Patente US5561139 - Substituted alicyclic-aliphatic amine-containing macrocyclic immunomodulators - Google Patentes\nCompounds having the formula ##STR1## and the pharmaceutically acceptable salts, esters, amides and prodrugs thereof, wherein one of R104 and R105 is hydrogen, and the other of R104 and R105 is a radical having the formula ##STR2## as well as pharmaceutically compositions containing such compounds and...http://www.google.es/patents/US5561139?utm_source=gb-gplus-sharePatente US5561139 - Substituted alicyclic-aliphatic amine-containing macrocyclic immunomodulators\nNúmero de publicación US5561139 A\nNúmero de solicitud US 08/419,784\nTambién publicado como US5530120, WO1994021634A1\nNúmero de publicación 08419784, 419784, US 5561139 A, US 5561139A, US-A-5561139, US5561139 A, US5561139A\nInventores Jay R. Luly, Megumi Kawai\nCitas de patentes (1), Citada por (5), Clasificaciones (7), Eventos legales (6)\nSubstituted alicyclic-aliphatic amine-containing macrocyclic immunomodulators\nUS 5561139 A\nCompounds having the formula ##STR1## and the pharmaceutically acceptable salts, esters, amides and prodrugs thereof, wherein one of R104 and R105 is hydrogen, and the other of R104 and R105 is a radical having the formula ##STR2## as well as pharmaceutically compositions containing such compounds and methods of immunomodulative therapy utilizing the same.\n1. A method for providing immunomodulation comprising administering to a human in need of such treatment a therapeutically effective amount of a compound having the formula: ##STR7## or a pharmaceutically acceptable salt, ester, amide or prodrug thereof, wherein;\nR100 is selected from the group consisting of hydrogen, hydroxy, halogen and --OR8 ;\nR101 is selected from the group consisting of methyl, ethyl; allyl and propyl;\nR102 is hydrogen and R103 is selected from the group consisting of (a) hydrogen, (b) hydroxy, and (c) hydroxy protected by a hydroxy-protecting group selected from tri(C1 -C8 -loweralkyl)silyl, C1 -C8 -loweralkyldiarylsilyl, triarylsilyl, [tri(arylC1 -C12 -alkyl)silyl]tri(aryl-C1 -C12 -alkyl)silyl, triphenylmethyl-dimethylsilyl, trimethylsilylethoxycarbonyl, methylthiomethyoxyethoxycarbonyl, benzenesulfonylethoxycarbonyl, trimethylsilylethoxymethyl and aryl--C(O)-- or, taken together, R102 and R103 form a bond; and\none of R104 and R105 is hydrogen, and the other of R104 and R105 is a radical having the formula ##STR8## where X is selected from the group consisting of --N=, --CH=, --NH(CH2)(CH2)N= and --NH(CH2)(CH2)(CH2)N=;\nm, p, and q are integers independently selected from the group consisting of zero, one, two and three, such that the sum (m+p+q) is between zero and six;\nW is selected from the group consisting of --CH=and --N=;\nY is selected from the group consisting of oxygen; --S(O)s -- where s is an integer selected from the group consisting of zero, one and two; --N(R8)-- and --C(R20)(R20')-- wherein R8, R20 and R20' are as defined below;\nZ is selected from the group consisting of --(CH2)n -- and (C2 -to-C6 alkylidene) substituted with between one and three radicals independently selected from selected from the group consisting of --OR8, --S(O)s R8, --S(O)2 NR8 R8', --NR8 R8', --SO3 H, =NOR8, --R399 and --R400 wherein R8, R8', R399 and R400 are independently as defined below; and\nR1 and R2 are independently selected from the group consisting of (i) hydrogen; (ii) aryl substituted by R301, R302 and R303 wherein R301, R302 and R303 are as defined below; (iii) heterocyclic substituted by R301, R302 and R303 wherein R301, R302 and R303 are as defined below; and (iv) alkyl having j carbon atoms, where j is an integer between 1 and 10, substituted with between zero and 5 but no more than j radicals selected from the group consisting of --OR8, --S(O)s R8 wherein s is independently defined as above, --S(O)2 NR8 R8', --NR8 R8', --SO3 H, =NOR8, --R399 and --R400 wherein R8, R8', R399 and R400 are independently as defined below;\nor, taken together, Y and R2 form a trivalent radical selected from the group consisting of --(CH2)3 --N= and --O--(CH2)2--N=;\nand where n is an integer between zero and five, inclusive, with the proviso that when Z is --(CH2)n -- and n is one, X is --CH=;\nR20 and R20° are independently selected from the group consisting of hydrogen, hydroxy, hydroxy-C1 -C8 -alkyl, R402 --C(O)--N(R401)--C1 -C8 -alkyl wherein R401 and R402 are independently selected from hydrogen, C1 -C8 -alkyl, aryl, aryl-C1 -C12 -alkyl and halosubstituted-C1 -C12 -alkyl and N,N-di-(C1 -C12 -alkyl)amino, or, taken together, R20 and R20° are selected from the group consisting of oxo, thiooxo and --O(CH2)i O--, where i is selected from the group consisting of two, three and four;\nR399 is selected from the group consisting of\n(iii) --C(O)OR8 wherein R8 is independently defined as below;\n(iv) --(C3 -to-C7 cycloalkyl);\n(x) --N3 ;\n(xi) --NO2 ;\n(xii) --OR11' wherein R11' is independently defined as below;\n(xiii) --OR12' wherein R12' is independently defined as below;\n(xiv) --OR12" wherein R12" is independently defined as below; and\n(xv) guanidino substituted by a radical selected from the group consisting of hydrogen, C1 -C8 -loweralkyl, aryl, C1 -C12 -alkyl--C(O)-- or aryl--C(O)--, arylsulfonyl, C1 -C8 -alkoxycarbonyl, aryl-C1 -C12 -alkoxycarbonyl, aryloxycarbonyl and C1 -C12 -alkylsulfonyl;\nR400 is selected from the group consisting of\n(i) aryl substituted by R301, R302 and R303 ;\n(ii) --Q--aryl where aryl is substituted by R301, R302 and R303 ;\n(iii) heterocyclic substituted by R301, R302 and R303 ;\n(iv) --Q--heterocyclic where heterocyclic is substituted by R301, R302 and R303 ;\n(v) biaryl substituted by R301, R302 and R303 ;\n(vi) --Q--biaryl where biaryl is substituted by R301, R302 and R303 ;\n(vii) -aryl--Q--aryl' where