EP0689545A4 - IMMUNOREGULATEURS A l'AMIDE MACROCYCLIQUE ET A L'UREE - Google Patents

IMMUNOREGULATEURS A l'AMIDE MACROCYCLIQUE ET A L'UREE

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Publication number
EP0689545A4
EP0689545A4 EP94910923A EP94910923A EP0689545A4 EP 0689545 A4 EP0689545 A4 EP 0689545A4 EP 94910923 A EP94910923 A EP 94910923A EP 94910923 A EP94910923 A EP 94910923A EP 0689545 A4 EP0689545 A4 EP 0689545A4
Authority
EP
European Patent Office
Prior art keywords
compound
ethyl
configuration
och2c
attaches
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Withdrawn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
EP94910923A
Other languages
German (de)
English (en)
Other versions
EP0689545A1 (fr
Inventor
Rolf Wagner
Jay R Luly
Yat Sun Or
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.)
Abbott Laboratories
Original Assignee
Abbott Laboratories
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Filing date
Publication date
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Publication of EP0689545A1 publication Critical patent/EP0689545A1/fr
Publication of EP0689545A4 publication Critical patent/EP0689545A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • 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

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, to means for their preparation, to pharmaceutical compositions containing such compounds and to methods of treatment employing the same.
  • cyclosporine (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.
  • FR-900520 also known as ascomycin, has been previously disclosed by Arai 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. 323865, published July 12, 1989.
  • the immunosuppressive activity of FK-506 has been clinically confirmed, its 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 macrocyples, 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 and aryl ether formation at C-32 and/or C-24, oxidation of 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 minimize undesired 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, one of the above compounds.
  • Yet another object of the invention is to provide a method of treating a variety of disease states, including post- transplant tissue rejection and autoimmune disfunction.
  • the present invention is directed to compounds having the formula:
  • n, R, R 1 , R la > R 2 , R 2a , R 3 , R 4 and R 5 are specifically defined, which possess immunosuppressive, antimicrobial, antifungal, antiviral, antunflammatory and antiproliferative activity, as well as the ability to reverse chemotherapeutic drug resistance; to pharmaceutical compositions comprising a compound of the invention in combination with a pharmaceutically-acceptable carrier; to processes for the preparation of these compounds; to synthetic intermediates useful in the preparations of these and other immunomodulator derivatives of ascomycin; to methods of formulating pharmaceutical compositions comprising these compounds; and to a method of immunomodulatory treatment of a human or veterinary subject in need of such treatment by the administration of a therapeutically-effective amount of a novel compound according to the present invention.
  • n zero or one
  • R is hydrogen, methyl, ethyl, allyl, propyl, 2-hydroxyethyl, cyclopropylmethyl, 2-oxopropyl or 2-ethanal;
  • R 1 and R la are selected such that one of R 1 and R la is hydrogen, -(C1-C6- alkyl)oxy or hydroxy, and the other is chosen from the group consisting of: (I) -O(CH )jC(O)R 12 , where j is one-to-five, and Rl 2 is:
  • aryl-(C ⁇ -C6-alkyl)- where aryl is as defined below, wherein the zero, one, two or three substituents on the aryl group, each designated R 301 , are independently selected from the group consisting of:
  • R 400 is selected from the group consisting of: a. mod-aryl, as defined below, wherein the one, two, or three substituents, each designated R 302 , are independently selected from the group consisting of:
  • NR 18 R 19 is either a nitrogen atom attached to R18 and R 19 , wherein Rl» and R* 9 are independently selected from the group consisting of hydrogen, -(Ci- C6-alkyl), unsubstituted aryl-, and unsubstituted aryl-(C ⁇ -C6-alkyl); or NR!8R 19 may be a 3-to- 7-membered heterocyclic ring comprising ring carbon atoms, the nitrogen atom shown, and zero, one or two additional heteroatoms independently selected from the group consisting of -O-, -NH-, -N(C ⁇ -to-C 6 -alkyl) and -S(O) s -, wherein s is zero, one or two;
  • R 10 is: (i) -PO(OH)O-M+, wherein M + is a proton or a positively charged inorganic or organic counterion, as defined below, (ii) -SO3"M + , wherein M + is as defined above, (iii) -C(O)(CH 2 ) m C(O)O-M+, wherein m and M + are as defined above;
  • any two adjacent R 302 substituents in a di- or trisubstituted mod-aryl group form a 5-, 6- or 7- membered carbocyclic ring or a 5-, 6- or 7-membered heterocyclic ring wherein " the ring atoms consist of carbon atoms and one or two heteroatoms independently selected from the group consisting of -O-, -S(O) s -, where s
  • -NR 8 R 9 may be a 3- to 7-membered heterocyclic ring, where the ring consists of carbon atoms, the nitrogen atom shown, and zero, one or two additional heteroatoms independendy selected from the group consisting of -O-, -S(O) s -, wherein s is as defined above, and -NR 8 -, wherein R 8 is as defined above;
  • any two adjacent R 301 substituents in a di- or trisubstituted aryl group form a 5-, 6- or 7-membered carbocyclic ring or a 5-, 6- or 7-membered heterocyclic ring wherein the ring atoms consist of carbon atoms and zero, one or two heteroatoms independently selected from the group consisting of -O-, -S(O) s -, where s is as defined above, and -NR 8 -
  • R 6 is selected from the group consisting of:
  • -NR 6 R 7 may be a 3- to 7-membered heterocyclic ring, where the ring consists of carbon atoms, the nitrogen atom shown, and zero, one, or two additional heteroatoms independently selected from the group consisting of -O-, -S(O) s -, wherein s is as defined above, and -NR 8 -, wherein R 8 is as defined above, which ring is unsubstituted or substituted with from one-to-six compatible radicals independently selected from the group consisting of:
  • R 399 is selected from the group consisting of:
  • each R 11 is independently -(Ci-C ⁇ -alkyl), aryl-(C ⁇ -C6- alkyl)-, or aryl;
  • (M) halogen; (II) -O(CH 2 ) m S(O) s R 12 , where m, s and R 12 are as defined above; (HI) -O(CH 2 ) j CN, where j is as defined above; (TV) -O(CH 2 ) j C( NOR 14 )R 12 , where j, R 12 and R 14 are as defined above;
  • R 2 and R 2a are independently hydrogen, halogen, or -OR 14 , wherein R 14 is as defined above, or one of R 2 and R 2 * 1 may be hydroxy, when the other of R 2 or R 21 is hydrogen, or R 2 and R 23 taken together is oxo or thiooxo;
  • R 3 and R 4 are chosen, when R 5 is hydrogen, such that one of R 3 and R 4 is hydrogen and the other is selected from hydrogen, hydroxy, -OCOR 8 , where R 8 is as defined above, or -OSi(R 11 )3, where each R 11 is independently as defined above, or one of R 3 and R 4 is joined with non-hydrogen R 5 to form a C-23/C-24 bond, with the other being hydrogen, hydroxy, -OCOR 8 , where R 8 is as defined above, or -OSi(R 11 )3, where each R 11 is independently as defined above;
  • R 5 is hydrogen, or taken together with either R 3 or R 4 , forms a C-23/C-24 bond.
  • R 1 may not be defined as, (I)-O(CH 2 )jC(O)R 20 , where j is as defined above and R 20 is selected from
  • R 21 is loweralkyl, cycloalkyl, cycloalkylalkyl or qualified- arylalkyl, where qualified-arylalkyl is defined below;
  • NR 22 R 23 is either: a nitrogen atom attached to R 22 and R 23 , where R 22 is selected from hydrogen, loweralkyl, qualified-arylalkyl, cycloalkyl and cycloalkylalkyl; and R 23 is selected from hydrogen, loweralkyl, qualified-arylalkyl, cycloalkyl, cycloalkylalkyl, aminoalkyl, hydroxyalkyl, carboxyalkyl, and thioloweralkyl; or a saturated heterocyclic ring, where taken together, R 22 and R 23 are
  • R 24 and R 25 are -(CH 2 )p-, wherein p is two to five; or ( ⁇ i) -O(CH 2 )jC(O)N(R )(CH 2 ) m CH(R 2 5)C(O)R 20 , where j, m and R 20 are as defined above and R 24 is selected from hydrogen, loweralkyl, qualified-arylalkyl, cycloalkyl and cycloalkylalkyl; and R 25 is selected from hydrogen, loweralkyl, hydroxyloweralkyl, carboxyalkyl, thioloweralkyl, thioalkoxyalkyl, guanidinoalkyl, aminoalkyl, qualified-arylalkyl and, if m is other than zero, amino or amidoalkyl; or taken together, R 24 and R 25 are -(CH 2 )p-, wherein p is two to five; or ( ⁇ i) -O(CH 2 )jC(O)N(
  • R 28 is selected from hydrogen, loweralkyl, qualified-arylalkyl, cycloalkyl and cycloalkylalkyl
  • R 29 is selected from hydrogen, loweralkyl, hydroxyloweralkyl, carboxyalkyl, thioloweralkyl, thioalkoxyalkyl, guanidinoalkyl, aminoalkyl, qualified-arylalkyl and, if m2 is other than zero, amino or amidoalkyl; or taken together, R 28 and R 29 are -(CH )p-, wherein p is as defined above.
  • n, R, R 2 , R 23 , R 3 , R 4 and R 5 are as defined above and A is selected from among: , where j, R 12 ,
  • R 13 , R 14 and R 15 are as defined above.
  • n, R, R 2 , R 2a , R 3 , R 4 and R 5 are as defined above and B is selected from:
  • n, R, R 2 , R 2 , R 3 , R 4 and R 5 are as defined above and D is selected from:
  • Preferred compounds according to the invention are the compounds of:
  • More preferred compounds according to the invention are the compounds of:
  • Acyl refers to an aryl or alkyl group, as defined below, appended to the remainder of the molecule via a carbonyl group. Examples include, but are not limited to, acetyl, pivaloyl, benzoyl, and the like.
  • Acylamino refers to an acyl group, as defined above, except that it is appended to the remainder of the molecule via an amino group. Examples include, but are not limited to, acetylamino, pivaloylamino, benzoylamino, and the like.
  • Acylguanidino refers to an acyl group, as defined above, except that it is attached to the remainder of the molecule via a nitrogen of a guanidino radical in one of three ways: HN(acyl)C(NH)NH- or H2NC(NH)N(acyl)- or (acyl)NC(NH2)HN-.
  • Alkenyl refers to straight- or branched-chain groups of a specified number of 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.
  • Alkoxy refers to an alkyl group, as defined below, attached to the remainder of the molecule through an oxygen atom. Examples include, but are not limited to, methoxy, ethoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy and the like.
  • Alkoxycarbonyl refers to an alkoxy group, as defined above, except that it is attached to the remainder of the molecule via a carbonyl group. Examples include, but are not limited to, methyloxycarbonyl, ethyloxycarbonyl, tert-butyloxycarbonyl, cyclohexyloxycarbonyl, and the like.
  • Alkoxycarbonylamino refers to an alkoxycarbonyl group, as defined above, except that it is attached to the remainder of the molecule via an amino group. Examples include, but are not limited to, methyloxy-carbonylamino, tert-butyloxycarbonylamino, and the like.
  • Alkoxycarbonylguanidino refers to an alkoxycarbonyl group, as defined above, except that it is attached to the remainder of the molecule via a nitrogen of a guanidino radical in one of three ways: HN(alkoxycarbonyl)C(NH)HN-, H 2 NC(NH)N(alkoxycarbonyl)- or (alkoxycarb ⁇ nyl)NC(NH 2 )HN-.
  • Alkyl refers to a straight- or branched-chain group of a specified number of carbon atoms including, as appropriate, but not necessarily limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like.
  • Alkylamino refers to a group having the structure -NH-(alkyl), where the alkyl portion is as defined above, including, for example, methylamino, ethylamino, isopropylamino, and the like.
  • Alkylsulfonyl refers to an alkyl group, as defined above, except that it is attached to the remainder of the molecule via a sulfur dioxide diradical. Examples include but are not limited to, methanesulfonyl, camphorsulfonyl and the like.
  • Alkylthioether and thioalkoxy refer to an alkyl group, as previously defined, except that it is attached to the remainder of the molecule via a sulfur atom. Examples include, but are not limited to, thiomethoxy, thioethoxy, thioisopropoxy, n-thiobutoxy, sec- thiobutoxy, isothiobutoxy, tert-thiobutoxy, and the like.
  • Alkynyl refers to straight- or branched-chain groups of a specified number of carbon atoms containing at least one carbon-carbon triple bond, including, but not limited to acetylenyl, propargyl, and the like.
  • “Amidoalkyl” refers to a group having the structure -NR 1 1 C(O)R 102 appended to the remainder of the molecule via an alkyl group, as previously defined, wherein R101 an d R 102 are independently hydrogen, alkyl, aryl, arylalkyl, or halosubstituted alkyl, or R 10 l and R 02 , taken together, may optionally be -(CH )aa-, where aa is an integer of from 2-to-6.
  • Aminoalkyl refers to a group having the structure -NR 0 3R104 appended to the remainder of the molecule via an alkyl group, as previously defined, wherein R103 and R 104 are independently hydrogen, alkyl, qualified-aryl or qualified-arylalkyl, or Rl°3 and R104, taken together, may optionally be -(CH 2 )bb-, where bb is an integer of from 2-to-6.
  • Aryl refers to mono-, di-, tri- or tetracyclic aromatic groups, charged or uncharged, the rings of which are comprised of from 3-to-7 carbon atoms.
  • aryl include, but are not limited to, phenyl, 1- or 2-naphthyl, azulenyl, fluorenyl, (1, 2)-dihydronaphthyl, (l,2,3,4)-tetrahydronaphthyl, indenyl, indanyl and the like, which are unsubstituted or substituted with from one, two or three independently-selected substituents, R 301 , as defined above.
  • Arylalkoxy and “arylalkylether” refer to an arylalkyl group, as defined below, attached to the parent molecular moiety through an oxygen atom. Examples include, but are not limited to, benzyloxy, 2-phenethyloxy, 1-naphthylmethyloxy, and the like.
  • Arylalkoxycarbonyl refers to an arylalkoxy group, as defined above, except that it is attached to the remainder of the molecule via a carbonyl group. Examples include, but are not limited to, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, and the like.
  • Arylalkoxycarbonylamino refers to an arylalkoxycarbonyl group, as defined above, except that it is attached to the remainder of the molecule via an amino group. Examples include, but are not Umited to, benzyloxycarbonylamino, 9- fluorenylmethyloxycarbonylamino, and the like.
  • Arylalkoxycarbonylguanidino refers to an arylalkoxycarbonyl group, as defined above, except that it is attached to the remainder of the molecule via a nitrogen of a guanidino radical in one of three ways: HN(arylalkoxycarbonyl)C(NH)HN-, H 2 NC(NH)N(arylalkoxycarbonyl)- or (arylalkoxycarbonyl)NC(NH 2 )HN-.
