WO1995015328A1 - Immunomodulateurs macrocycliques a noveaux substituants du cycle clyclohexyle - Google Patents

Immunomodulateurs macrocycliques a noveaux substituants du cycle clyclohexyle Download PDF

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Publication number
WO1995015328A1
WO1995015328A1 PCT/US1994/013210 US9413210W WO9515328A1 WO 1995015328 A1 WO1995015328 A1 WO 1995015328A1 US 9413210 W US9413210 W US 9413210W WO 9515328 A1 WO9515328 A1 WO 9515328A1
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hydrogen
aryl
hydroxy
heterocyclic
taken together
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PCT/US1994/013210
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English (en)
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Yat Sun Or
Jay R. Luly
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Abbott Laboratories
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    • 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
    • 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

  • the present invention relates to novel chemical compounds having immunomodulatory activity, and in particular to macrolide immunosuppressants. More particularly, the invention relates to semisynthetic analogs of ascomycin and FK-506, intermediates and processes for their preparation, pharmaceutical compositions containing such compounds and methods of treatment employing the same.
  • cyclospoiine (cyclosporin A) has found wide use since its introduction in the fields of organ transplantation and immunomodulation, and has brought about a significant increase in the success rate for transplantation procedures. Unsatisfactory side-effects associated with cyclospoiine, however, such as nephrotoxicity, have led to a continued search for immunosuppressant compounds having improved efficacy and safety.
  • FR-900520 also known as ascomycin
  • ascomycin has been previously disclosed by Aral et al. in U.S. Patent No. 3,244,592, issued April 5, 1966, where the compound is described as an antifungal agent.
  • Monaghan, R.L., et al . describe the use of ascomycin as an immunosuppressant in European Patent Application No. 323,865, published July 12, 1989.
  • FK-506 Although the immunosuppressive activity of FK-506 has been clinically confirmed, toxicity in mammals has limited its utility. The activity of FK-506 has, however, prompted efforts to discover novel analogs of FK-type compounds which possess superior properties. These efforts include the isolation of new fermentation products, the microbial transformation of existing chemical entities, the chemical modification of these macrocycles, and the synthesis of hybrid species derived from smaller synthetic fragments.
  • Fermentation products of FK-type compounds include C-21-epi derivatives of FK-506; a 31-demethylated derivative of FK-506; 31-oxo-FK-506; and compounds derived from FK-506, FR-900523 and FR-900525 which are characterized by the introduction of hydroxy-protecting groups, formation of a double bond by elimination of water between carbons 23 and 24, oxidation of the hydroxy group at carbon 24 to the ketone, and reduction of the allyl side-chain at carbon 21 via hydrogenation.
  • Other published derivatives include those derived from FK-506 and FR-900520 where the lactone ring is contracted to give a macrocyclic ring containing two fewer carbons.
  • FK-type compounds Numerous chemical modifications of the FK-type compounds have been attempted. These include the preparation of small synthetic fragments of FK-type derivatives; a thermal rearrangement of a variety of derivatives of FK-506 which expands the macrocyclic ring by two carbons; and modifications which include methyl ether formation at C-32 and/or C-24, oxidation of the C-32 alcohol to the ketone, and epoxide formation at C-9.
  • one object of the invention is to provide novel semisynthetic macrolides which possess the desired immunomodulatory activity but which may be found to ⁇ tinimize untoward side effects.
  • Another object of the present invention is to provide synthetic processes for the preparation of such compounds from starting materials obtained by fermentation, as well as chemical intermediates useful in such synthetic processes.
  • a further object of the invention is to provide pharmaceutical compositions containing, as an active ingredient, at least one of the above compounds.
  • Yet another object of the invention is to provide a method of treating a variety of immune system- related disease states, including post-transplant tissue rejection and autoimmune disfunction. Disclosure of the Invention
  • n is zero or one
  • R! is selected from the group consisting of methyl, ethyl, propyl, cyclopropylmethyl, 2- oxopropyl, 2-ethanal, 2-hydroxyethyl and allyl;
  • R 2 is hydrogen or R 2 taken together with R 3 forms a C-22/C-23 bond
  • R3 is selected from the group consisting of hydrogen, hydroxy and protected hydroxy; or R 2 taken together with R 3 forms a C-22/C-23 bond; or R 3 taken together with R 4 is oxo;
  • R 4 is hydrogen or R 4 taken together with R 3 is oxo
  • R5 is selected from hydrogen, hydroxy, protected hydroxy and fluoro
  • R 6 and R 7 are independently selected from hydrogen, hydroxy and protected hydroxy, with the proviso that at least one of R 6 and R 7 is hydrogen; or R 6 and R 7 taken together are oxo;
  • X is a substituent selected from the group of radicals having the following subformulae:
  • A is -O- or -S-;
  • Y is -O- or -NR21- wherein R ⁇ l is selected from the group consisting of: (1) hydrogen,
  • Z is selected from the group consisting of hydrogen, hydroxy, -(Cl-ClO-alkyl), aryl, heterocyclic, -(Cl-ClO-alkoxy) and -NR ⁇ R 24 , wherein R 23 and R 24 are independently selected from: (1) hydrogen,
  • -NR ⁇ R 24 represents a 3- to 7-membered heterocyclic ring, with the proviso that in subformulae (Ed), (Ilk) and (Hm) Z is other than hydroxy;
  • R-- is hydrogen, hydroxy or methoxy
  • Rl2 is selected from the group consisting of:
  • Rl3 is selected from the group consisting of -CHO, hydroxy, protected hydroxy,
  • R 13 is other than -CHO
  • Rl4 and R*4a are independently selected from hydrogen, aryl, heterocyclic and -(C1-C10- alkyl) or, taken together with the carbon atoms to which they are attached, R 14 and R 14 a form an aryl group or a heterocyclic group;
  • Rl5 is hydrogen or hydroxy
  • Rl6 is selected from the group consisting of
  • n is one, R 1 and R 3 are defined as above and X is a substituent selected from the group of radicals having the following subformulae:
  • A, Y, Z, R 12 , R 14 , R 14a and R 16 are defined as above and R 11 and R 15 are each hydrogen.
  • Y, Z and R 16 are defined as above and R 11 and R 15 are each hydrogen. More particularly preferred among the compounds of the present invention are those represented by formula IE in which n is one and X is a substituent selected from the group of radicals having the following subformulae:
  • Z is -(Cl-C10-alkyl), aryl, heterocyclic or -NR ⁇ R 24 , wherein R 23 and R 24 are independently selected from: (1) hydrogen,
  • the compounds prepared in Examples 11, 37 and 56 are the compounds prepared in Examples 11, 37 and 56 (described below).