aryl and aryl' are the same or different and are independently substituted by R301, R302 and R303 ;\n(viii) -aryl--Q--heterocyclic where heterocyclic and aryl are independently substituted by R301, R302 and R303 ;\n(ix) -heterocyclic--Q--aryl where heterocyclic and aryl are independently substituted by R301, R302 and R303 ;\n(x) -heterocyclic-aryl where heterocyclic and aryl are independently substituted by R301, R302 and R303 ; and\n(xi) -aryl-heterocyclic where heterocyclic and aryl are independently substituted by R301, R302 and R303 wherein R301, R302 and R303 are independently defined as below;\n--Q--is selected from the group consisting of\n(i) --(C1 -to-C6 alkyl)--,\n(ii) --(C2 -to-C6 alkenyl)--,\n(iii) --(C2 -to-C6 alkynyl)--,\n(iv) --(CH2)m "O-- where m" is an integer between zero and six, inclusive,\n(v) --O(CH2)m "-- wherein m" is defined as above,\n(vi) --N(R8)C(O)-- wherein R8 is independently defined as below,\n(vii) --C(O)N(R8)-- wherein R8 is independently defined as below,\n(viii) --S(O)s -- wherein s is independently defined as above,\n(ix) --N(R8)-- wherein R8 is independently defined as below,\n(x) --N(R8)S(O)2 -- wherein R8 is independently defined as below,\n(xi) --S(O)2 N(R8)-- wherein R8 is independently defined as below,\n(xvi) --ONCH--, and\nR8 and R8' are independently selected from the group consisting of\n(ii) aryl substituted by R301, R302 and R303 ;\n(iv) --(C1 -to-C6 alkyl) substituted by R331, R332 and R333 ;\n(v) --(C3 -to-C6 alkenyl) substituted by R331, R332 and R333 ; and\n(vi) --(C3 -to-C6 alkynyl) substituted by R331, R332 and R333 wherein R301, R302, R303, R331, R332 and R333 are independently defined as below;\nR331, R332 and R333 are independently selected from the group consisting of\n(C) [[mono-- or dialkylamino]]C1 -C12 -alkylamino, di--(C1 -C12 -alkyl)amino, C3 -C8 -cycloalkylamino, di--(C3 -C8 -cycloalkyl)amino or (C3 -C8 -cycloalkyl)(C1 -C12 -alkyl)amino,\n(G) C1 -C8 -alkylthioether,\n(H) C1 -C8 -alkylether,\n(J) C1 -C8 -alkoxycarbonyl,\n(K) aryl-C1 -C12 -alkoxycarbonyl,\n(L) C1 -C8 -alkoxycarbonylamino,\n(M) C1 -C12 -alkyl--C(O)--NH-- or aryl--C(O)--NH--,\n(N) aryl-C1 -C12 -alkoxycarbonylamino,\n(P) acylguanidino wherein acyl is C1 -C12 -alkyl--C(O)-- or aryl-C(O)--,\n(R) C1 -C8 -alkoxycarbonylguanidino,\n(T) aryl-C1 -C12 -alkoxycarbonylguanidino,\n(V) (C1 -C12 -alkyl)NHC(O)--,\n(X) (C1 -C12 -alkyl)(C1 -C12 -alkyl)NHO(O)--,\n(AA) --OSO2 R11, where R11 is independently selected from the group consisting of C1 -C8 -loweralkyl, aryl-C1 -C12 -alkyl substituted by R301, R302 and R303, and aryl substituted by R301, R302 and R303 wherein R301, R302 and R303 are independently defined as below;\n(FF) aryl-C1 -C12 -alkylether,\n(GG) aryl-C1 -C12 -alkylthioether,\n(JJ) (heterocylic)-C1 -C12 -alkylether,\n(KK) (heterocyclic)-C1 -C12 -alkylthioether,\n(NN) --SO3 H,\n(OO) --S(O)2 NR16' R16" wherein R16 and R16' are independently defined as below, and\n(PP) --S(O)s R14',\nwhere each aryl and heterocyclic moiety is independently substituted by R301, R302 and R303,\nR14' is selected from the group consisting of hydrogen, C1 -C8 -loweralkyl, aryl-C1 -C12 -alkyl, C3 -C8 -cycloalkyl and C3 -C8 -cycloalkyl-C1 -C8 -alkyl, and\nR16' and R16" are independently selected from the group consisting of hydrogen, C1 -C8 -loweralkyl, hydroxy-C1 -C8 -loweralkyl, carboxy-C1 -C8 -alkyl, C1 -C8 -thioloweralkyl, C1 -C8 -thioalkoxy-C1 -C8 -alkyl, guanidino-C1 -C8 -alkyl, aminoalkyl of the formula (R403)(R404)N--C1 -C8 -alkyl wherein R403 and R404 are independently selected from hydrogen, C1 -C8 -alkyl, aryl and aryl-C1 -C12 -alkyl or R403 and R404, taken together, are --(CH2)bb -- wherein bb is 2-6 and aryl-C1 -C12 -alkyl,\nor, when appended to a nitrogen atom, R8 and R8' and the nitrogen atom to which they are connected form a 3- to 7-membered heterocyclic ring;\nR301, R302 and R303 are independently selected from the group consisting of\n(ii) --(C1 -to-C7 alkyl);\n(iii) --(C2 -to-C6 alkenyl);\n(v) --(CH2)m NR8 R8' wherein m, R8 and R8' are independently defined as above where m is an integer between zero and six, inclusive;\n(viii) mono-, di-, tri-, or perhalogenated-C1 -C12 -alkyl;\n(ix) --S(O)s R8 wherein s and R8 are independently defined as above;\n(x) --C(O)NR8 R8' wherein R8 and R8' are independently defined as above;\n(xi) --(CH2)m OR8 wherein m and R8 are independently defined as above;\n(xii) --CH(OR12')(OR12"), where R12' and R12" are independently --(C1 -to-C3 alkyl) or, taken together, form an ethylene or propylene bridge;\n(xiii) --(CH2)m OC(O)R8 wherein m and R8 are independently defined as above;\n(xiv) --(CH2)m C(O)OR8 wherein m and R8 are independently defined as above;\n(xv) --OR11', where R11' is selected from the group consisting of\n(B) --SO3 H, and\n(C) --C(O)(CH2)m C(O)OH wherein m is independently defined as above;\n(xvi) --S(O)2 NR8 R8', where t is one or two and R8 and R8' are independently defined as above;\n(xvii) --NO2 ;\n(xviii) --N3 ; and\n(xviv) guanidino optionally substituted by a radical selected from the group consisting of C1 -C8 -loweralkyl, aryl, C1 -C12 -alkyl--C(O)-- or aryl--C(O)--, arylsulfonyl, C1 -C8 -alkoxycarbonyl, aryl-C1 -C12 -alkoxycarbonyl, aryloxycarbonyl and C1 -C12 -alkylsulfonyl,\nsubject to the proviso that each of substituents R301, R302 and R303 may comprise no more than twenty non-hydrogen atoms;\nor, taken together, any two adjacent R301, R302 and R303 and the atoms to which they are attached may form a carbocyclic or heterocyclic ring;\nwherein at each occurrence aryl is independently selected from phenyl, 1-naphthyl, 2-naphthyl, fluorenyl, (1,2)-dihydronaphthyl, (1,2,3,4--)-tetrahydronaphthyl, indenyl and indanyl; and at each occurrence heterocyclic is independently selected from the group consisting of pyrrolyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, cytosinyl, thiocytosinyl. imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, xanthenyl, xanthonyl, xanthopterinyl, oxazoyl, oxazolidinyl, thiouracilyl, isoxazolyl, isoxazolidinyl, morpholinyl, indolyl, quinolinyl, uracilyl, urazolyl, uricyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, isoquinolinyl, thyminyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thienyl and benzothienyl wherein any carbon or heteroatom with suitable valence may bear a substituent selected at each occurrence from R301,R302 and R303 independently as defined above.