  • Arylalkyl refers to an aryl group, as previously defined, except that it is attached to the remainder of the molecule via an alkyl group.
  • Arylalkylamino refers to a group having the structure -NH- (arylalkyl), where the arylalkyl portion is as previously defined, except that it is attached to the remainder of the molecule via an amino group. Examples include benzylamino, 1-phenylethylamino, and the like.
  • Arylalkylthioether and “thioarylalkoxy” refer to an arylalkyl group, as previously defined, except that it is attached to the remainder of the molecule via a sulfur atom.
  • Arylamino refers to an aryl group, as defined above, except that it is attached to the remainder of the molecule via an amino group. Examples include, but are not limited to, anilino, naphthylamino, and the like.
  • Arylether and "aryloxy” refer to an aryl group, as previously defined, attached to the parent molecular moiety through an oxygen atom. Examples include, but are not limited to, phenoxy, 1-naphthoxy, 2-naphthoxy, and the like.
  • Aryloxycarbonyl refers to an aryloxygroup, as defined above, except that it is attached to the remainder of the molecule via a carbonyl group. Examples include, but are not limited to, phenyloxycarbonyl, and the like.
  • Aryloxycarbonylamino refers to an aryloxycarbonyl group, as defined above, except that it is attached to the remainder of the molecule via an amino group. Examples include, but are not Umited to, phenyloxycarbonylamino, and the like.
  • Aryloxycarbonylguanidino refers to an aryloxycarbonyl group, as defined above, except that it is attached to the remainder of the molecule via a nitrogen of a guanidino moiety in one of three ways: HN(aryloxycarbonyl)C(NH)HN-, H 2 NC(NH)N(aryloxycarbonyl)- or (aryloxycarbonyl)NC(NH 2 )HN-.
  • Arylsulfonyl refers to an aryl group, as defined above, except that it is attached to the remainder of the molecule via a sulfur dioxide group. Examples include, but are not limited to /?-toluenesulfonyl, benzenesulfonyl, and the like.
  • Arylsulfonylguanidino refers to an arylsulfonyl group, as defined above, except that it is attached to the remainder of the molecule via a guanidino group in one of three ways: HN(arylsulfonyl)C(NH)HN- or H 2 NC(NH)N(arylsulfonyl)- or (arylsulfonyl)NC(NH 2 )HN-.
  • Arylthioether and “thioaryloxy” refer to an aryl group, as defined above, except that it is attached to the remainder of the molecule via a sulfur atom.
  • Biaryl refers to a mod-aryl group, as defined below, which carries as a substituent another independently selected mod-aryl group, such that the two are connected by a single carbon-carbon bond.
  • Carboxamido refers to an amino group attached to the remainder of the molecule via a carbonyl group, and having the formula H 2 NC(O)-.
  • Carboxyalkyl refers to a carboxyl group, -CO H, appended to the remainder of the molecule via an alkyl group, as previously defined.
  • Counterion refers to a positively-charged atom or molecular species, with a net charge of +1, which includes, but is not limited to Li + , Na + , Ca(OC(O)CH 3 )+, MgCl+, K+, NH 4 + , (n-butyl) 4 N+, and the like.
  • Cycloalkenyl refers to cyclic groups of 5-to-10 carbons possessing one or more carbon-carbon double bonds including, but not limited to, cyclopentenyl, cyclohexenyl, 1,3,3-trimethylcyclohexenyl, and the like, in which the point of attachment may occur at any available valency on the carbocylic ring.
  • Cycloalkyl refers to saturated cyclic groups of 3-to-8 carbons including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • Cycloalkylalkenyl refers to cycloalkyl, as defined above, except that it is attached to the remainder of the molecule via an alkenyl group, as defined above.
  • Cycloalkylalkyl refers to a cycloalkyl group, as defined above, except that it is attached to the remainder of the molecule via an alkyl group. Examples include, but are not limited to, cyclohexylmethyl, cyclohexylethyl, and the like.
  • Cycloalkylalkynyl refers to cycloalkyl, as defined above, except that it is attached to the remainder of the molecule via an alkynyl group, as defined above.
  • Halo and halogen refer to an atom selected from fluorine, chlorine, bromine and iodine.
  • Het- refers to any aromatic 5-, 6- or 7-membered monocyclic ring or a bi- or tri-cycUc group comprising fused five- or six-membered rings having ring carbon atoms and between one and three heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein (i) each 5-membered ring has 2 double bonds and each 6- or 7- membered ring has 3 double bonds, (ii) the nitrogen and sulfur heteroatoms as well as the carbon atoms may optionally be oxidized, (iii) the nitrogen heteroatom may optionaUy be quaternized, (iv) any of these rings may be fused to a benzene ring, and (v) any carbon or heteroatom with suitable valence may bear a substituent, R 301 , as defined above.
  • Any two adjacent R 301 substituents in a di-, tri-, tetra- or penta-substituted Het group may form a 5-, 6- or 7-membered ring consisting of carbon atoms and zero, one or two heteroatoms independently selected from the group consisting of -O-, -S(O) s -, where s is as defined above, and -NR 8 -, where R 8 is as defined above.
  • Het groups include, but are not limited to, pyrrolyl, pyrazolyl, cytosinyl, thiocytosinyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, xanthenyl, xanthonyl, xanthopterinyl, oxazolyl, thiouracilyl, isoxazolyl, indolyl, quinolinyl, uracilyl, urazolyl, uricyl, thiazolyl, isothiazolyl, isoquinolinyl, thyminyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thienyl, benzothienyl, and the like.
  • Heterocyclic refers to any non- aromatic 5-, 6- or 7-membered monocyclic ring or a bi- or tri-cyclic group comprising fused five- or six-membered rings, having ring carbon atoms and between one-and-three heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein (i) each 5- membered ring has 0 or 1 double bond and each 6-membered ring has 0 to 2 double bonds, (ii) the nitrogen and sulfur heteroatoms as well as the carbon atoms may optionally be oxidized, (iii) the nitrogen heteroatom may optionally be quaternized, (iv) any of these rings may be fused to a benzene ring, and (v) any carbon or heteroatom with suitable valence may bear a substituent, R 301 , as defined above.
  • Any two adjacent R 301 substituents in a di-, tri-, tetra- or penta-substituted heterocyclic group may form a 5-, 6- or 7-membered ring consisting of ring carbon atoms and zero, one or two heteroatoms independently selected from the group consisting of -O-, -S(O) s -, where s is as defined above, and -NR 8 -, where R 8 is as defined above.
  • heterocycles include, but are not Umited to, aziridinyl, thiomorpholine, thiomorpholine-oxide, thiomorpholine dioxide, and pyrrolidinyl, pyrazolinyl, pyrazoUdinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazoUdinyl, isoxazoUdinyl, morpholinyl, thiazolidinyl, and isothiazolidinyl, and the like.
  • Heterocyclic alkyl refers to a heterocyclic group, as defined above, except that it is attached to the remainder of the molecule via an alkyl group, as previously defined.
  • HeterocycUc alkylether refers to a heterocycUc alkyl moiety, as defined above, except that it is attached to the remainder of the molecule via an oxygen atom.
  • Heterocyclic alkenyl refers to a heterocyclic group, as defined above, except that it is attached to the remainder of the molecule via an alkenyl group, as previously defined.
  • HeterocycUc alkylthioether refers to a heterocyclic alkyl moiety, as defined above, except that it is attached to the remainder of the molecule via a sulfur atom.
  • Heterocyclic alkynyl refers to a heterocyclic group, as defined above, except that it is attached to the remainder of the molecule via an alkynyl group, as previously defined.
  • Heterocyclic ether refers to a heterocyclic moiety, as defined above, except that it is attached to the remainder of the molecule via an oxygen atom.
  • Heterocyclic thioether refers to a heterocyclic moiety, as defined above, except that it is attached to the remainder of the molecule via a sulfur atom.
  • Hydroalkyl refers to an -OH appended to an alkyl group, as defined above.
  • Hydroxy-protecting group refers to those groups which are known in the art to protect a hydroxyl group against undesirable reactions during synthetic procedures and to be selectively removable including, but not Umited to, methylthiomethyl, tert- butyldimethylsilyl, tert-butyldiphenylsilyl, acyl substituted with an aryl group, where acyl and aryl are defined above, and the like.
  • Leaving group refers to an alkyl-, alkenyl-, or aryl-substituent, where alkyl, alkenyl, and aryl are as defined above, which in a reaction becomes cleaved to either produce a site of unsaturation or to introduce another substituent.
  • Mod-aryl refers to an aryl group, as defined above, except that the aryl group is unsubstituted or substituted with from one-to-three independently selected substituents, R 302 , rather than R 301 , where R 302 is as defined above.
  • Any two adjacent R 302 substituents in a di- or tri-substituted mod-aryl group may form a 5-, 6- or 7-membered carbocyclic ring or 5-, 6- or 7-membered heterocyclic-ring where the ring atoms are carbon atoms and one or two heteroatoms independently selected from the group consisting of -O-, -S(O) s -, where s is as defined above, and -NR 18 -, where R 18 is as defined above.
  • Mod-Ci-to-Cio-alkyl refers to a -(Ci-to-Cio-alkyl) group substituted with from one-to-six radicals selected from:
  • Mod-C3-to-C ⁇ o-alkenyl refers to a -(C3-to-C ⁇ o-alkenyl) group substituted with from one-to-six radicals selected from:
  • Mod-C 3 -to-C ⁇ o-alkynyl refers to a -(C3-to-C ⁇ o-alkynyl) group substituted with from one-to-six radicals selected from:
  • Mod-cyclo-C3-to-C ⁇ o-alkyl refers to a -(cyclo-C3-to-C ⁇ o-alkyl) group substituted with from one-to-six radicals selected from:
  • Mod-cyclo-C4-to-C ⁇ o-alkenyl refers to a -(cyclo-C4-to-C ⁇ o- alkenyl) group substituted with from one-to-six radicals selected from:
  • Mod-bicyclo-C6-to-C ⁇ o-alkyl refers to a -(bicyclo-C6-to-C ⁇ o-alkyl) group substituted with from one-to-six radicals selected from:
  • Mod-bicyclo-C6-to-C ⁇ o-alkenyl refers to a -(bicyclo-C6-to-C ⁇ o- alkenyl) group substituted with from one-to-six radicals selected from:
  • Mod-Het- refers to a Het group, as defined above, except that the Het group may bear one or more substituents R 302 , rather than R 301 , where R 302 is as defined above or any two adjacent R 302 substituents in a di-, tri-, tetra- or penta-substituted mod-Het group may form a 5-, 6- or 7-membered ring consisting of ring carbon atoms and zero, one or two ring heteroatoms independently selected from the group consisting of -O-, -S(O) s -, where s is as defined above, and -NR 18 -, where R 18 is as defined above.
  • Mod-heterocyclic refers to a heterocycUc group, as defined above, except that the heterocycUc group may bear one or more substituents R 302 , rather than R 301 , where R 302 is as defined above or any two adjacent R 302 substituents in a di-, tri-, tetra- or penta-substituted mod-heterocylic group may form a 5-, 6- or 7-membered ring consisting of carbon atoms and zero, one or two heteroatoms independently selected from the group consisting of -O-, -S(O) s -, where s is as defined above, and -NR 18 -, where R 18 is as defined above.
  • “Monoalkylamino” and “dialkylamino” refer respectively to one and two alkyl groups, as defined above, except that they are appended to the remainder of the molecule via an amino group. Examples include, but are not Umited to, methylamino, isopropylamino, dimethylamino, N,N-methylisopropylamino, and the like.
  • “Monocycloalkylamino” and “dicycloalkylamino” refer respectively to one and two cycloalkyl groups, as defined above, except that they are appended to the remainder of the molecule via an amino group. Examples include, but are not limited to, cyclohexylamino, b._.-(cyclohexyl)amino, and the like.
  • “Mono-halogenated alkyl”, “di-halogenated alkyl” or “tri-halogenated alkyl” refer to alkyl groups, as defined above, of specified and compatible length, respectively substituted with one, two, or three halogen atoms, as defined above.
  • N-alkylcarboxamido refers to an alkylamino group, as defined above, except that it is appended to the remainder of the molecule via a carbonyl group and has the formula HN(alkyl)C(O)-.
  • N-arylcarboxamido refers to an arylamino group, as defined above, except that it is appended to the remainder of the molecule via a carbonyl group and having the formula HN(aryl)C(O)-.
  • “Naturally occuring amino acid” and “standard amino acid” refer to an amino acid selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proUne, serine, threonine, tryptophan, tyrosine and valine.
  • N,N-dialkylcarboxamido refers to dialkylamino group, defined above, except that it is appended to the remainder of the molecule via a carbonyl group and has the formula N(alkyl)(alkyl')C(O)-.
  • N-terminal protecting group refers to those groups known in the art to protect the N-terminus against undesirable reactions during synthetic procedures or to prevent the attack of exopeptidases on the final compounds or to increase the solubility of the final compounds and includes, but is not limited to acyl, acetyl, pivaloyl, tert-butylacetyl, tert- butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), benzoyl groups, and the like. Other such groups are described by Gross, E. and Meienhofer, J. in The Peptides. Volume 3; Academic Press, 1981. "
  • Oxo refers to an oxygen atom forming a carbonyl group.
  • Per-halogenated alkyl refers to alkyl groups, as defined above, of specified length, substituted with halogen atoms, as defined above, at every available valency.
  • Qualified-aryl refers to substituted and unsubstituted carbocycUc aromatic groups including, but not Umited to, phenyl, 1- or 2-naphthyl, fluorenyl, (1,2)- dihydronaphthyl, (l,2,3 . 4)-tetrahydronaphthyl, indenyl, indanyl and the like, optionally substituted with 1, 2 or 3 substituents independently selected from halo, nitro, cyano, -(Cj-to-Cio-alkyl), alkoxy and halosubstituted alkyl.
  • Qualified-arylalkyl refers to a qualified-aryl group, as previously defined, attached to the remainder of the molecule via an alkyl group.