  • the compounds of the invention are seen to be potent immunosuppressant agents.
  • the compounds of this invention possess immunosuppressive, antimicrobial, antifungal, antiviral, antiinflammatory, and antiproliferative activity, as well as the ability to reverse chemotherapeutic drug resistance.
  • the compounds of the invention possess the ability to reverse chemotherapeutic drug resistance.
  • agents which block T-cell activation, a prerequisite for HTV proliferation the compounds are useful as prophylactics for the prevention of HTV replication.
  • immunosuppressant agents include but are not limited to FK-506, rapamycin, cyclosporin A, mycophenolic acid, azathioprine, prednisolone, cyclophosphamide, brequinar and leflunomide.
  • compositions comprising a compound of the invention in combination with a pharmaceutically acceptable carrier.
  • Suitable carriers and methods of formulation are also disclosed.
  • a methos of immunomodulatory treatment in a human or lower mammal comprising the administration of a therapeutically effective amount of at least one compound of the invention to a patient in need of such treatment.
  • acyl refers to -C(O)R 30 wherein R 30 is aryl, (C1-C10- alkyl), (C2-C10-alkenyl) or heterocyclic. Examples include, but are not limited to, acetyl, pivaloyl, benzoyl and the like.
  • C2-C10-alkenyl refers to a straight or branched chain group of 2 to 10 carbon atoms containing at least one carbon-carbon double bond including, but not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-l-propenyl, 1-butenyl, 2-butenyl and the like.
  • Cl-C6-alkoxy refers to -OR 31 wherein R 31 is (Cl-C6-alkyl) including, but not limited to, methoxy, ethoxy, isopropoxy, n-butoxy, -fec-butoxy, tert-butoxy and the like.
  • Cl-ClO-alkyl refers to a monovalent straight chain or branched chain group of 1 to 10 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl and the like.
  • C2-C10-alkynyl refers to a straight or branched chain group of 2 to 10 carbon atoms containing at least one carbon-carbon triple bond including, but not limited to, propargyl, 1-propynyl, 1-butenyl, 2-butynyl and the like.
  • aryl refers to mono-, bi- or tricyclic carbocyclic ring system having one or two aromatic rings.
  • aryl include, but are not limited to, phenyl, 1- or 2-naphthyl, fluorenyl, (l,2)-dihydronaphthyl, (l,2,3,4)-tetrahydronaphthyl, indenyl and the like.
  • Aryl groups can be unsubstituted or substituted with one, two or three substituents independently selected from the group consisting of -(Cl-to-ClO-alkyl), -(C2-to-C10-alkenyl), halogen, -(CH2) m N(Cl-C6-alkyl)2, wherein m is zero to six, -CN, -CHO, mono-, di-, tri-, or perhalogenated -(Cl-C6-alkyl), -S(O) p (Cl-C6-alkyl), wherein p is 0, 1 or 2, -C(O)N(Cl-C6-alkyl), -(CH 2 )mO(Cl-C6-alkyl), where m is as defined above, -(CH2)qOC(O)(Cl-C6-alkyl), wherein q is zero to six, -(CH 2 ) r C(O)O(Cl-C6
  • cyclo(C3-C10-alkyl) refers to a cyclic group of 3 to 10 carbons including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • heterocyclic ring or “heterocyclic” or “heterocycle” as used herein refers to any 3- or 4-membered ring containing a heteroatom selected from oxygen, nitrogen and sulfur; or a 5-, 6- or 7-membered ring containing one, two or three nitrogen atoms; one oxygen atom; one sulfur atom; one nitrogen and one sulfur atom; one nitrogen and one oxygen atom; two oxygen atoms in non-adjacent positions; one oxygen and one sulfur atom in non-adjacent positions; or two sulfur atoms in non-adjacent positions.
  • heterocyclic also includes bicyclic groups in which any of the above heterocyclic rings is fused to a benzene ring or a cyclohexane ring or another heterocyclic ring (for example, indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl, dihydrobenzofuryl or benzothienyl and the like).
  • Heterocyclics include: azetidinyl, oxetanyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, i idazolyl, imidazolinyl, i idazolidinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiomoipholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothi
  • Heterocyclics also include compounds of the formula where X* is
  • Y* is -C(O)- or [-C(R") 2 -] V where R" is hydrogen or C ⁇ -C4-alkyl and v is 1, 2 or 3 such as 1,3-benzodioxolyl, 1,4-benzodioxanyl and the like.
  • Heterocyclics can be unsubstituted or monosubstituted or disubstituted with substituents independently selected from -(Cl-to-ClO-alkyl), -(C2-to-C10-alkenyl), halogen, amino, -(CH )fN(Cl-C6-alkyl) wherein f is zero to six, -CN, -CHO, mono-, di-, tri-, or perhalogenated -(Cl-C6-alkyl), -S(O) g (Cl-C6-alkyl) wherein g is 0, 1 or 2, -C(O)N(Cl-C6-alkyl), -(CH 2 ) h O(Cl-C6-alkyl) wherein h is 0 to 6, -(CH 2 )iOC(O)(Cl-C6-alkyl) wherein i is 0 to 6, -(CH 2 ) j C(
  • protected hydroxy group refers to a hydroxy group which has been protected by a group which is known in the art of organic synthesis to protect a hydroxyl group against undesirable reaction during synthetic procedures and to be selectively removable such as those hydroxy protecting groups disclosed in T.W.
  • hydroxy protecting groups include, but are not limited to, substituted methyl ethers, for example, methoxymethyl, methylthiomethyl, 2-methoxyethoxymethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, t-butyl, benzyl and triphenylmethyl; tetrahydropyranyl ethers; substituted ethyl ethers, for example, 2,2,2-trichoroethyl; silyl ethers, for example, dimethylthexylsilyl, trisubstituted silyl such as tris(loweralkyl)silyl (e.g., trimethylsilyl, triethylsilyl, tributylsilyl, tri-isopropylsily
  • pharmaceutically acceptable salts, esters, amides and prodrugs refers to those carboxylate salts, amino acid addition salts, esters, amides and prodrugs of the compounds of the present invention which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, or the like, commensurate with a reasonable benefit risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
  • salts refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention, which may be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate and laurylsulphonate salts and the like.
  • alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium and the like
  • nontoxic ammonium, quaternary ammonium and arnine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, etiiylarnine, and the like (see, for example S. M. Berge, et al., "Pharmaceutical Salts," L Pharm. Sci.. 66: 1- 19 (1977)).