\n2. A method according to claim 1 wherein R100 is hydrogen.\n3. A method according to claim 1 wherein R101 is ethyl.\n4. A method according to claim 1 wherein R102 is hydrogen.\n5. A method according to claim 1 wherein R103 is hydroxy.\n6. A method according to claim 1 wherein R104 is hydrogen.\n7. A method according to claim 1 wherein R105 is a radical having the formula ##STR9## where X is --N=, and W, Y, Z, R1, R2, m, p and q are as defined therein.\n8. A method according to claim 7 wherein W is --CH=.\n9. A method according to claim 8 wherein Z is --(CH2)3 --.\n10. A method for providing immunomodulation comprising administering to a human in need of such treatment a therapeutically effective amount of a compound having the formula; ##STR10## wherein one of R104 and R105 is hydrogen, and the other of R104 and R105 is a radical having the formula: ##STR11## wherein (a) R100 =H; R101 =ethyl; R102 =H; R103 =tert-butyldimethylsilyloxy; R104 =H; R1 =H; Z=(CH2)2 ; W=CH; X=--N=; R2 =H; m=1; p=2; q=0; and Y=O;\n(b) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; R1 =H; Z=(CH2)2; W=CH; X=--N=; R2 =H; m=1; p=2; q=0; and Y=O;\n(c) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)2; W=CH; X=--CH=; R2 =H; m=2; p=0; q=0; and Y=NMe;\n(d) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)3; W=CH; X=--N=; R2 =CH3; m=1; p=2; q=0; and Y=CH2 ;\n(e) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)0; W=CH; X=--CH=; R2 =H; m=1; p=2; q=0; and Y=N(benzyl);\n(f) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)3; W=CH; X=--N=; R2 =H; m=1; p=2; q=0; and Y=CH2 ;\n(g) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)3; W=CH; X=--N=; R2 =H; m=2; p=2; q=0; and Y=CH2 ;\n(h) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)3; W=CH; X=--N=; R2 =H; m=1; p=1; q=0; and Y=CH2 ;\n(i) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)3; W=CH; X=--N=; R2 =H; m=1; p=2; q=0; and Y=NCH3 ;\n(j) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)0; W=CH; X=--CH=; R2 =H; m=1; p=1; q=0; and Y=N(benzyl);\n(k) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)0; W=CH; X=--CH=; R2 and Y taken together=--N--CH2 CH2 --; m=2; and p=1;\n(k) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)2; W=CH; X=--N=; R2 =H; m=1; p=2; q=0; and Y=CH2 ;\n(l) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)1; W=CH; X=--CH=; R2 =H; m=2; p=0; q=0; and Y=NEt;\n(m) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)3 ; W=CH; X=--N=; R2 =H; m=0; p=2; q=1; and Y=O;\n(n) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)2 ; W=CH; X=--N=; R2 =H; m=1; p=2; q=0; and Y=NH;\n(o) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)2 ; W=CH; X=--N=; R2 =H; m=0; p=0; q=2; and CH2 ;\n(p) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)0; W=CH; X=--CH=; R2 =H; m=2; p=1; q=0; and Y=NEt;\n(q) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)2 ; W=CH; X=--N=; R2 =H; m=0; p=0; q=0; and Y=CH2 ;\n(r) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)2 ; W=CH; X=--N=; R2 =H; m=2; p=2; q=0; and Y=CH2 ;\n(s) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)2 ; W=CH; X=--NH--CH2CH2N=; R2 =H; m=1; p=1; q=0; and Y=CH2 ;\n(t) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)2 ; W=CH; X=--NH--CH2CH2N=; R2 =H; m=1; p=2; q=0; and Y=O;\n(u) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)2 ; W=CH; X=--NH--CH2CH2N=; R2 =H; m=1; p=2; q=0; and Y=CH2 ;\n(v) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =Me; Z=(CH2)0; W=CH; X=--CH=; R2 =H; m=1; p=2; q=0; and Y=NMe;\n(w) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =Me; Z=(CH2)0; W=CH; X=--CH=; R2 =H; m=1; p=1; q=0; and Y=NMe;\n(x) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =Et; Z=(CH2)0; W=CH; X=--CH=; R2 =H; m=1; q=0; and Y=NEt;\n(y) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =--CH2-(3-pyridyl); Z=(CH2)2 ; W=CH; X=--N=; R2 =H; m=1; p=2; q=0; and Y=NH;\n(z) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =--(CH2)2--OH; Z=(CH2)2 ; W=CH; X=--N=; R2 =H; m=1; p=2; q=0; and Y=O;\n(aa) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =--(CH2)2--NH2; Z=(CH2)2 ; W=CH; X=--N=; R2 =H; m=1; p=1; q=0; and Y=CH2 ;\n(bb) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =--(CH2)2--NH2; Z=(CH2)2 ; W=CH; X=--N=; R2 =H; m=1; p=2; q=0; and Y=O;\n(cc) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =--(CH2)2--NH2; Z=(CH2)2 ; W=CH; X=--N=; R2 =H; m=1; p=2; q=0; and Y=CH2 ;\n(dd) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =--(CH2)2--CO2H; Z=(CH2)3 ; W=CH; X=--N=; R2 =H; m=1; p=1; q=0; and Y=CH2 ;\n(ee) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)3; W=CH; X=--N=; R2 =CO2H; m=1; p=1; q=0; and Y=CH2 ;\n(ff) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)2; W=CH; X=--CO--N=; R2 =H; m=1; p=1; q=0; and Y=CH2 ;\n(gg) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)2; W=CH; X=--O--(CH2)2N=; R2 =H; m=1; p=1; q=0; and Y=CH2 ;\n(hh) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)3; W=CH; X=--N=; R2 =H; m=1; p=2; q=0; and Y=N(acetyl);\n(ii) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)3; W=CH; X=--N=; R2 =H; m=1; p=2; q=0; and Y=S;\n(jj) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)0; W=CH; X=--CH=; R2 =H; m=1; p=2; q=0; and