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WO1993014771A1 - Composes macrocycliques servant au traitement prophylactique du sida - Google Patents

Composes macrocycliques servant au traitement prophylactique du sida Download PDF

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Publication number
WO1993014771A1
WO1993014771A1 PCT/GB1993/000207 GB9300207W WO9314771A1 WO 1993014771 A1 WO1993014771 A1 WO 1993014771A1 GB 9300207 W GB9300207 W GB 9300207W WO 9314771 A1 WO9314771 A1 WO 9314771A1
Authority
WO
WIPO (PCT)
Prior art keywords
octacos
dioxa
ene
tetramethyl
azatricyclo
Prior art date
Application number
PCT/GB1993/000207
Other languages
English (en)
Inventor
Thomas Samuel Campbell Orr
Original Assignee
Fisons Plc
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
Application filed by Fisons Plc filed Critical Fisons Plc
Publication of WO1993014771A1 publication Critical patent/WO1993014771A1/fr

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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof

Definitions

  • This invention relates to a new use of known macrocvclic compounds in the prophylactic treatment of acquired immunodeficiency syndrome (AIDS).
  • AIDS acquired immunodeficiency syndrome
  • AIDS is characterized by a degeneration of the patient's immune system, making the patient susceptible to opportunistic infections such as pneumonia which generally lead to death.
  • HIN human immunodeficiency virus
  • the drugs presently administered to patients infected with HIN and to patients suffering i5 from AIDS include 3'-azido-3'-deoxythymidine (AZT, Retrovir), which interferes with viral replication.
  • AZT 3'-azido-3'-deoxythymidine
  • patients infected with HIN who are treated with AZT generally go on to develop AIDS eventually.
  • European Patent Application 184162 discloses a number of macrocvclic compounds which are indicated as immunosuppressants.
  • the compounds may be described as derivatives and homologues of the basic structure 12-(2-cyclohexyl-l-methylvinyl)- 13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0 4 ' 9 ]octacos-18-ene, and include JO 17-allyl-l,14-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-l-methylvinyl]-23,25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0 4 ' 9 ]octacos-18-ene- 2,3,10,16-tetraone (FR-900506, FK 506) and 16-allyl-l,13-dihydroxy-ll-[2-
  • a group of such derivatives or homologues which may be mentioned are those having immunosuppressive activity. It is especially unexpected that compounds having this activity find utility in the prophylaxis of AIDS.
  • R 1 and R 2 represent two vicinal hydrogen atoms, or form a second bond between the vicinal carbon atoms to which they are attached;
  • R 7 represents H, OH, protected hydroxy or alkoxy C ;
  • R 10 represents alkyl C, ⁇ or alkenyl C ⁇
  • X represents O, (H,H), (H,OH) or -CH 2 0-;
  • Y represents O, N-NR n R 12 or N-OR 13 ;
  • R u and R 12 independently represent H, alkyl C ⁇ , phenyl or tosyl; R 13 represents H or alkyl C w ;
  • R 20 and R 21 independently represent O, or they may independently represent (R ⁇ a.H) and (R 21 a,H) respectively;
  • R 20 a and R 21 a independently represent OH, protected hydroxy, alkoxy C w or OCH 2 OCH 2 CH 2 OCH 3 ; in addition R ⁇ a and R 21 a may together represent an oxygen atom in an epoxide ring;
  • R 23 represents H;
  • n is 1 or 2; in addition to their significances above, Y, R 10 and R 23 , together with the carbon atoms to which they are attached, may represent a 5- or 6-membered N-, S- or O-containing heterocyclic ring, which may be saturated or unsaturated, and which may be substituted by one or more groups selected from alkyl C ⁇ , hydroxy, alkyl C w substituted by one or more hydroxy groups, alkoxy C ⁇ , benzyl and -CH 2 Se(C 6 H 5 ); in addition, when the vicinal pair of substituents
  • compositions of formula I include acid addition salts (for example hydrochloride), of any amine groups present.
  • Preferred groups of compounds of formula I include those in which: R 10 represents methyl, ethyl, propyl or allyl; at least one of R ⁇ a and R 21 a represents OH or OCH 3 ; n is 2; any ring formed by Y, R 10 and R 23 is a pyrrole or tetrahydrofuran ring; and
  • R 7 is H or OH.
  • the derivatives and homologues for use in the invention may be administered by any convenient means.
  • they may be introduced parenterally by injection eg intravenously, intramuscularly or subcutaneously; orally; by inhalation eg in the form of s a pressurised or non-pressurised powder formulation; topically; or by plasmapheresis.
  • Suitable adjuvants, diluents or carriers are: for tablets, capsules and dragees - microcrystalline cellulose, calcium phosphate, diatomaceous earth, lactose, starch, talc or stearic acid; 0 for i ⁇ jectable solutions - water, alcohols, glycerin or vegetable oils; for inhalation compositions - lactose.
  • compositions may also contain suitable preserving, stabilising and wetting agents, solubilisers (eg a water-soluble cellulose polymer such as hydroxypropyl methylcellulose, 5 or a water-soluble glycol such as propylene glycol), sweetening and colouring agents and flavourings.
  • solubilisers eg a water-soluble cellulose polymer such as hydroxypropyl methylcellulose, 5 or a water-soluble glycol such as propylene glycol
  • sweetening and colouring agents and flavourings eg. a water-soluble cellulose polymer such as hydroxypropyl methylcellulose, 5 or a water-soluble glycol such as propylene glycol
  • sweetening and colouring agents and flavourings eg. a water-soluble cellulose polymer such as hydroxypropyl methylcellulose, 5 or a water-soluble glycol such as propylene glycol
  • sweetening and colouring agents and flavourings eg. a water-soluble cellulose polymer such as
  • the dosage administered will vary with the compound employed and the mode of administration. However, in general, satisfactory results are obtained when the o compounds are administered at a dosage which produces a concentration in the blood stream of from 0.1-150 ⁇ g/ml, preferably l-150 ⁇ g/ml.
  • the indicated total daily dosage is in the range of from O.lmg to 3000mg and preferably from lmg to 2000mg, which may be administered, for example, in divided doses from 1 to 6 times a day or in sustained release form.
  • a method of prophylaxis of AIDS which comprises administering a therapeutically effective amount of a derivative or homologue of 12-(2-cyclohexyl-l-methylvinyl)-13,19,21,27-tetramethyl- ll,28-dioxa-4-azatricyclo[22.3.1.0 4,9 ]octacos-18-ene to a patient infected with HIN.
  • the biological activity of the derivatives and homologues for use in the invention may be demonstrated using the methods disclosed by Karpas et al, Proc ⁇ atl Acad Sci USA, 89, pp8351-8355.
  • Karpas et al demonstrated therein that FR-900506 interferes with HIN production and selectively inhibits the growth of uninfected cells.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention décrit l'utilisation de dérivés et d'homologues de 12-2-cyclohexyle-1-méthylvinyle-13,19,21,27-tétraméthyle-11,22-dioxa-4-azatricyclo(22.3.1.04,9)octacos-18-ène dans le traitement prophylactique du SIDA.
PCT/GB1993/000207 1992-02-01 1993-02-01 Composes macrocycliques servant au traitement prophylactique du sida WO1993014771A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9202196.3 1992-02-01
GB929202196A GB9202196D0 (en) 1992-02-01 1992-02-01 Method of treatment