  • esters of the compounds of this invention include Cl-to-C6-alkyl esters wherein the alkyl group is a straight or branched chain. Acceptable esters also include C5-to-C7-cycloalkyl esters as well as arylalkyl esters such as, but not limited to benzyl. Cl-to-C4 alkyl esters are preferred. Esters of the compounds of the present invention may be prepared according to conventional methods.
  • non-toxic esters of alcoholic moieties on the compounds of the invention may be constructed by condensing these alcohols with Cl-to- C6-alkyl carboxylic acids, Cl-to-C6-alkyl dicarboxylic acids or aryl-carboxylic acids.
  • esters include, but are not limited to acetyl, benzoyl or hemi-succinyl.
  • Examples of pharmaceutically-acceptable, non-toxic amides of the compounds of this invention include amides derived from ammonia, primary Cl-to-C6-alkyl amines and secondary di-Cl-to-C6-alkyl amines. In the case of secondary amines the amine may also be in the form of a 5-or- 6 membered heterocycle containing one nitrogen atom. Amides derived from ammonia, Cl-to-C3-alkyl primary amides and di-Cl-to-C2-alkyl secondary amides are preferred. Amides of the compounds of the invention may be prepared according to conventional methods.
  • Prodrug refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and N. Stella, "Pro-drugs as Novel Delivery
  • Prodrugs of compounds of the present invention may be prepared by any suitable method.
  • the condensation of the drug's amino group with amino acids and peptides may be effected in accordance with conventional condensation methods such as the azide method, the mixed acid anhydride method, the DCC (dicyclohexylcarbodiimide) method, the active ester method (p-nitrophenyl ester method, ⁇ -hydroxysuccinic acid imide ester method, cyanomethyl ester method and the like), the Woodward reagent K method, the
  • DCC-HOBT (1-hydroxy-benzotriazole) method and the like.
  • Classical methods for amino acid condensation reactions are described in "Peptide Synthesis” Second Edition, M. Bodansky, Y.S. Klausner and M.A. Ondetti (1976).
  • branched chain amino and carboxyl groups at alpha and omega positions in amino acids may be protected and deprotected if necessary.
  • the protecting groups for amino groups which can be used involve, for example, benzyloxycarbonyl (Z or Cbz), o-chlorobenzyloxycarbonyl ((2-Cl)Z)), p-nitrobenzyloxycarbonyl (Z( ⁇ 2)), p-methoxybenzyloxycarbonyl (Z(OMe)), t-amyloxycarbonyl (Aoc), isobornealoxycarbonyl, adamantyloxycarbonyl (Adoc), 2-(4-biphenyl)-2-propyloxy carbonyl (Bpoc), 9-fluorenyl-methoxycarbonyl (Fmoc), methylsulfonylethoxy carbonyl (Msc), trifluoroacetyl, phthalyl, formyl, 2-nitrophenylsulfonyl (Nps), diphenylphosphinothioyl (Ppt), dimethylphosphino-thioyl (Mpt
  • protecting groups for carboxyl groups involve, for example, benzyl ester (OBzl), cyclohexyl ester, 4-nitrobenzyl ester (OBzlNO2), t-butyl ester (OtBu), 4-pyridylmethyl ester (OPic) and the like.
  • the guanidino group (NG) in arginine may be protected with nitro, p-toluenesulfonyl (Tos), benzyloxycarbonyl (Z), adamantyloxycarbonyl (Adoc), p-methoxybenzene-sulfonyl, 4-methoxy-2,6-dimethyl-benzenesulfonyl (Mts) and the like;
  • the thiol group in cysteine may be protected with benzyl, p-methoxybenzyl, triphenylmethyl, acetamidomethyl, ethylcarbamyl, 4-methylbenzyl (4-MeBzl), 2,4,6-trimethylbenzyl (Tmb) and the like; and the hydroxy group in serine may be protected with benzyl (Bzl), t-butyl, acetyl, tetrahydropyranyl (THP) and the like
  • the compounds of the invention are those described by the general formula (E), as well as the pharmaceutically acceptable salts, esters amides and prodrugs thereof.
  • the compounds of the invention are formed by modification of FR- 900520 (ascomycin) or one of its congeners (such as FK-506, etc.) by oxidative cleavage at the C-32 position with optional modifications exercised at the C-9, C-18, C-23 and/or C-24 positions. Multiple modifications are also possible by the careful selection of syntheses from those disclosed herein, as by the use of other synthetic methods known to those skilled in the art.
  • the compounds of the invention may be prepared using one or more processes.
  • the starting materials for use in these processes are preferably one of the macrolides isolated from culture media obtained in accordance with known methods by fermentation of microorganisms of the genus Streptomyces. which are disclosed in European Patent Application No. 0184162. Samples are available from the Fermentation Research Institute, Tsukuba, Ibaraki 305, Japan under the provisions of the Budapest Treaty, under deposit No. FERM BP-927. This strain has been redeposited on April 27, 1989 with the Agricultural Research Culture Collection International Depository, Peoria, Illinois 61604, USA under the provisions of the Budapest Treaty, under deposit No. NRRL 18488.
  • the macrolide FR-900520 (European Patent Application 0184162), also known as ascomycin, may be prepared in accordance to the published methods of (i) H. Hatanaka, M. Iwami, T. Kino, T. Goto and M. Okuhara, FR-900520 and FR-900523, Novel immunosuppressants isolated from A streptomyces. I. Taxonomy of the producing strain. J . Ant ⁇ biot., 1988, XLI(ll), 1586-1591; ( ⁇ ) H. Hatanaka, T. Kino, S. Miyata, N. Inamura, A. Kuroda, T. Goto, H. Tanaka and M.
  • Such processes comprise:
  • a suitable reagent for Baeyer-Villiger oxidation is an organic or inorgnic peracid such as m-chloroperbenzoic acid, trifluoroperacetic acid, nitro-perbenzoic acid, monopermaleic acid, monoperphthalic acid, performaic acid or peracetic acid etc.
  • the oxidation may be carried in a solvent which does not adversely affect the reaction (e.g. methylene chloride, chloroform, carbon tetrachloride, dichloroethane or chlorobenzene).
  • the reaction may require cooling or heating (°0c to 100 °C), depending on the method used. Further, the reaction is preferably conducted in the presence of an inorganic base such as cesium carbonate, cesium bicarbonate, potassium carbonate, potassium bicarbonate and the like. The reaction may require 20 minutes to 24 hours to complete, depending on the reagents chosen.
  • a suitable reagent for lactonization is Mukaiyama reagent (Mukaiyama T., Challenges in Synthetic Organic Chemistry, p.118, Clarendon Press, Oxford, 1990), alkyl chloroformate, carbodiimide, diphenylphosphoryl azide or carbonyldiimidazole.
