WO1991004025A1 - Novel macrocyclic compounds and novel method of treatment - Google Patents
Novel macrocyclic compounds and novel method of treatment Download PDFInfo
- Publication number
- WO1991004025A1 WO1991004025A1 PCT/GB1990/001412 GB9001412W WO9104025A1 WO 1991004025 A1 WO1991004025 A1 WO 1991004025A1 GB 9001412 W GB9001412 W GB 9001412W WO 9104025 A1 WO9104025 A1 WO 9104025A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- hydroxy
- formula
- tetramethyl
- methylvinyl
- Prior art date
Links
Classifications
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/18—Bridged systems
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more 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
Abstract
Compounds of formula (I), wherein R?1 and R2¿ independently represent H or OH, or a second carbon-carbon bond; R3 represents optionally substituted methyl, ethyl or propyl; R4 represents H; R?5 and R6¿ represent a second carbon-carbon bond; R7 represents H or OH; R8 represents OCH¿3; R?9 represents OH or OCH¿3?; X and Y independently represent O or (H, OH); n represents 1 or 2; and in addition some of the substituents form rings with each other; with various provisos; are indicated in the treatment of immunodepression. A number of novel compounds of formula (I) are also provided.
Description
NOVEL MACROCYCLIC COMPOUNDS AND NOVEL METHOD OF TREATMENT
This invention relates to novel pharmaceutical uses o certain known macrocyclic compounds, and to nove macrocyclic compounds which have the same novel utility. 5 European patent application No 184162 (to Fujisaw Pharmaceuticals Co Ltd) discloses several macrocycli compounds which are derivatives of 12-(2-cyclohexyl- 1-methylvinyl)-13,19,21,27-tetramethyl-ll,28-dioxa-4- azatricyclo[22.3.l.04'9]octacos-18-ene (numbere
10 FR-900506, FR-900520, FR-900523 and FR-900525) and whic are isolated from microorganisms belonging to the genu Streptomyces. The macrocyclic compounds and a number o their derivatives are indicated as immunosuppressiv agents. ,c International patent application No WO 89/05304 (als European Patent application No 323042, both to Fisons pic) discloses a large number of macrocyclic compounds which ma be derived from those disclosed in European patent application No 184162. Again, the compounds are primarily 2Q indicated as immunosuppressive agents.
European patent applications Nos 349049 and 349061 (both to Merck & Co Inc) each disclose a macrocyclic compound which is indicated as an immunosuppressive agent.
The compounds and methods disclosed in the patent
25 applications mentioned above may be used in the production of the novel compounds of the present invention.
Alternatively, the novel compounds may be produced by total synthesis.
We have now found a novel group of macrocyclic compounds which act as antagonists of immunosuppressive compounds, particularly macrocyclic immunosuppressive compounds including derivatives of 12-(2-cyclohexyl-l-methylvinyl)-13,19,21,27-tetramethyl- 11,28-dioxa-4-azatricyclo[22.3.1.04 >9]octacos-18-ene and rapamycin, as shown in the mixed lymphocyte reaction (MLR) (described in WO 89/05304, Example A). The novel group of compounds are therefore useful inter alia in the treatment of immunodepression or a disorder involving immunodepressio .
Thus, according to the present invention, there is provided the use of a compound of formula I,
wherein
R1 and R2 independently represent H or OH, or they may together represent a second carbon-carbon bond between
the carbon atoms to which they are attached;
R3 represents methyl optionally substituted b
-C02H or an ester or amide thereof; ethyl optionally substituted by O, OH or -C02H or an ester or amide thereof; propyl optionally substituted by OH or O; or allyl optionally substituted by OH;
R4 represents H;
R5 and R6 together represent a second carbon-carbon bond between the carbon atoms to which they are attached;
R7 represents H or OH; R8 represents OCH3; R9 represents OH or OCH3; X represents O or (H,OH) ; Y represents O or (H,OH) ; and n represents 1 or 2; in addition to their significances above
R1 and R5 may together represent an oxygen atom, in which case R6 and R7 together represent a second carbon-carbon bond between the carbon atoms to which they are attached;
R7 and R8 may together represent an oxygen atom; ar
R3, R4 and Y, together with the carbon atoms to which they are attached, may represent a methyl-substituted furanyl ring; provided that i) when R2 represents H; R3 represents methyl, ethyl,
propyl or allyl; R5 and R6 together represent a second carbon-carbon bond between the carbon atoms to which they are attached; R8 represents OCH3; and Y represents O; then R7 represents OH; and ii) when n is 1, then R3 is not methyl or ethyl; in the manufacture of a medicament for the treatment of immunodepression or a disorder involving immunodepression.
Examples of disorders involving immunodepression include AIDS, cancer, senile dementia, trauma (including wound healing, surgery and shock) , chronic bacterial infection, and certain central nervous system disorders.
The immunodepression to be treated may be caused by an overdose of an immunosuppressive macrocyclic compound, for example derivatives of 12-(2-cyclohexyl-l-methylvinyl)- 13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo [22.3.1.04' ]octacos-18-ene such as FR-900506, or rapamycin. Overdosing of such medicaments by patients is quite common upon their realising that they have forgotten to take their medication at the prescribed time, and can lead to serious side effects.
A further situation in which the compounds of formula I may be used to treat immunodepression is in vaccination. It is sometimes found that the antigen introduced into the body for the acquisition of immunity from disease acts as an immunosuppressive agent, and so antibodies are not produced by the body and immunity is not acquired. By introducing a compound of formula I into the body (for
example in the vaccine) the undesired immunosuppression may be overcome and immunity acquired.
The present invention further provides the novel compounds of formula I, as defined above, provided that i) when R1 represents OH; R2 represents H; R5 and R6 together represent a second carbon-carbon bond between the carbon atoms to which they are attached; R7 represents H; R9 represents OCH3; X and Y each represent O; and n represents 2; then R3 does not represent 2-oxopropyl, 2,3-dihydroxypropyl or ethanalyl; ii) when R1 represents OH; R2 represents H; R5 and R6 together represent a second carbon-carbon bond between the carbon atoms to which they are attached; R7 represents OH; R9 represents OCH3; X and Y each represent O; and n represents 2; then R3 does not represent allyl or l-hydroxyprop-2-enyl; and iii) when R~ represents OH; R2 represents H; R5 and
R6 together represent a second carbon-carbon bond between the carbon atoms to which they are attached; R7 represents H; R9 represents OCH3; X and Y each represent (H,OH) ; and n represents 2; then R3 does not represent allyl.
In the novel use or the novel compounds, we prefer R3 to be ethyl substituted by 0 or propyl substituted by 0-
Desirably, R7 is OH.
We prefer R2 to be OH, more preferably (S)-OH (ie to have S absolute stereochemistry at its point of attachment
to the molecule) .
When R3 comprises an ester or amide group, we prefer the alcohol or amine moiety to contain from 1 to 10 carbon atoms, for example the alcohol moiety may be methanol. 5 Known compounds of formula I (as first defined above) from WO 89/05304 include:
17-Allyl-l,14,20-trihydroxy-12-[2-(4-hydroxy-3- methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy- 13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo 0 [22.3.1.04'9]octacos-18-ene-2,3,10,16-tetraone,
17-(l-Hydroxyprop-2-enyl)-1,14,20-trihydroxy-12-[2- (4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl]-23,25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo [22.3.1.04'9]octacos-18-ene-2,3,10,16-tetraone, 5 17-(2,3-Dihydroxypropyl)-l,14-dihydroxy-12-[2- (4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl]-23,25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo [22.3.1.04'9]octacos-18-ene-2,3,10,16-tetraone,
17-Ethanalyl-l,14-dihydroxy-12-[2-(4-hydroxy-3- 0 methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy- 13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo [22.3.1.04'9]octacos-18-ene-2,3,10,16-tetraone,
17-(2-Oxopropyl)-l,14-dihydroxy-12-[2-(4-hydroxy-3- methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy- 25 13 ,19,21, 7-tetramethyl-ll,28-dioxa-4-azatricyclo [22.3.1.04'9]octacos-18-ene-2,3,10,16-tetraone,
17-Allyl-l,2,14,16-tetrahydroxy-12-[2-(4-hydroxy-3- methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy-
13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo [22.3.1.04'9]octacos-18-ene-3,10-dione.
According to the invention there is further provided a process for the production of a novel compound of formula I, which comprises: a) producing a compound of formula I, in which R3 represents propyl substituted by 0, by oxidation of a corresponding compound in which represents allyl; b) producing a compound of formula I, which contains a vicinal diol, by oxidation of a carbon-carbon double bond in a corresponding compound; c) producing a compound of formula I, in which R3 represents ethyl substituted by O, by oxidative cleavage of a corresponding compound in which R3 represents 2,3-dihydroxypropy1; d) producing a compound of formula I, in which R3 represents methyl substituted by -C02H or ethyl substituted by -C02H, by oxidation of a corresponding compound in which R3 represents ethanalyl or propanalyl; e) producing a compound of formula I, which contains two vicinal hydrogen atoms, by reduction of a corresponding compound which contains a carbon-carbon double bond; f) producing a compound of formula I, in which X or Y represents (H,0H) , by reduction of a corresponding compound in which X or Y represents O; g) producing a compound of formula I, in which R3, R4 and Y, together with the carbon atoms to which they are attached, represent a methyl-substituted furanyl ring, by
the action of acid on a corresponding compound in which R3 represents 2-oxopropyl, R4 represents H and Y represents O; h) producing a compound of formula I, in which R1 and R5 together represent an oxygen atom and R6 and R7 together represent a second carbon-carbon bond between the carbon atoms to which they are attached, by the action of acid on a corresponding compound in which R1 represents OH, R5 and R6 together represent a second carbon-carbon bond between the carbon atoms to which they are attached, and R7 represents OH; i) producing a compound of formula I, in which R7 and R8 together represent an oxygen atom, by the action of a dehydrating agent on a corresponding compound of formula I in which R7 represents OH and R8 represents OCH3; j) producing a compound of formula I, in which R7 represents OH, by allylic oxidation of a corresponding compound in which R7 represents H; or k) producing a compound of formula I, in which R3 represents allyl substituted by hydroxy, by allylic oxidation of a corresponding compound in which R3 represents allyl.