Y=N--(CH2)3-NH-(t-butyloxycarbonyl);\n(kk) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)0; W=CH; X=--CH=; R2 =H; m=1; p=2; q=0; and Y=N--(CH2)3--NH2 ;\n(ll) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)3; W=CH; X=--N=; R2 =H; m=1; p=2; q=0; and Y=CH--NHBoc;\n(mm) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)3; W=CH; X=--N=; R2 =H; m=1; p=2; q=0; and Y=CH--NH2 ;\n(nn) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R105 =H; R1 =H; Z=(CH2)3; W=CH; X=--N=; R2 =H; m=1; p=2; q=0; and Y=CH2 ;\n(oo) R100 =H; R101 =ethyl; R102 and R103 taken together form a bond; R104 =H; R1 =H; Z=(CH2)3; W=CH; X=--N=; R2 =H; m=1; p=2; q=0; and Y=CH2 ;\n(pp) R100 =H; R101 =ethyl; R102 =H; R103 =H; R104 =H; R1 =H; Z=(CH2)3; W=CH; X=--N=; R2 =H; m=1; p=2; q=0; and Y=CH2 ;\n(qq) R100 =H; R101 =propyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)3; W=CH; X=--N=; R2 =H; m=1; p=2; q=0; and Y=CH2 ;\n(rr) R100 =H; R101 =methyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)3; W=CH; X=--N=; R2 =H; m=1; p=2; q=0; and Y=CH2 ;\n(ss) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)1; W=N; X=--CH=; R2 =benzyl; m=2; p=0; q=1; and Y=O;\n(tt) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)1; W=N; X=--CH=; R2 =benzyl; m=3; p=0; q=1; and Y=O;\n(uu) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)0; W=CH; X=--CH=; R2 and Y taken together are --(CH2)3--N--; m=1; p=1; and q=0 (exo isomer);\n(vv) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)0; W=CH; X=--CH=; R2 and Y taken together are --(CH2)3--N--; m=1; p=1; and q=0 (endo isomer);\n(ww) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)0; W=CH; x=--CH=; R2 and Y taken together are --O--(CH2)2 -N-; m=1; p=2; and q=0 (endo isomer);\n(xx) R100 =OH; R101 =ethyl; R102 =H; R103 =H; R104 =H; R1 =H; Z=(CH2)3; W=CH; X=--N=; R2 =H; m=1; p=2; q=0; and Y=CH2 ;\n(yy) R100 =F; R101 =ethyl; R102 =H; R103 =H; R104 =H; R1 =H; Z=(CH2)3; W=CH; X=--N=; R2 =H; m=1; p=2; q=0; and Y=CH2 ;\n(zz) R100 =OC(O)CH3 ; R101 =ethyl; R102 =H; R103 =H; R104 =H; R1 =H; Z=(CH2)3; W=CH; X=--N=; R2 =H; m=1; p=2; q=0; and Y=CH2 ; and\n(aaa) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)3; W=CH; X=--N=; R2 =H; m=1; p=2; q=0; and Y=CH2 ;\nor a pharmaceutically acceptable salt, ester, amide or prodrug thereof.\n11. A method for providing immunomodulation comprising administering to a human in need of such treatment a therapeutically effective amount of a compound having the formula: ##STR12## wherein one of R104 and R105 is hydrogen, and the other of R104 and R105 is a radical having the formula ##STR13## wherein (a) R100 =H; R101 =ethyl; R102 =H; R103 =tert-butyldimethylsilyloxy; R104 =H; R1 =H; Z=(CH2)2 ; W=CH; X=--N=; R2 =H; m=1; p=2; q=0; and Y=O;\n(b) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)2 ; W=CH; X=--N=; R2 =H; m=1; p=2; q=0; and Y=O;\n(e) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)0 ; W=CH; X=--CH=; R2 =H; m=1; p=2; q=0; and Y=N(benzyl);\n(f) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)3 ; W=CH; X=--N=; R2 =H; m=1; p=2; q=0; and Y=CH2 ;\n(o) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)2 ; W=CH; X=--N=; R2 =H; m=0; p=0; q=2; and Y=CH2 ;\n(z) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; --(CH2)2--OH; Z=(CH2)2 ; W=CH; X=--N=; R2 =H; m=1; p=2; q=0; and Y=O;\n(mm) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R105 =H; R1 =H; Z=(CH2)3; W=CH; X=--N=; R2 =H; m=1; p=2; q=0; and Y=CH2 ; and\n(zz) R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)3; W=CH; X=--N=; R2 =H; m=1; p=2; q=0; and Y=CH2 ;\nThis application is a division of U.S. patent application Ser. No. 08/343,266, filed Nov. 21, 1994, which is a continuation of U.S. patent application Ser. No. 08/100,512, filed Jul. 30, 1993, which is a continuation-in-part of the U.S. patent application Ser. No. 08/032,958, filed on Mar. 17, 1993 now abandoned.\nThe present invention relates to novel chemical compounds having immunomodulatory activity, and in particular to macrotide immunosuppressants. More particularly, the invention relates to semisynthetic analogs of ascomycin and FK-506, means for their preparation, pharmaceutical compositions containing such compounds and methods of treatment employing the same.\nRecently, several classes of macrocyclic compounds having potent immunomodulatory activity have been discovered. Okuhara et al., in European Patent Application No. 184162, published Jun. 11, 1986, disclose a number of macrocyclic compounds isolated from the genus Streptomyces. Immunosuppressant FK-506, isolated from a strain of S. tsukubaensis, is a 23-membered macrocyclic lactone represented by formula 1a, below. Other related natural products, such as FR-900520 (1b) and FR-900523 (1c), which differ from FK-506 in their alkyl substituent at C-21, have been isolated from S. hygroscopicus yakushimnaensis. Yet another analog, FR-900525, produced by S. tsukubaensis, differs from FK-506 in the replacement of a pipecolic acid moiety with a proline group.\nFR-900520, also known as ascomycin, has been previously disclosed by Aral et al. in U.S. Pat. No. 3,244,592, issued Apr. 5, 1966, where the compound is described as an antifungal agent. Monaghan, R. L., et al., on the other hand, describe the use of ascomycin as an immunosuppressant in European Patent Application No. 323865, published Jul. 12, 1989.\nFermentation products of FK-type compounds include C-21-epi derivatives of FK-506; a 31-demethylatod 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. Several microbial transformations of FK-type compounds at carbon 13 have been published, such as the microbial demethylation of FR-900520 to form the bis-demethylated 13,31-dihydroxy ring-rearranged derivative of FR-900520; the microbial monodemethylation of FK-506 and FR-900520, respectively; and the microbial demethylation of FR-900520 at C-31, as well as a number of other macrocyclic microbial transformation products.