  • the intramolecular cyclization may be carried out in a solvent which does not adversely affect the reaction (e.g. tetiahydrofuran, methylene chloride, chloroform, N,N-dimethylformamide, N-methylpyrrolidone, pyridine or a mixture therof).
  • the reaction may require cooling or heating, depending on the method used.
  • reaction is preferably conducted in the presence of an organic or inorganic base such as cesium carbonate, lutidine, picoline, quinoline, dnsopropylethylamine and the like.
  • an organic or inorganic base such as cesium carbonate, lutidine, picoline, quinoline, dnsopropylethylamine and the like.
  • the reaction temperature is preferably from -30 °C to 60 °C.
  • the reaction may rqeuire 20 minutes to 24 hours to complete, depending on the reagent used.
  • a suitable acid catalyst is p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, fluorosulfonic acid, hydrofluoric acid, hydrochloric acid, formic acid, acetic acid and the like.
  • the reaction may be carried out in acetone, acetaldehyde, diethylketone, n-butaldehyde and the like. The reaction may require cooling or heating, depending on the method used.
  • a suitable reducing agent is trialkylsilane such as triethylsilane, hydrogen in the presence of catalyst, sodium cyanoborohydride and the like.
  • the reaction may be carried in a solvent which does not adversely affect the reaction (e.g. tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone, formic acid, acetic acid or a mixture thereof).
  • the reaction may require cooling or heating, depend on the reagents used.
  • the reaction is preferably conducted in the presence of amine, R 21 -NH 2 , in the presence of an organic acid such as formic acid, acetic acid, trifluoroacetic acid and the like.
  • a suitable reagent for lactamization is Mukaiyama reagent
  • the intramolecular cyclization may be carried out in a solvent which does not adversely affect the reaction (e.g. tetiahydrofuran, methylene chloride, chloroform, N,N-dimethylformamide, N-methylpyrrolidone, pyridine or a mixture therof).
  • a solvent which does not adversely affect the reaction (e.g. tetiahydrofuran, methylene chloride, chloroform, N,N-dimethylformamide, N-methylpyrrolidone, pyridine or a mixture therof).
  • the reaction may require cooling or heating, depending on the method used.
  • reaction is preferably conducted in the presence of an organic or inorganic base such as cesium carbonate, lutidine, picoline, quinoline, d opropylethylamine and the like.
  • an organic or inorganic base such as cesium carbonate, lutidine, picoline, quinoline, d opropylethylamine and the like.
  • the reaction temperature is preferably from -30 °C to 60 °C.
  • the reaction may rqeuire 20 minutes to 24 hours to complete, depending on the reagent used.
  • a suitable reducing reagent is sodium borohydride, sodium cyanoborohydride, lithium triacetoxyborohydride, L-selectride and the like.
  • the reaction may be carried out in a solvent which does not adversely affect the reaction (e.g. diethyl ether, tetrahydrofuran, N,N-dimethylformamide or a mixture thereof).
  • the reaction temperature is preferably from -78 °C to 40 °C. The reaction may require 20 minutes to 24 hours to complete, depending on the reagent used.
  • the condensation of the amino group with carboxylic acid may be affected in accordance with conventional condensation methods such as the azide method, the mixed acid anhydride method, the carbodiimide method, the active ester method (p- nitropohenyl ester method, N-hydroxysuccinic acid imide ester method, cyanomethyl ester method and the like), the Woodward reagent K method, the DCC-HOBt (dicUohexylcarbod-irnide-1-hydroxybenzotriazole), Mukaiyama method and the like.
  • Classical methods for amide bond formation reactions are described in "Peptide Synthesis: Second Edition, M.Bodansky, Y.S.Klausner and M.A. Ondetti, 1976).
  • the carboxylic acid group is first activated with chloroformate and converted to acyl azide with sodium azide.
  • the carboxylic acid is directly converted to acyl azide using diphenylphosphoryl azide.
  • the acyl azide may be used in Curtius rearrangement with or without further purification.
  • the prefered solvent for the acyl azide formation is acetone-water, tetrahydrofuran-water, dioxane- water, tetrahydrofuran, dichloromethane, chloroform, chlorobenzene and the like.
  • the Curtius rearrangement reaction may be carried in a solvent which does not adversely affect the reaction (e.g.
  • reaction temperature is preferably from 25 °C to 100 °C.
  • the reaction may require 20 minutes to 24 hours to complete, depending on the reagent chosen.
  • the carboxylic acid, R 21 -COOH is directly reacted with the isocyante in a solvent which does not adversely affect the reaction (e.g toluene, chlorobenzene, chloroform, methylene chloride or a mixture thereof).
  • the reaction temperature is preferably from 25 °C to 100 °C.
  • the reaction may require 20 minutes to 24 hours to complete, depending on the reagent chosen.
  • the alcohol, (Cl-ClO-alkyl) alcohol is directly reacted with the isocyante in a solvent which does not adversely affect the reaction (e.g toluene, chlorobenzene, chloroform, methylene chloride or a mixture thereof).
  • the reaction temperature is preferably from 25 °C to 100 °C. Further, the reaction is carried out in the presence of organic base such as diisopropylethylamine, tirethylaierine, pyridine, lutidine and the like. The reaction may require 20 minutes to 24 hours to complete, depending on the reagent chosen. Li process (k), the amine, R ⁇ R ⁇ NH is directly reacted with the isocyante in a solvent which does not adversely affect the reaction (e.g toluene, chlorobenzene, chloroform, methylene chloride or a mixture thereof). The reaction temperature is preferably from 25 °C to 100 °C.
  • reaction is carried out in the presence of organic base such as diisopropylethylamine, tirethylamine, pyridine, lutidine and the like.
  • organic base such as diisopropylethylamine, tirethylamine, pyridine, lutidine and the like.
  • the reaction may require 20 minutes to 24 hours to complete, depending on the reagent chosen.
  • a suitable reducing reagent is sodium borohydride, sodium cyanoborohydride, lithium triacetoxyborohydride, L-selectride and the like.
  • the reaction may be carried out in a solvent which does not adversely affect the reaction (e.g. diethyl ether, tetrahydrofuran, N,N-dimethylformamide or a mixture thereof).
  • the reaction temperature is preferably from -78 °C to 40 °C. The reaction may require 20 minutes to 24 hours to complete, depending on the reagent used.
  • an amino alcohol or thioamino alcohol is reacted directly with a compound of subformula Eb (R 12 is -CHO, Z is -OH) in the presence of a drying agent.
