.21~27-tetramethYl-11,28-dioxa-4-azatricyclo[~2.3.1.04~91sctacos 25 -18-ene~2 3,10 16-t~traone A sample sf the title cvmpound of Example 3 was dissolved in mPthanol (20ml) and 10% Pd-on-carbon (lOmg) was added.
The mixture was stirred in an atmosphere of hydrogen ~or 2(~23~
1.5 hours at room temperature and pressure, and was then filtered through celite and evaporated to an oil in vacuo.
Column chromatography on silica eluting with hexane/acetone [2:1] gave the title compound as a foam (50mg).
5 MS (FAB): 776 [M~H]+, 798 [M+Na]+; 860 [M+Rb]+
13C NMR ~: (major rotamer) 212.34 (C16); 196.42 ~C2);
169.3~ (C10); 165.16 tC3~; 138.9 (Cl9); 124.16 (C18); 97.41 (Cl); 84.19 (C34)
Claims (9)
1. A compound of formula I, I
wherein R1 represents H or OH;
R2 represents H;
in addition, R1 and R2 may together represent a second carbon-carbon bond between the carbon atoms to which they are attached;
R3 represents OH or OCH3;
X represents O or (H,OH); and Y represents O or N-OR4, in which R4 represents H
or alkyl C1-6;
provided that when R1 is OH, R2 is H and X is O, then Y
does not represent O.
wherein R1 represents H or OH;
R2 represents H;
in addition, R1 and R2 may together represent a second carbon-carbon bond between the carbon atoms to which they are attached;
R3 represents OH or OCH3;
X represents O or (H,OH); and Y represents O or N-OR4, in which R4 represents H
or alkyl C1-6;
provided that when R1 is OH, R2 is H and X is O, then Y
does not represent O.
2. A compound of formula I as defined in claim 1, which is 1,2,14-trihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy-17-ethyl-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-3,10,16-trione.
3. A compound of formula I as defined in claim 1, which is 1,14-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl}-23,25-dimethoxy-17-ethyl-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone C16-oxime.
4. A compound of formula I as defined in claim 1, which is l-hydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy-17-ethyl-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacosa -14,18-diene-2,3,10,16-tetraone.
5. A compound of formula I as defined in claim 1, which is 1-hydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy-17-ethyl-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos -18-ene-2,3,10,16-tetraone.
6. The use of a compound of formula I, as defined in claim 1, as a pharmaceutical.
7. A pharmaceutical composition comprising a compound of formula I, as defined in claim 1, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
8. The use of a compound of formula I, as defined in claim 1, in the manufacture of a medicament for use as an immunosuppressive agent.
9. A process for the production of a compound of formula I as defined in claim 1, which comprises:
a) dehydration of a compound of formula I as defined in claim 1, but without proviso, in which R1 represents OH
and R2 represents H, to give a corresponding compound of formula I in which R1 and R2 together represent a second carbon-carbon bond between the carbon atoms to which they are attached;
b) reduction of a compound of formula I as defined in claim 1 in which R1 and R2 together represent a second carbon-carbon bond between the carbon atoms to which they are attached, to give a corresponding compound of formula I
in which R1 and R2 each represent hydrogen;
c) reacting a compound of formula NH2-OR4; where R4 is as defined in claim 1, or a derivative thereof, with a compound of formula I as defined in claim 1, but without proviso, in which Y represents O, to give a corresponding compound of formula I in which Y represents N-OR4; or d) reduction of a compound of formula I as defined in claim 1, but without proviso, in which X represents O, to give a corresponding compound of formula I in which X
represents (H,OH).
a) dehydration of a compound of formula I as defined in claim 1, but without proviso, in which R1 represents OH
and R2 represents H, to give a corresponding compound of formula I in which R1 and R2 together represent a second carbon-carbon bond between the carbon atoms to which they are attached;
b) reduction of a compound of formula I as defined in claim 1 in which R1 and R2 together represent a second carbon-carbon bond between the carbon atoms to which they are attached, to give a corresponding compound of formula I
in which R1 and R2 each represent hydrogen;
c) reacting a compound of formula NH2-OR4; where R4 is as defined in claim 1, or a derivative thereof, with a compound of formula I as defined in claim 1, but without proviso, in which Y represents O, to give a corresponding compound of formula I in which Y represents N-OR4; or d) reduction of a compound of formula I as defined in claim 1, but without proviso, in which X represents O, to give a corresponding compound of formula I in which X
represents (H,OH).