\nNumerous chemical modifications of the FK-type compounds have been attempted. These include the preparation of small synthetic fragments of FK-type derivatives; a thermal rearrangement of a variety of derivatives of FK-506 which expands the macrocyclic ring by two carbons; and modifications which include methyl ether formation at C-32 and/or C-24, oxidation of C-32 alcohol to the ketone, and epoxide formation at C-9.\nAlthough some of these modified compounds exhibit immunosuppressive activity, the need remains for macrocyclic immunosuppressants which do not have the serious side effects frequently associated with immunosuppressant therapy. Accordingly, one object of the invention is to provide novel semisynthetic macrolides which possess the desired immunomodulatory activity but which may be found to minimize-untoward side effects.\nA further object of the invention is to provide pharmaceutic-al 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.\nIn one aspect of the present invention are disclosed compounds having the formula ##STR4## and the pharmaceutically acceptable salts, esters, amides and prodrugs thereof, wherein:\nR100 is hydrogen, hydroxy, halogen or --OR8 ;\nR101 is methyl, ethyl, allyl or propyl;\nR102 is hydrogen and R103 is (a) hydrogen, (b) hydroxy, or (c) hydroxy protected by a hydroxy-protecting group or, taken together, R102 and R103 form a bond; and\none of R104 and R105 is hydrogen, and the other of R104 and R105 is a radical having the formula ##STR5## where X is --N*═, --C*H═, --NH(CH2)(CH2)N*=, or --NH(CH2)(CH2)(CH2)N*═such that the atom labeled with an asterisk (*) is joined to ring members (CH2)p and (CH2)q ;\nm, p, and q are independently zero, one, two or three, the sum (m+p+q) being between zero and six, inclusive;\nW is --CH═ or --N═;\nY is oxygen, --N(RS)--, --C(R20)(R20')--, and --S(O)s -- where s at each of this and any other occurrence is zero, one or two;\nZ is --(CH2)n -- or --(C2 --to--C6 alkylidene)-- substituted with one, two or three radicals independently selected from --OR8, --S(O)s R8, --S(O)2 NR8 R8', --NR8 R8', --SO3 H, ═NOR8, --R399 and --R400, and\nR1 and R2 are independently chosen from (i) hydrogen; (ii) aryl substituted by R301, R302 and R303 ; (iii) heterocyclic substituted by R301, R302 and R303 ; and (iv) alkyl having j carbon atoms where j is an integer between 1 and 10, inclusive, substituted with between zero and 5 but no more than j radicals --OR8, --S(O)s R8, --S(O)2 NR8 R8', --NR8 R8', --SO3 H, ═NOR8, --R399 or --R400.\nAlternatively, Y and R2 taken together may form --(CH2)3 --N═ or 'O--(CH2)2 --N═ such that the nitrogen atom in each instance is joined to the ring members (CH2)q and (CH2)m.\nThe number n in the above is an integer between zero and five, inclusive, with the proviso that when Z is --(CH2)n -- and n is one, X is --CH═.\nThe radicals R20 and R20' in the above are independently hydrogen, hydroxy, hydroxyalkyl, amidoalkyl or N,N-dialkylamino; or, taken together, R20 and R20' are oxo, thiooxo or --O(CH2)i O--, where i is two, three or four.\nThe radical R399 in the above is\n(iii) --C(O)OR8 ;\n(iv) --(C3 --to--C7 cycloalkyl);\n(xii) --OR11' ;\n(xiii) --OR12' ;\n(xiv) --OR12" ; or\n(xv) guanidino substituted by hydrogen, loweralkyl, aryl, acyl, arylsulfonyl, alkoxycarbonyl, arylalkoxycarbonyl, aryloxycarbonyl or alkylsulfonyl.\nThe radical R400 in the above is\n(vii) --aryl--Q--aryl' where aryl and aryl are the same or different and are independently substituted by R301, R302 and R303 ;\n(viii) --aryl--Q--heterocyclic where heterocyclic and aryl are independently substituted by R301, R302 and R303 ;\n(ix) --heterocyclic--Q--aryl where heterocyclic and aryl are independently substituted by R301, R302 and R303 ;\n(x) --heterocyclic--aryl where heterocyclic and aryl are independently substituted by R301, R302 and R303 ; and\n(xi) --aryl--heterocyclic where heterocyclic and aryl are independently substituted by R301, R302 and R303,\nwhere the divalent radical --Q--is\n(i) --(C1 --to--C6 alkyl)--,\n(ii) --(C2 --to--C6 alkenyl)--,\n(iii) --(C2 --to--C6 alkynyl)--,\n(iv) --(CH2)m" O-- where m" is between zero and six, inclusive,\n(v) --O(CH2)m" --,\n(viii) ----S(O)s --,\n(x) --N(R8)S(O)2 --,\n(xi) --S(O)2 N(R8)--,\n(xvi) --ONCH--, or\nThe radicals R8 and R8' in the above are independently\n(iv) --(C1 --to--C6 alkyl) substituted by R331, R332 and R333 ;\n(v) --(C3 --to--C6 alkenyl) substituted by R331, R332 and R333 ; and\n(vi) --(C3 --to--C6 alkynyl) substituted by R331, R332 and R333.\nThe radicals R331, R332 and R333 in the above are independently\n(C) mono- or dialkylamino,\n(AA) --OSO2 R11, where R11 is loweralkyl, arylalkyl substituted by R301, R302 and R303, or aryl substituted by R301, R302 and R303 ;\n(OO) --S(O)2 NR16' R16", or\nR14' is hydrogen, loweralkyl, arylalkyl, cycloalkyl or cycloalkylalkyl, and\nR16' and R16" are independently selected from hydrogen, loweralkyl, hydroxyloweralkyl, carboxyalkyl, thioloweralkyl, thioalkoxyalkyl, guanidinoalkyl, aminoalkyl and arylalkyl.\nAlternatively, when appended to a nitrogen atom, R8 and R8' and the nitrogen atom to which they are connected may form a 3- to 7-membered heterocyclic ring which optionally includes up to two additional heteroatoms independently selected from the group consisting of --O--, --S(O)s -- and --NR8 --.