  • Sub-C ⁇ -to-C ⁇ o-alkyl refers to a -(C ⁇ -to-C ⁇ o-alkyl) substituted with from one-to-six radicals independently selected from the group consisting of:
  • Sub-cyclo-C3-to-C ⁇ o-alkyl refers to a -(cyclo-C3-to-C ⁇ o-alkyl) substituted with from one-to-six radicals independently selected from the group consisting of:
  • Sub-cyclo-C3-to-C ⁇ o-alkyl-C ⁇ -to-C3-alkyl refers to a -(cyclo- C 3 -to-C ⁇ o-alkyl-C ⁇ -to-C3-alkyl) substituted with from one-to-six radicals independently selected from the group consisting of:
  • Sub-C3-to-C ⁇ o-alkenyl refers to a -(C3-to-C ⁇ o-alkenyl) substituted with from one-to-six radicals independently selected from the group consisting of:
  • Sub-cyclo-C4-to-C ⁇ o-alkenyl refers to a -(cyclo- -to-Cio-alkenyl) substituted with from one-to-six radicals independently selected from the group consisting of:
  • Sub-cyclo-C6-to-C ⁇ o-alkyl-C3-C5-alkenyl refers to a -(cyclo- C6-to-C ⁇ o-alkyl-C3-C5-alkenyl) substituted with from one-to-six radicals independently selected from the group consisting of:
  • Sub-C3-to-C ⁇ o-alkynyl refers to a -(C3-to-C ⁇ o-alkynyl) substituted with from one-to-six radicals independently selected from the group consisting of:
  • Sub-cyclo-C6-to-C ⁇ o-alkyl-C3-C5-alkynyl refers to a -(cyclo- C6 ⁇ to-C ⁇ o-alkyl-C 3 -C5-alkynyl) substituted with from one-to-six radicals independently selected from the group consisting of:
  • Sub-bicyclo-C6-to-C ⁇ o-alkyl refers to a -(bicyclo-Cg-to-Cio-alkyl) substituted with from one-to-six radicals independently selected from the group consisting of:
  • Sub-bicyclo-Cg-to-Cio-alkenyl refers to a -(bicyclo-Cg-to- o- alkenyl) substituted with from one-to-six radicals independently selected from the group consisting of:
  • Substituted-bicyclo-C6-to-C ⁇ o-alkyl refers to a -(bicyclo-C6-to-C ⁇ o- alkyl) group substituted with from one-to- three radicals selected from: halogen; -OH; (C ⁇ -C 6 -alkyl)NH-; di(C ⁇ -C 6 -alkyl)N-; -CO 2 H; -CONH 2 ; -SH; (C ⁇ -C6-alkyl)S-; (C ⁇ -C6-alkyl)O-; (C ⁇ -C 6 -alkyl)OC(O)-;mod-aryl-(C ⁇ -C 6 - alkyl)OC(O)-; (C ⁇ -C 6 -alkyl)OC(O)NH-; (C ⁇ -C 6 -alkyl)C(O)NH-; mod-aryl- (C ⁇ -C 6 -a_kyl)OC(O)NH—; halogen;
  • Substituted-C3-to-C6-alkenyl refers to a -(C3-to-C6-alkenyl) group substituted with from one-to-three radicals selected from: halogen; -OH; (C ⁇ -C 6 -alkyl)NH-; di(C ⁇ -C6-alkyl)N-; -CO 2 H; -CONH 2 ; -SH; (C ⁇ -C 6 -alkyl)S-; (C ⁇ -C 6 -alkyl)O-; (C ⁇ -C6-alkyl)OC(O)-;mod-aryl-(C ⁇ -C6- alkyl)OC(O)-; (C ⁇ -C 6 -alkyl)OC(O)NH-; (C ⁇ -C 6 -alkyl)C(O)NH-; mod-aryl- (C ⁇ -C6-alkyl)OC(O)NH-; mod-aryl- (C ⁇ -C6-alkyl
  • Substituted-C ⁇ -to-C6-alkyl refers to a -(Ci-to- -alkyl) group substituted with from one-to-three radicals selected from: halogen; -OH; (C ⁇ -C 6 -alkyl)NH-; di(C ⁇ -C 6 -alkyl)N-; -CO 2 H; -CONH 2 ; -SH; (C ⁇ -C6-alkyl)S-; (C ⁇ -C6-alkyl)O-; (C ⁇ -C6-alkyl)OC(O)-;mod-aryl-(C ⁇ -C 6 - alkyl)OC(O)-; (C ⁇ -C 6 -alkyl)OC(O)NH-; (C ⁇ -C 6 -alkyl)C(O)NH-; mod-aryl- (C ⁇ -C 6 -alkyl)OC(O)NH-; mod-aryl- (C ⁇ -C 6 -alkyl)
  • Substituted-C3-to-C6-alkynyl refers to a -(C3-to-C6-alkynyl) group substituted with from one-to-three radicals selected from: halogen; -OH; (C ⁇ - -alkyl)NH-; di(C ⁇ -C 6 -alkyl)N-; -CO 2 H; -CONH 2 ; -SH; (C ⁇ -C 6 -alkyl)S-; (C ⁇ -C 6 -alkyl)O-; (C ⁇ -C 6 -alkyl)OC(O)-;mod-aryl-(C ⁇ -C 6 - alkyl)OC(O)-; (C ⁇ -C 6 -alkyl)OC(O)NH-; (C ⁇ -C 6 -alkyl)C(O)NH-; mod-aryl- (C ⁇ -C 6 -alkyl)OC(O)NH-; mod-aryl- (C ⁇ -C 6
  • Substituted-cyclo-C4-to-C ⁇ o-alkenyl refers to a -(cyclo-C4-to-C ⁇ o- alkenyl) group substituted with from one-to-three radicals selected from: halogen; -OH; (C ⁇ -C 6 -alkyl)NH-; di(C ⁇ -C6-alkyl)N-; -CO 2 H; -CONH 2 ; -SH; (C ⁇ -C6-alkyl)S-; (C ⁇ -C6-alkyl)O-; (C ⁇ -C 6 -alkyl)OC(O)-;mod-aryl-(C ⁇ -C 6 - alkyl)OC(O)-; (C ⁇ -C 6 -alkyl)OC(O)NH-; (C ⁇ -C 6 -alkyl)C(O)NH-; mod-aryl- (C ⁇ -C 6 -alkyl)OC(O)NH-;
  • Substituted-cyclo-C3-to-C ⁇ o-alkyl refers to a -(cyclo-C3-to-C ⁇ o- alkyl) group substituted with from one-to-three radicals selected from: halogen; -OH; (C ⁇ -C 6 -alkyl)NH-; di(C ⁇ -C6-alkyl)N-; -CO 2 H; -CONH 2 ; -SH;
  • Substituted-bicyclo-C6-to-C ⁇ o-alkenyl-C ⁇ -to-C6-alkyl refers to a -(bicyclo-C6-to-C ⁇ o-alkenyl)-C ⁇ -to-C6-alkyl group substituted with from one-to-three radicals selected from: halogen; -OH; (C ⁇ -C 6 -alkyl)NH-; di(C ⁇ -C6-alkyl)N-; -CO 2 H; -CONH 2 ; -SH; (C ⁇ -C 6 -alkyl)S-; (C ⁇ -C 6 -alkyl)O-; (C ⁇ -C 6 -alkyl)OC(O)-;mod-aryl-(C ⁇ -C 6 - alkyl)OC(O)-; (C ⁇ -C 6 -alkyl)OC(O)NH-; (C ⁇ -C 6 -alkyl)C(O
  • “Thiolalkyl” refers to an alkyl group, as defined above, substituted with an -SH group.
  • Thiooxo refers to a sulfur atom forming a thiocarbonyl group.
  • Unsubstituted aryl refers to mono-, di-, tri- or tetracyclic aromatic groups, charged or uncharged, the rings of which are comprised of from 3-to-7 carbon atoms. Examples of unsubstituted aryl include, but are not Umited to, phenyl, 1- or 2-naphthyl, azulenyl, fluorenyl, (1, 2)-dihydronaphthyl, (l,2,3 . 4)-tetrahydronaphthyl, indenyl, indanyl and the like, which are solely substituted by hydrogen.
  • “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 amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like (see, for example S. M. Berge, et al., "Pharmaceutical Salts.” J. Pharm. Sci. 66: 1-19 (1977)).
  • esters of the compounds of this invention examples include C ⁇ -to-C6-alkyl esters wherein the alkyl group is a straight or branched chain. Acceptable esters also include Cs-to-C ⁇ -cycloalkyl esters as well as arylalkyl esters such as, but not Umited to benzyl. C ⁇ -to-C4 alkyl esters are prefe ⁇ ed. 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 C ⁇ -to-C6-alkyl carboxylic acids, C ⁇ -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 C ⁇ -to-C6- alkyl amines and secondary di-C ⁇ -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, C ⁇ -to-C3-alkyl primary amides and di-C ⁇ -to-C 2 -alkyl secondary amides are prefe ⁇ ed. 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 V. Stella, "Pro-drugs as Novel DeUvery Systems", Vol 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
  • Prodrugs of compounds of the present invention may be prepared by suitable methods.
  • 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, N-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(NO2)), 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- nitrophenylsulf
  • 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-methoxybenzenesulfonyl, 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
  • 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, antunflammatory, and antiproliferative activity, and possess the abiUty to reverse chemotherapeutic drug resistance.
  • the compounds are useful as prophylactics for the prevention of HIV replication.
  • 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 meduUa ossium transplantation.
  • the regulation of the immune response by the compounds of the invention would also find utility in the treatment of autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes, uveitis, allergic encephalomyeutis, glomerulonephritis, and the like; and further infectious diseases caused by pathogenic microorganisms, such as HIV.
  • autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes, uveitis, allergic encephalomyeutis, glomerulonephritis, and the like
  • infectious diseases caused by pathogenic microorganisms, such as HIV.
  • pathogenic microorganisms such as HIV.
  • inhibition of T-cell mitosis would suppress
  • 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, sebo ⁇ hoeis dermatitis, Lichen planus, Pemphigus, bullous pemphigoid, Epidermolysis bullosa, urticaria, angioedemas, vasculitides, erythemas, cutaneous eosinophilias, Lupus erythematosus, acne, diseases or syndromes resulting in hair loss including but not limited to Alopecia areata.
  • immunologically-mediated illnesses such as psoriasis, atopical dermatitis, contact dermatitis and further eczematous dermatitises, sebo ⁇ hoeis dermatitis, Lichen planus, Pemphigus, bullous
  • a compound of the invention would be useful include various eye diseases (autoimmune and otherwise) such as keratoconjunctivitis, vernal conjunctivitis, keratitis, herpetic keratitis, conical cornea, dystrophia epithelialis comeae, corneal leukoma, ocular pemphigus, Mooren's ulcer, Scleritis, Graves' opthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, etc.; reversible obstructive airway disease, which includes conditions such as asthma (for example, bronchial asthma, aUergic asthma, intrinsic asthma, extrinsic asthma and dust asthma), particularly chronic or inveterate asthma (for example, late asthma and airway hyper-responsiveness), bronchitis and the like; inflammation of mucosa and blood vessels such as gastric ulcers, vascular damage caused by ischemic diseases and thrombosis.
  • hyperproU stea
  • Other treatable conditions would include but are not Umited to ischemic bowel diseases, inflammatory bowel diseases, necrotizing enterocolitis, intestinal lesions associated with thermal burns and leukotriene B4-mediated diseases; intestinal inflammations/allergies such as Coeliac diseases, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease and ulcerative coUtis; food-related aUergic diseases which have symptomatic manifestation remote from the gastro-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-Barre syndrome, Meniere's disease, polyneuritis, multiple neuritis, mononeuritis and radiculopathy; endocrine diseases such as hyperthyroidism and Basedow's disease; he
  • 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 ci ⁇ hosis 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 ci ⁇ hosis) and hepatic failure such as fulminant hepatic failure, late-onset hepatic failure and "acute-on-chronic" liver failure (acute Uver failure on chronic liver diseases), and moreover are useful for various diseases because of their useful activity such as augmention of chemotherapeutic effect, preventing or treating activity of cytomegalovirus infection, particularly HCMV infection, anti-inflammatory activity, and so on.
  • some compounds also possess FK-506 antagonistic properties, and are thus useful in the treatment of immunodepression or a disorder involving immunodepression.
  • disorders involving immunodepression include AIDS, cancer, senile dementia, trauma (including wound heaUng, 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-l l,28-dioxa-4-azatricyclo[22.3.1.0 4 ' 9 ] octacos-18-ene such as FK-506, or rapamycin. Overdosing of such medicants by patients is quite common upon their reaUzing that they have forgotten to take their medication at the prescribed time and can lead to serious side effects.
  • a further situation in which the compounds of the present invention may be used to treat immunosuppression is in vaccination. It is sometimes found that the antigen introduced into the body for the acquisition of immunity from disease also acts as an immunosuppressive agent, and therefore antibodies are not produced by the body and immunity is not acquired. By introducing a compound of the present invention into the body (as in a vaccine), the undesired immunosuppression may be overcome and immunity acquired.
  • the compounds of the present invention may also find utility in the chemosensitization of drug resistant target cells.
  • Cyclosporin A and FK-506 are known to be effective modulators of P-glycoprotein, a substance which binds to and inhibits the action of anticancer drugs; by inhibiting P-glycoprotein, they are capable of increasing the sensitivity of multidrug resistant (MDR) ceUs to chemotherapeutic agents.
  • MDR multidrug resistant
  • the compounds of the invention may likewise be effective at overcoming resistance expressed to clinically useful antitumour drugs such as 5-fluorouracil, cisplatin, methotrexat ⁇ , vincristine, vinblastine and adriamycin, colchicine and vincristine.
  • the steroid receptor-associated heat shock proteins hsp56 or hsp59, belong to the FK506 family of immunophiUn proteins.
  • the ability of a steroid receptor-associated heat shock protein to bind the immunosuppressive macrolide FK506 may suggest that the steroid receptor and immunophi n signal transduction pathways are functionally interrelated.
  • the combined treatment of compounds of the present invention and low concentrations of a steroid Ugand eg. progesterone, dexamethasone
  • the compounds of the present invention may potentiate steroid-mediated transactivation.
  • Aqueous liquid compositions of the present invention may be particularly useful for the treatment and prevention of various diseases of the eye such as autoimmune diseases (including, for example, conical cornea, keratitis, dysophia epithelialis corneae, leukoma, Mooren's ulcer, sclevitis and Graves' ophthalmopathy) and rejection of corneal transplantation.
  • autoimmune diseases including, for example, conical cornea, keratitis, dysophia epithelialis corneae, leukoma, Mooren's ulcer, sclevitis and Graves' ophthalmopathy
  • a therapeutically-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 pharmaceuticaUy - acceptable excipients. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgement.
  • the specific therapeuticaUy-effective dose level for any particular patient wUl depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the 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 the skill of the art to start doses of the compound at levels lower than required to achieve the desired therapeutic 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 the 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; consequently, 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 earner or excipient, meaning a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type, which may be administered orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, drops or transdermal patch), bucally, or as an oral or nasal spray.
  • parenteral refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.
  • compositions of this invention for parenteral injection comprise pharmaceuticaUy-acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as weU as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • suitable aqueous and nonaqueous earners, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), carboxymethylceUulose 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 the 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.
  • adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents.