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB89/18886 | 1989-08-18 | ||
GB898918929A GB8918929D0 (en) | 1989-08-18 | 1989-08-18 | Compound |
GB898918886A GB8918886D0 (en) | 1989-08-18 | 1989-08-18 | Compound |
GB89/18929 | 1989-08-18 |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2023485A1 true CA2023485A1 (en) | 1991-02-19 |
Family
ID=26295787
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002023485A Abandoned CA2023485A1 (en) | 1989-08-18 | 1990-08-17 | Macrocyclic compounds |
Country Status (9)
Country | Link |
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US (1) | US5179087A (en) |
EP (1) | EP0413532A3 (en) |
JP (1) | JPH03118385A (en) |
KR (1) | KR910004647A (en) |
CA (1) | CA2023485A1 (en) |
FI (1) | FI904072A0 (en) |
IE (1) | IE902994A1 (en) |
NO (1) | NO903636L (en) |
PT (1) | PT95038A (en) |
Families Citing this family (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5064835A (en) * | 1990-03-01 | 1991-11-12 | Merck & Co., Inc. | Hydroxymacrolide derivatives having immunosuppressive activity |
EP0455427A1 (en) * | 1990-04-30 | 1991-11-06 | Merck & Co. Inc. | Deoxymacrolide derivatives having immunosuppressive activity |
GB2245561A (en) * | 1990-07-05 | 1992-01-08 | Fujisawa Pharmaceutical Co | Tricyclo compounds, a process for their production and a pharmaceutical composition containing the same |
US5143918A (en) * | 1990-10-11 | 1992-09-01 | Merck & Co., Inc. | Halomacrolides and derivatives having immunosuppressive activity |
US5565560A (en) * | 1991-05-13 | 1996-10-15 | Merck & Co., Inc. | O-Aryl,O-alkyl,O-alkenyl and O-alkynylmacrolides having immunosuppressive activity |
US5162334A (en) * | 1991-05-13 | 1992-11-10 | Merck & Co., Inc. | Amino O-alkyl, O-alkenyl and O-alkynlmacrolides having immunosuppressive activity |
US5250678A (en) * | 1991-05-13 | 1993-10-05 | Merck & Co., Inc. | O-aryl, O-alkyl, O-alkenyl and O-alkynylmacrolides having immunosuppressive activity |
US5776943A (en) * | 1991-05-14 | 1998-07-07 | American Home Products Corporation | Rapamycin metabolites |
US5189042A (en) * | 1991-08-22 | 1993-02-23 | Merck & Co. Inc. | Fluoromacrolides having immunosuppressive activity |
US5208241A (en) * | 1991-09-09 | 1993-05-04 | Merck & Co., Inc. | N-heteroaryl, n-alkylheteroaryl, n-alkenylheteroaryl and n-alkynylheteroarylmacrolides having immunosuppressive activity |
GB9203265D0 (en) * | 1992-02-15 | 1992-04-01 | Fisons Plc | Pharmaceutically active compound |
HUT66531A (en) * | 1992-05-07 | 1994-12-28 | Sandoz Ag | Heteroatoms-containing tricyclic compounds, pharmaceutical prepns contg. them and process for producing them |
US5284877A (en) * | 1992-06-12 | 1994-02-08 | Merck & Co., Inc. | Alkyl and alkenyl macrolides having immunosuppressive activity |
US5284840A (en) * | 1992-06-12 | 1994-02-08 | Merck & Co., Inc. | Alkylidene macrolides having immunosuppressive activity |
US5693648A (en) * | 1994-09-30 | 1997-12-02 | Merck & Co., Inc. | O-aryl, O-alkyl, O-alkenyl and O-alkynyl-macrolides having immunosuppressive activity |
US7521420B2 (en) | 2003-06-18 | 2009-04-21 | Tranzyme Pharma, Inc. | Macrocyclic antagonists of the motilin receptor |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
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US4275149A (en) * | 1978-11-24 | 1981-06-23 | Syva Company | Macromolecular environment control in specific receptor assays |
US4894366A (en) * | 1984-12-03 | 1990-01-16 | Fujisawa Pharmaceutical Company, Ltd. | Tricyclo compounds, a process for their production and a pharmaceutical composition containing the same |
EP0323042A1 (en) * | 1987-12-09 | 1989-07-05 | FISONS plc | Process to macrocyclic compounds |
DE68921934T2 (en) * | 1988-06-29 | 1995-10-19 | Merck & Co Inc | Immunosuppressive agent. |
US4981792A (en) * | 1988-06-29 | 1991-01-01 | Merck & Co., Inc. | Immunosuppressant compound |
ATE131536T1 (en) * | 1988-08-01 | 1995-12-15 | Fujisawa Pharmaceutical Co | FR-901154 AND FR-901155 DERIVATIVES, PROCESS FOR THEIR PRODUCTION |
EP0356399A3 (en) * | 1988-08-26 | 1991-03-20 | Sandoz Ag | Substituted 4-azatricyclo (22.3.1.04.9) octacos-18-ene derivatives, their preparation and pharmaceutical compositions containing them |
-
1990
- 1990-08-10 EP EP19900308853 patent/EP0413532A3/en not_active Withdrawn
- 1990-08-17 US US07/568,855 patent/US5179087A/en not_active Expired - Fee Related
- 1990-08-17 PT PT95038A patent/PT95038A/en not_active Application Discontinuation
- 1990-08-17 JP JP2215969A patent/JPH03118385A/en active Pending
- 1990-08-17 CA CA002023485A patent/CA2023485A1/en not_active Abandoned
- 1990-08-17 NO NO90903636A patent/NO903636L/en unknown
- 1990-08-17 FI FI904072A patent/FI904072A0/en not_active IP Right Cessation
- 1990-08-17 IE IE299490A patent/IE902994A1/en unknown
- 1990-08-18 KR KR1019900012770A patent/KR910004647A/en not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
EP0413532A2 (en) | 1991-02-20 |
NO903636D0 (en) | 1990-08-17 |
US5179087A (en) | 1993-01-12 |
NO903636L (en) | 1991-02-19 |
PT95038A (en) | 1991-04-18 |
KR910004647A (en) | 1991-03-29 |
IE902994A1 (en) | 1991-02-27 |
EP0413532A3 (en) | 1991-05-15 |
JPH03118385A (en) | 1991-05-20 |
FI904072A0 (en) | 1990-08-17 |
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