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EP0491797A1 - Nouveaux composes macrocycliques et nouvelle methode de traitement - Google Patents

Nouveaux composes macrocycliques et nouvelle methode de traitement

Info

Publication number
EP0491797A1
EP0491797A1 EP90913838A EP90913838A EP0491797A1 EP 0491797 A1 EP0491797 A1 EP 0491797A1 EP 90913838 A EP90913838 A EP 90913838A EP 90913838 A EP90913838 A EP 90913838A EP 0491797 A1 EP0491797 A1 EP 0491797A1
Authority
EP
European Patent Office
Prior art keywords
compound
hydroxy
formula
tetramethyl
methylvinyl
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.)
Withdrawn
Application number
EP90913838A
Other languages
German (de)
English (en)
Inventor
David Keith Donald
Mark Furber
David Norman Hardern
Paul Leff
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Fisons Ltd
Original Assignee
Fisons Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from GB898920849A external-priority patent/GB8920849D0/en
Priority claimed from GB898920985A external-priority patent/GB8920985D0/en
Priority claimed from GB909006449A external-priority patent/GB9006449D0/en
Priority claimed from GB909012795A external-priority patent/GB9012795D0/en
Priority claimed from GB909014959A external-priority patent/GB9014959D0/en
Application filed by Fisons Ltd filed Critical Fisons Ltd
Publication of EP0491797A1 publication Critical patent/EP0491797A1/fr
Withdrawn legal-status Critical Current

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

Definitions

  • 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 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.0 4 ' 9 ]octacos-18-ene (numbere
  • the novel compounds may be produced by total synthesis.
  • 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[22.3.1.0 4 > 9 ]octacos-18-ene and rapamycin, as shown in the mixed lymphocyte reaction (MLR) (described in WO 89/05304, Example A).
  • MLR mixed lymphocyte reaction
  • the novel group of compounds are therefore useful inter alia in the treatment of immunodepression or a disorder involving immunodepressio .
  • R 1 and R 2 independently represent H or OH, or they may together represent a second carbon-carbon bond between the carbon atoms to which they are attached;
  • R 3 represents methyl optionally substituted b
  • R 4 represents H
  • R 5 and R 6 together represent a second carbon-carbon bond between the carbon atoms to which they are attached;
  • R 7 represents H or OH;
  • R 8 represents OCH 3 ;
  • R 9 represents OH or OCH 3 ;
  • X represents O or (H,OH) ;
  • Y represents O or (H,OH) ;
  • n represents 1 or 2; in addition to their significances above
  • R 1 and R 5 may together represent an oxygen atom, in which case R 6 and R 7 together represent a second carbon-carbon bond between the carbon atoms to which they are attached;
  • R 7 and R 8 may together represent an oxygen atom
  • R 3 , R 4 and Y together with the carbon atoms to which they are attached, may represent a methyl-substituted furanyl ring; provided that i) when R 2 represents H; R 3 represents methyl, ethyl, propyl or allyl; R 5 and R 6 together represent a second carbon-carbon bond between the carbon atoms to which they are attached; R 8 represents OCH 3 ; and Y represents O; then R 7 represents OH; and ii) when n is 1, then R 3 is not methyl or ethyl; in the manufacture of a medicament for the treatment of immunodepression or a disorder involving immunodepression.
  • 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 [22.3.1.0 4 ' ]octacos-18-ene such as FR-900506, or rapamycin.
  • an immunosuppressive macrocyclic compound for example derivatives of 12-(2-cyclohexyl-l-methylvinyl)- 13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo [22.3.1.0 4 ' ]octacos-18-ene
  • FR-900506 rapamycin
  • 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 R 1 represents OH; R 2 represents H; R 5 and R 6 together represent a second carbon-carbon bond between the carbon atoms to which they are attached; R 7 represents H; R 9 represents OCH 3 ; X and Y each represent O; and n represents 2; then R 3 does not represent 2-oxopropyl, 2,3-dihydroxypropyl or ethanalyl; ii) when R 1 represents OH; R 2 represents H; R 5 and R 6 together represent a second carbon-carbon bond between the carbon atoms to which they are attached; R 7 represents OH; R 9 represents OCH 3 ; X and Y each represent O; and n represents 2; then R 3 does not represent allyl or l-hydroxyprop-2-enyl; and iii) when R ⁇ represents OH; R 2 represents H; R 5 and
  • R 6 together represent a second carbon-carbon bond between the carbon atoms to which they are attached;
  • R 7 represents H;
  • R 9 represents OCH 3 ;
  • X and Y each represent (H,OH) ; and
  • n represents 2; then R 3 does not represent allyl.
  • R 3 is ethyl substituted by 0 or propyl substituted by 0 -
  • R 7 is OH.
  • R 2 we prefer R 2 to be OH, more preferably (S)-OH (ie to have S absolute stereochemistry at its point of attachment to the molecule) .
  • R 3 comprises an ester or amide group
  • the alcohol or amine moiety to contain from 1 to 10 carbon atoms, for example the alcohol moiety may be methanol.
  • Known compounds of formula I (as first defined above) from WO 89/05304 include:
  • a process for the production of a novel compound of formula I which comprises: a) producing a compound of formula I, in which R 3 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 R 3 represents ethyl substituted by O, by oxidative cleavage of a corresponding compound in which R 3 represents 2,3-dihydroxypropy1; d) producing a compound of formula I, in which R 3 represents methyl substituted by -C0 2 H or ethyl substituted by -C0 2 H, by oxidation of a corresponding compound in which R 3 represents ethanalyl or propanalyl; e) producing a compound of formula I, which contains two vicinal hydrogen atoms,
  • Esters and amides of carboxylic acids that R 3 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.
  • 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.
  • 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) .
  • THF tetrahydrofuran
  • aqueous alkaline conditions are preferred.
  • the reaction is preferably carried out at a temperature of from 0 to 100 ⁇ C, more preferably at or around room temperature.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 -30 ⁇ C.
  • Suitable reagents include
  • Se0 2 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.
  • 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.
  • unit dosage forms suitable for administration 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 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.
  • 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.
  • 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.
  • immunosuppressive compounds particularly immunosuppressive macrocyclic compounds including derivatives of 12-(2-cyclohexyl-1-methylvinyl)-13,19,21,27-tetramethyl- ll,28-dioxa-4-azatricyclo[22.3.1.0 4 ' 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.
  • a pharmaceutical mixture comprising a compound of formula I (as first defined above) and an immunosuppressive compound.
  • 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.
  • R 1 to R 8 , X, Y and n are as defined above.
  • Example 1 The invention is illustrated by the following examples.
  • Example 1 The invention is illustrated by the following examples.
  • step (a) 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) .
  • 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-azatetracvclor25.3.1.0 4 ' 9 .0 16 ' 20 1 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 [22.3.1.0 4 ' 9 ]octacos-18-ene-2,3,10,16-tetraone (th compound of Example