  • the reaction may be carried in a solvent which does not adversely affect the reation (e.g. tetrahydrofuran, chloroform, dichlorethane, methylene chloride, chlorobenzene, toluene, benzene or a mixture thereof).
  • Suitable solid drying agents are powdered anhydrous magnesium sulfate, molecular sieves and the like.
  • the intermediate is then cyclized by a standard amide bond formation reaction.
  • the condensation of the amino group with carboxylic acid may be affected in accordance with conventional condensation methods such as the azide method, the mixed acid anhydride method, the carbodiimide method, the active ester method (p-nitropohenyl ester method, N-hydroxysuccinic acid imide ester method, cyanomethyl ester method and the like), the Woodward reagent K method, the DCC-HOBt (dicMohexylcarbodiimide-l-hydroxybenzotriazole), Mukaiyama method and the like.
  • Classical methods for amide bond formation reactions are described int "Peptide Synthesis: Second Edition, M.Bodansky, Y.S.Klausner and M.A. Ondetti, 1976).
  • the carboxylic acid group is first activated with chloroformate and converted to acyl azide with excess sodium azide.
  • the carboxylic acid is directly converted to acyl azide using excess diphenylphosphoryl azide.
  • the acyl azide may be used in Curtius rearrangement followed by cyclization reaction without further purification.
  • the prefered solvent for the acyl azide formation is acetone- water, tetrahydrofuran-water, dioxane-water, tetrahydrofuran, dichloromethane, chloroform, chlorobenzene and the like.
  • the Curtius rearrangement reaction may be carried in a solvent which does not adversely affect the reaction (e.g.
  • the reaction temperature is preferably from 25 °C to 100 °C.
  • the reaction may require 20 minutes to 24 hours to complete, depending on the reagent chosen.
  • a compound of subformulae Ec (R 13 is -CHO) is reacted with one to five equivalents of 48% hydrofluoric acid in a solvent which does not adversely affect the reaction (e.g. tetrahydrofuran, acetonitrile, acetone, dioxane or a mixture thereof).
  • the reaction temperature is preferably -78 to 0 °C. The reaction may require 1 to 24 hours to complete.
  • the hydrofluoric acid is neutralized by an inorgnic base such as cesium carbonate, cesium bicarbonate, potassium bicarbonate and the like.
  • a suitable catalyst for aromatization is palladium on carbon or platinum.
  • a suitable oxidizing agent is air, oxygen, an olefin and the like.
  • the reaction is preferably carried out in a solvent which does not adversely affect the reaction (e.g. tetrahydrofuran, acetone, diethyl ether, dioxane or a mixture thereof). The reaction may take 1 to 14 days to complete, depending on the conditions chosen.
  • a suitable reducing agent is trialkylsilane such as triethylsilane, hydrogen in the presence of catalyst, sodium cyanoborohydride and the like.
  • the reaction may be carried in a solvent which does not adversely affect the reaction (e.g. tetrahydrofuran, N,N-dimethylformamide, N-methylpyirolidone, formic acid, acetic acid or a mixture thereof).
  • the reaction may require cooling or heating, depend on the reagents used.
  • the reaction is preferably conducted in the presence of amine, R 21 -NH 2 , in the presence of an organic acid such as formic acid, acetic acid, trifluoroacetic acid and the like.
  • the prefered organic base is tri-alkyl amine such as triethylamine, diisopropylethylamine, pyridine, lutidine and the like.
  • the dehydration reaction is preferably carried in a solvent which does not adversely affect the reaction (e.g. methylene chloride, chloroform, dichloroethane, chlorobenzene or a mixture thereof). The reaction may require cooling or heating, depending on the conditions used.
  • a suitable reducing agent is trialkylsilane such as triethylsilane, hydrogen in the presence of catalyst, sodium cyanoborohydride and the like.
  • the reaction may be carried in a solvent which does not adversely affect the reaction (e.g. tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone, formic acid, acetic acid or a mixture thereof).
  • the reaction may require cooling or heating, depend on the reagents used.
  • the reaction is preferably conducted in the presence of amine, R 21 -NH 2 , in the presence of an organic acid such as formic acid, acetic acid, trifluoroacetic acid and the like.
  • the present invention can be illustrated by the following non-limiting, representative examples.
  • the aqueous phase was extracted with ether (3x150 mL).
  • the combined organic phase was washed with 1 N hydrochloric acid (3x150 mL), brine (300 mL), dried over magnesium sulfate and solvent remove in vacua.
  • a solution of hydrofluoric acid 0.5 mL of 48% hydrofluoric acid in 10 mL of acetonitrile
  • acetonitrile 50 mL
  • the cooling bath was removed and the reaction mixture was stirred at room temperature for 1 hour.
  • the reaction mixture was cooled to 0 oC and powdered sodium bicarbonate (5 g) was added followed by powdered magnesium sulfate (10 g).
  • the title compound was prepared from the title compound of Example 5 (0.6 g), 1- hydroxybenzotriazole (0.09 g), aminoethanol (0.05 mL) and l-(3-dimethylaminopropyl)-
  • the title compound was prepared from the title compound of Example 5 (0.6 g), 1- hydroxybenzotriazole (0.09 g), n-propyla ⁇ r ⁇ ine(0.05 mL) and l-(3-dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride (0.19 g) in N,N-dimethylformamide (5 mL) according to the procedure described in Example 6. Yield: 0.59 g.
  • the tide compound was prepared from the tide compound of Example 12 (0.39 g) and HF according to the procedures described in Example 7. Yield: 0.27 g;
  • the tide compound was prepared from the tide compound of Example 5 (0.6 g), 1- hydroxybenzotriazole (0.09 g), morpholine (0.1 mL) and l-(3-dimethylamino ⁇ ropyl)-3- ethylcarbodiimide hydrochloride (0.19 g) in N,N-dimethylformamide (5 mL) according to the procedure described in Example 6.
  • the tide compound was prepared from the tide compound of Example 12 (0.46 g) and HF according to the procedures described in Example 7. Yield: 0.32 g;
  • the tide compound is prepared from the tide compound of Example 4, benzylamine and sodium cyanoborohydride in acetic acid at 0 °C.
  • the product is purified by reverse phase HPLC. Example 17.
  • the tide compound is prepared from the tide compound of Example 16 and hydrofluoric acid according to the procedure described in Example 7.
  • the tide compound is prepared from the tide compound of Example 17 and morpholine according to the procedure described in Example 6.
  • the tide compound is prepared from the tide compound of Example 3 and N-methylamine according to die procedure described in Example 16.
  • the tide compound is prepared from the tide compound of Example 19 and morpholine according to the procedure described in Example 6.