\nThe radicals R301, R302 and R303 in the above are independently\n(ii) --(C1 --to--C7 alkyl);\n(iii) --(C2 --to--C6 alkenyl);\n(v) --(CH2)m NR8 R8', where m is between zero and six, inclusive;\n(viii) mono-, di-, tri-, or perhalogenated alkyl;\n(ix) --S(O)s R8 ;\n(x) --C(O)NR8 R8' ;\n(xi) --(CH2)m OR8 ;\n(Xii) --CH(OR12 ')(OR12"), where R12' and R12" are independently --(C1 --to--C3 alkyl) or, taken together, form an ethylene or propylene bridge;\n(xiii) --(CH2)m OC(O)R8 ;\n(xiv) --(CH2)m C(O)OR8 ;\n(A) --PO(OH)O--M+, wherein M+ is a proton or a positively charged inorganic or organic counterion,\n(B) --SO3 --M+, and\n(C) --C(O)(CH2)m C(O)O- M+ ;\n(xvi) --S(O)2 NR8 R8' ;\n(xviii) --N3 ; or\n(xviv) guanidino optionally substituted by a radical selected from the group consisting of loweralkyl, aryl, acyl, arylsulfonyl, alkoxycarbonyl, arylalkoxycarbonyl, aryloxycarbonyl and alkylsulfonyl,\nsubject to the proviso that each of substituents R301, R302 and R303 may comprise no more than twenty non-hydrogen atoms.\nAlternatively, taken together, any two adjacent R301, R302 and R303 and the atoms to which they are attached may form a carbocyclic or heterocyclic ring having 5, 6 or 7 ring atoms which optionally includes one or two additional heteroatoms independently selected from the group consisting of --O--,--S(O)s -- and --NR8 --.\nIn another aspect of the present invention are disclosed pharmaceutical compositions, comprising a compound of the invention in combination with a pharmaceutically acceptable carrier.\nIn a further aspect of the present invention is disclosed a method for treating a patient in need of immunomodulative therapy, comprising administering to such a patient a therapeutically effective amount of a compound of the invention for such time as is necessary to obtain the desired therapeutic effect.\nPreferred among the compounds of the present invention are those having the structural formula (I) in which R100 is hydrogen; R101 is ethyl; R102 is hydrogen; R103 is hydroxy; and/or R104 is hydrogen. Also preferred are those compounds of formula (I) in which R105 is a radical having the formula ##STR6## where X is --N═, and W, Y, Z, R1, R2, m, p and q are as previously defined. Among these, especially preferred are those in which W is --CH═ and/or Z is --(CH2)3 --.\nRepresentative of the compounds of the present invention are those which are demonstrated in Examples 4-43, 47, 54-65 and 67, below, and especially those of Examples 4, 5, 8, 9, 12, 17-19, 30, 47 and 67. The most preferred of these compounds, and that contemplated as the best mode thereof, is the compound described in Example 9 hereof.\nThe term "acylamino" as used herein refers to an aryl or alkyl group, as defined below, appended to a carbonyl group including, but not limited to, acetyl, pivaloyl, benzoyl and the like.\nThe term "acylguanidino" as used herein refers to an acyl group, as defined above, appended to a nitrogen of a guanidino radical in one of three ways: HN(acyl)C(NH)NH-- or H2 NC(NH)N(acyl)-- or (acyl)NC(NH2)HN--.\nThe term "alkenyl" as used herein refers to straight or branched chain groups of 2 to 12 carbon atoms containing a carbon-carbon double bond including, but not limited to ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like.\nThe terms "alkoxy" and "alkylether" as used herein refer to a loweralkyl group, as defined below, attached to the remainder of the molecule through an oxygen atom including, but not limited to, methoxy, ethoxy, isopropoxy, n-butoxy, secobutoxy, isobutoxy, tert-butoxy and the like.\nThe term "alkoxycarbonylamino" as used herein refers to an alkoxycarbonyl group, as defined above, appended to an amino group including, but not limited to, methyloxycarbonylamino, tert-butyloxycarbonylamino and the like.\nThe term "alkoxycarbonylguanidino" as used herein refers to an alkoxycarbonyl group, as defined above, appended to a nitrogen of a guanidino radical in one of three ways: HN(alkoxycarbonyl)C(NH)HN--, H2 NC(NH)N(alkoxycarbonyl)-- or (alkoxycarbonyl)NC(NH2)HN--.\nThe term "allcylcarboxamido" as used herein refers to an alkylamino group, as defined above, attached via a carbonyl group and having the formula HN(alkyl)C(O)--.\nThe term "alkylidene" as used herein refers to a divalent straight or branched chain radical of 2 to 6 carbon atoms including, but not limited to, ethylidine (or --CH2 --CH2 --), isopropylidine (or --CH(CH3)--CH2 --) and the like.\nThe term "alkylsulfonyl" as used herein refers to an alkyl group, as defined above, attached via a sulfur dioxide diradical including, but not limited to, methanesulfonyl, camphorsulfonyl and the like.\nThe terms "alkylthioether", "thioalkoxy" and "thioloweralkoxy" as used herein refer to a loweralkyl group, as previously defined, attached via a sulfur atom including, but not limited to, thiomethoxy, thioethoxy, thioisopropoxy, n-thiobutoxy, sec-thiobutoxy, isothiobutoxy, tert-thiobutoxy and the like.\nThe term "alkynyl" as used herein refers to straight or branched chain groups of 2 to 12 carbon atoms containing a carbon-carbon triple bond including, but not limited to acetylenyl, propargyl and the like.\nThe term "amidoalkyl" as used herein refers to a group having the structure --N(R401)C(O)R402 appended to a loweralkyl group, as previously defined. The groups R401 and R402 are independently selected from hydrogen, lower alkyl, aryl, arylalkyl, and halosubstituted alkyl. Alternatively, R401 and R402, taken together, may be --(CH2)aa -- where aa is an integer of from two to six, inclusive.\nThe term "aminoalkyl" as used herein refers to a group having the structure --NR403 R404 appended to a loweralkyl group, as previously defined. The groups R403 and R404 are independently selected from hydrogen, lower alkyl, aryl and arylalkyl. Alternatively, R403 and R404, taken together, may be --(CH2)bb- where bb is an integer of from two to six, inclusive.\nThe terms "aryl" as used herein refers to carbocyclic aromatic groups including, but not limited to, phenyl, 1- or 2-naphthyl, fluorenyl, (1,2)-dihydronaphthyl, (1,2,3,4)-tetrahydronaphthyl, indenyl, indanyl and the like.