Publications (1)

Publication Number Publication Date
WO1993014771A1 true WO1993014771A1 (fr) 1993-08-05

Family

ID=10709693

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1993/000207 WO1993014771A1 (fr) 1992-02-01 1993-02-01 Composes macrocycliques servant au traitement prophylactique du sida

Country Status (4)

Country Link
AU (1) AU3456793A (fr)
GB (1) GB9202196D0 (fr)
WO (1) WO1993014771A1 (fr)
ZA (1) ZA93691B (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001005385A3 (fr) * 1999-07-21 2001-08-02 Fujisawa Pharmaceutical Co Nouvelle utilisation d'un compose de macrolide
EP1353671A4 (fr) * 2000-12-29 2004-07-14 Fujisawa Pharmaceutical Co Analogues de tacrolimus neurotrophiques
WO2005067928A1 (fr) * 2004-01-20 2005-07-28 Astellas Pharma Inc. Methode de traitement des troubles de l'erection
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection
US10259827B2 (en) 2016-11-10 2019-04-16 Novartis Ag BMP potentiators

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
AIDS RES. HUM. RETROVIRUSES vol. 8, no. 5, 1992, page 910 P. H\LLSBERG ET AL. 'HTLV-I induced spontaneous T-cell clonal proliferation is rapamycin sensitive' *
PROC. NATL. ACAD. SCI. USA vol. 89, September 1992, pages 8531 - 8355 A. KARPAS ET AL. 'Inhibition of human immunodeficiency virus and growth of infected T cells by the immunosuppressive drugs cyclosporin A and FK 506' cited in the application *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001005385A3 (fr) * 1999-07-21 2001-08-02 Fujisawa Pharmaceutical Co Nouvelle utilisation d'un compose de macrolide
EP1353671A4 (fr) * 2000-12-29 2004-07-14 Fujisawa Pharmaceutical Co Analogues de tacrolimus neurotrophiques
WO2005067928A1 (fr) * 2004-01-20 2005-07-28 Astellas Pharma Inc. Methode de traitement des troubles de l'erection
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection
US10259827B2 (en) 2016-11-10 2019-04-16 Novartis Ag BMP potentiators

Also Published As

Publication number Publication date
AU3456793A (en) 1993-09-01
ZA93691B (en) 1993-09-06
GB9202196D0 (en) 1992-03-18

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