Esters and amides of carboxylic acids that R3 may represent may be produced by conventional methods. Where desired or necessary, hydroxy groups may be protected and deprotected using conventional protecting group chemistry [as described in "Protective Groups in Organic Chemistry", ed: J W F McOmie, Plenum Press (1973),
and "Protective Groups in Organic Synthesis", T W Greene, Wiley-Interscience (1981) ] . In addition, European paten application No 184162 describes the use of protectin groups in macrocyclic compounds. In process (a) , suitable oxidizing agents include a palladium (II) halide, for example palladium (II) chloride, in conjunction with a cuprous halide, for example copper (I) chloride. Suitable solvents include those that do not adversely affect the reaction, for example dimethylformamide (DMF) and water. The reaction is preferably carried out at a temperature of from 0 to 100°C, more preferably at or around room temperature.
In process (b) , suitable oxidizing agents include osmium tetroxide, potassium permanganate, and iodine in conjunction with silver acetate. Osmium tetroxide is preferably used in conjunction with a regenerating agent such as 4-methylmorpholine N-oxide. Suitable solvents include those that do not adversely affect the reaction, for example diethyl ether or tetrahydrofuran (THF) . In the case of potassium permanganate, aqueous alkaline conditions are preferred. The reaction is preferably carried out at a temperature of from 0 to 100βC, more preferably at or around room temperature.
In process (c) , suitable reagents include lead tetraacetate and phenyliodoso acetate. Suitable solvents include those that do not adversely affect the reaction, for example benzene and glacial acetic acid. The reaction is preferably carried out at a temperature of from 0 to
100°C, more preferably at or around room temperature.
In process (d) , suitable oxidizing agents include sodium chlorite in conjunction with sodium hydrogen phosphate. Suitable solvents include those that do not adversely affect the reaction, for example water. The reaction is preferably carried out at a temperature of from 0 to 100"C, more preferably at or around room temperature.
In process (e) , the reduction may be carries out catalytically using hydrogen. Suitable catalysts include platinum catalysts (for example platinum black), and palladium catalysts (for example palladium-on-carbon) . Suitable solvents include those that do not adversely affect the reaction, for example methanol and ethanol. The reaction may be carried out at or around room temperature. In process (f) , suitable reducing agents include borane (for example in the form of borane-ammonia complex) and sodium borohydride. Suitable solvents include those that do not adversely affect the reaction, for example diethyl ether and dichloromethane. The reaction may be carried out at or around room temperature. Where desired or necessary, the (H,OH) group may be oxidized back to O by the action of copper (II) acetate in acetic acid.
In processes (g) and (h) , suitable acids include p-toluenesulphonic acid. Suitable solvents include those that do not adversely affect the reaction, for example toluene. The reaction is preferably carried out at a temperature above room temperature, for example on a steam bath.
In process (i) , suitable reagents include Martin' sulphurane reagent. Suitable solvents include those tha do not adversely affect the reaction, for exampl dichloromethane. The reaction is preferably carried out a a temperature below room temperature, for example -30βC.
In processes (j) and (k) , suitable reagents include
Se02, preferably in the presence of ^utyl hydrogen peroxide. Suitable solvents include dichloromethane, and the reaction may be carried out at or around room temperature.
The invention further provides the use of the novel compounds of formula I as pharmaceuticals, and a pharmaceutical composition comprising such a compound in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired (eg topical, parenteral or oral) and the disease indicated. However, in general, satisfactory results are obtained when the compounds are administered at a dosage of from 0.1 to 200mg per kg of animal body weight.
For man the indicated total daily dosage is in the range of from lmg to lOOmg and preferably from lOmg to 500mg, 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 2mg to
500mg, and preferably lmg to 500mg of the compound preferably admixed with a solid or liquid pharmaceutically acceptable diluent, carrier or adjuvant.
Suitable pharmaceutical compositions for administration of compounds of formula I (as first defined above) comprise (preferably less than 80%, and more preferably less than 50% by weight) of a compound of formula I (as first defined above) in combination with a pharmaceutically acceptable adjuvant, diluent or carrier. Examples of suitable adjuvants, diluents or carriers are: for tablets, 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 - coarse lactose. The compound of formula I (as first defined above) is preferably in a form having a mass median diameter of from 0.01 to 10 microns. The compositions may also contain suitable preserving, stabilising and wetting agents, solubilisers, sweetening and colouring agents and flavourings. The compositions may, if desired, be formulated in sustained release form. We prefer compositions which are designed to be taken oesophageally and to release their contents in the gastrointestinal tract.
We have also found that the toxicity of immunosuppressive compounds, particularly immunosuppressive macrocyclic compounds including derivatives of
12-(2-cyclohexyl-1-methylvinyl)-13,19,21,27-tetramethyl- ll,28-dioxa-4-azatricyclo[22.3.1.04'9]octacos-18-ene (fo example FR-900506) and rapamycin, may be reduced by administering them in association with a compound of formula I as first defined above.
Thus, according to a second aspect of the invention, there is provided a pharmaceutical mixture comprising a compound of formula I (as first defined above) and an immunosuppressive compound. Preferably, the greater proportion of active ingredient in such a mixture is the compound of formula I, for example the compound of formula I may be present at a ratio of greater than 10:1 by weight, for example 99:1.
The invention also provides a method of treatment of immunodepression or a disorder involving immunodepression which comprises administering a therapeutically efficacious amount of a compound of formula I, as first defined above, to a patient suffering from such a condition.
The compounds of formula I (as first defined have the advantage that they are less toxic, more efficacious, are longer acting, have a broader range of activity, are more potent, produce fewer side effects, are more easily absorbed or have other useful pharmacological properties, than compounds previously used in the therapeutic fields mentioned above.
The compounds of formula I (as first defined above) have a number of chiral centres and may exist in a variety of stereoisomers. The invention provides the use of all
optical and stereoisomers, as well as racemic mixtures, and all optical and stereoisomers of the novel compounds of formula I per se.
However, the preferred stereochemistry of various chiral carbon atoms are shown in formula la,
wherein R1 to R8, X, Y and n are as defined above.
The invention is illustrated by the following examples. Example 1
17-(2-Oxopropyl)-l-hydroxy-12-r2-(4-hvdroxy-3- methoxycvclohexyl)-1-methylvinyl]-23.25-dimethoxy- 13.19.21.27-tetramethyl-ll.28-dioxa-4-azatricyclo r22.3.1.0 '9]octacos-18-ene-2.3.10.16-tetraone a) 17-f2-0xopropyl^-l-hvdroxy-12-r2-(4-hvdroxy-3- methoxycyclohexyl)-1-methylvinyl1-23.25-dimethoxy- 13.19.21.27-tetramethyl-ll.28-dioxa-4-azatricyclo
T22.3.1.0 '91octacosa-14,18-diene-2.3.10.16-tetraone To a solution of palladium (II) chloride (25mg) and copp (I) chloride (50mg) in DMF (dimethylformamide) (6ml) a water (1ml) which had been previously oxygenated by havin air bubbled through it for 30 minutes at room temperatur was added a solution of 17-allyl-l-hydroxy-12-[2-(4- hydroxy-3-methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy 13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo [22.3.1.04'9]octacosa-14,18-diene-2,3,10,16-tetraone (th compound of Example 4, WO 89/05304) (lOO g) in DMF (-2ml) The reaction mixture was then stirred and oxygenated for hours at room temperature after which it was diluted wit diethyl ether. The organic extract was then washed wit dilute aqueous hydrochloric acid (1M) and brine befor being dried (MgS04) , filtered and evaporated to give th subtitle compound as an oil. b) 17-(2-Oxopropyl)-l-hγdroxy-12-r2-(4-hydroxy-3- methoxycyclohexyl)-1-methylvinyl1-23.25-dimethoxy- 13.19.21.27-tetramethyl-ll.28-dioxa-4-azatricyclo r22.3.1.04'91octacos-18-ene-2.3.10.16-tetraone
The crude product of step (a) was then re-dissolved in dr methanol and was stirred with 10% Pd-on-carbon (lOmg) unde an atmosphere of hydrogen for 4 hours. The reactio mixture was then filtered, concentrated in vacuo an chromatographed on silica eluting with acetone/hexane [2:3] to give the title compound as a foam (84mg) .