  • the absorption of the drug 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 the use of a Uquid 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. Alternatively, 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 controUed. 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 steriUzed, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile soUd 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, piUs, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically-acceptable excipient or earner, such as sodium citrate or dicalcium phosphate and/or a) fiUers or extenders such as starches, lactose, sucrose, glucose, mannitol, and siUcic acid, b) binders such as, for example, carboxymethylceUulose, 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 sUicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as
  • compositions of a similar type may also be employed as fillers in soft and hard- fiUed 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 they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of 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 administration include pharmaceutically-acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • the Uquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubiUzing 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, oUs (in particular, cottonseed, groundnut, corn, germ, oUve, castor, and sesame oUs), glycerol, tetrahydrofurfuryl 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,
  • 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 thereof.
  • Topical administration includes administration to the skin or mucosa, including surfaces of the lung and eye.
  • Compositions for topical administration, including those for inhalation, 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 in diameter.
  • Suitable inert earners 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 propeUant.
  • a compressed gas such as nitrogen or a liquified gas propeUant.
  • the Uquified propeUant 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 Uquid or soUd non-ionic surface active agent or may be a solid anionic surface active agent. It is prefe ⁇ ed to use the 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 the invention is deUvered in a pharmaceuticaUy acceptable ophthalmic vehicle, such that the compound is maintained in contact with the 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/diary, lens, choroid/retina and sclera.
  • the pharmaceuticaUy-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 with suitable non-irritating excipients or earners such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but Uquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or earners such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but Uquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Liposomes are generally derived from phosphoUpids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated Uquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically-acceptable and metaboUzable lipid capable of forming liposomes can be used.
  • the present compositions in liposome form can contain, in addition to a compound of the present invention, stabiUzers, preservatives, excipients, and the like.
  • the prefe ⁇ ed lipids are the phosphoUpids and the phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.
  • 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 avaUable 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 CoUection Intemational 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 . Antibiot., 1988. XLI(ll), 1586-1591; (ii) H. Hatanaka, T. Kino, S. Miyata, N. Inamura, A. Kuroda, T. Goto, H. Tanaka and M.
  • Such processes comprise:
  • suitable reagents for activation of an alcohol include acetic anhydride, trifluoromethanesulfonic anhydride (triflic anhydride), methanesulfonyl chloride (mesyl chloride), /.-toluenesulfonyl chloride (tosyl chloride), trifluoroacetic anhydride, trifluoroacetyl chloride, methoxysulfonyl fluoride (magic methyl), o-nitrobenzenesulfonyl chloride, l-methyl-2-fluoropyridinium salt and the like.
  • the activation may be carried out in a solvent which does not adversely affect the reaction (e.g., diethylether, dichloromethane, tetrahydrofuran, chloroform or NN- dimethylformamide or a mixture thereof).
  • the reaction may require cooling or heating, depending on the activation method chosen.
  • the reaction is preferably conducted in the presence of an organic or inorganic base such as an alkaUne earth metal (e.g. calcium, etc.), alkali metal hydride (e.g. sodium hydride, etc.), alkaU metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), alkaU metal carbonate (e.g.
  • alkaU metal hydrogen carbonate e.g. sodium hydrogen carbonate, potassium hydrogen carbonate, etc.
  • alkaU metal alkoxide e.g. sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.
  • alkali metal alkanoic acid e.g. sodium acetate, etc.
  • tiialkylamine e.g. triethylamine, etc.
  • pyridine compounds e.g. pyridine, lutidine, picoline, 4-N,N-dimethylaminopyridine, etc.
  • quinoline preferably in the presence of organic bases such as triethylamine or pyridine.
  • the activation may also be ca ⁇ ied out using a starting material having an opposite configuration at a carbon center.
  • the following two additional steps are required to yield a starting material having an epimeric hydroxyl moiety, i.e. (1) the alcohol is oxidized to its co ⁇ esponding ketone, (2) the obtained ketone is reduced under selective conditions.
  • Both chiral centers having either [Rj- or [S] -configuration can be obtained selectively and separately.
  • suitable azide reagents include well-estabUshed alkali metal azides such as sodium or Uthium azides (NaN3 or L1N3) in the presence or absence of crown ethers, more reactive tetraalkylammonium azides (Danishefski, S. J.; DeNinno, M. P.; Chen, S.-H. J. Am. Chem. Soc. 1988, 110, 3929), tetramethylguanidinium azide, (Papa, A. J. J. Org. Chem. 1966, 31, 1426), a copper-assisted azide reaction (Yamamoto, Y.; Asao, N. /. Org. Chem.
  • the azide displacement reaction may be ca ⁇ ied out in a solvent which does not adversely affect the reaction (e.g. chloroform, dichloromethane, tetrahydrofuran, pyridine, dimethylsulfoxide, NN-dimethylformamide, hexamethylphosphoramide, etc. or a mixture thereof).
  • the reaction may be conducted above, at, or below ambient temperature.
  • the reduction may be carried out catalytically using hydrogen.
  • Suitable catalysts include, but are not limited to platinum catalysts (e.g. platinum oxide, platinum black), palladium catalysts (e.g. palladium oxide, paUadium on charcoal, palladium black, palladium hydroxide on charcoal, palladium on calcium carbonate poisoned with lead, palladium on barium carbonate with quinoline), nickel catalysts (e.g. nickel oxide, Raney nickel), rhodium catalysts (e.g. rhodium on alumina). Reduction may also be carried out using metal reducing reagents (see Review; Scriven, E. F. V.; Turnbull, K. Chem Rev.
  • the reduction may be carried out in a solvent which does not adversely affect the reaction (e.g., alcohols, water, acetone, dichloromethane, tetrahydrofuran, pyridine or NN- dimethylformamide or a mixture thereof).
  • a solvent which does not adversely affect the reaction
  • the reaction may be conducted above, at, or below ambient temperature.
  • suitable N-acylations may be carried out using the methods of symmetric carboxylic acid anhydrides, carboxylic acid halides, mixed carbonic-carboxylic anhydrides, active esters (p-nitrophenylester, trichlorophenyl ester, pentafluorophenyl ester, N-hydroxysuccinimide, cyanoethyl, 2,2,2-trichloroethyl and the like), and carboxylic acid with suitable condensing reagents such as DCC (N,N-dicyclohexylcarbodiimide and its related condensing agents), DCC-HOBt (NN-dicyclohexylcarbodiimide-1- hydroxybenzotriazole), Woodward reagent K method, NJV-carbonyldiimidazole and phosphonium containing reagents (e.g.
  • Suitable reagents for amide formation include, but are not limited to formyl derivatives, acetyl halides (chloroacetyl, trichloroacetyl, ⁇ -nitrophenylacetyl, o-nitrophenoxyacetyl, acetoacetyl, [N'-dithiobenzyloxycarbonylaminojacetyl and the like), and substituted propionyl derivatives (3-phenylpropionyl, isobutyryl, picoUnoyl, and the like).
  • Other groups may be found in volume 3 of The Peptides Gross, E. and Meinhofer, J. Academic Press, 1981 and Protective Groups in Organic Synthesis Greene, T. W.
  • the N-acylation may be carried out in a solvent which does not adversely affect the reaction (e.g. acetone, dichloromethane, chloroform, tetrahydrofuran, NN-dimethylformamide, dimethylsulf oxide, diethylether, and the like, or a mixture thereof).
  • a solvent which does not adversely affect the reaction (e.g. acetone, dichloromethane, chloroform, tetrahydrofuran, NN-dimethylformamide, dimethylsulf oxide, diethylether, and the like, or a mixture thereof).
  • the reaction may be conducted above, at, or below ambient temperature.
  • metal salts may be formed from the desired amines and then condensed with an ester which may or may not be activated.
  • salts may be formed by treatment of the neutral amine with trialkylaluminums (See J. I. Levin, E. Turos, S. M. Weinreb Synthetic Communications 1982, 12, 989-93), Sn[ ⁇ (Si(CH 3 ) 3 )] 2 (See W. Wang, E. J. Roskamp /. Org. Chem. 1992, 57, 6101-3), or grignard reagents. For other methods see A. SoUadie-Cavallo, M. Bencheqroun J. Org. Chem. 1992, 57, 5831-4 as well as footnotes 2, 3, 4, 5, 6 and 7 therein.
  • N-alkylations may be carried out using aldehydes or ketones-foUowed by reduction of the initiaUy formed iminium ion ⁇
  • the following reagents can be used for the reduction; sodium cyanoborohydride-boron trifluoride or the reducing reagents cited in process (c) ⁇ , co ⁇ esponding halides in the presence of bases Usted in process (a), or lithium dialkyl cuprate (King, F. E.; King, T. J.; Muir, I. H. M. J. Chem. Soc. 1946, 5; Yamamoto, H.; Maruoka, K. J. Org. Chem. 1980, 45, 2739).
  • Suitable reagents for N-alkylation include, but are not Umited to benzyl halide, 3,4-dimethoxybenzyl haUde, nitrobenzyl halide, di(p- methoxyphenyl)methyl halide, triphenylmethyl halide, and the like.
  • Other groups may be found in volume 3 of The Peptides, Gross, E. and Meinhofer, J. Academic Press, 1981 and Protective Groups in Organic Synthesis, Greene, T. W. John Wiley & Sons, New York, Chapter 7, 1981.
  • the N-alkylation may be ca ⁇ ied out in a solvent which does not adversely affect the reaction (e.g., acetone, dichloromethane, tetrahydrofuran, pyridine or NN- dimethylformamide or a mixture thereof).
  • the reaction may be conducted above, at, or below ambient temperature.
  • urea formation may be ca ⁇ ied out from the following reactions; reaction with silicon tetraisocyanate or sUicon tetraisothiocyanate (NeviUe, R. G.; McGee, J. J. Can. J. Chem.
  • reaction with NN-carbonyldiimidazole or NN- thiocarbonyldiimidazole foUowed by N-substituted primary or secondary amines or ammonia (Staab, H. A.; Wendel, K. Org. Synth. 1968, 48, 44), and reaction with phosgene or thiophosgene in the presence of tert-amine, followed by N-substituted primary or secondary amines or ammonia.
  • the ureido formation may be carried out in a solvent which does not adversely affect the reaction (e.g. acetone, toluene, dichloromethane, tetrahydrofuran, pyridine, NN-dimethylformamide, etc. or a mixture thereof).
  • the reaction may be conducted above, at, or below ambient temperature.
  • urea formation may be ca ⁇ ied out by first forming an acyl azide by activating a carboxyUc acid in the molecule with a chloroformate, such as isobutyl chloroformate, in the presence of a tertiary amine, such as ⁇ -methyl-morpholine or ⁇ - methyl-piperidine, and treating with an azide source, such as sodium azide, hydrazoic acid, trimethylsilylazide, or tetramethylguanidinium azide.
  • the acyl azide may also be formed directly using diphenylphophorylazide in the presence of a tertiary amine.
  • the reaction mixture is then heated at from 40 °C to 100 °C for 0.5 to 6 hours, whereupon the amine H ⁇ R 14 R 15 is added at a temperature at from 23 °C to 100 °C.
  • the reaction is conducted in an inert organic solvent such as diethyl ether, tetrahydrofuran, 1,4-dioxane, chloroform, methylene chloride, benzene, or toluene.
  • N-sulfonylation may be ca ⁇ ied out using substituted sulfonylhaUdes in the presence of suitable tert-amines such as tiialkylamine, pyridine, and the like (Remers, W. A.; Roth, R. H.; Gibs, G. J.; Weiss, M. J. J. Org. Chem. 1971, 36, 1232).
  • suitable tert-amines such as tiialkylamine, pyridine, and the like
  • Suitable reagents include, but are not Umited to benzenesulf onyl haUde, p-methyoxybenzenesulf onyl haUde, 2,4,6-trimethylbenzenesulf onyl haUde, toluenesulfonyl haUde, benzylsulf onyl halide, p- methoxybenzylsulfonyl haUde, trifluoromethylsulfonyl haUde, phenacylsulfonyl halide, and the like. Some other representative groups may be found in volume 3 of The Peptides, Gross, E. and Meinhofer, J.
  • N-aryl- or -dkylsulfonylation may be carried out in a solvent which does not adversely affect the reaction (e.g., acetone, dichloromethane, tetrahydrofuran, pyridine or NN- dimethylformamide or a mixture thereof).
  • the reaction may be conducted above, at, or below ambient temperature.
  • N-carbamate formations may be ca ⁇ ied out using common protecting groups for amino group such as, but not Umited to methylcarbamates (cyclopropylmethyl, 9- fluorenylmethyl, and the like), substituted ethylcarbamates (2,2,2-trichloroethyl, 2- phosphonoethyl, 2-methylthioethyl, and the like), substituted propyl and isopropylcarbamates (1,1-dimethylpropynyl, 1 -methyl- l-(4-biphenylyl)ethyl, tert-butyl, phenyl, p-nitrobenzyl, 8- quinolyl, N-hydroxypiperidinyl, benzyl, dimethoxybenzyl, 9-anthrylmethyl, 1-adamantyl, cyclohexyl, tert-amyl, cinnamoyl, isobutyl, N'-p-
  • N-carbamates and other groups may be found in volume 3 of The Peptides, Gross, E. and Meinhofer, J. Academic Press, 1981 and Protective Groups in Organic Synthesis, Greene, T. W. John Wiley & Sons, New York, Chapter 7, 1981.
  • the N-carbamate formation may be carried out in a solvent which does not adversely affect the reaction (e.g., acetone, dichloromethane, tetrahydrofuran, pyridine or NN-dimethylformamide or a mixture thereof).
  • the reaction may be conducted above, at, or below ambient temperature.
  • N-guanidium formation may be ca ⁇ ied out using several common reagents such as l-guanyl-3,5-dimethylpyrazole (Salvadori, S.; Sarto, G. P.; Tomatis, R. Eur. J. Med. Chem. Chim. Ther. 1983, 18, 489), O-methylisourea (Van ⁇ ispen, J. W.; Tesser, G. I.; ⁇ ivard, R. J. F. Int. J. Peptide Protein Res. 1977, 9, 193), and thiourea sulf onylate (Maryanoff, C. A.; Stanzione, R. C; Plampin, J.
  • the N-guanidinium formation may be carried out in a solvent which does not adversely affect the reaction (e.g., acetone, dichloromethane, tetrahydrofuran, pyridine or NN-dimethylformamide or a mixture thereof).
  • the reaction may be conducted above, at, or below ambient temperature.
  • N-sulfenamides may be prepared from an amine and a sulfenyl halide (Davis, F. A.; Nadir, U. K. Org. Prep. Proc. Int. 1979, 11, 33; Kobayashi, T.; lino, K.; Hiraoka, T. /. Am. Chem. Soc. 1977, 99, 5505; Zervas, L.; Borovas, D.; Gazis, E. J. Am. Chem. Soc. 1963, 85, 3660).