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Transplantation (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

Composés de formule (I), où R 1 et R2 représentent indépendamment H ou OH, ou une seconde liaison carbone-carbone; R3 représente au choix un méthyle substitué, un éthyle substitué ou un propyle substitué; R4 repésente H; R5 et R6 représentent une seconde liaison carbone-carbone; R7 représente H ou OH; R8 représente OCH3; R9 représente OH ou OCH3; X et Y représentent indépendamment O ou (H, OH); n représente 1 ou 2; et de plus, certains substituants forment des anneaux les uns avec les autres; avec plusieurs conditions. Ces composés sont indiqués dans le traitement de l'immunodépression. Sont également fournis un certain nombre de nouveaux composés de formule (I).
EP90913838A 1989-09-14 1990-09-13 Nouveaux composes macrocycliques et nouvelle methode de traitement Withdrawn EP0491797A1 (fr)

Applications Claiming Priority (10)

Application Number Priority Date Filing Date Title
GB898920849A GB8920849D0 (en) 1989-09-14 1989-09-14 Compound
GB8920849 1989-09-14
GB898920985A GB8920985D0 (en) 1989-09-15 1989-09-15 Method of treatment
GB8920985 1989-09-15
GB909006449A GB9006449D0 (en) 1990-03-22 1990-03-22 Compounds
GB9006449 1990-03-22
GB9012795 1990-06-08
GB909012795A GB9012795D0 (en) 1990-06-08 1990-06-08 Compounds
GB909014959A GB9014959D0 (en) 1990-07-06 1990-07-06 Method of treatment
GB9014959 1990-07-06

Publications (1)

Publication Number Publication Date
EP0491797A1 true EP0491797A1 (fr) 1992-07-01

Family

ID=27516937

Family Applications (1)

Application Number Title Priority Date Filing Date
EP90913838A Withdrawn EP0491797A1 (fr) 1989-09-14 1990-09-13 Nouveaux composes macrocycliques et nouvelle methode de traitement