MS (FAB): 889 [M+Rb]+; 827 [M+Na]+; 805 [M+H]+; 787 [M-OH]+
13C NMR (CDC13) <5: 211.1 (C16) ; 207 (C41) ; 196.3 (C2) ; 169.1 (CIO); 166.1 (C3) ; 138.7 (C19) ; 132 (C31) ; 131 (C29) ; 121.8 (C18); 97.3 (Cl) ; 84 (C34) ; 82.4 (C12) ; 75.1 (C23); 56.2 (C9) ; 48.9 (C20) ; 47.6 (C17) ; 13.3 (C39) Example 2
2-(1.14-Dihydroxy-12- 2-(4-hydroxy-3-methoxycvclohexyl)-1- methylvinyl1-23.25-dimethoxγ-13.19.21.27-tetramethyl-ll.28- dioxa-4-azatricvclof22.3.1.04'91octacos-18-ene-2.3.10.16- tetraone-17-yl>-ethanoic acid A solution of FR-900506 (1.2g), 4-methylmorpholine N-oxide (1.3g) and osmium tetroxide (0.7ml of a 4% solution in water) in THF (tetrahydrofuran) (25ml) and water (14ml) was stirred for 3.5 hours at room temperature. Solid sodium metabisulphite was then added followed by ethyl acetate and Florisil (registered trade mark) and the combined mixture was filtered through celite. The separated organic extract (after washing with saturated aqueous sodium hydrogen carbonate solution) was dried (MgS04) , filtered and evaporated in vacuo to give the crude 17-(2,3- dihydroxypropyl) compound as an oil. This was then dissolved in benzene (40ml) and lead tetraacetate (1.46g) was added. After stirring for 3 minutes at room temperature the reaction mixture was diluted with diethyl ether and was filtered, concentrated in vacuo, redissolved in diethyl ether, re-filtered and re-concentrated in vacuo to give the crude 17-(ethanalyl) compound as an oil. This was then dissolved in butanol (25ml) and 1-methyl cyclohex-1-ene (6ml) and to this was added portionwise over
10 minutes solutions of sodium chlorite (0.8g) and sodi hydrogen phosphate (0.81g) each dissolved in 5ml of wate After stirring for 0.5 hours at room temperature t reaction mixture was quenched by the addition of eth acetate. Dilute aqueous hydrochloric acid (2M) was th added and the organic extracts (after washing wit saturated aqueous sodium hydrogen carbonate solution) wer dried (MgS04) , filtered and evaporated to an oil i vacuo. Chromatography on silica eluting with diethy ether/methanol/acetic acid [190:9:1] and then furthe chromatography on silica eluting with dichloromethane/ methanol/acetic acid [170:9:1] gave the title compound as foam (402mg, 32%) . MS (FAB) : 906 [M+Rb]+ 13C NMR (CDC13) δ : 196.3 (C2) ; 177.7(C41); 168 (CIO); 164.6 (C3) ; 139.7 (C19) ; 132.7 (C29) ; 129.3 (C31) 120.6 (C18) ; 97.3 (Cl) ; 84.2 (C34) ; 70.5 (C14) ; 9.8 (C39) Example 3
2-(1.14-Dihydroxγ-12-f2-(4-hydroxy-3-methoxycyclohexyl)-l- methylvinyll-23.25-dimethoxy-13f19.21.27-tetramethyl-ll.28- dioxa-4-azatricyclof22.3.1.0 '9]octacos-18-ene-2f3.10.16- tetraone-17-yl)-ethanoic acid Methyl ester
To a solution of the title compound of Example 2 (50mg) i dichloromethane (3ml) at room temperature was added solution of diazomethane in diethyl ether until no startin material remained. The reaction mixture was the concentrated in vacuo and chromatographed on silica elutin with acetone/hexane [1:2] to give the title compound as
foam (48mg) . S (FAB): 920 [M+Rb]+; 858 [M+Na]+; 818 [M-OH]+
13C NMR (CDC13) δ : 212.7 (C16) ; 196 (C2) ; 173 (C41) ;
168.8 (CIO); 164.6 (C3) ; 139.5 (C19) ; 132.9 (C29) ; 129.1 (C31) ; 120.6 (C18) ; 97.2 (Cl) ; 84.2 (C34) ; 70.8 (C14) ; 14.5
(C30) ; 9.7 (C39)
Example 4
2-11.14-Dihydroxy-12-f2-(4-hydroxy-3-methoxycyclohexyl)-1- methylvinyn-23.25-dimethoxy-13.19.21.27-tetramethyl-ll.28- dioxa-4-azatricyclof22.3.1.0 '91octacos-18-ene-2.3.10.16- tetraone-17-yll-ethanoic acid N-Morpholine amide A solution of the title compound of Example 2 (63.1mg), morpholine (20mg) , l-(3-dimethylaminopropyl)-3- ethylcarbodii ide hydrochloride (28mg) and 4-dimethylaminopyridine (2mg) in dry dichloromethane (4ml) was stirred at room temperature for 2.5 hours. Water was then added and the reaction mixture was extracted with dichloromethane. After washing with dilute aqueous hydrochloric acid (1M) and saturated aqueous sodium hydrogen carbonate solution, the dichloromethane extracts were dried (MgS04) , filtered and evaporated to an oil in vacuo. Chromatography on silica eluting with hexane/acetone [1:1] then gave the title compound as a foam (58mg, 84%) . MS (FAB): 975 [M+Rb]+; 891 [M+H]+; 873 [M-0H]+.
13C NMR (CDC13) δ : 213.2 (C16) ; 195.9 (C2) ; 170.1 (C41) ; 168.8 (CIO); 164.8 (C3) ; 139.1 (C19) ; 133.2 (C29) ;
128.9 (C31) ; 121.5 (C18) ; 97.4 (Cl) ; 84.2 (C34) ; 66.3 and
65.8 (CO of morpholine) ; 10.1 (C39) . Example 5
2-(lP14-Dihγdroxy-12-r2-(4-hydroxy-3-methoxγcyclohexyl)-1- methylvinyll-23.25-dimethoxγ-13.19.21.27-tetramethyl-ll.28- 5 dιoxa-4-azatricγclor22.3♦1.0 'J]octacos-18-ene-2.3.10.16- tetraone-17-yl)-ethanoic acid N-Ethanolamide A solution of the title compound of Example 2 (22.8mg) and 1,3-dic/clohexyl carbodiimide (6.7mg) in dry dichloromethane (2ml) was stirred at room temperature for 5
10 minutes. Ethanolamine (lOmg) was then added and the reaction mixture was stirred at room temperature for 1.5 hours. Dilute aqueous hydrochloric acid (1M) was then added and the reaction mixture was extracted with dichloromethane. The organic extracts, after washing with
15 saturated aqueous sodium hydrogen carbonate solution, were dried (MgS04) , filtered and evaporated to an oil in vacuo. Chromatography on silica eluting with dichloromethane/methanol/acetic acid [140:9:1] then gave the title compound as a glass (19.4mg, 81%).
20 MS (FAB): 950 [M+Rb]+; 888 [M+Na]+; 866 [M+H]+; 848 [M-0H]+ 13C NMR (CDC13) δ : 198.7 (C2) ; 173.8 (C41) ; 169. (CIO); 16".6 (C3) ; 140 (C19) ; 133.2 (C29) ; 129 (C31) ; 122.4 (C18) ; 97.8 (Cl) ; 84.2 (C34) ; 61.2 (CO of ethanolamine) ;
25 44.0 (CN of ethanolamine); 16.2 (C47) ; 15.8 (C43) ; 14.7 (C30) ; 9.7 (C39) Example 6 2-(1.14-Dihvdroxy-12-T2-(4-hvdroxy-3-methoxycvclohexγl)-1-
methylvinyl]-23.25-dimethoxy-13.19.21.27-tetramethyl-ll.28- dioxa-4-azatricyclof22.3.1.04'9]octacos-18-ene-2.3.10.16- tetraone-17-yl)-ethanoic acid amide with σlvcine methyl ester To a solution of the title compound of Example 2 (43.6mg) and methyl glycinate (3mg) in dichloromethane (3ml) was added triethylamine (22μl) and 2-chloro-l- methylpyridinium tosylate (24.2mg). After stirring at room temperature for 15 minutes dilute aqueous hydrochloric acid (2M) was added and the reaction mixture was extracted with dichloromethane. The organic extracts, after washing with saturated aqueous sodium hydrogen carbonate solution, were then dried (MgS04) , filtered and evaporated to an oil in vacuo. Chromatography on silica eluting with hexane/ acetone [1:1] then gave the title compound as a foam (34.1mg, 72%).
MS (FAB): 977 [M+Rb]+; 915 [M+Na]+; 893 [M+H]+; 875 [M-OH]+ 13C NMR (CDC13) 6 : 213 (C16) ; 195.9 (C2) ; 171.7 (glycine carbonyl) ;170.3 (C41) ; 168.7 (CIO); 164.7 (C3) ; 139.2 (C19) ; 132.9 (C29) ; 128.9 (C31) ; 120.9 (C18) ; 97.2 (Cl) ; 84.1 (C34) ; 72.4 (C24) ; 71.1 (C14) ; 52.4 (OCH3 of glycine); 9.9 (C39) Example 7 2-{1.14-Dihvdroxγ-12-r2-(4-hvdroxy-3-methoxycyclohexγl)-l- methylvinyl1-23.25-dimethoxy-13.19.21.27-tetramethyl-ll.28- dioxa-4-azatricγcloT22.3.1.04 '9]octacos-18-ene-2.3.10.16- tetraone-17-yl)-ethanoic acid N-Piperidine amide
To a solution of 2-chloro-l-methylpyridinium tosylat (24.9mg) in dry dichloromethane (1ml) under nitrogen a room temperature was added a solution of the title compoun of Example 2 (42.3mg), piperidine (lOmg) and triethylamin (22μl) in dry dichloromethane (1.5ml). After 3 hours a room temperature a further portion of 2-chloro-l- methylpyridinium tosylate (15mg) and triethylamine (15μl) was added and stirring was continued for further two hours at room temperature. Water was then added and the reaction mixture was extracted with dichloromethane. After washing with dilute aqueous hydrochloric acid (1M) and saturated aqueous sodium hydrogen carbonate solution, the dichloromethane extracts were dried (MgS04) , filtered and evaporated to an oil in vacuo. Chromatography on silica eluting with dichloromethane/methanol [29:1] then gave the title compound as a foam (13.3 mg, 29%). MS (FAB): 973 [M+Rb]+; 911 [M+Na]+; 889 [M+H]+ 13C TMR (CDC13) δ : 213.4 (C16) ; 196 (C2) ; 169. (CIO); 168.6 (C41) ; 164.7 (C3) ; 138.8 (C19) ; 133.3 (C29) ; 128.7 (C.31) ; 121.7 (C18) ; 97.3 (Cl) ; 84.1 (C34) ; 10.1 (C39) Example 8
2-(l.14-Dihγdroxy-12-r2-(4-hvdroxγ-3-methoxycyclohexyl)-l- methylvinyl]-23.25-dimethoxy-13.19.21.27-tetramethyl-ll.28- dioxa-4-azatricyclof22.3.1.04' ]octacos-18-ene-2.3.10.16- tetraone-17-yl>-ethanoic acid N-Benzylamide A solution of the title compound of Example 2 (48mg) , 2-chloro-l-methylpyridinium tosylate (27.lmg),
triethylamine (25μl) and benzylamine (lOmg) in THF (3ml) was stirred at room temperature for 1.5 hours. Dilute aqueous hydrochloric acid (2M) was then added and the mixture was extracted with ethyl acetate. The organic extracts, after washing with saturated aqueous sodium hydrogen carbonate solution, were dried (MgS04) , filtered and evaporated to an oil in vacuo. Chromatography on silica eluting with hexane/acetone [3:2] then gave the title compound as a foam (33.6 mg, 63%). MS (FAB): 995 [M+Rb]+; 933 [M+Na]+; 911 [M+H]+; 893 [M-OH]+
13C NMR (CDC13) δ : 213.3 (C16) ; 196.1 (C2) ; 171.6 (C41) ; 168.9 (CIO); 164.9 (C3) ; 139.3 (C19) ; 133.2 (C29) ; 128.9 (Car) ; 128 (Car) ; 121.4 (C18) ; 97.5 (Cl) ; 84.3 (C34) ; 10.2 (C39) Example 9
2-(1.14-Dihvdroxγ-12-r2-(4-hvdroxy-3-methoxycvclohexyl)-1- methylvinyll-23.25-dimethoxy-13.19.21.27-tetramethyl-ll.28- dioxa-4-azatricγclor22.3.1.04 '9]octacos-18-ene-2.3.10.16- tetraone-17-γl>-ethanoic acid N-Butylamide
A solution of the title compound of Example 2 (57.8mg), 2-chloro-l-methylpyridinium tosylate (37.8mg), triethylamine (11.5μl) and butylamine (12mg) in THF (2ml) was stirred at room temperature for 3 hours. A further portion of 2-chloro-l-methylpyridinium tosylate (37.8mg) and triethylamine (11.5μl) were then added and stirring was continued for an additional 2 hours at room temperature, after which dilute aqueous hydrochloric acid
(2M) was added and the organic extracts (after washing wit saturated aqueous sodium hydrogen carbonate solution) wer dried (MgS04) , filtered and evaporated to an oil i vacuo. Chromatography on silica eluting wit dichloromethane/methanol [29:1] then gave the titl compound as a foam (36.3mg, 59%).