  • Suitable reagents include, but are not Umited to benzenesulfenyl halide, o-nitrobenzenesulfenyl halide, 2,4-dinitrosulfenyl halide, pentachlorobenzenesulfenyl halide, 2-nitro-4-methoxybenzenesulfenyl halide, triphenylmethylsulfenyl hatide, and the like.
  • Other groups may be found in volume 3 of The Peptides, Gross, E. and Meinhofer, J. Academic Press, 1981 and Protective Groups in Organic Synthesis, Greene, T. W. John Wiley & Sons, New York, Chapter 7, 1981.
  • the N-sulfenylation may be carried out in a solvent which does not adversely affect the reaction (e.g., acetone, dichloromethane, tetrahydrofuran, pyridine or NN-dimethylformamide or a mixture thereof).
  • a solvent which does not adversely affect the reaction
  • the reaction may be conducted above, at, or below ambient temperature.
  • suitable halogenation reagents include, but are not Umited to triphenylphosphine with halogens (Verheyden, J. P. H.; Moffatt, J. G. /. Am. Chem. Soc. 1964, 86, 2093; Bergman, R. G. ibid., 1969, 91, 7405; Hrubiec, R. T.; Smith, M. B. /. Org. Chem., 1983, 48, 3667), triphenylphosphine with cyanogen halides (Homer, L.; Oediger, H.; Hoffmann, H. Annalen Chem.
  • halogenation may also be accompUshed by other reagents such as mono- or tri-alkylsUyl halides with or without sodium halides (Olah, G. A.; Husain, A.; Singh, B. P.; Mehrota, A. K. /. Org. Chem. 1983, 48, 3667; Balme, G.; Fournet, G.; Gore, J. Tetrahedron Lett.
  • the halogenation may be ca ⁇ ied out in a solvent which does not adversely affect the reaction (e.g., acetone, dichloromethane, tetrahydrofuran, pyridine or NN- dimethylformamide or a mixture thereof).
  • a solvent which does not adversely affect the reaction
  • the reaction may be conducted above, at, or below ambient temperature.
  • phosphonic acid ester formation may be ca ⁇ ied out using Michaelis- Arbuzov reactions (Bhattacharya, A. K.; Thyagarajan, G. Chem. Rev. 1981, 81, 415; Bauer, G.; Haegele, G. Angew. Chem. Int. Ed. Engl. 1977, 16, 477).
  • the phosphonic acid ester formation may be carried out in a solvent which does not adversely affect the reaction (e.g., acetone, dichloromethane, tetrahydrofuran, pyridine or NN-dimethylformamide or a mixture thereof).
  • a solvent which does not adversely affect the reaction e.g., acetone, dichloromethane, tetrahydrofuran, pyridine or NN-dimethylformamide or a mixture thereof.
  • the reaction may be conducted above, at, or below ambient temperature.
  • phosphorylation may be carried out using, but is not Umited to the 2- halo-2-oxo- 1, 3, 2-dioxaphospholane-triethylamine reaction (Chandrarakumar, ⁇ . S.; Hajdu, J. J. Org. Chem. 1983, 48, 1197).
  • the phosphorylation may be carried out in a solvent which does not adversely affect the reaction (e.g., benzene, toluene, acetone, dichloromethane, tetrahydrofuran or N,N-dimethylformamide or a mixture thereof).
  • reaction is preferably conducted in the presence of organic or inorganic bases, as described in process (a), preferably in the presence of organic bases such as triethylamine, pyridine etc.
  • organic bases such as triethylamine, pyridine etc.
  • the reaction may be conducted above, at, or below ambient temperature, more preferably from 0 to 50 °C.
  • thioether formation may be ca ⁇ ied out using, but is not limited to aryl- or alkylmercaptan in the presence of suitable tert-amines such as tiialkylamine, pyridine, and the like.
  • the reaction may also be carried out by a metal-catalyzed thioether formation (Guindon, Y; Frenette, R; Fortin, R.; Rokach, J. J. Org. Chem. 1983, 48, 1357), alkali metal salts of aryl- or alkylmercaptans with a compound of formula I which contains CH-OLg group (OLg is the leaving group).
  • the alkali metal may be selected from sodium, potassium, lithium, and cesium.
  • the thioether formation may be ca ⁇ ied out in a solvent which does not adversely affect the reaction (e.g. acetone, dichloromethane, tetrahydrofuran, pyridine, NN- dimethylformamide, etc. or a mixture thereof).
  • a solvent which does not adversely affect the reaction (e.g. acetone, dichloromethane, tetrahydrofuran, pyridine, NN- dimethylformamide, etc. or a mixture thereof).
  • the reaction may be conducted above, at, or below ambient temperature.
  • aryl- or alkyloxythiocarbonylation may be carried out using aryl- or alkyloxythiocarbonylchloride or co ⁇ esponding halides in the presence of suitable tert-amines such as tiialkylamine, pyridine, and the like.
  • suitable tert-amines such as tiialkylamine, pyridine, and the like.
  • the aryl- or alkylthiocarbonylation may be ca ⁇ ied out in a solvent which does not adversely affect the reaction (e.g. acetone, dichloromethane, tetrahydrofuran, pyridine, NN-dimethylformamide etc. or a mixture thereof).
  • the reaction may be conducted above, at, or below ambient temperature.
  • ether formation may be ca ⁇ ied out using, for example, aryl-, arylalkyl- , (heterocyclic)alkyl-, (heterocyclic)alkenyl-, (heterocyclic)alkynyl-, loweralkoxycarbonylalkyl-, arylalkoxycarbonylalkyl-, arylalkylcarbonylalkyl-, trialkylsilylcarbonylalkyl-, trialkyl-stannylcarbonylalkyl-, amidocarbonylalkyl-, alkylamidocarbonylalkyl-, dialkylamido-carbonylalkyl-, arylamidocarbonylalkyl-, alkylamidocarbonylalkyl-, heterocyclicamido-carbonylalkyl-, heterocycUc or alkylhalides in the presence of KY-zeoUte (Onaka, M.; Kawai, M.
  • the ether formation may also be carried out with dialkyl- or diarylphosphoric acid in the presence of p-toluenesulfonic acid (Kashman, Y. J. Org. Chem. 1972, 37, 912), with diazo compounds with tin(E) chloride (Christensen, L. F.; Broom, A. D. J. Org. Chem. 1972, 37, 3398), or with 2,2,2-trichloroalkanols in the presence of base (Corey, E. J.; Link, J. O.
  • ether formation may be accomplished with a suitable trichloroacetimidate in the presence of an acid catalyst (Wessel, H. P.; Iversen, T.; Bundle, D. R. J. Chem. Soc. Perk Trans. 1985, 7, 2247.)
  • the ether formation may be carried out in a solvent which does not adversely affect the reaction (e.g. acetone, dichloromethane, tetrahydrofuran, pyridine, NN-dimethylformamide, ether, cyclohexane, etc. or a mixture thereof).
  • the reaction may be conducted above, at, or below ambient temperature. More specifically, O-alkylation may be carried out using bromoacetic acid derivatives, iodoacetic acid derivatives, trifluoromethanesulfonyloxy acetic acid derivatives, chloro- bromo- or iodomethanesulfonic acid derivatives, chloro- bromo- or iodoacetyltrimethylsUane and the like in the presence of an appropriate base such as triethylamine, potassium fluoride or silver(I) oxide.
  • the reaction is performed in an inert solvent such as N,N-dimethylformamide, acetonitrile or dichloromethane, preferably between -50 °C and 80 °C.
  • alkylation can be carried out using alkyl-, or arylalkyl- diazoacetates in the presence of a metal catalyst, for example Rh(OAc) 2 in an inert solvent such as dichloromethane preferably between -20 °C and 80 °C.
  • a metal catalyst for example Rh(OAc) 2 in an inert solvent such as dichloromethane preferably between -20 °C and 80 °C.
  • N-cyclic imide formations may be carried out using phthalic anhydride (Sasaki, T.; Minamoto, K.; Itoh, H. J. Org. Chem. 1978, 43, 2320), o -methoxycarbonyl- benzoyl chloride with trialkylamine (Hoogwater, D. A.; Reinhoudt, D. ⁇ .; Lie, T. S.; Gunneweg, J. J.; Beyerman, H. C. Reel. Trav. Chim. Pays-Bas. 1973, 92, 819), orN- ethoxycarbonylphthalimide ( ⁇ efkens, G. H. L.; Tesser, G.
  • N- cyclic imide formation may be ca ⁇ ied out in a solvent which does not adversely affect the reaction (e.g. acetone, dichloromethane, tetrahydrofuran, pyridine, NN-dimethylformamide, etc. or a mixture thereof).
  • the reaction may be conducted above, at, or below ambient temperature.
  • deoxygenation may be carried out using, but is not Umited to phenoxythiocarbonyl derivative with tributyltin hydride and 2,2-azobis-2-methylpropionitrile (AIB ⁇ ) (Robins, M. J.; Wilson, J. S.; Hansske, F. J. Am. Chem. Soc. 1983, 705, 4059; Barton, D. H. R.; McCombie, S. W. J. Chem.
  • suitable oxidizing reagents include activated dialkyl sulfoxides (e.g. dimethylsulfoxide, methylethylsulfoxide) (Mancuso, A. J.; Swem, D. Synthesis 1981, 165), organo chromates [e.g. pyridinium chlorochromate (Corey, E. J.; Suggs, J. W. Tetrahedron Lett. 1975, 2647; Corey, E. J.; Boger, D. L. Tetrahedron Lett. 1978, 2461), pyridinium dichromate (Corey, E. J.; Schmidt, G. Tetrahedron Lett. 1979, 5, 399), Collins reagent (Collins, J.
  • activated dialkyl sulfoxides e.g. dimethylsulfoxide, methylethylsulfoxide
  • organo chromates e.g. pyridinium chlorochromate (Corey, E. J.; Suggs,
  • the oxidation may be carried out in a solvent which does not adversely affect the reaction (e.g. acetone, dichloromethane, tetrahydrofuran, pyridine, NN-dimethylformamide, etc. or a mixture thereof).
  • the reaction may be conducted above, at, or below ambient temperature.
  • suitable alkylating reagents include, but are not limited to aldehydes and ketones in the presence of reducing agents (Hrubowchak, D. M.; Smith, F. X. Tetrahedron Lett. 1983, 24, 4951), alkyl-, aryl, or arylalkyl haUdes (Shono, T.; Kashimura, S.; Sawamura, M.; Soejima, T. J. Org. Chem. 1988, 53, 907).
  • an organic or inorganic bases such as an alkaUne earth metal (e.g. calcium, balium, magnesium, thallium etc.), an alkali metal hydride (e.g.
  • an alkali metal hydroxide e.g. sodium hydroxide, potassium hydroxide, etc.
  • an alkali metal carbonate e.g. sodium carbonate, potassium carbonate, etc.
  • an alkali metal hydrogen carbonate e.g. sodium hydrogen carbonate, potassium hydrogen carbonate, etc.
  • an alkali metal alkoxide e.g. sodium methoxide, sodium ethoxide, thalUum ethoxide, potassium tert-butoxide, etc.
  • an alkali metal alkanoic acid e.g. sodium acetate, etc.
  • a trialkylamine e.g.
  • a pyridine compound e.g. pyridine, lutidine, picoUne, 4-N ⁇ V-dimethylaminopyridine, etc.
  • quinoUne and the like.
  • the alkylation may be carried out in a solvent which does not adversely affect the reaction (e.g. acetone, dichloromethane, tetrahydrofuran, pyridine, NN-dimethylformamide, etc. or a mixture thereof).
  • the reaction may be conducted above, at, or below ambient temperature.
  • suitable halogenation reagents include, but are not limited to halogens treated by i ⁇ adiation (sun lamp) for several hours (Heffher, R.; Safaryn, J. E.; Joullie, M. M.; Tetrahedron Lett. 1987, 28, 6539) or oxalyl chloride (Evans, D. A.; Dow, R. L.; Shih, T. L.; Takecs, J. M.; Zahler, R. J. Am. Chem. Soc. 1990, 772, 5290).
  • the halogenation may be ca ⁇ ied out in a solvent which does not adversely affect the reaction (e.g. acetone, dichloromethane, tetrahydrofuran, pyridine, NN-dimethylformamide, etc. or a mixture thereof).
  • the reaction may be conducted above, at, or below ambient temperature.
  • suitable oxidation reagents include, but are not limited to oxodiperoxymolybdenum yridine)- 1 ,3-dimethyl-3,4,5,6-tetrahydro-2( lH)-pyrimidinone (Anderson, J. C; Smith, S. C. S1W E7T 1990, 2, 107) and oxodiperoxymolybdenum(pyridine)-hexamethylphosphoramide (Vedejs, E. J. Am. Chem. Soc. 1974, 96, 5944; Vedejs, E.; Engler, D. A.; Telschow, J. E. J. Org. Chem. 1978, 43, 188).
  • the oxidation may be carried out in a solvent which does not adversely affect the reaction (e.g. acetone, dichloromethane, tetrahydrofuran, pyridine, NN-dimethylformamide, etc., or a mixture thereof).
  • a solvent which does not adversely affect the reaction
  • the reaction may be conducted above, at, or below ambient temperature.
  • suitable olefination reagents include, but are not Umited to Wittig reagents (Maecker, M., Org. React. 1965, 14, 270; Johnson, A. W., " Ylid Chemistry,” Academic Press, New York, 1966) and CH 2 I 2 -Zn-TiCl4 [or Ti(NEt 2 )4] reagent (Hibino, J.; Okazoe, T.; Takai, K.; Nozaki, H. Tetrahedron Lett. 1985, 26, 5579; Okazoe, T.; Hibino, J.; Takai, K.; Nozaki, H. ibid. 1985, 26, 5581).
  • the carbonyl olefination may be carried out in a solvent which . does not adversely affect the reaction (e.g. acetone, dichloromethane, tetrahydrofuran, pyridine, NN-dimethylformamide, etc., or a mixture thereof).
  • the reaction may be conducted at room temperature.
  • suitable O-acylation reagents include, but are not Umited to alkyl, aryl, or arylalkyl acyl halides (Lakhvich, F. A.; Khlebnicova, T. S.; Akhrem, A. A. Synthesis 1985, 8, 784).
  • the O-acylation may be carried out in a solvent which does not adversely affect the reaction (e.g. acetone, dichloromethane, tetrahydrofuran, pyridine, NN- dimethylformamide, etc., or a mixture thereof).
  • the reaction may be conducted above, at, or below ambient temperature.
  • suitable amination reagents include, but are not Umited to amino acid derivatives and lower alkyl, aryl, or arylalkyl amines (Winkler, J. D.; Hershberger, P. M.; Springer, J. P. Tetrahedron Lett. 1986, 27, 5177).