  • Lithium bis(trimeti ⁇ ylsilyl)amide (2.3 mL, 1.0 M in tetrahydrofuran) is added into a suspension of methyltriphenylphosphonium bromide (0.97 g) in dry toluene (7 mL) at 0 °C and stirred for 1 hour.
  • a precooled solution of the product of Example 4 (0.7 g, in 14 mL of dry toluene) is added into the ylide over 7 minutes. After being sti ⁇ ed at 0 °C for
  • the reaction mixture is applied on a column of silica gel (50 g) in 40% acetone/hexanes and eluted with 40% acetone/hexanes to give the tide compound.
  • the tide compound is prepared from the tide compound of Example 23 and hydrofluoric acid according to the procedure described in Example 7.
  • the tide compound is prepared by hydrogenation of the tide compound of Example 24 in the presence of Pd/C in ethanol. Exa ple 26.
  • N-methylmorpholine N-oxide (0.73 g) and osmium tetraoxide (1 mL, 4wt% in water) are added into a stirred solution of the product of Example 24 (0.7 g) in tetrahydrofuran (52 mL) and stirred at room temperature for 5 hours. Excess oxidizing agent is quenched with sodium bisulfite (0.9 g) and florisil.
  • reaction is then diluted with ethyl acetate and solid filtered off through celite.
  • the filtrate is washed with 1 N sodium bicarbonate, brine, dried over magnesium sulfate and solvent removed in vacuo.
  • the product is purified by silica gel chromatography.
  • the tide compound is prepared from the tide compound of Example 3 and benzyl- tiiphenylphosphonium bromide according to the procedure described in Example 23.
  • the tide compound is prepared from the tide compound of Example 27 and hydrogen in the presence of Pd/C according to the procedure described in Example 25.
  • the tide compound is prepared from the tide compound of Example 24, isobutyl chloroformate and sodium azide according to the procedure described in Example 21. Example 30.
  • the tide compoxind is prepared from the tide compound of Example 25, isobutyl chloroformate and sodium azide according to die procedure described in Example 21.
  • the tide compound is prepared from the tide compound of Example 5 and hydrofluoric acid according to the procedure described in Example 7.
  • the tide compound is prepared from the tide compound of Example 31, isobutyl chloroformate and sodium azide according to the procedure described in Example 21.
  • Morpholine (0.6 mL) is added into a stirred solution of the tide compound of Example 30 (2.5 g) in dry tetrahydrofuran (25 mL) at room temperature for 1 hour. Solvent is removed in vacuo and product purified by silica gel chromatography.
  • the tide compound is prepared from the tide compound of Example 29 and morpholine in dry tetrahydrofuran according to the procedure described in Example 33. Exa ple 35.
  • the tide compound is prepared from me tide compound of Example 29 and benzylamine in dry tetrahydrofuran according to the procedure described in Example 33.
  • the tide compound is prepared from the tide compound of Example 36b and hydrofluoric acid according to the procedure described in Example 7.
  • Example 37 The tide compound is prepared from the tide compound of Example 36b and hydrofluoric acid according to the procedure described in Example 7.
  • Example 37 is prepared from the tide compound of Example 36b and hydrofluoric acid according to the procedure described in Example 7.
  • the tide compound of Example 4 (0.7 g) was dissolved in a solution of ethanol (freshly distilled from sodium, 5 mL) containing aminothioethanol hydrogen chloride (0.2 g) under nitrogen at room temperature.
  • Dusopropylethylamine (0.14 mL) was added to the reaction mixture followed by powdered magnesium sulfate. After being stirred at room temperature for 1.5 hour, the solids were filtered off and solvent removed in vacuo.
  • the intermediate was purified by silica gel chromatography. Yield: 0.56 g.
  • the intermediate (0.56 g) was dissolved in dry THF (5 mL) under nitrogen at room temperature.
  • the tide compound is prepared from the tide compound of Example 3 and aminoethanol according to the procedure described in Example 38.
  • the tide compound is prepared from the tide compound of Example 3 and o- phneylenediamine according to the procedure described in Example 38.
  • the tide compound was prepared from d e tide compound of Example 3 and diphenylphosphoryl azide according to the procedure described in Example 43.
  • MS (FAB) m/z: M+K 870. m.p. 135-143°C. 13 CNMR:(CDCl3-2 rotamers)
  • a suspension of 10% Pd/C in a solution of die tide compound of Example 45 in tetrahydrofuran is sti ⁇ ed under an atmosphere of oxygen at room temperature for 10 days. Solids are filtered off and solvent removed in vacuo. The product is purified by silica gel chromatography.
  • the tide compound is prepared from the tide compound of Example 47 and hydrogen according to the procedure described in Example 47.
  • the tide compound is prepared from the tide compound of Example 47, methyl iodide and triethylamine according to the procedure described in Example 49.
  • Example 51 The tide compound is prepared from the tide compound of Example 47, methyl iodide and triethylamine according to the procedure described in Example 49.
  • Example 51 The tide compound is prepared from the tide compound of Example 47, methyl iodide and triethylamine according to the procedure described in Example 49.
  • Example 51 Example 51.
  • the tide compound is prepared from the tide compound of Example 47, ethylene oxide and triethylamine according to the procedure described in Example 49.
  • Example 55 Example 55.
  • Aqueous phosphoric acid (1 wt %, 2 mL) was added into a stirred solution of the tide compound of Example 21 (1.05 g) in dioxane (12 mL) and stirred at room temperature for
  • the tide compound is prepared from the tide compound of Example 54 and hydrofluoric acid according to the procedure described in Example 7.
  • the tide compound is prepared from die tide compound of Example 29 and hydrofluoric acid according to the procedure described in Example 7. The product is purified by reverse phase HPLC.
  • Example 61 In Vitro Assay of Biological Activity
  • the immunosuppressant activity of the compounds of the present invention was determined using the human mixed lymphocyte reaction (MLR) assay described by T. Kinoet al. in Transplantation Proceedings, XIX(5):36-39, Suppl. 6 (1987).
  • MLR human mixed lymphocyte reaction
  • the compounds of the invention possess immunomodulatory activity in mammals (especially humans).
  • the potent immunomodulatory activity which compounds of the instant invention demonstrate in common in vitro biological assays indicate that these compounds possess immunosuppressive, antimicrobial, antifungal, antiviral, antiinflammatory, and antiproliferative activity, and possess the ability to reverse chemotherapeutic drug resistance.
  • the compounds are useful as prophylactics for the prevention of HIV replication.
  • While the compounds of the invention are useful when used alone, combination therapy with other immunosuppressants, such as, FK506, rapamycin, cyclosporin A, picibanil, mycophenolic acid, azathioprine, prednisolone, cyclophosphamide, brequinar and leflunomide, is also beneficial.