MS (FAB): 961 [M+Rb]+; 899 [M+Na]+; 877 [M+H]+; 85 [M-OH]+ 13C NMR (CDC13) δ : 213.4 (C16) ; 196.1 (C2) ; 171. (C41) ; 168.9 (CIO); 165 (C3) ; 139.2 (C19) ; 133.3 (C29) ; 129.2 (C31) ; 121.6 (C18) ; 97.5 (Cl) ; 84.4 (C34) ; 10.2 (C39) Example 10
2-(l.14-Dihydroxy-12-r2-(4-hydroxy-3-methoxycyclohexγl)-l- methylvinyl]-23.25-dimethoxy-13.19.21.27-tetramethyl-ll.28- dioxa-4-azatricγclo[22.3.1.04'9]octacos-18-ene-2.3.10.16- tetraone-l7-yl)-ethanoic acid p-Cvanophenγl ester A solution of the title compound of Example 2 (51mg) , 2-chloro-l-methylpyridinium tosylate (33.4mg), triethylamine (29μ) and p-cyanophenol (10.2mg) in TH (2ml) was stirred at room temperature for 2 hours. Dilute aqueous hydrochloric acid (2M) was then added and the organic extracts (after washing with saturated aqueous sodium hydrogen carbonate solution) were dried (MgS0 ) , filtered and evaporated to an oil in vacuo. Chromatography on silica eluting with dichloromethane/methanol [39:1] then gave the title compound as a foam (24.9 mg, 43%). MS (FAB): 1007 [M+Rb]+, 905 [M-OH]+ 13C NMR (CDC13) δ : 212.4 (C16) , 196 (C2) , 170.
(C41) , 168.8 (CIO), 164.4 (C3), 153.8 (0Car) , 140.4 (C19) , 133.6 (Car) , 132.7 (C29) , 129.1 (C31) , 122.6 (Car) , 120.1 (C18) , 118.2 (CN of p-cyanophenol) , 109.7 (CarCN) , 97 (Cl) , 84.1 (C34) , 14.4 (C30) , 9.9 (C39)
5 Example 11
2-f1.14-Dihγdroxy-12-r2-f4-hvdroxγ-3-methoxycvclohexyl)-1- methylvinyl]-23.25-dimethoxy-13.19.21.27-tetramethyl-ll.28- dioxa-4-azatricvclor22.3.1.0 /91octacos-18-ene-2.3.10.16- tetraone-17-yll-ethanoic acid Phenyl ester 0 A solution of the title compound of Example 2 (45mg) , 2-chloro-l-methylpyridinium tosylate (32.3mg), triethylamine (30μl) and phenol (28mg) in dry dichloromethane (2ml) was stirred at room temperature for 2 hours. Dilute aqueous hydrochloric acid (1M) was then 5 added and the organic extracts (after washing with saturated aqueous sodium hydrogen carbonate solution) were dried (MgS04) , filtered and evaporated to an oil in vacuo. Chromatography on silica eluting with hexane/ acetone [3:2] then gave the title compound as a foam 0 (17.6mg, 36%).
MS (FAB); 982 [M+Rb]+; 920 [M+Na]+; 898 [M+H]+; 880
[M-0H]+ 13C NMR (CDC13) δ : 212.4 (C16) ; 195.9 (C2) ; 171.1
(C41) ; 168.8 (CIO); 164.5 (C3) ; 150.5 (0Car) ; 140 (C19) ;
25 132.7 (C29);- 129.4 (Car) ; 129.3 (C31) ; 125.8 (Car) ; 121.4 (Car) ; 120.7 (C18) ; 97.2 (Cl) ; 84.1 (C34) ; 9.7 (C39) Example 12
2-(1.14-Dihydroxy-12-r2-(4-hydroxγ-3-methoxycvclohexyl)-1- methylvinyl]-23.25-dimethoxy-13.19.21.27-tetramethyl-ll.28- dioxa-4-azatricγclor22.3.1.04'91octacos-18-ene-2.3.10.16- tetraone-17-yl)-ethanoic acid p-Nitrophenyl ester 5 A solution of the title compound of Example 2 (150mg) , 2-chloro-l-methylpyridinium tosylate (77mg) , triethylamin (77μl) and p-nitrophenol (47mg) in dry dichlorometha (2ml) was stirred at room temperature for 2.5 hours. Th reaction mixture was then concentrated in vacuo an 10 purified directly by chromatography on silica eluting with hexane/diethyl ether [3:2] to give the title compound as a foam (135mg, 78%) .
MS (FAB): 1027 [M+Rb]+; 925 [M-0H]+ 13C NMR (CDC13) δ : 212.6 (C16) ; 196.2 (C2) ; 170. 15 (C41) ; 169 (CIO); 164.7 (C3) ; 155.4 (OCar) ; 145.5 (NCar) ; 140.6 (C19) ; 132.9 (C29) ; 129.3 (C31) ; 125.4 (Car) ; 122.6 (Car) ; 120.3 (C18) ; 97.2 (Cl) ; 84.3 (C34); 9.8 (C39) Example 13 2017-Allyl-1.14.16-trihvdroxy-12-r2-f4-hvdroxy-3- methoxycyclohexyl)-1-methylvinyl1-23f25-dimethoxy- 13.19.21 f27-tetramethyl-ll.28-dioxa-4-azatricyclo r22.3.1.04,9]octacos-18-ene-2f3,10-trione
To a solution of FR-900506 (lOOmg) in diethyl 25 ether/dichloromethane was added excess borane ammonia complex (150mg) . After stirring for 2 hours at room temperature dilute aqueous hydrochloric acid (IM) was added and the ethereal extract was dried (Na2S04) , filtered
and evaporated in vacuo to give the crude 1,2,14,16- tetrahydroxy compound as an oil. This was taken up in acetic acid and copper (II) acetate (lOOmg) was added. After heating on a steam bath for 10 minutes the reaction 5 mixture was cooled to room temperature and water was added. The reaction mixture was then extracted with ethyl acetate and the organic extracts, after washing with saturated aqueous sodium hydrogen carbonate solution, were dried (MgS04) , filtered and evaporated to an oil in 0 vacuo. Chromatography on silica eluting with acetone/hexane [1:2] then gave the title compound (30mg) with R-stereochemistry at C16 followed by the title compound (24mg) with S-stereochemistry at C16. (16R)-Stereoisomer 5 MS (FAB): 890 [M+Rb]+ 13C NMR (CDC13) δ : 199.4 (C2) ; 169.1 (CIO); 165.8
(C3) ; 136.9 (C41) ; 136.3 (C19) ; 132.6 (C29) ; 128.2 (C31) ; 125.4 (C18) ; 115.9 (C42) ; 98.7 (Cl) ; 84.2 (C34) ; 56.5 (C9) ; 49 (C20) ; 43.2 (C17) ; 10.4 (C39) 0 (16S)-Stereoisomer
MS (FAB): 890 [M+Rb]+; 828 [M+Na]+; 806 [M+H]+; 788 [M-OH]+ 13C NMR (CDC13) δ 196.5 (C2) ; 169.3 (CIO); 165.3
(C3) ; 137.8 (C41) ; 136.2 (C19) ; 132.9 (C29) ; 128.5 (C31) ;
25 126.6 (C18) ; 115.7 (C42) ,* 97 (Cl) ; 84.3 (C34) ; 56.4 (C9) ; 9 (C39)
Example 14 1.14-Dihvdroxy-12-r2-f4-hvdroxy-3-methoxycvclohexyl)-l-
methylvinyl1-26.28-dimeth_)_>rv-13.18.22.24,30-pentamethyl- 11.17.31-trioxa-4-azatetracvclor25.3.1.04 ' 9.016'201 hentriaconta-16 (20) .18.21-triene-2.3.10-trione A solution of 1,14-dihydroxy-12-[2-(4-hydroxy-3- methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy-17-(2- oxopropyl)-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricycl [22.3.1.04'9]octacos-18-ene-2,3,10,16-tetraone (th compound of Example 29, WO 89/05304) (lOOmg) in dr dichloromethane (25ml) containing p-toluenesulphonic acid (5mg) was heated under reflux for 30 minutes. Volatiles were then removed in vacuo and the residue was chromatographed on silica eluting with acetone/hexane [3:2] to give the title compound (19mg) as a foam.