Country Status (7)

Country Link
EP (1) EP0491797A1 (fr)
JP (1) JPH05500215A (fr)
KR (1) KR920702219A (fr)
GR (1) GR1001225B (fr)
IE (1) IE903334A1 (fr)
PT (1) PT95305A (fr)
WO (1) WO1991004025A1 (fr)

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US5208228A (en) * 1989-11-13 1993-05-04 Merck & Co., Inc. Aminomacrolides and derivatives having immunosuppressive activity
US5342935A (en) * 1990-06-25 1994-08-30 Merck & Co., Inc. Antagonists of immunosuppressive macrolides
US5190950A (en) * 1990-06-25 1993-03-02 Merck & Co., Inc. Antagonists of immunosuppressive macrolides
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
US5250678A (en) * 1991-05-13 1993-10-05 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
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
KR100351222B1 (ko) * 1991-09-05 2002-09-05 아보트 러보러터리즈 매크로사이클릭 면역 조절제 및 이의 제조방법
US5708002A (en) * 1991-09-05 1998-01-13 Abbott Laboratories Macrocyclic immunomodulators
ZA926812B (en) 1991-09-09 1993-04-28 Merck & Co Inc O-heteroaryl,o-alkylheteroaryl,o-alkenylheteroaryl and o-alkynylheteroaryl macrolides having immunosupressive activity
US5208241A (en) * 1991-09-09 1993-05-04 Merck & Co., Inc. N-heteroaryl, n-alkylheteroaryl, n-alkenylheteroaryl and n-alkynylheteroarylmacrolides having immunosuppressive activity
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
GB9218597D0 (en) * 1992-08-25 1992-10-14 Fisons Plc Novel method of treatment
GB9218027D0 (en) * 1992-08-25 1992-10-14 Fisons Plc Novel method of treatment
US5693648A (en) * 1994-09-30 1997-12-02 Merck & Co., Inc. O-aryl, O-alkyl, O-alkenyl and O-alkynyl-macrolides having immunosuppressive activity
GB9917158D0 (en) * 1999-07-21 1999-09-22 Fujisawa Pharmaceutical Co New use
AR035411A1 (es) * 2000-12-29 2004-05-26 Fujisawa Pharmaceutical Co Uso de un derivado de tacrolimus para fabricar un agente neurotrofico, composiciones y articulos de fabricacion o kits que lo comprenden, metodo para fabricar un agente que lo comprende y tejidos e injertos con una celula nerviosa tratada con este compuesto
AU2003901023A0 (en) * 2003-03-04 2003-03-20 Fujisawa Pharmaceutical Co., Ltd. New use
KR20060125849A (ko) * 2004-01-20 2006-12-06 아스텔라스세이야쿠 가부시키가이샤 발기부전 치료 방법
SI1963280T1 (sl) * 2005-12-22 2016-02-29 Newron Pharmaceuticals S.P.A. 2-feniletilamino derivati kot modulatorji kalcijevih in/ali natrijevih kanalčkov
JP2009203162A (ja) * 2006-06-05 2009-09-10 Astellas Pharma Inc マクロライド化合物の新規製造法
JP2019534302A (ja) 2016-11-10 2019-11-28 ノバルティス アーゲー Ｂｍｐ増強剤
WO2020163594A1 (fr) * 2019-02-07 2020-08-13 The Regents Of The University Of California Agents de liaison à l'immunophiline et leurs utilisations
CA3180348A1 (fr) * 2020-06-09 2021-12-16 James Wells Compose pour la prevention ou le traitement d'un cancer de la peau ou d'un precancer de la peau

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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
ES2071681T3 (es) * 1987-12-09 1995-07-01 Fisons Plc Compuestos macrociclicos.
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DE68921934T2 (de) * 1988-06-29 1995-10-19 Merck & Co Inc Immunsuppressives Agens.
EP0356399A3 (fr) * 1988-08-26 1991-03-20 Sandoz Ag Dérivés substitués du 4-azatricyclo (22.3.1.04.9) octacos-18-ène, leur préparation et les compositions pharmaceutiques les contenant

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Title
See references of WO9104025A1 *

Also Published As

Publication number Publication date
PT95305A (pt) 1991-06-25
GR900100688A (en) 1992-01-20
WO1991004025A1 (fr) 1991-04-04
JPH05500215A (ja) 1993-01-21
GR1001225B (el) 1993-06-30
IE903334A1 (en) 1991-04-10
KR920702219A (ko) 1992-09-03

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