  • the reaction may be carried out in refluxing in benzene, toluene or a solvent which does not adversely affect the reaction (e.g. tetrahydrofuran, pyridine, NN-dimethylformamide, etc., or a mixture thereof).
  • the reaction may be conducted at room temperature.
  • the alkyUdene formation may be ca ⁇ ied out using, but is not Umited to aldehydes and ketones with active methylene compounds. (Schonberg, A.; Singer, E. Chem. Ber. 1970, 103, 3871; Chatterjee, S. . Chem. Soc. B, 1969, 725).
  • the alkyUdene formation may be carried out in a solvent which does not adversely affect the reaction (eg. acetone, dichloromethane, tetrahydrofuran, pyridine, NN-dimethylformamide, etc., or a mixture thereof).
  • the reaction may be conducted under cooling to heating.
  • L may be hydroxy, or a good leaving group (halogen, tosylate, mesylate or ttiflate, for example).
  • the elimination of H 2 O may be carried out in a solvent which is inert under the reaction conditions (e.g. toluene) with a trace of acid (e.g. toluenesulfonic acid), at a temperature selected from 50 to 100 °C.
  • the precursor compound contains a good leaving group
  • the elimination may be carried out in the presence of a base (e.g. triethyl amine or potassium carbonate), at a temperature selected from 0 to 100 °C.
  • suitable diamines include phenylene diamine and substituted 1,2- phenyl diamines, 2,3-diaminopyridine, 3,4-diaminopyridine, 4,5-diaminopyridazine, 4,5- diaminopyrimidine and their acid salts, preferably in the presence of tertiary amines (e.g. N- methylmorpholine).
  • Suitable solvents include methanol, ethanol, propanol, acetonitrile, 2- butanone and NN-dimethylformamide, and a reaction temperature selected from 50 to 100 °C.
  • suitable reagents include sodium borohydride, zinc in acetic acid, sodium triacetoxyborohydride in acetic acid, lithium trialkoxyaluminum hydride in tetrahydrofuran, potassium or lithium tri-_.ec-butylborohydride in tetrahydrofuran, and borane/t-butylamine complex in a solvent such as methanol or ethanol.
  • the reduction may be conducted at -70 °C to room temperature.
  • suitable 2-aminothiophenols include substituted 1,2- aminothiophenols, preferably in the presence of tertiary amine (e.g. N-methylmorpholine).
  • Suitable solvents include methanol, ethanol and n-propanol; and the reaction may be conducted at a temperature selected from 50 to 100 °C.
  • the reagent to be used in this reaction may include di(lower)alkyl sulfoxide (e.g. dimethyl sulfoxide, ethyl methyl sulfoxide, propyl methyl sulfoxide, isobutyl methyl sulfoxide, butyl methyl sulfoxide, isobutyl methyl sulfoxide, hexyl methyl sulfoxide, etc).
  • di(lower)alkyl sulfoxide e.g. dimethyl sulfoxide, ethyl methyl sulfoxide, propyl methyl sulfoxide, isobutyl methyl sulfoxide, butyl methyl sulfoxide, isobutyl methyl sulfoxide, hexyl methyl sulfoxide, etc).
  • This reaction is usually conducted in the presence of oxalyl chloride, acid chlorides, lower alkanoic anhydride such as acetic anhydride in a conventional solvent that does not adversely influence the reaction such as dichloromethane, acetone, ethyl acetate, tetrahydrofuran, pyridine, N ⁇ V-dimethylformamide, etc., followed by the addition of a tertiary amine (e.g. triethyl amine).
  • a tertiary amine e.g. triethyl amine
  • the dithiols are lower alkyl dithiols (e.g. ethanedithiol, propanedithiol or butanedithiol) and 1,2-aryl dithiols (e.g. 1,2-benzenedithiol) in the presence of a Lewis acid (e.g. boron trifluoride etherate or lanthanum trichloride) in a conventional solvent that does not adversely influence the reaction such as dichloromethane, tettahydrofuran or ether.
  • a Lewis acid e.g. boron trifluoride etherate or lanthanum trichloride
  • the reaction may be conducted at -70 °C and room temperature.
  • suitable oxygen-substituted amines include hydroxyl amine, O- alkylhydroxyl amines, and O-arylalkyl hydroxyl amines, for example O-benzyl hydroxyl amine.
  • Suitable solvents include those that do not adversely affect the reaction, for example ethanol or methanol. The reaction is preferably carried out with one equivalent of hydroxyl amine, and at a temperature of 25 to 100 °C, more preferably at the reflux temperature of the solvent.
  • suitable hydrazines include alkylhydrazines (e.g. butylhydrazine), arylhydrazines (e.g. phenylhydrazine), acylhydrazines (e.g. acetylhydrazine), semicarbazides (e.g. t-butyloxycarbonyl hydrazine) and sulfonyl hydrazines (e.g. tosyl hydrazine) in a conventional solvent that does not adversely affect the reaction such as tettahydrofuran, methanol or ethanol.
  • the reaction may be conducted at 20 to 100 °C.
  • 2-substitutions on the pyrimidine may be hydrogen, alkyl, aryl, hydroxyl, alkoxy, thiol, amino, alkylamino, arylamino, acylamino, carbamylamino, and sulphonylamino groups.
  • the appropriate pyrimidine containing compounds may be prepared according to the methods described in " The Chemistry of Heterocyclic Compounds, Vol.16, supplement II, Chapter E, pp 21-60", D. J. Brown, John Wiley & Sons, 1985.
  • the furan containing compounds may be prepared according to the method described by Paulissen, R., et. al. in Tetrahedron Lett. 1974, 607.
  • process (oo) one equivalent of hydroxyl amine hydrochloride and tertiary amine (e.g. N-methylmorphoUne) in a conventional solvent that does not adversely affect the reaction such as tetrahydrofuran, methanol, ethanol or isopropanol is used to prepare the compound.
  • the reaction is conducted at 20 to 100 °C.
  • the pyridine containing compounds may be prepared according to the literature: Osman, A. ⁇ .; Ismail, M. M.; Barakat, M. A. Rev. Roum. Chim. 1986, 31, 615- 624; Ried W.; Meyer, A., Ber. Deutsch. Chem. Ges. 1957, 90, 2841; Troschutz, R.; Troschultz, J.; SoUhuberkretzer, M. Arch Pharm. 1985, 318, 777-781.
  • a substituted 2-aminothiophenol, a 2-aminophenol or an aromatic 1,2- diamine is used in a conventional solvent that does not adversely affect the reaction such as tetrahydrofuran, ethanol, isopropanol, acetonitrile or NN-dimethylformamide.
  • the reaction may be conducted at 20 to 100 °C.
  • the keto-substituted furan containing compound may be prepared according to the literature: WilUams, P. H. et al, /. Am. Chem. Soc. 1960, 82, 4883; E. J. Corey et al., Chem. Lett. 1987, 223.
  • suitable l-halo-2-nitroaromatics may be substituted l-fluoro-2- nitrobenzene, o-fluoro-nitropyridines, or o-bromo-nitto-naphthalene, etc.
  • the arylation may be carried out in a solvent which does not adversely affect the reaction (e.g. tettahydrofuran, NN-dimethylformamide, dimethoxyethane, diglyme, etc.).
  • the base used to generate the anion may be isopropyl magnesium chloride, lithium diisopropyl amine or sodium hydride.
  • the reaction may be conducted at a temperature selected from -70 °C to 100 °C.
  • a nittile oxide may be formed either by oxidation of an aldoxime or dehydration of a nitro compound as described in the following references or literature cited therein: (1) Torssell, K. G. B. " ⁇ ittile Oxides, ⁇ itrones and ⁇ ittonates in Organic Synthesis”; VCH Publishers: New York, 1988, p 64; (2) Kim, J. N.; Ryu, E. K. Synthetic Communications 1990, 20, 1373; (3) Chow, Y. L.; Shy, Y. Y.; Bakker, B. H.; PUlay, K. S. Heterocycles 1989, 29, 2245.
  • the nittile oxide is placed in the presence of an alpha,beta- unsaturated enone in an inert solvent to yield an 2-isoxazoUnes. Any isomers may subsequently be chomatographically separated.
  • an isoxazoUne may be transformed to the co ⁇ esponding beta-hydroxy ketone using but is not limited to molybenum hexacarbonyl in wet acetonitrile according to: Baraldi, P. G.; Barco, A.; Benetti, S.; Manfredini, S.; Simoni, D. Synthesis 1987, 276.
  • Ti 3+ may be employed to attain N-O bond cleavage: Das, N. B.; Torssell, K. B. G. Tetrahedron 1983, 39, 2227.
  • Raney-nickel may also selectively cleave the N-O bond without reducing the imino functionality as described in the following reference and literature cited therein: Torssell, K. G. B. "Nittile Oxides, Nittones and Nittonates in Organic Synthesis"; VCH Publishers: New York, 1988, p 16 and 290. During the course of this transformation, a significant amount of dehydration occurs to produce alpha-beta unsaturated enones which may be separated from the beta-hydroxy ketones.
  • an aryl- or alkylsulfonyl hydrazone may be formed by treatment of a ketone with an aryl- or alkylsulfonyl hydrazide in the presence of an acid catalyst in a solvent suitable for the reaction such as methanol or ethanol at temperatures ranging from ambient to the reflux temperature of the solvent.
  • an allyUc alcohol may be produced by selective reduction of an alpha-beta unsaturated enone. This is accomplished with but not Umited to sodium borohydride in the presence of cerium(IE) chloride heptahydrate in a suitable solvent such as methanol at or near 0 "C.
  • an epoxide may be produced on the central carbonyl of a tricarbonyl moiety by but not Umited to excess diazomethane as described in: Fisher, M. J.; Chow, K.; Villalobos, A.; Danishefsky, S. J. /. Org. Chem. 1991, 56, 2900-2907.
  • Uberation of the ester to the acid may be achieved by the cleavage of a suitably substituted ester function.
  • a suitably substituted ester function may be benzyl, 2,2,2- trichloroethyl, 9-fluorenylmethyl and the like. These are cleaved by methods well known to those skilled in the art.
  • condensation of an amine with the acid may be performed using the mixed or symmetrical anhydride of said acid, or an ester of the acid, preferably activated, such as the ester derived from hydroxybenzotriazole, or the co ⁇ esponding acylcyanide, acylimidazole, or acylazide of the aforementioned acid.
  • selective protection of the 32-hydroxyl moiety may be achieved using one of a variety of trialkylsilyl groups. This then leaves exposed a lone secondary alcohol on C-24 for selective inversion, which may be accomplished by activation of the 24-hydroxy as a mesylate, tosylate, etc., followed by inversion with a suitable nucleophile such as water, benzoic acid, formic acid, etc.
  • inversion of the unactivated 24-hydroxy group may be achieved using well described Mitsunobu conditions.
  • condensation of an alkyloxy or substituted alklyoxy carbonyl hydrazine with ascomycin, FK506, similar compounds, or a suitable derivative thereof wherein the C-22 is available as a reactive center, including but not Umited to a carbonyl is performed in an inert solvent such as methanol, ethanol, 2-propanol, etc., in the presence of a catalyst which may be an acid such as formic acid, p-toluenesulfonic acid, or camphor sulfonic acid.
  • L may be a hydroxyl group, or a good leaving group (halogen, tosylate, nittobenzenesulfonate, mesylate or ttiflate, for example).
  • the condensation may be ca ⁇ ied out in a solvent which does not adversely affect the reaction (e.g. isopropanol, acetonitrile, dioxane, NN-dimethylformamide, tettahydrofuran, etc.).
  • the reaction may be ca ⁇ ied out in the presence of base (e.g. triethylamine, 4- methylmorphoUne or magnesium carbonate, etc.), at a temperature selected from 0 to 100 °C.
  • base e.g. triethylamine, 4- methylmorphoUne or magnesium carbonate, etc.
  • the appropriate thiazole containing compound may be prepared according to Hantzsch's synthesis described by: Katritzky, A.R.; Rees, C.W. "Comprehensive Heterocyclic Chemistry”; Pergamon Press: Oxford, 1984, Vol. 6, Part 4B, p.294-299.
  • L may be a hydroxyl group, or a good leaving group (halogen, tosylate, nittobenzenesulfonate, mesylate or ttiflate, for example).
  • the condensation may be ca ⁇ ied out in a solvent which does not adversely affect the reaction (e.g. isopropanol, t-butanol, acetonitrile, dioxane, NN-dimethylformamide, tettahydrofuran, etc.).
  • the reaction may be ca ⁇ ied out in the presence of base (e.g. triethylamine, 4-methylmorpholine, potassium carbonate or magnesium carbonate, etc.), at a temperature selected from 0 to 100 °C.
  • Suitable amidines include formamidine, alkylamidines, arylamidines and alkylisoureas.
  • Suitable guanidines include N-arylguanidines, N-acylated guanidines and N- sulfonylated guanidines.
  • L may be a hydroxyl group, or a good leaving group (halogen, tosylate, nittobenzenesulfonate, mesylate or ttiflate, for example).
  • the condensation may be carried out in a solvent which does not adversely affect the reaction (e.g. isopropanol, t-butanol, acetonitrile, dioxane, NN-dimethylformamide, tettahydrofuran, etc.).
  • the reaction may be carried out in the presence of a base (e.g., triethylamine, 4-methylmorphotine, potassium carbonate or magnesium carbonate), at a temperature selected from 0 to 100 °C.
  • a base e.g., triethylamine, 4-methylmorphotine, potassium carbonate or magnesium carbonate
  • the amides are primary amides such as formamide, alkylacylamides and arylacylamides.
  • the organometalUc reagent may be a Grignard reagent, an alkyllithium, or an aryllithium reagents.
  • the selective addition may be ca ⁇ ied out in a solvent which does not adversely affect the reaction (e.g., hexanes, ether, tettahydrofuran, dimethoxyethane or 2-methoxyethyl ether).
  • the reaction may be ca ⁇ ied out in the presence of cerium (IE) at a temperature selected from -100 °C to O °C.
  • IE cerium
  • the gamma amino alpha hydroxy carbonyl or a masked gamma amino alpha hydroxy carbonyl of a co ⁇ esponding compound prepared by process (sss) may have substitutions (e.g. alkyl, aryl groups, etc.) at the alpha and/or beta positions. Furthermore, the amino group may have N-alkyl or aryl substitutions.
  • the condensation may be carried out in a solvent which does not adversely affect the reaction (e.g. isopropanol, t-butanol, acetonitrile, dioxane, N,N-dimethylformamide, tetrahydrofuran, etc.).
  • the reaction may be ca ⁇ ied out in the presence of a base (e.g. triethylamine, 4-methylmorpholine, potassium carbonate or magnesium carbonate, etc.), at a temperature selected from 0 to 100 °C.