  • immunosuppressants such as, FK506, rapamycin, cyclosporin A, picibanil, mycophenolic acid, azathioprine, prednisolone, cyclophosphamide, brequinar and leflunomide.
  • the compounds of the present invention are useful when administered for the prevention immune-mediated tissue or organ graft rejection.
  • transplanted tissues and organs which suffer from these effects are heart, kidney, liver, medulla ossium, skin, cornea, lung, pancreas, intestinum ***, limb, muscle, nervus, duodenum, small-bowel, pancreatic-islet-cell, and the like; as well as graft-versus-host diseases brought about by medulla ossium transplantation.
  • the regulation of the immune response by the compounds of the invention means die compounds are useful in die treatment of autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myastiienia gravis, type I diabetes, uveitis, allergic encephalomyelitis, glomerulonephritis, and the like; and further infectious diseases caused by pathogenic microorganisms, such as HIN.
  • autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myastiienia gravis, type I diabetes, uveitis, allergic encephalomyelitis, glomerulonephritis, and the like
  • pathogenic microorganisms such as HIN.
  • HIN pathogenic microorganisms
  • Further uses include the treatment and prophylaxis of inflammatory and hyperproliferative skin diseases and cutaneous manifestations of immunologically- mediated illnesses, such as psoriasis, atopical dermatitis, contact dermatitis and further eczematous dermatitises, seborrhoeis dermatitis, Lichen planus, Pemphigus, bullous pemphigoid, Epidermolysis bullosa, urticaria, angioedemas, vasculitides, erythemas, cutaneous eosinophilias, Lupus erythematosus, acne and Alopecia areata; various eye diseases (autoimmune and otherwise) such as keratoconjunctivitis, vernal conjunctivitis, keratitis, herpetic keratitis, conical cornea, dystrophia epithelialis corneae, corneal leukoma, ocular pemphigus, Mooren's ulcer, S
  • hyperproliferative vascular diseases such as intimal smooth muscle cell hyperplasia, restenosis and vascular occlusion, particularly following biologically- or mechanically-mediated vascular injury can be treated or prevented by the compounds of die invention.
  • Other treatable conditions include but are not limited to ischemic bowel diseases, inflammatory bowel diseases, necrotizing enterocolitis, intestinal lesions associated with thermal bums and leukotriene B-t-mediated diseases; intestinal inflammations/allergies such as Coeliac diseases, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease and ulcerative colitis; food-related allergic diseases which have symptomatic manifestation remote from the gastto-intestinal tract (e.g., migraine, rhinitis and eczema); renal diseases such as interstitial nephritis, Goodpasture's syndrome, hemolytic-uremic syndrome and diabetic nephropathy; nervous diseases such as multiple myositis, Guillain
  • the compounds of the invention are useful for the treatment and prevention of hepatic disease such as immunogenic diseases (for example, chronic autoimmune liver diseases such as the group consisting of autoimmune hepatitis, primary biliary cirrhosis and sclerosing.cholangitis), partial liver resection, acute liver necrosis (e.g., necrosis caused by toxin, viral hepatitis, shock or anoxia), B-virus hepatitis, non- A/non-B hepatitis, cirrhosis (such as alcoholic cirrhosis) and hepatic failure such as fulminant hepatic failure, late-onset hepatic failure and "acute-on-chronic" liver failure
  • immunogenic diseases for example, chronic autoimmune liver diseases such as the group consisting of autoimmune hepatitis, primary biliary cirrhosis and sclerosing.cholangitis
  • partial liver resection e.g., necrosis caused by tox
  • 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-azatiicyclo[22.3.1.0 ' 9 ] octacos-18-ene such as FK-506, or rapamycin.
  • an immunosuppressive macrocyclic compound for example derivatives of 12-(2- cyclohexyl-l-methylvinyl)-13, 19,21,27-tetramethyl-ll,28-dioxa-4-azatiicyclo[22.3.1.0 ' 9 ] octacos-18-ene
  • Overdosing of such medicants by patients is quite common upon tiieir realizing that tiiey have forgotten to take tiieir medication at the prescribed time and can lead to serious side effects.
  • Proliferative diseases include smooth muscle proliferation, systemic sclerosis, cirrhosis of the liver, adult respiratory distress syndrome, idiopathic cardiomyopathy, lupus erythematosus, diabetic retinopathy or other retinopathies, psoriasis, scleroderma, prostatic hyperplasia, cardiac hyperplasia, restenosis following arterial injury or other pathologic stenosis of blood vessels.
  • Aqueous liquid compositions of die present invention are particularly useful for die treatment and prevention of various diseases of the eye such as autoimmune diseases (including, for example, conical cornea, keratitis, dysophia epithelialis comeae, leukoma, Mooren's ulcer, sclevitis and Graves' ophthalmopathy) and rejection of corneal transplantation.
  • autoimmune diseases including, for example, conical cornea, keratitis, dysophia epithelialis comeae, leukoma, Mooren's ulcer, sclevitis and Graves' ophthalmopathy
  • a dierapeutically-effective amount of one of the compounds of the present invention meaning a sufficient amount of the compound to treat a particular disorder, at a reasonable benefit/risk ratio, may be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt, ester or prodrug form.
  • the compound may be administered as pharmaceutical compositions containing the compound of interest in combination with one or more pharmaceutically-acceptable excipients. It will be understood, however, that the total daily usage of die compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgement
  • the specific dierapeutically-effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of die specific compound employed; die specific composition employed; the age, body weight, general health, sex and diet of the patient; die time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts. For example, it is well within die skill of die art to start doses of the compound at levels lower than required to achieve the desired tiierapeutic effect and to gradually increase the dosage until the desired effect is achieved.
  • the total daily dose of the compounds of this invention administered to a human or lower animal may range from about 0.001 to about 10 mg kg of patients body mass/day.
  • more preferable doses may be in die range of from about 0.005 to about 3 mg kg/day.
  • the effective daily dose may be divided into multiple doses for purposes of administration; consequentiy, single dose compositions may contain such amounts or submultiples thereof to make up the daily dose.
  • compositions of the present invention comprise a compound of the invention and a pharmaceutically-acceptable carrier or excipient, meaning a non-toxic solid, semi-solid or Uquid filler, diluent, encapsulating material or formulation auxiliary of any type, which may be administered orally, rectally, parenterally, intracisternally, intravaginally, inttaperitoneally, topically (as by powders, ointments, drops or tiansdermal patch), bucally, or as an oral or nasal spray.
  • parenteral refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and inttaarticular injection and infusion.