\nThe terms "arylalkoxy" and "arylalkylether" as used herein refer to an arylalkyl group, as defined below, attached to the parent molecular moiety through an oxygen atom. Arylalkoxy includes, but is not limited to, benzyloxy, 2-phenethyloxy, 1-naphthylmethyloxy and the like.\nThe term "arylalkoxycarbonyl" as used herein refers to an arylalkoxy group, as defined above, attached via a carbonyl group including, but not limited to, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl and the like.\nThe term "arylalkoxycarbonylamino" as used herein refers to an arylalkoxy group, as defined above, attached via a carbonyl group including, but not limited to, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl and the like.\nThe term "arylalkoxycarbonylguanidino" as used herein refers to an arylalkoxycarbonyl group, as defined above, appended to a nitrogen of a guanidino radical in one of three ways:. HN(arylalkoxycarbonyl)C(NH)HN--, H2 NC(NH)N(arylalkoxycarbonyl)-- or (arylalkoxycarbonyl)NC(NH2)HN--.\nThe terms "arylalkylthioether" and "thioarylalkoxy" as used herein refer to an arylalkyl group, as previously defined, attached via a sulfur atom.\nThe term "arylcarboxamido" as used herein refers to an arylamino group, as defined above, attached via a carbonyl group and having the formula HN(aryl)C(O)--.\nThe terms "arylether" and "aryloxy" as used herein refer to an aryl group, as previously defined, attached to the parent molecular moiety through an oxygen atom. Aryloxy and arylether include, but are not limited to, phenoxy, 1-naphthoxy, 2-naphthoxy and the like.\nThe term "aryloxycarbonylamino" as used herein refers to an aryloxycarbonyl group, as defined above, appended to an amino group including, but not limited to, phenyloxycarbonylamino.\nThe term "aryloxycarbonylguanidino" as used herein refers to an aryloxycarbonyl group, as defined above, appended to a nitrogen of a guanidino moiety in one of three ways: HN(aryloxycarbonyl)C(NH)HN--, H2 NC(NH)N(aryloxycarbonyl)-- or (aryloxycarbonyl)NC(NH2)HN--.\nThe term "arylsulfonyl" as used herein refers to an aryl group, as defined above, attached via a sulfur dioxide diradical including, but not limited to p-toluenesulfonyl, benzenesulfonyl and the like.\nThe term "arylsulfonylguanidino" as used herein refers to an arylsulfonyl group, as defined above, bonded to a nitrogen of a guanidino radical in one of three ways: HN(arylsulfonyl)C(NH)HN-- or H2 NC(NH)N(arylsulfonyl)-- or (arylsulfonyl)NC(NH2)HN--.\nThe terms "arylthioether" and "thioaryloxy" as used herein refer to an aryl group, as defined above, attached via a sulfur atom.\nThe term "biaryl" as used herein refers to an aryl group, as defined above, appended to an aryl group, wherein the two aryl groups need not be identical including, but not limited to, biphenyl, phenyl-[2-naphthyl]-- and the like.\nThe term "carboxamido" as used herein refers to an amino group attached via a carbonyl group and having the formula --C(O)NH2.\nThe term "carboxyalkyl" as used herein refers to a carboxyl group, --CO2 H, appended to a loweralkyl group, as defined below.\nThe term "cycloalkyl" as used herein refers to a cyclic group of 3 to 8 carbon atoms including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.\nThe term "cycloalkylalkyl" as used herein refers to a cycloalkyl group appended to a loweralkyl group as defined below including, but not limited to, cyclohexylmethyl and cyclohexylethyl.\nThe term "dialkylamino" as used herein refers to a group having the structure --N(loweralkyl)(loweralkyl'), where the loweralkyl and loweralkyl' portions are the same or different and are as defined below. Dilkylamino groups include, for example, N,N-methylethylamino, N,N-methylisopropylamino, N,N-ethylisopropylamino and the like.\nThe term "dialkylcarboxamido" as used herein refers to an amino group substituted with two alkyl groups, as defined above, wherein the two alkyl groups need not be identical, attached via a carbonyl group and having the formula N(alkyl)(alkyl')C(O)--.\nThe term "diarylcarboxamido" as used herein refers to an amino group substituted with two aryl groups, as defined above, wherein the two aryl groups need not be identical, attached via a carbonyl group and having the formula N(aryl)(aryl')C(O)--.\nThe term "guanidinoalkyl" as used herein refers to a group of the structure --N(R405)C(═NR406)NHR407 appended to a loweralkyl group, as defined below. R405, R406 and R407 are independently selected from hydrogen, loweralkyl, heterocyclic, aminoalkyl and aryl. Alternatively, R406 and R407, taken together, may be --(CH2)cc -- where cc is an integer of from two to six, inclusive.\nThe term "heterocyclic" as used herein, except where otherwise specified, refers to any aromatic or non-aromatic 5-, 6- or 7-membered ring or a bi- or tri-cyclic group comprising fused six-membered rings having between one and three heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein (i) each 5-membered ring has 0 to 2 double bonds and each 6-membered ring has 0 to 3 double bonds, (ii) the nitrogen and sulfur heteroatoms as well as the carbon atoms may optionally be oxidized by unsaturation and/or substitution by hydroxy, thiol, oxo or thiooxo, (iii) the nitrogen heteroatom may optionally be quaternized, (iv) any of the above heterocyclic rings may be fused to a benzene ting. Representative heterocycles include, but are not limited to, pyrrolyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, cytosinyl, thiocytosinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, xanthenyl, xanthonyl, xanthopterinyl, oxazoyl, oxazolidinyl, thiouracilyl, isoxazolyl, isoxazolidinyl, morpholinyl, indolyl, quinolinyl, uracilyl, urazolyl, uricyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, isoquinolinyl, thyminyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thienyl and benzothienyl.