  • a base e.g. triethylamine, 4-methylmorph
  • the reaction is generally carried out in two steps: first the condensation of an alpha diketone or a masked alpha diketone with an l,2-diaminoalk__ne gives a dihydropyrazine. Once the dihydropyrazine has been prepared, it may be oxidized by air in the presence of Pd/C, PtO 2 or other catalysts. Metal oxides (e.g. Mn ⁇ 2 or CuO) may also be used for the aromatization.
  • the condensation and oxidation may be carried out in a solvent which does not adversely affect the reactions (e.g. isopropanol, acetonitrile, dioxane, benzene, toluene, etc.).
  • the reaction may be carried out in the presence of drying agent such as magnesium sulfate or molecular sieves at a temperature selected from 0 °C to 100 °C.
  • a 1,5-dicarbonyl group or a masked 1,5-dicarbonyl group prepared by process (sss) may have substitutions (e.g. alkyl, aryl groups etc.) at the alpha and/or beta positions.
  • the condensation may be carried out with anhydrous ammonia in a solvent which does not adversely affect the reactions (e.g. Uquid ammonia, isopropanol, acetonitrile, dioxane, benzene, toluene, etc.).
  • the reaction may be carried out at a temperature selected from -40 °C to 100 °C.
  • a 1,4-dicarbonyl group or a masked 1,4-dicarbonyl group prepared by process (sss) may have substitutions (e.g. alkyl, aryl groups, etc.) at the alpha position.
  • the condensation and oxidation may be ca ⁇ ied out with anhydrous hydrazine in a solvent which does not adversely affect the reactions (e.g. isopropanol, acetonitrile, dioxane, benzene, toluene, etc.).
  • a drying agent such as magnesium sulfate or molecular sieves at a temperature selected from 0 °C to 100 °C.
  • the thiocarbonate formation may be carried out in a solvent which does not adversely affect the reactions (e.g. toluene, acetone, methylene chloride, tetrahydrofuran or pyridine, etc.).
  • the reaction may be carried out in the presence of a base such as triethylamine, pyridine, dimethylaminopyridine and sodium carbonate at a temperature selected from 0 °C to 100 °C.
  • the thiocarbonylating reagent may be N,N'-thiocarbonyl-diimidazole, N,N-thiocarbonylbis(2-pyridone), thiophosgene, or O-phenylthiochloroformate.
  • the carbonate formation may be carried out in a solvent which does not adversely affect the reactions (e.g. toluene, acetone, butanone, methylene chloride, tettahydrofuran or pyridine etc.).
  • the reaction may be carried out in the presence of a base such as triethylamine, pyridine, dimethylaminopyridine and sodium carbonate at a temperature selected from 0 °C to 100 °C.
  • the carbonylating reagent may be N,N'-carbonyldiimidazole, N,N'-carbonyl-b I y- (2-pyridone), phosgene, triphosgene, ethyl chloroformate, ethyl trichloroacetate, or o- phenylchloroformate.
  • the cyclic phosphonate formation may be ca ⁇ ied out by first reacting a diol from a selected compound with phosphorous trichloride followed by the addition of an appropriate alcohol and amine.
  • the alcohol used may be an alkyl alcohol, or an aryl alcohol.
  • the amine used may be primary or secondary.
  • the cyclic phosphonate formation may be ca ⁇ ied out by directly reacting the diol from a co ⁇ esponding compound with an appropriate alkoxyphophoryl dichloride.
  • the phosphonate formation may be carried out in a solvent which does not adversely affect the reactions (e.g. carbon tettachloride, chloroform, methylene chloride, toluene, tetrahydrofuran, etc.).
  • the reaction may be carried out in the presence of a base such as triethylamine, pyridine, dimethylaminopyridine, and sodium carbonate at a temperature selected from 0 °C to 100 °C.
  • the reduction of thiocarbonate may be carried out in a solvent which does not adversely affect the reactions (e.g., toluene or tettahydrofuran) at a temperature selected from 0 °C to 100 °C.
  • a solvent which does not adversely affect the reactions (e.g., toluene or tettahydrofuran) at a temperature selected from 0 °C to 100 °C.
  • the reducing agent used may be trimethylphosphite, triethylphosphite, trialkylphosphite or tti-n-butyltin hydride.
  • the reduction of a 1,2-dicarbonyl group of a co ⁇ esponding compound may be ca ⁇ ied out in a solvent which does not adversely affect the reactions (e.g., methanol, ethanol, ethanol, pyridine or N,N-dimethylformamide).
  • a solvent which does not adversely affect the reactions (e.g., methanol, ethanol, ethanol, pyridine or N,N-dimethylformamide).
  • the reducing agents used may be tin amalgam, aluminum amalgam with hydrogen chloride in ethanol, or may be hydrogen sulfide in pyridine or N,N-dimethylformamide.
  • the reducing agents used may be hydrogen gas over Pd/C, or Pt/C, zinc dust with ammonium chloride, zinc dust with hydrochloric acid at a temperature selected from 0 °C to 100 °C.
  • triazole formation may be ca ⁇ ied out using, but is not Umited to an azide derivative with suitable acetylene analogues include diethylacetylene dicarboxylate, dimethylacetylene dicarboxylate, methyl cyanoacetylenecarboxylate, and the likes.
  • the reaction may be conducted above, or below ambient temperature, more preferably from 0 to 50 °C.
  • py ⁇ ole formation may be carried out using, but is not limited to amine compounds with 1,4-dicarbonyl analogues, such as acetonylacetone, and the likes.
  • Suitable solvents include methanol, ethanol, n-propanol, isopropanol, acetonitrile and N,N-dimethylformamide.
  • the reaction may be conducted above, or below ambient temperature, more preferably from 50 to 100 °C.
  • suitable reagents for vicinal hydroxylation include osmium tettaoxide, potassium permanganate, and iodine in conjunction with silver acetate.
  • Osmium tettoxide is preferably used with a regenerating agent such as hydrogen peroxide, alkaline t- butyl hydroperoxide or N-methylmorphoUne-N-oxide, and a solvent that does not adversely affect the reaction, for example diethyl ether or tettahydrofuran.
  • Potassium permanganate is preferably used in mild conditions, for example alkaUne aqueous solution or suspensions. Co-solvents such as t-butanol or acetic acid may also be used.
  • Iodine-silver acetate under 'wet' conditions yields ci-diols.
  • iodine is used in aqueous acetic acid in the presence of silver acetate.
  • Iodine-silver acetate under 'dry' conditions yields trans-diols.
  • the initial reaction is carried out in the absence of water, and final hydrolysis yields the diol.
  • the oxidation is preferably ca ⁇ ied out at a temperature of 0 to 100 °C.
  • Suitable reagents for the oxidative cleavage of the vicinal diol include lead tetraacetate, phenyliodoso acetate, periodic acid or sodium metaperiodate.
  • Suitable solvents for the first two reagents include benzene and glacial acetic acid.
  • the second two reagents are preferably used in aqueous solution. The reaction is preferably carried out at a temperature of 0 to 100 °C.
  • suitable reagents for the oxidation of an aldehyde of the co ⁇ esponding compound may include silver oxide, chromic acid and potassium permanganate.
  • oxygen may also be used in converting an aldehyde to a carboxylic acid of a co ⁇ esponding compound.
  • the catalysts may be palladium or platinum oxide.
  • the air oxidation may be ca ⁇ ied out in a solvent which does not adversely affect the reaction (e.g., ethanol, water, acetonitrile, aqueous acetone or pyridine) at a temperature of 0 to 100 °C.
  • esters of a co ⁇ esponding carboxylic acid may be prepared under neuttal conditions at room temperature by the reaction of the carboxyUc acid with alcohols in the presence of molar amounts of activating reagents such as triphenyl phosphine and diethyl azodicarboxylate, carbodnmides, N,N'-carbonyldiimidazole and l-methyl-2-halopyridinium iodide.
  • activating reagents such as triphenyl phosphine and diethyl azodicarboxylate, carbodnmides, N,N'-carbonyldiimidazole and l-methyl-2-halopyridinium iodide.
  • Esters may also be formed by reacting the co ⁇ esponding carboxylic acid with diazoalkanes in a solvent which does not adversely affect the reaciton (e.g., ether, tetrahydrofuran or methylene chloride) at a temperature of from 0 to 100 °C.
  • a solvent which does not adversely affect the reaciton (e.g., ether, tetrahydrofuran or methylene chloride) at a temperature of from 0 to 100 °C.
  • the cyclopropanation of the allyl group of a co ⁇ esponding compound may be ca ⁇ ied out with diazoalkanes in a solvent which does not adversely affect the reaction (e.g., ether, methylene chloride or tettahydrofuran) in the presence of a catalyst such as palladium (II) acetate.
  • a solvent which does not adversely affect the reaction (e.g., ether, methylene chloride or tettahydrofuran) in the presence of a catalyst such as palladium (II) acetate.
  • the temperature of the reaction is of -15 to 5 °C.
  • a py ⁇ le ring may be produced by reacting a 1,4-dicarbonyl group of a co ⁇ esponding compound with ammonia, or a substituted amine such as benzylamine or 2- aminoethanol.
  • Suitable solvents include those which do not adversely affect the reaction (e.g., methylene chloride, tetrahydrofuran or dioxane). The reaction is preferably ca ⁇ ied out at a temperature of 0 to 100 °C.
  • the cyclization of a 1,4-dicarbonyl group of a co ⁇ esponding compound may be carried out in the presence of a catalytic amount of acid (e.g., acetic acid or arylsulfonic acid).
  • the reaction may be ca ⁇ ied out in a solvent which does not adversely affect the reaction (e.g., methylene chloride, ether, benzene or toluene).
  • the reaction is preferably carried out at a temperature of 0 to 60 °C.
  • suitable reagents include air, a palladium (E) haUde (e.g. palladium (E) chloride), in conjunction with a cuprous halide (e.g. cupper (I) chloride).
  • Suitable solvents include those that do not adversely affect the reaction (e.g. DMF and water). The reaction is preferably ca ⁇ ied out at a temperature of 0 to 100 °C.
  • suitable reducing agents include but are not limited to sodium cyanoborohydride, lithium aluminum hydride, borane-pyridine, or hydrogen in the presence of such catalysts as Raney nickel, platinum, platinum oxide, or palladium.
  • An acidic environment may promote the reduction in some cases, and acids such as hydrochloric acid or p-toluenesulfonic acid may be added for this purpose.
  • the reduction may be ca ⁇ ied out in a solvent which does not adversely affect the reaction (e.g. ethanol, ethyl acetate).
  • reduction of an oxime to the co ⁇ esponding amine may be accomplished with but not Umited to hydrogenation with a suitable catalyst such as palladium on carbon in a solvent inert to the reaction conditions (e.g. ethanol) at temperatures ranging from 0 to 100 °C.
  • a suitable catalyst such as palladium on carbon in a solvent inert to the reaction conditions (e.g. ethanol) at temperatures ranging from 0 to 100 °C.
  • reduction of an enone to the co ⁇ esponding saturated ketone may be accomplished with but not limited to hydrogenation with a suitable catalyst such as either palladium on carbon or rhodium on alumina in a solvent inert to the reaction conditions (e.g. methanol, ethanol, isopropanol, ethyl acetate) in a temperature range from -78 to 100 °C.
  • a suitable catalyst such as either palladium on carbon or rhodium on alumina in a solvent inert to the reaction conditions (e.g. methanol, ethanol, isopropanol, ethyl acetate) in a temperature range from -78 to 100 °C.
  • isoxazoline formation may be accompUshed by, but not Umited to the following sets of reaction conditions involving a beta-hydroxy oxime.
  • One possible method is to treat the beta-hydroxy oxime with Martin's sulfurane dehydrating reagent at or near room temperature in a solvent inert to the reaction conditions such as methylene chloride.
  • the beta-hydroxy oxime may be tteated with p-toluenesulfonyl chloride in a solvent such as pyridine at temperatures ranging from 0 to 100 °C.
  • an intramolecular aldol reaction may be accomplished by, but is not limited to treatment of a carbonyl with a base such as potassium or sodium hydride in a solvent which is inert to the reaction conditions (e.g. tettahydrofuran or N,N- dimethylformamide) at a temperature range from -78 to 150 °C.
  • a base such as potassium or sodium hydride
  • a solvent which is inert to the reaction conditions (e.g. tettahydrofuran or N,N- dimethylformamide) at a temperature range from -78 to 150 °C.
  • a cyclic imine may be formed by, but is not Umited to treatment of an alpha,beta-unsaturated enone with the sodium enolate of a glycine ester imine in an inert solvent such as tetrahydrofuran in a temperature range from -78 to 100 "C.
  • an inert solvent such as tetrahydrofuran in a temperature range from -78 to 100 "C.
  • a substituted py ⁇ ole may be formed by but is not Umited to a 1,3-dipolar cycloaddition between an alpha,beta-unsaturated enone with a glycine ester imine in the presence of a suitable catalyst such as lithium bromide and triethylamine in a solvent inert to the reaction conditions (e.g. tettahydrofuran) at or near room temperature.
  • a suitable catalyst such as lithium bromide and triethylamine in a solvent inert
  • alpha diazoketones can be decomposed by exposure to UV light or by heating.
  • Wolff rea ⁇ angements often ensue yielding beta-keto carboxylic acids when run in a solvent mixture containing water, beta-keto esters when run in a solvent containing an alcohol, or beta-keto amides when run in a solvent containing ammonia, a primary or a secondary amine.
  • aryl-, heterocyclic-, or alkyloxycarbonylation may be ca ⁇ ied out using aryl-, heterocycUc-, or alkyl- chloroformate in the presence of amines like triethylamine, dUsopropylethylamine, pyridine and the like.
  • the reaction may be carried out by reacting the co ⁇ esponding aryl-OH, heterocycUc-OH or alkyl-OH with -CHOC(O)Cl or -CHOC(O)-(p-nittophenyl) in a co ⁇ esponding compound in the presence of amine base.
  • the reaction may be carried out in a solvent which does not adversely affect the reaction (e.g. acetone, dichloromethane, tetrahydrofuran, pyridine and N,N- dimethylformamide, or a mixture thereof).
  • a solvent which does not adversely affect the reaction (e.g. acetone, dichloromethane, tetrahydrofuran, pyridine and N,N- dimethylformamide, or a mixture thereof).
  • the reaction may be conducted above, at or below ambient temperature.
  • In process (zzzz) allylic oxidations may be ca ⁇ ied out using selenium dioxide with or without a co-oxidant, such as tert-butyl hydroperoxide, in an inert solvent such as tettahydrofuran, ether, ethylacetate, water, or a combination thereof.
  • a co-oxidant such as tert-butyl hydroperoxide
  • an inert solvent such as tettahydrofuran, ether, ethylacetate, water, or a combination thereof.