  • compositions of this invention for parenteral injection comprise pharmaceutically-acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), carboxymediylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.
  • Proper fluidity may be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and die like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like, Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption, such as aluminum monostearate and gelatin. In some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by die use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form.
  • adjuvants such as preservative, wetting agents,
  • delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters) and poly(anhydrides). Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • the injectable formulations may be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically-acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that tiiey release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • the active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral adudinistration include pharmaceutically-acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • die liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tettahydroftirfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benz
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions may contain, in addition to the active compounds, suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures tiiereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures tiiereof.
  • Topical administration includes administration to the skin or mucosa, including surfaces of the lung and eye.
  • Compositions for topical administration may be prepared as a dry powder which may be pressurized or non- pressurized.
  • the active ingredient in finely divided form may be used in admixture with a larger-sized pharmaceutically-acceptable inert carrier comprising particles having a size, for example, of up to 100 micrometers ⁇ diameter.
  • suitable inert carriers include sugars such as lactose.
  • at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 micrometers.
  • the composition may be pressurized and contain a compressed gas, such as nitrogen or a liquified gas propellant
  • a compressed gas such as nitrogen or a liquified gas propellant
  • the liquified propellant medium and indeed the total composition is preferably such that the active ingredient does not dissolve therein to any substantial extent
  • the pressurized composition may also contain a surface active agent, such as a liquid or solid non-ionic surface active agent or may be a solid anionic surface active agent It is preferred to use die solid anionic surface active agent in the form of a sodium salt
  • a further form of topical administration is to the eye, as for the treatment of immune-mediated conditions of the eye such as automimmue diseases, allergic or inflammatory conditions, and corneal transplants.
  • the compound of die invention is delivered in a pharmaceutically acceptable ophthalmic vehicle, such that the compound is maintained in contact with die ocular surface for a sufficient time period to allow the compound to penetrate the corneal and internal regions of the eye, as for example the anterior chamber, posterior chamber, vitreous body, aqueous humor, vitreous humor, cornea, iris/cilary, lens, choroid/retina and sclera.
  • the pharmaceutically-acceptable ophthalmic vehicle may, for example, be an ointment, vegetable oil or an encapsulating material.
  • compositions for rectal or vaginal administration are preferably suppositories which may be prepared by mixing the compounds of this invention witii suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and tiierefore melt in the rectum or vaginal cavity and release die active compound.
  • suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and tiierefore melt in the rectum or vaginal cavity and release die active compound.
  • Liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically- acceptable and metabolizable lipid capable of forming liposomes can be used.
  • the present compositions in liposome form can contain, in addition to a compound of die present invention, stabilizers, preservatives, excipients, and die like.
  • the preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic.

Abstract

Nouveaux composés de macrolide (analogues semi-synthétiques d'asomycine et de FK-506) de la formule (II), ainsi que leur sels, esters, amides, et promédicaments pharmaceutiquement acceptable, formule dans laquelle X représente un substituant choisi parmi les radicaux ayant les sous formules (IIa), (IIe), (IIj) et (IIk), ainsi que d'autres radicaux hétérocycliques, et compositions pharmaceutiques et procédés de traitement immunomodulateur les utilisant.
PCT/US1994/013210 1993-11-30 1994-11-14 Immunomodulateurs macrocycliques a noveaux substituants du cycle clyclohexyle WO1995015328A1 (fr)

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WO1997002285A1 (fr) * 1995-07-04 1997-01-23 Novartis Ag Macrolides
EP0766685A1 (fr) * 1994-06-15 1997-04-09 Merck & Co. Inc. Macrolides arylés, alkylés, alcénylés et alcynylés
WO1998007743A1 (fr) * 1996-08-22 1998-02-26 Novartis Ag Macrolides
US6187757B1 (en) 1995-06-07 2001-02-13 Ariad Pharmaceuticals, Inc. Regulation of biological events using novel compounds
US7067526B1 (en) 1999-08-24 2006-06-27 Ariad Gene Therapeutics, Inc. 28-epirapalogs
US7196192B2 (en) 1999-08-24 2007-03-27 Ariad Gene Therapeutics, Inc. 28-epirapalogs
WO2010004304A1 (fr) * 2008-06-17 2010-01-14 Biotica Technology Limited Nouveaux composés et leurs procédés de production
EP2181704A2 (fr) 2002-12-30 2010-05-05 Angiotech International Ag Liberation de medicaments a partir d'une compostion polymere a gelification rapide
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection
US8921642B2 (en) 2008-01-11 2014-12-30 Massachusetts Eye And Ear Infirmary Conditional-stop dimerizable caspase transgenic animals
EP3663405A1 (fr) 2013-06-11 2020-06-10 Takara Bio USA, Inc. Microvésicules enrichies en protéines et leurs procédés de fabrication et d'utilisation

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EP0766685A1 (fr) * 1994-06-15 1997-04-09 Merck & Co. Inc. Macrolides arylés, alkylés, alcénylés et alcynylés
EP0766685A4 (fr) * 1994-06-15 1997-07-16 Merck & Co Inc Macrolides aryles, alkyles, alcenyles et alcynyles
US6649595B2 (en) 1995-06-07 2003-11-18 Ariad Gene Therapeutics, Inc. Regulation of biological events using novel compounds
US6187757B1 (en) 1995-06-07 2001-02-13 Ariad Pharmaceuticals, Inc. Regulation of biological events using novel compounds
WO1997002285A1 (fr) * 1995-07-04 1997-01-23 Novartis Ag Macrolides
US6124453A (en) * 1995-07-04 2000-09-26 Novartis Ag Macrolides
WO1998007743A1 (fr) * 1996-08-22 1998-02-26 Novartis Ag Macrolides
US7067526B1 (en) 1999-08-24 2006-06-27 Ariad Gene Therapeutics, Inc. 28-epirapalogs
US7196192B2 (en) 1999-08-24 2007-03-27 Ariad Gene Therapeutics, Inc. 28-epirapalogs
EP2181704A2 (fr) 2002-12-30 2010-05-05 Angiotech International Ag Liberation de medicaments a partir d'une compostion polymere a gelification rapide
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection
US8921642B2 (en) 2008-01-11 2014-12-30 Massachusetts Eye And Ear Infirmary Conditional-stop dimerizable caspase transgenic animals
WO2010004304A1 (fr) * 2008-06-17 2010-01-14 Biotica Technology Limited Nouveaux composés et leurs procédés de production
EP3663405A1 (fr) 2013-06-11 2020-06-10 Takara Bio USA, Inc. Microvésicules enrichies en protéines et leurs procédés de fabrication et d'utilisation

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