MS (FAB): 887 [M+Rb]+; 825 [M+Na]+;803 [M+H]+; 785 [M-OH]+ 13C NMR (CDC13) δ i 195.9 (C2) ; 168.9 (CIO); 164.
(C3); 150.8 (C16) ; 148.3 (C18) ; 106.3 (C19) ; 97 (Cl) ; 84.1 (C37); 8.5 (C42) Example 15 1.14-dihγdroxy-12-r2-(4-hydroxy-3-methoxycyclohexγl)-1- methylvinyll-23.25-dimethoxy-17-propanalyl-13.19.21.27- tetramethyl-ll.28-dioxa-4-azatricyclor22.3.1.04'9]octacos- 18-ene-2.3.10.16-tetraone
A solution of FR-900506 (3g) in DMF (90ml) and water (15ml) containing palladium (II) chloride (0.4g) and copper (I) chloride (l*8g) was stirred at room temperature while air was bubbled through the reaction mixture for 2 hours. The reaction mixture was then diluted with diethyl ether and
the organic extract (after washing with dilute aqueous hydrochloric acid (IM) , water and brine) was dried (MgS04) , filtered and evaporated to an oil in vacuo. Chromatography on silica eluting with hexane in an 5 increasing acetone gradient then gave the title compound as a foam (30mg) . MS (FAB) : 821 [M+H]
13C NMR (CDC13) δ : 213.1 (C16) , 202.1 (C42) , 196.3 (C2) , 169 (CIO), 164.7 (C3), 139.8 (C19) , 132.6 (C29) ,
10 129.6 (C31) , 121.9 (C18) , 97.1 (Cl) , 84.2 (C34) , 70.3 (C14) , 9.6 (C39) Example 16
17-Allyl-l-hydroxy-12-r2-(4-hγdroxy-3-methoxycvclohexyl) -1- methylvinyll-23.25-dimethoxγ-13.19.21.27-tetramethyl-
15 11.28.29-trioxa-4-azatetracvcloT22.3.1.114'18.04'91 nonacos-19-ene-2.3.10.16-tetraone
A sample of 17-allyl-l,14,20-trihydroxy-12-[2-(4-hydroxy-3- methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy- 13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo
20 [22.3.1.0 '9]octacos-18-ene-2,3,10,16-tetraone (as prepared in Example 13 of WO 89/05304, 60mg) was heated in toluene (10ml) containing p-toluenesulphonic acid for 10 minutes. Evaporation of the solvent in vacuo and chromatography on silica then gave the title compound as an
25 oil (30mg) .
13C NMR (CDC13) δ : (single rotamer) 210.22 (C16) ; 195.96 (C2); 168.96 (CIO); 165.24 (C3) ; 135.92 (C20) ; 134.69 (C41) ; 131.13 (C29) ; 128.78, 128.65 (C19, C31) ;
117.60 (C42); 97.53 (Cl) ; 84.19 (C34) ; 80.79 (C18) ; 73.167 (C14) ; 52.47 (C17) ; 44.638 (C15) ; 29.992 (C21) MS (FAB): 802.47 [M+H]+; 886.2 [M+Rb]+ -Example 17 17-Propyl-l-hydroxy-12-r2-(4-hydroxγ-3-methoxycγclohexyl)-1- ethylvinyl]-25-dimethoxγ-13.19.21.27-tetramethyl-ll.28.29- trioxa-4-azatetracyclor22.3.1.120'23.0 '9]nonacos-18-ene -2.3.10.16-tetraone
A sample of 17-allyl-l,14,20-trihydroxy-12-[2-(4-hydroxy-3- methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy- 13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo [22.3.1.04'9]octacos-18-ene-2,3,10,16-tetraone (as prepared in Example 13 of WO 89/05304, 121mg) was dissolved in dry dichloromethane (10ml) and to this was added Martin's sulphurane reagent at -30βC. After warming to 0°C, volatiles were removed in vacuo and the residue was chromatographed on silica to give a foam. To a solution of this in dry methanol (5ml) was added 10% Pd-on-carbon (lOmg) and the resulting suspension was stirred in an atmosphere of hydrogen for 7 hours at room temperature. Volatiles were then removed in vacuo and the residue was purified by column chromatography on silica to yield the title compound as an oil (19mg).
MS (FAB): 770.76 [M+H]+, 792.74 [M+Na]+, 854.44 [M+Rb]+
13C NMR (CDC13) δ (single rotamer) 197.81 (C16) ; 196.11 (C2); 168.96 (CIO); 165.21 (C3) ; 146.16 (C14) ; 139.46 (C19) ; 135.92 (C41) ; 134.63 (C31) ; 129.51 (C29) ;
129.40 (C15) ; 125.31 (C18) ; 116.29 (C42) ; 97.33 (Cl) ; 92.07 (C20) ; 84.09 (C34) ; 81.75 (C12) ; 80.03 (C23); 77.10 (C25) ; 74.67 (C24) ; 73.43 (C35) ; 56.78 (C9) ; 56.47 (OCH3); 55.95 (OCH3) ; 51.37 (C17)
5 Example 18
17-Allyl-l-hydroxy-12-r2-(4-hydroxy-3-methoxycyclohexyl)-1- methylvinyn-25-methoxy-13.19.21.27-tetramethyl-ll,28,29- trioxa-4-azatetracyclor22.3.1.120'23.04'91nonacosa- 14.18-diene-2.3,10.16-tetraone 0 A sample of 17-allyl-l,14,20-trihydroxy-12-[2-(4-hydroxy-3- methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy- 13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo [22.3.1.04'9]octacos-18-ene-2,3,10,16-tetraone (as prepared in Example 13 of WO 89/05304, 80mg) was dissolved 5 in dry dichloromethane (5ml) and to this was added excess Martin's sulphurane reagent at -30βC portionwise until all the starting material had disappeared (30 minutes) . The reaction mixture was then diluted with ethyl acetate and washed with water and then brine. The organic extract was
20 dried (MgS04) , filtered and evaporated in vacuo to an oil. Chromatography on silica then gave the title compound as an oil (20mg) .
13C NMR (CDC13) 6: (mixture of rotamers) 212.05, 211.04 (C16) ; 197.47, 194.95 (C2) ; 169.24, 169.09 (CIO);
25165.21, 164.72 (C3) ; 136.85, 137.44 (C19) ; 131.43, 130.97 (C29) ; 131.25, 128.90 (C31) ; 125.02, 124.35 (C18) ; 98.82, 97.44 (Cl) ; 91.56, 91.29 (C20) ; 84.17 (C34) MS (FAB): 775.11 [M+H]+; 797.09 [M+Na]+; 858.79
[M+Rb]+ Example 19
12-f2-(4-Hydroxy-3-methoxycyclohexyl)-1-methylvinyll-23.25- dimethoxy-17-propyl-13.19.21.27-tetramethγl-l.14.15- trihγdroxy-11.28-dioxa-4-azatricyclof22.3.1.04'9J. octacos-18-ene-2.3.10.16-tetraone
A sample of l-hydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl) -1-methylvinyl]-23,25-dimethoxy-17-propyl-13,19,21,27- tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04'9]octacosa -14,18-diene-2,3,10,16-tetraone as an oil (the compound o Example 11 of WO 89/05304, 510mg) was dissolved in dr tetrahydrofuran (12ml) and N-methyl morpholine N-oxid (0.3g) and osmium tetroxide (3ml of a 4% aqueous solution) were added. After stirring for 1 hour at room temperatur solid sodium metabisulphite (lg) was added followed after 5 minutes by celite to produce a thick slurry. The reactio mixture was then diluted with ethyl acetate and filtered. The organic extract after washing with saturated aqueous sodium bicarbonate solution and brine was dried (magnesiu sulphate), filtered and concentrated in vacuo to an oil. Column chromatogarphy on silica eluting with acetone/hexane [2:5] give two isomers of the title compound which differed in stereochemistry at C14 and/or C15. Isomer 1 (180mg) 13C NMR δ z (For the major rotamer) 211.82 (C16) 196.03 (C2); 169.10 (CIO); 164.26 (C3) ; 139.28 (C19) ; 132.12 (C29) ; 128.22 (C31) ; 121.92 (C18) ; 95.65 (Cl) ; 83.94 (C34); 75.76 (C12); 74.81 (C23) ; 74.63 (C15) ; 73.26 (C25) ;
73.26 (C35) ; 72.22 (C24) ; 71.66 (C14) ; 56.02 (C9) ; 48.05 (C20) ; 47.29 (C17) ; 39.08 (C5) ; 37.90 (C13) ; 34.92 (C33) ; 34.69 (C32) ; 34.47 (C27);33.66 (C22) ; 32.78 (C40) ; 32.63 (C26) ; 31.14 (C36) ; 30.57 (C37) ; 28.66 (C8) ; 25.78 (C21) ;
5 24.47 (C6) ; 21.24 (C7) ; 19.83 (C41) ; 19.83 (C44) ; 16.08 (C47) ; 15.66 (C43) ; 14.68 (C30) ; 14.07 (C42) ; 8.62 (C39) XH NMR δ : (For the Major rotamer) 5.48 (lH,brs,H-12) ; 5.15 (lH,d,J=9.6Hz,H-18) ; 5.08 (lH,d, =8.8Hz,H-31) ; 3.79 (lH,dd,J=1.5 and 8Hz,H-24) ; 1.66 (3H,brs,H-30) ; 1.60 0 (3H,brs,H-43) ; 1.02 (3H,d,J=6.5Hz,H-47) ; 0.92 (3H,t,J=7.6 Hz,H-42); 0.90 (3H,d,J=7.6Hz,H-44) ; 0.83 (3H,d,J=7 Hz,H-39) MS: 823 [M+H]+; 845 [M+Na]+; 906 [M+Rb]+ Isomer 2 (32mg) 13 C NMR δ : (For the major rotamer) 212.99 (C16) ;
15 194.39 (C2); 169.60 (CIO); 164.85 (C3) ; 138.33 (C19) ; 131.44 (C29) ; 129.95 (C31) ; 123.16 (C18) ; 97.79 (Cl) ; 84.17 (C34) ; 76.54 (C12) ; 75.73 (C23) ; 75.68 (C15) ; 73.52 (C25) ; 73.52 (C35) ; 72.78 (C24) ; 71.88 (C14) ; 55.85 (C9) ; 49.21 (C17) ; 48.78 (C20) ; 39.36 (C5) ; 38.83 (C13) ; 36.04 (C40) ;
20 35.34 (C32) ; 34.83 (C33) ; 34.46 (C27) ; 33.21 (C22) ; 32.35 (C26) ; 31.21 (C36) ; 30.58 (C37) ; 28.34 (C8) ; 26.33 (C21) ; 24.75 (C6) ; 20.76 (C41) ; 20.63 (C7) ; 20.42 (C44) ; 16.31 (C47) ; 15.31 (C43) ; 14.17 (C30) ; 13.95 (C42) ; 9.64 (C39) . 1H NMR δ : (For the major rotamer) 5.24 (lH,brs,H-12) ;
254.74 (lH,t,J=3.4Hz,H-9) ; 3.66 (lH,dd,J=1.4 and 9.6Hz,H-24); 1.63 (3H,brs,H-30) ; 1.57 (3H,brs,H-43) ; 0.99 (3H,d,J=6.4Hz,H-47) ; 0.94 (3H,d,J=7.3Hz,H-39) ; 0.92 (3H,d,J=4.5Hz,H-44) ; 0.90 (3H,t,J=7.5 Hz,H-42)
MS: 823 [M+H]+; 845 [M+Na]+; 906 [M+Rb]+ Example 20
In the mixed lymphocyte reaction (MLR) (described in W 89/05304, Example A) , 17-(2-Oxopropyl)-l,14-dihydroxy- 12-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl]-23,25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo [22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone, was found to have a pA2 value of 8.3 with agonist compound FR-900506. This means that a concentration of 5xlO~9M of the antagonist compound is required to occupy 50% of the available receptor sites in the screen for which it competes with FR-900506.