  • the reaction may be conducted at room temperature to 100 °C.
  • the compounds of the present invention are formed by modification of FR-900520 (ascomycin) or one of its congeners (such as FK-506, etc.) by alkylation of the C-32- hydroxyl group with optional modifications exercised at C-18 and/or C-21 and/or C-23 and/or C-24.
  • FR-900520 ascomycin
  • FK-506, etc. congeners
  • alkylation of the C-32- hydroxyl group with optional modifications exercised at C-18 and/or C-21 and/or C-23 and/or C-24.
  • Example 3 The product of Example 3 (0.50 g, 0.59 mmol) was dissolved in dichloromethane (5 mL) and the solution cooled to 0°C. 4-Dimethylaminopyridine (DMAP) (14.4 mg, .0.118 mmol) was added foUowed by l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (ED AC) (206 mg, 1.07 mmol) then benzylamine (128.3 uL, 1.18 mmol). The reaction was warmed to room temperature and sti ⁇ ed overnight.
  • DMAP 4-Dimethylaminopyridine
  • ED AC l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • the resultant product of Example 3 (0.8 g, 0.94 mmol) was dissolved in THF (3 mL) and the solution cooled to 0°C before adding N-methylmorpholine (103.4 uL, 0.94 mmol) followed by isobutyl chloroformate (122.2 uL, 0.94 mmol). The resulting suspension was sti ⁇ ed for 20 minutes at 0 °C after which N-methylbenzylamine (243 uL, 1.88 mmol) was added. Sti ⁇ ing was continued overnight as the ice melted.
  • Example 81 The crude isolate from Example 81 (1.5 g, ⁇ 1.2 mmol ) was dissolved in THF (4 mL) and the solution cooled to 0°C before adding N-methylmorpholine (129.4 uL, 1.2 mmol) followed by isobutyl chloroformate (152.8 uL, 0.59 mmol). The resulting suspension was sti ⁇ ed for 20 minutes at 0°C after which ammonium hydroxide (14.8M, 159.2 uL, 2.4 mmol) was added. Sti ⁇ ing was continued overnight as the ice melted.
  • N-methylmorpholine 129.4 uL, 1.2 mmol
  • isobutyl chloroformate 152.8 uL, 0.59 mmol
  • reaction mixture was loaded onto silica (80 mL) in a fritted funnel then eluted with dichloromethane (200 mL), 2:1 hexane/acetone (400 mL), 1:1 hexane/acetone (400 mL), and acetone (200 mL).
  • Fractions containing product were combined and solvent removed in vacuo to give 358 mg yellow foam.
  • the crude product was further purified by RP-HPLC (Rainin Dynamax 41.4 mm phenyl column) eluting with a gradient of 20% methanol/water and acetonitrile to provide the title compound (188.7 mg, 19% yield) as a white foam.
  • MS (FAB)w/z: (M+K) 887.
  • Example 3 The product of Example 3 is activated as in Example 5 and then tteated with methylamine instead of N-methylbenzylamine to provide the title compound.
  • Example 3 The product of Example 3 is activated as in Example 5 and then tteated with dimethylamine instead of N-methylbenzylamine to provide the title compound.
  • the product of Example 3 is activated as in Example 5 and then tteated with ethylamine instead of N-methylbenzylamine to provide the title compound.
  • Example 3 The product of Example 3 is activated as in Example 5 and then treated with N,N- methyl,ethylamine instead of N-methylbenzylamine to provide the title compound.
  • Example 3 The product of Example 3 is activated as in Example 5 and then tteated with propylamine instead of N-methylbenzylamine to provide the title compound.
  • Example 3 The product of Example 3 is activated as in Example 5 and then tteated with N,N-methyl,propylamine instead of N-methylbenzylamine to provide the title compound.
  • the product of Example 3 is activated as in Example 5 and then treated with 2-aminopropane instead of N-methylbenzylamine to provide the title compound.
  • Example 3 The product of Example 3 is activated as in Example 5 and then tteated with N,N-methyl, 2- propylamine instead of N-methylbenzylamine to provide the title compound.
  • Example 3 The product of Example 3 is activated as in Example 5 and then tteated with cyclopropylamine instead of N-methylbenzylamine to provide the title compound.
  • Example 3 The product of Example 3 is activated as in Example 5 and then treated with n-butylamine instead of N-methylbenzylamine to provide the title compound.
  • Example 3 The product of Example 3 is activated as in Example 5 and then tteated with N,N-methylbutylamine instead of N-methylbenzylamine to provide the title compound.
  • the product of Example 3 is activated as in Example 5 and then tteated with isobutylamine instead of N-methylbenzylamine to provide the title compound.
  • the product of Example 3 is activated as in Example 5 and then tteated with N,N-methyl,isobutylamine instead of N-methylbenzylamine to provide the title compound.
  • the product of Example 3 is activated as in Example 5 and then tteated with cyclobutylamine instead of N-methylbenzylamine to provide the title compound.
  • Example 3 The product of Example 3 is activated as in Example 5 and then treated with pentylamine instead of N-methylbenzylamine to provide the title compound.
  • Example 3 The product of Example 3 is activated as in Example 5 and then treated with
  • Example 3 The product of Example 3 is activated as in Example 5 and then tteated with 3-methylbutylamine instead of N-methylbenzylamine to provide the title compound.
  • Example 3 The product of Example 3 is activated as in Example 5 and then treated with N,N-methyl,3- methylbutylamine instead of N-methylbenzylamine to provide the title compound.
  • Example 3 The product of Example 3 is activated as in Example 5 and then treated with cyclopentylamine instead of N-methylbenzylamine to provide the title compound.
  • Example 3 The product of Example 3 is activated as in Example 5 and then tteated with
  • Example 3 The product of Example 3 was activated as in Example 5 and then tteated with
  • Example 3 The product of Example 3 is activated as in Example 5 and then treated with
  • Example 3 The product of Example 3 is activated as in Example 5, and then tteated with 1,2-diaminoethane instead of N-methylbenzylamine to provide the title compound.
  • the product of Example 3 is activated as in Example 5, and then tteated with 1,3-diaminopropane instead of N-methylbenzylamine to provide the title compound.
  • Example 3 The product of Example 3 is activated as in Example 5, and then tteated with
  • Example 3 The product of Example 3 is activated as in Example 5, and then tteated with
  • Example 3 The product of Example 3 is activated as in Example 5, and then tteated with
  • Example 3 The product of Example 3 is activated as in Example 5, and then tteated with
  • the product of Example 3 is activated as in Example 5 and then tteated with 3-biphenylamine instead of N-methylbenzylamine to give the title compound.
  • Example 3 The product of Example 3 is activated as in Example 5 and then treated with N,N-(ethanol-2- yl)-(3-biphenyl)-amine instead of N-methylbenzylamine to give the title compound.
  • Example 3 The product of Example 3 is activated as in Example 5 and then treated with N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-
  • Example 3 The product of Example 3 is activated as in Example 5 and then treated with N-phenyl-N',N'- dimethyl-ethyldiamine instead of N-methylbenzylamine to give the title compound.
  • Example 3 The product of Example 3 was activated as in Example 5 and then tteated with
  • the product of Example 3 is activated as in Example 5 and then treated with dicyclohexylamine instead of N-methylbenzylamine to give the title compound.
  • the product of Example 3 was activated as in Example 5 and then treated with 1 equivalent of 4-aminomorpholine and 0.1 equivalents of 4-dimethylaminopyridine instead of N- methylbenzylamine to give the title compound.
  • MS (FAB) m/z: M+K 972.
  • Example 3 The product of Example 3 was activated as in Example 5 and then tteated with thiomorpholine instead of N-methylbenzylamine to give the title compound.
  • MS (FAB) m/z: M+K 973.
  • Example 3 The product of Example 3 was activated as in Example 4 and then tteated with
  • Example 3 The product of Example 3 is activated as in Example 5 and then tteated with methylcarbazate instead of N-methylbenzylamine to give the title compound.
  • the product of Example 3 is activated as in Example 5 and then tteated with L-prolinecarboxamide instead of N-methylbenzylamine to give the title compound.
  • Example 3 The product of Example 3 is activated as in Example 5 and then tteated with L-prolinol instead of N-methylbenzylamine to give the title compound.
  • Example 3 The product of Example 3 is activated as in Example 5 and then treated with D-prolinol instead of N-methylbenzylamine to give the title compound.
  • Example 3 The product of Example 3 is activated as in Example 5 and then tteated with N-(ethanol-)
  • Example 3 The product of Example 3 is activated as in Example 5 and then tteated with
  • Example 3 The product of Example 3 is activated as in Example 5 and then treated with 3-(4- fluoroanilino)-l-propanol instead of N-methylbenzylamine to give the title compound.
  • Example 68 The product of Example 68 is tteated with succinic anhydride, as published in Tetrahedron Letts. 1989, 30, 5045-48, to give the title compound.
  • Example 3 The product of Example 3 was activated as in Example 5 and then tteated with isonicotinic acid hydrazide instead of N-methylbenzylamine to give the tide compound.
  • the product of Example 3 was activated as in Example 5 and then treated with m-fluoroamline instead of N-methylbenzylamine to give the title compound.
  • MS (FAB) m/z: M+2K-H 1045.
  • Example 3 The product of Example 3 is activated as in Example 5 and then tteated with
  • Example 3 The product of Example 3 is activated as in Example 5 and then tteated with 1-naphthylamine instead of N-methylbenzylamine to give the title compound.
  • Example 3 The product of Example 3 is activated as in Example 5 and then tteated with py ⁇ olidine instead of N-methylbenzylamine to provide the title compound.
  • Ascomycin (10 g, .012 mol) was dissolved in distiUed CH2CI2 (50 ml).
  • Rhodium (E) acetate dimer 100 mg was added and the mixture cooled to 0 °C.
  • 9-Fluorenylmethyl diazoacetate (3.35 g, .012 mol) was dissolved in CH2CI2 (10 mL) and the solution added to the reaction via syringe pump at a rate of approximately 0.5 mL/hour. Addition was complete in approximately 24 hours.
  • the reaction was sti ⁇ ed at 0 °C for an additional 24 hours then loaded onto siUca (230-400 mesh, 400 g) and the solvent evaporated by airflow in the hood.
  • the adsorbed siUca was layered over fresh silica (800 g) in a 1 L fritted glass funnel.
  • the silica plug was eluted with the following solvents: CH2CI2 (2 L), 3:1 CH2CI2/CH3CN (4 L), 2:1 CH2CI2/CH3CN (3 L), and 1:1 CH2CI2/CH3CN (3 L).
  • Example 80 The resultant product of Example 80 (5.10 g, 5 mmol) was dissolved in CH2CI2 ( 4 5 mL), whereupon piperidine (5 ml) was added. The solution was sti ⁇ ed at room temperature for 2 hours then transfe ⁇ ed to a separatory funnel, diluted with additional CH2CI2 (100 mL), then washed with IN HC1 (2 x 100 mL) and brine (2 x 100 mL). The organic layer was dried (Na2SO4), filtered, and the solvent removed in vacuo to give 5.08 g of a mixture of the title compound and N-(9-fluorenylmethyl)piperidine. MS (FAB) m/z 888 (M+K), 926 (M+2K- H).
  • Example 81 The product of Example 81 (100 mg, .118 mmol) was dissolved in dichloromethane (1 mL) and the solution cooled to 0 °C. HOBT ⁇ 2O (21.6 mg, .142 mmol) was added followed by ED AC (27.1 mg, .142 mmol) then phenethylamine (26.7 ⁇ L, .212 mmol). The reaction was warmed to room temperature and sti ⁇ ed overnight. Dichloromethane (10 mL) was added and the organic phase washed with IN HC1 (2 x 20 mL), saturated bicarbonate solution (2 x 20 mL), and then brine (2 x 20 mL).

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Abstract

L'invention concerne des composés macrocycliques immunorégulateurs représentés par la formule (I) ainsi que des sels pharmaceutiquement acceptables, des esters, des amides et des promédicaments de ces derniers, et des compositions pharmaceutiques les contenant et présentant une activité immunodépressive, antimicrobienne, antivirale, anti-inflammatoire et antiproliférative ainsi que la capacité d'inverser la résistance aux médicaments chimiothérapeutiques.
EP94910923A 1993-03-17 1994-03-11 IMMUNOREGULATEURS A l'AMIDE MACROCYCLIQUE ET A L'UREE Withdrawn EP0689545A4 (fr)

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US6376517B1 (en) * 1998-08-14 2002-04-23 Gpi Nil Holdings, Inc. Pipecolic acid derivatives for vision and memory disorders
US6121257A (en) * 1999-03-31 2000-09-19 Abbott Laboratories Sulfamate containing macrocyclic immunomodulators
GB0125443D0 (en) 2001-10-23 2001-12-12 Novartis Ag Organic Compounds
AU2003272471B2 (en) 2002-09-18 2010-10-07 Trustees Of The University Of Pennsylvania Method of inhibiting choroidal neovascularization
US7920906B2 (en) 2005-03-10 2011-04-05 Dexcom, Inc. System and methods for processing analyte sensor data for sensor calibration
US9247900B2 (en) 2004-07-13 2016-02-02 Dexcom, Inc. Analyte sensor
US20060270922A1 (en) 2004-07-13 2006-11-30 Brauker James H Analyte sensor
MX2007008662A (es) * 2005-01-20 2007-09-06 Array Biopharma Inc Analogos macrociclicos para el tratamiento de trastornos inmunorreguladores y enfermedades respiratorias.
AU2006213673A1 (en) 2005-02-09 2006-08-17 Santen Pharmaceutical Co., Ltd. Formulations for ocular treatment
CA2635797C (fr) 2006-02-09 2015-03-31 Macusight, Inc. Formulations stables et leurs procedes de preparation et d'utilisation
JP5506378B2 (ja) 2006-03-23 2014-05-28 参天製薬株式会社 血管透過性に関連する疾患または病気のための製剤および方法

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WO1995009857A1 (fr) * 1993-10-04 1995-04-13 Merck & Co., Inc. Macrolides o-aryle, o-alkyle, o-alcenyle et o-alcynyles immunosuppresseurs

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US5250678A (en) * 1991-05-13 1993-10-05 Merck & Co., Inc. O-aryl, O-alkyl, O-alkenyl and O-alkynylmacrolides having immunosuppressive activity

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CA2103454A1 (fr) * 1991-09-05 1993-03-06 Jay R. Luly Immunomodulateurs macrocycliques
WO1993004680A1 (fr) * 1991-09-05 1993-03-18 Abbott Laboratories Immunomodulateurs macrocycliques
WO1995009857A1 (fr) * 1993-10-04 1995-04-13 Merck & Co., Inc. Macrolides o-aryle, o-alkyle, o-alcenyle et o-alcynyles immunosuppresseurs

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