Claims
1. The use of a compound of formula I,
wherein
R1 and R2 independently represent H or OH, or they may together represent a second carbon-carbon bond between the carbon atoms to which they are attached;
R3 represents methyl optionally substituted by
-C02H or an ester or amide thereof; ethyl optionally substituted by O, OH or -C02H or an ester or amide thereof; propyl optionally substituted by OH or 0; or allyl optionally substituted by OH;
R4 represents H;
R5 and R6 together represent a second carbon-carbon bond between the carbon atoms to which they are attached;
R7 represents H or OH; R8 represents OCH3; R9 represents OH or OCH3; X represents 0 or (H,OH) ;
Y represents O or (H,OH) ; and n represents 1 or 2; in addition to their significances above
R1 and R5 may together represent an oxygen atom, in which case R6 and R7 together represent a secon carbon-carbon bond between the carbon atoms to which the are attached;
R7 and R8 may together represent an oxygen atom; and R3, R4 and Y, together with the carbon atoms to which they are attached, may represent a methyl-substituted furanyl ring; provided that i) when R2 represents H; R3 represents methyl, ethyl, propyl or allyl; R5 and R6 together represent a second carbon-carbon bond between the carbon atoms to which they are attached; R8 represents OCH3; and Y represents O; then R7 represents OH; and ii) when n is 1, then R3 is not methyl or ethyl; in the manufacture of a medicament for the treatment of immunodepression or a disorder involving immunodepression. 2. A compound of formula I, as defined in claim 1, provided that i) when R1 represents OH; R2 represents H; R5 and R together represent a second carbon-carbon bond between the carbon atoms to which they are attached; R7 represents H; R9 represents OCH3; X and Y each represent O; and n represents 2; then R3 does not represent 2-oxopropyl,
2,3-dihydroxypropyl or ethanalyl; ii) when R1 represents OH; R2 represents H; R5 and R together represent a second carbon-carbon bond between the carbon atoms to which they are attached.; R7 represents OH; R9 represents OCH3; X and Y each represent O; and n represents 2; then R3 does not represent allyl or l-hydroxyprop-2-enyl; and iii) when R1 represents OH; R2 represents H; R5 and R together represent a second carbon-carbon bond between the carbon atoms to which they are attached; R7 represents H; R9 represents OCH3; X and Y each represent (H,OH) ; and n represents 2; then R3 does not represent allyl.
3. The use of a compound of formula I, as defined in claim 1, or a compound of formula I as defined in claim 2, wherein R3 is ethyl substituted by O or propyl substituted by O.
4. The use of a compound of formula I, as defined in claim 1, or a compound of formula I as defined in claim 2, wherein R7 is OH.
5. The use of a compound of formula I, as defined in claim 1, or a compound of formula I as defined in claim 2, wherein R2 is OH.
6. The use of a compound of formula I, as defined i claim 1, wherein the compound of formula I is:
17-Allyl-l,14,20-trihydroxy-12-[2-(4-hydroxy-3- methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy- 13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo [22.3.1.04'9]octacos-18-ene-2,3,10,16-tetraone,
17-(l-Hydroxyprop-2-enyl)-1,14,20-trihydroxy-12-[2- (4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl]-23,25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo [22.3.1.04'9]octacos-18-ene-2,3,10,16-tetraone,
17-(2,3-Dihydroxypropyl)-1,14-dihydroxy-12-[2- (4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl]-23,25- dimethoxy-13,19,21,27-tetramethyl-ll ,28-dioxa-4-azatricyclo [22.3.1.04 *9]octacos-18-ene-2,3,10,16-tetraone,
17-Ethanalyl-l,14-dihydroxy-12-[2-(4-hydroxy-3- methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy- 13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo [22.3.1.04'9]octacos-18-ene-2,3,10,16-tetraone, 17-(2-0xopropyl)-l,14-dihydroxy-12-[2-(4-hydroxy-3- methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy- 13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo [22.3.1.04'9]octacos-18-ene-2,3,10,16-tetraone, or
17-Allyl-l,2,1 ,16-tetrahydroxy-12-[2-(4-hydroxy-3- methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy- 13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo [22.3.1.04'9]octacos-18-ene-3 ,10-dione. 7. A compound of formula I, as defined in claim 2, which s:
17-(2-Oxopropyl)-l-hydroxy-12-[2-(4-hydroxy-3- methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy- 13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo 5 [22.3.1.04'9]octacosa-14,18-diene-2,3,10,16-tetraone, 17-(2-Oxopropyl)-l-hydroxy-12-[2-(4-hydroxy-3- methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy- 13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo [22.3.1.04'9]octacos-18-ene-2,3,10,16-tetraone, 0 2-{l,14-Dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl) -1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl- ll,28-dioxa-4-azatricyclo[22.3.1.04'9]octacos-18-ene- 2,3,10,16-tetraone-17-yl}-ethanoic acid,
2-{1,14-Dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl) 5 -1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl- ll,28-dioxa-4-azatricyclo[22.3.1.04'9]octacos-18-ene- 2,3,10,16-tetraone-17-yl}-ethanoic acid Methyl ester,
2-{l,14-Dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl) -1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl- 20 11,28-dioxa-4-azatricyclo[22.3.1.0 '9]octacos-18-ene-
2,3,10,16-tetraone-17-yl}-ethanoic acid N-Morpholine amide,
2-(1,14-Dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl) -1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl- ll,28-dioxa-4-azatricyclo[22.3.1.04'9]octacos-18-ene- 252,3,10,16-tetraone-17-yl}-ethanoic acid N-Ethanolamide,
2-{l,14-Dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl) -1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl- ll,28-dioxa-4-azatricyclo[22.3.1.04'9]octacos-18-ene- 2,3,10,16-tetraone-17-yl}-ethanoic acid amide with glycin methyl ester,
2-{1,14-Dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl) -1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl- 11,28-dioxa-4-azatricyclo[22.3.1.04'9]octacos-18-ene-
2,3,10,16-tetraone-17-yl}-ethanoic acid N-Piperidine amide,
2-(l,14-Dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl) -1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl- ll,28-dioxa-4-azatricyclo[22.3.1.04'9]octacos-18-ene- 2,3,10,16-tetraone-17-yl)-ethanoic acid N-Benzylamide,
2-{l,14-Dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl) -1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl- ll,28-dioxa-4-azatricyclo[22.3.1.04'9]octacos-18-ene- 2,3,10,16-tetraone-17-yl)-ethanoic acid N-Butylamide, 2-{l,14-Dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl) -1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl- ll,28-dioxa-4-azatricyclo[22.3.1.04'9]octacos-18-ene- 2,3,10,16-tetraone-17-yl}-ethanoic acid p-Cyanophenyl ester, 2-{l,14-Dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl) -1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl- ll,28-dioxa-4-azatricyclo[22.3.1.04'9]octacos-18-ene- 2,3,10,16-tetraone-17-yl)-ethanoic acid Phenyl ester,
2-{l,14-Dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl) -1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl- ll ,28-dioxa-4-azatricyclo[22.3.1.04'9]octacos-18-ene- 2,3,10,16-tetraone-17-yl)-ethanoic acid p-Nitrophenyl ester, 17-Allyl-l,14,16-trihydroxy-l2-[2-(4-hydroxy-3- methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy- 13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo [22.3.1.04'9]octacos-18-ene-2,3,10-trione 1,14-Dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-1- methylvinyl]-26,28-dimethoxy-13,18,22,24,30-pentamethyl- 11,17,3l-trioxa-4-azatetracyclo[25.3.1.04'9.016'20] hentriaconta-16(20) ,18,21-triene-2,3,10-trione,
1,14-dihydroxy-12-[2-( -hydroxy-3-methoxycyclohexyl)-1- methylvinyl]-23,25-dimethoxy-17-propanalyl-13,19,21,27- tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04'9]octacos- 18-ene-2,3,10,16-tetraone,
17-Allyl-l-hydroxy-12-[2-(4-hydroxy-3- methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy- 13,19,21,27-tetramethyl-ll,28,29-trioxa-4-azatetracyclo [22.3.1.I14'18.04'9]nonacos-19-ene-2,3,10,16-tetraone,
17-Propyl-l-hydroxy-12-[2-(4-hydroxy-3- methoxycyclohexyl)-1-methylvinyl]-25-dimethoxy-13,19,21,27- tetramethyl-ll,28,29-trioxa-4-azatetracyclo[22.3.1.120'23. ° ' ]nonacos-18-ene-2,3,10,16-tetraone,
17-Allyl-l-hydroxy-12-[2-(4-hydroxy-3- methoxycyclohexyl)-1-methylvinyl]-25-methoxy-13,19,21,27- tetramethyl-ll,28,29-trioxa-4-azatetracyclo[22.3.1.I20'23. 04'9]nonacosa-14,18-diene-2,3,10,16-tetraone, or 12-[2-(4-Hydroxy-3-methoxycyclohexyl)-1-methylvinyl]- 23,25-dimethoxy-17-propyl-13,19,21 ,27-tetramethyl-l,14,15- trihydroxy-11,28-dioxa-4-azatricyclo[22.3.1.0 '9] octacos-18-ene-2,3,10,16-tetraone.
8. The use of a compound of formula I, as defined claim 2, as a pharmaceutical.
9. A pharmaceutical composition comprising a compound o formula I, as defined in claim 2, in association with
5 pharmaceutically acceptable adjuvant, diluent or carrier.
10. A pharmaceutical mixture comprising a compound o formula I as defined in claim 1 or claim 2, and a immunosuppressive compound.
11. A process for the production of a compound of formul 0 I, as defined in claim 2, which comprises: a) producing a compound of formula I, in which R represents propyl substituted by O, by oxidation of corresponding compound in which R3 represents allyl; b) producing a compound of formula I, which contains 5 vicinal diol, by oxidation of a carbon-carbon double bon in a corresponding compound; c) producing a compound of formula I, in which R represents ethyl substituted by O, by oxidative cleavage o a corresponding compound in which R3 represent Q 2,3-dihydroxypropyl; d) producing a compound of formula I, in which R represents methyl substituted by ~ 02H or ethy substituted by -C02H, by oxidation of a correspondin compound in which R3 represents ethanalyl or propaτ -lyl; _ e) producing a compound of formula I, which co;_ ins tw vicinal hydrogen atoms, by reduction of a correspondin compound which contains a carbon-carbon double bond; f) producing a compound of formula I, in which X or represents (H,OH) , by reduction of a corresponding compound in which X or Y represents O; g) producing a compound of formula I, in which R3, R4 and Y, together with the carbon atoms to which they are attached, represent a methyl-substituted furanyl ring, by the action of acid on a corresponding compound in which R3 represents 2-oxopropyl, R4 represents H and Y represents O; h) producing a compound of formula I, in which R1 and R together represent an oxygen atom and R6 and R7 together represent a second carbon-carbon bond between the carbon atoms to which they are attached, by the action of acid on a corresponding compound in which R1 represents OH, R5 and R6 together represent a second carbon-carbon bond between the carbon atoms to which they are attached, and R7 represents OH; i) producing a compound of formula I, in which R7 and
Q
R together represent an oxygen atom, by the action of a dehydrating agent on a corresponding compound of formula I in which R7 represents OH and R8 represents OCH3; j) producing a compound of formula I, in which R7 represents OH, by allylic oxidation of a corresponding compound in which R7 represents H; or k) producing a compound of formula I, in which R3 represents allyl substituted by hydroxy, by allylic oxidation of a corresponding compound in which R3 represents allyl.
12. A method of treatment of immunodepression, or a disorder involving immunodepression, which comprise administering a therapeutically efficacious amount of compound of formula I, as defined in claim 1, to a patien suffering from such a condition. 5
10
15
20
25
4002cαnplete/jrh
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019920700584A KR920702219A (en) | 1989-09-14 | 1990-09-13 | New Macrocyclic Compounds and New Treatment Methods |
Applications Claiming Priority (10)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8920849.0 | 1989-09-14 | ||
| GB898920849A GB8920849D0 (en) | 1989-09-14 | 1989-09-14 | Compound |
| GB8920985.2 | 1989-09-15 | ||
| GB898920985A GB8920985D0 (en) | 1989-09-15 | 1989-09-15 | Method of treatment |
| GB909006449A GB9006449D0 (en) | 1990-03-22 | 1990-03-22 | Compounds |
| GB9006449.4 | 1990-03-22 | ||
| GB909012795A GB9012795D0 (en) | 1990-06-08 | 1990-06-08 | Compounds |
| GB9012795.2 | 1990-06-08 | ||
| GB9014959.2 | 1990-07-06 | ||
| GB909014959A GB9014959D0 (en) | 1990-07-06 | 1990-07-06 | Method of treatment |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1991004025A1 true WO1991004025A1 (en) | 1991-04-04 |
Family
ID=27516937
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/GB1990/001412 WO1991004025A1 (en) | 1989-09-14 | 1990-09-13 | Novel macrocyclic compounds and novel method of treatment |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0491797A1 (en) |
| JP (1) | JPH05500215A (en) |
| KR (1) | KR920702219A (en) |
| GR (1) | GR1001225B (en) |
| IE (1) | IE903334A1 (en) |
| PT (1) | PT95305A (en) |
| WO (1) | WO1991004025A1 (en) |
Cited By (24)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5143918A (en) * | 1990-10-11 | 1992-09-01 | Merck & Co., Inc. | Halomacrolides and derivatives 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 |
| US5189042A (en) * | 1991-08-22 | 1993-02-23 | Merck & Co. Inc. | Fluoromacrolides having immunosuppressive activity |
| US5190950A (en) * | 1990-06-25 | 1993-03-02 | Merck & Co., Inc. | Antagonists of immunosuppressive macrolides |
| US5208228A (en) * | 1989-11-13 | 1993-05-04 | Merck & Co., Inc. | Aminomacrolides and derivatives 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 |
| US5250678A (en) * | 1991-05-13 | 1993-10-05 | Merck & Co., Inc. | O-aryl, O-alkyl, O-alkenyl and O-alkynylmacrolides having immunosuppressive activity |
| US5262533A (en) * | 1991-05-13 | 1993-11-16 | Merck & Co., Inc. | Amino O-aryl macrolides having immunosuppressive activity |
| US5284840A (en) * | 1992-06-12 | 1994-02-08 | Merck & Co., Inc. | Alkylidene macrolides having immunosuppressive activity |
| US5284877A (en) * | 1992-06-12 | 1994-02-08 | Merck & Co., Inc. | Alkyl and alkenyl macrolides having immunosuppressive activity |
| WO1994004149A1 (en) * | 1992-08-25 | 1994-03-03 | Fisons Plc | Use of macrolide compounds for the treatment of skin diseases |
| WO1994004148A1 (en) * | 1992-08-25 | 1994-03-03 | Fisons Plc | Use of macrolide compounds for the treatment of reversible obstructive airways disease |
| EP0642516A4 (en) * | 1991-09-05 | 1994-06-15 | Abbott Lab | Macrocyclic immunomodulators. |
| US5342935A (en) * | 1990-06-25 | 1994-08-30 | Merck & Co., Inc. | Antagonists of immunosuppressive macrolides |
| LT3533B (en) | 1991-09-09 | 1995-11-27 | Merck & Co Inc | O-heyteroaryl, o-alkylheteroaryl, o-alkenylheteroaryl and o-alkynylheteroaryl macrolides |
| US5532248A (en) * | 1991-05-13 | 1996-07-02 | Merck Co., Inc. | O-aryl,O-alkyl, and O-alkenyl-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 |
| US5708002A (en) * | 1991-09-05 | 1998-01-13 | Abbott Laboratories | Macrocyclic immunomodulators |
| WO2001005385A2 (en) * | 1999-07-21 | 2001-01-25 | Fujisawa Pharmaceutical Co Ltd | New use of a macrolide compound for treating neurodegenerative disorders |
| WO2002053159A1 (en) * | 2000-12-29 | 2002-07-11 | Fujisawa Pharmaceutical Co., Ltd. | Neurotrophic tacrolimus analogs |
| WO2005067928A1 (en) * | 2004-01-20 | 2005-07-28 | Astellas Pharma Inc. | Method for treating erectile dysfunction |
| EP1599195A1 (en) * | 2003-03-04 | 2005-11-30 | Astellas Pharma Inc. | Use of non-immunosuppressive pipecolic acid derivatives for inducing chondrogenic differentiation |
| US10259827B2 (en) | 2016-11-10 | 2019-04-16 | Novartis Ag | BMP potentiators |
| WO2021248189A1 (en) * | 2020-06-09 | 2021-12-16 | Uniquest Pty Ltd | Compound for prevention or treatment of a skin cancer or skin precancer |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2006329040C1 (en) * | 2005-12-22 | 2011-12-08 | Newron Pharmaceuticals S.P.A. | 2 -Phenylethylamino derivatives as calcium and/or sodium channel modulators |
| JP2009203162A (en) * | 2006-06-05 | 2009-09-10 | Astellas Pharma Inc | New method for producing macrolide compound |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0184162A2 (en) * | 1984-12-03 | 1986-06-11 | Fujisawa Pharmaceutical Co., Ltd. | Tricyclo compounds, a process for their production and a pharmaceutical composition containing the same |
| WO1989005304A1 (en) * | 1987-12-09 | 1989-06-15 | Fisons Plc | Macrocyclic compounds |
| EP0349061A2 (en) * | 1988-06-29 | 1990-01-03 | Merck & Co. Inc. | Immunosuppressant agent |
| EP0349049A2 (en) * | 1988-06-29 | 1990-01-03 | Merck & Co. Inc. | Immunosuppressant compound |
| EP0356399A2 (en) * | 1988-08-26 | 1990-02-28 | Sandoz Ag | Substituted 4-azatricyclo (22.3.1.04.9) octacos-18-ene derivatives, their preparation and pharmaceutical compositions containing them |
-
1990
- 1990-09-12 GR GR900100688A patent/GR1001225B/en unknown
- 1990-09-13 WO PCT/GB1990/001412 patent/WO1991004025A1/en not_active Application Discontinuation
- 1990-09-13 PT PT95305A patent/PT95305A/en not_active Application Discontinuation
- 1990-09-13 KR KR1019920700584A patent/KR920702219A/en not_active Application Discontinuation
- 1990-09-13 JP JP2512909A patent/JPH05500215A/en active Pending
- 1990-09-13 IE IE333490A patent/IE903334A1/en unknown
- 1990-09-13 EP EP90913838A patent/EP0491797A1/en not_active Withdrawn
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0184162A2 (en) * | 1984-12-03 | 1986-06-11 | Fujisawa Pharmaceutical Co., Ltd. | Tricyclo compounds, a process for their production and a pharmaceutical composition containing the same |
| WO1989005304A1 (en) * | 1987-12-09 | 1989-06-15 | Fisons Plc | Macrocyclic compounds |
| EP0349061A2 (en) * | 1988-06-29 | 1990-01-03 | Merck & Co. Inc. | Immunosuppressant agent |
| EP0349049A2 (en) * | 1988-06-29 | 1990-01-03 | Merck & Co. Inc. | Immunosuppressant compound |
| EP0356399A2 (en) * | 1988-08-26 | 1990-02-28 | Sandoz Ag | Substituted 4-azatricyclo (22.3.1.04.9) octacos-18-ene derivatives, their preparation and pharmaceutical compositions containing them |
Cited By (27)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5208228A (en) * | 1989-11-13 | 1993-05-04 | Merck & Co., Inc. | Aminomacrolides and derivatives having immunosuppressive activity |
| US5190950A (en) * | 1990-06-25 | 1993-03-02 | Merck & Co., Inc. | Antagonists of immunosuppressive macrolides |
| US5342935A (en) * | 1990-06-25 | 1994-08-30 | Merck & Co., Inc. | Antagonists of immunosuppressive macrolides |
| US5143918A (en) * | 1990-10-11 | 1992-09-01 | Merck & Co., Inc. | Halomacrolides and derivatives 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 |
| US5532248A (en) * | 1991-05-13 | 1996-07-02 | Merck Co., Inc. | O-aryl,O-alkyl, and O-alkenyl-macrolides 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 |
| US5262533A (en) * | 1991-05-13 | 1993-11-16 | Merck & Co., Inc. | Amino O-aryl macrolides having immunosuppressive activity |
| US5189042A (en) * | 1991-08-22 | 1993-02-23 | Merck & Co. Inc. | Fluoromacrolides having immunosuppressive activity |
| EP0642516A4 (en) * | 1991-09-05 | 1994-06-15 | Abbott Lab | Macrocyclic immunomodulators. |
| US5708002A (en) * | 1991-09-05 | 1998-01-13 | Abbott Laboratories | Macrocyclic immunomodulators |
| EP0642516A1 (en) * | 1991-09-05 | 1995-03-15 | Abbott Laboratories | Macrocyclic immunomodulators |
| US5208241A (en) * | 1991-09-09 | 1993-05-04 | Merck & Co., Inc. | N-heteroaryl, n-alkylheteroaryl, n-alkenylheteroaryl and n-alkynylheteroarylmacrolides having immunosuppressive activity |
| LT3533B (en) | 1991-09-09 | 1995-11-27 | Merck & Co Inc | O-heyteroaryl, o-alkylheteroaryl, o-alkenylheteroaryl and o-alkynylheteroaryl macrolides |
| US5284840A (en) * | 1992-06-12 | 1994-02-08 | Merck & Co., Inc. | Alkylidene macrolides having immunosuppressive activity |
| US5284877A (en) * | 1992-06-12 | 1994-02-08 | Merck & Co., Inc. | Alkyl and alkenyl macrolides having immunosuppressive activity |
| WO1994004149A1 (en) * | 1992-08-25 | 1994-03-03 | Fisons Plc | Use of macrolide compounds for the treatment of skin diseases |
| WO1994004148A1 (en) * | 1992-08-25 | 1994-03-03 | Fisons Plc | Use of macrolide compounds for the treatment of reversible obstructive airways disease |
| US5693648A (en) * | 1994-09-30 | 1997-12-02 | Merck & Co., Inc. | O-aryl, O-alkyl, O-alkenyl and O-alkynyl-macrolides having immunosuppressive activity |
| WO2001005385A2 (en) * | 1999-07-21 | 2001-01-25 | Fujisawa Pharmaceutical Co Ltd | New use of a macrolide compound for treating neurodegenerative disorders |
| WO2001005385A3 (en) * | 1999-07-21 | 2001-08-02 | Fujisawa Pharmaceutical Co | New use of a macrolide compound for treating neurodegenerative disorders |
| WO2002053159A1 (en) * | 2000-12-29 | 2002-07-11 | Fujisawa Pharmaceutical Co., Ltd. | Neurotrophic tacrolimus analogs |
| CN1293877C (en) * | 2000-12-29 | 2007-01-10 | 安斯泰来制药有限公司 | Neurotrophic tacrolimus analogs |
| EP1599195A1 (en) * | 2003-03-04 | 2005-11-30 | Astellas Pharma Inc. | Use of non-immunosuppressive pipecolic acid derivatives for inducing chondrogenic differentiation |
| WO2005067928A1 (en) * | 2004-01-20 | 2005-07-28 | Astellas Pharma Inc. | Method for treating erectile dysfunction |
| US10259827B2 (en) | 2016-11-10 | 2019-04-16 | Novartis Ag | BMP potentiators |
| WO2021248189A1 (en) * | 2020-06-09 | 2021-12-16 | Uniquest Pty Ltd | Compound for prevention or treatment of a skin cancer or skin precancer |
Also Published As
| Publication number | Publication date |
|---|---|
| KR920702219A (en) | 1992-09-03 |
| EP0491797A1 (en) | 1992-07-01 |
| PT95305A (en) | 1991-06-25 |
| JPH05500215A (en) | 1993-01-21 |
| GR1001225B (en) | 1993-06-30 |
| IE903334A1 (en) | 1991-04-10 |
| GR900100688A (en) | 1992-01-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO1991004025A1 (en) | Novel macrocyclic compounds and novel method of treatment | |
| AU630866B2 (en) | Macrocyclic compounds | |
| KR100330800B1 (en) | Rapamycin hydroxyesters, process for their preparation and pharmaceutical compositions containing them | |
| IE910847A1 (en) | Immunosuppressive macrocyclic compounds | |
| JPH05163280A (en) | Bicyclic rapamycin | |
| HUT73418A (en) | Process for preparing rapamycin carbonate esters and pharmaceutical compositions of immunosuppressive activity containing said compounds | |
| JPH05194530A (en) | Fluoromacrolide having immunosuppressive activity | |
| JPH089623B2 (en) | 4a-substituted avermectin derivative | |
| JPH06192269A (en) | 21-norrapamycin | |
| JP2012254984A (en) | Synthesis of metabolically stable analgesic, pain medication and other agent | |
| EP0629203B1 (en) | Desosamino derivatives of macrolides as immunosuppressants and antifungal agents | |
| US5179087A (en) | Macrocyclic compounds | |
| HU211135A9 (en) | Heteroatoms-containing tricyclic compounds | |
| EP0543879A1 (en) | Macrocyclic compounds | |
| US6121257A (en) | Sulfamate containing macrocyclic immunomodulators | |
| US5376663A (en) | Macrocyclic compounds | |
| US4920218A (en) | Novel hydroxide mediated FK-506 rearrangement process | |
| JPH10502058A (en) | Aryl, alkyl, alkenyl and alkynyl macrolides | |
| US5210227A (en) | Immunosuppressive compounds | |
| EP0364031B1 (en) | Hydroxide mediated fk-506 rearrangement process | |
| JPH0774220B2 (en) | Novel hydroxide mediated FK-506 rearrangement product | |
| CA2065425A1 (en) | Macrocyclic compounds and novel method of treatment | |
| WO2002012217A1 (en) | New agarofuran derivatives, their preparations, pharmaceutical compositions containing them and their uses as medicaments | |
| JPH05239064A (en) | Semi-synthetic immunosuppressive macrolide | |
| US4980466A (en) | Hydroxide mediated FK-506 rearrangement product |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| AK | Designated states |
Kind code of ref document: A1 Designated state(s): CA JP KR US |
|
| AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FR GB IT LU NL SE |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 1990913838 Country of ref document: EP |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 2065425 Country of ref document: CA |
|
| WWP | Wipo information: published in national office |
Ref document number: 1990913838 Country of ref document: EP |
|
| WWW | Wipo information: withdrawn in national office |
Ref document number: 1990913838 Country of ref document: EP |