\nThe term "(heterocyclic)alkylether" as used herein refers to a (heterocyclic)alkyl moiety, as defined above, attached via an oxygen atom.\nThe term "(heterocyclic)alkylthioether" as used herein refers to a (heterocyclic)alkyl moiety, as defined above, attached via a sulfur atom.\nThe term "(heterocyclic)ether" as used herein refers to a heterocyclic moiety, as defined above, attached via an oxygen atom.\nThe term "(heterocyclic)thioether" as used herein refers to a heterocyclic moiety, as defined above, attached via a sulfur atom.\nThe terms "hydroxyalkyl" and "hydroxyloweralkyl" as used herein refer to -0H appended to a loweralkyl group, as defined below.\nThe term "hydroxy-protecting group" as used herein refers to those groups which are known in the art to protect a hydroxy group against undesirable reaction during synthetic procedures and to be selectively removable including, but not limited to, dimethylthexylsilyl, trisubstituted silyl such as tri(lower)alkylsilyl (e.g. trimethylsilyl, triethylsilyl, tributylsilyl, tri-i-propylsilyl, tert-butyl-dimethylsilyl, tri-tert-butylsilyl, triphenylmethyl-dimethylsilyl, etc.); lower alkyldiarylsilyl (e.g. methyl-diphenylsilyl, ethyl-diphenylsilyl, propyl-diphenylsilyl, tert-butyl-diphenylsilyl, etc.), and the like; triarysilyl (e.g. triphenylsilyl, tri-p-xylylsilyl, etc.); triarylalkylsilyl (e.g. tribenzylsilyl, etc.), acyl substituted with an aromatic group and the like. Other classes of hydroxy-protecting group which may be useful include, but are not limited to, chlorocarbonate analogues such as trimethylsilylethoxycarbonyl, methylthiomethoxyethoxycarbonyl or benzenesulfonylethoxycarbonyl; trimethylsilylethoxymethyl and the like.\nThe terms "monoalkylamino" and "dialkylamino" refer respectively to one and two alkyl or cycloalkyl groups, as defined above, appended to an amino group including, but not limited to, methylamino, isopropylamino, cyclohexylamino, dimethylamino, N,N-methylisopropylamino; bis-(cyclohexyl)amino and the like.\nThe term "thioalkoxyalkyl" as used herein refers to a thioalkoxy group, as defined above, appended to a loweralkyl group.\nThe terms "thioalkyl" and "thioloweralkyl" as used herein refer to a loweralkyl group, as defined above, attached via a sulfur atom.\nThe term "pharmaceutically acceptable salts, esters, amides and prodrugs" as used herein 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 with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and 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. The term "salts" refers to the relatively nontoxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can 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. These may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium and the like, as well as 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 at., "Pharmaceutical Salts," J. Pharm. Sci., 66:1-19 (1977) which is incorporated herein by reference.)\nExamples of pharmaceutically acceptable, non-toxic esters of the compounds of this invention include C1 --to--C6 alkyl esters wherein the alkyl group is-a straight or branched chain. Acceptable esters also include C5 --to--C7 cycloalkyl esters as well as arylallcyl esters such as, but not limited to benzyl. C1 --to--C4 alkyl esters are preferred. Esters of the compounds of the present invention may be prepared according to conventional methods.\nExamples of pharmaceutically acceptable, non-toxic amides of the compounds of this invention include amides derived from ammonia, primary C1 --to--C6 alkyl amines and secondary C1 --to--C6 dialkyl amines wherein the alkyl groups are straight or branched chain. 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, C1 --to--C3 alkyl primary amides and C1 --to--C2 dialkyl secondary amides are preferred. Amides of the compounds of the invention may be prepared according to conventional methods.\nWhere appropriate, prodrugs of derivatives of compounds of the present invention may be prepared by any suitable method. For those compounds in which the prodrug moiety is an amino acid or peptide functionality, the condensation of the 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 (dicyclohexylcarbodiimede) 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).\nAs in conventional peptide sysnthesis, 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), o-chlorobenzyloxycarbonyl ((2-Cl)Z)), p-nitrobenzyloxycarbonyl (Z(NO2)), p-methoxybenzyloxycarbonyl (Z(OMe)), t-amyloxycarbonyl (Aoc), isobomealoxycarbonyl, adamantyloxycarbonyl (Adoc), 2-(4-biphenyl)-2-propyloxy carbonyl (Bpoc), 9-fluorenyl-methoxycarbonyl (Fmoc), methylsulfonylethoxy carbonyl (Msc), trifluoroacetyl, phthalyl, formyl, 2-nitrophenylsulfonyl (Nps), diphenylphosphinothioyl (Ppt) and dimethylphosphino-thioyl (Mpt).\nNumerous asymmetric centers may exist in the compounds of the present invention. Except where otherwise noted, the present invention contemplates the various stereoisomers and mixtures thereof. Accordingly, whenever a bond is represented by a wavy line, it is intended that both steric orientations are intended.\nThe compounds of the invention, including but not limited to those specified in the examples, possess immunomodulatory activity in animals. As immunosuppressants, the compounds of the present invention may be useful for the treatment and prevention of immune-mediated diseases such as the resistance by transplantation of organs or tissue such as heart, kidney, liver, medulla ossium, skin, cornea, lung, pancreas, intestinum tenue, limb, muscle, nervus, duodenum, small-bowel, pancreatic-islet-cell, etc.; graft-versus-host diseases brought about by medulla ossium transplantation; autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes uveitis, allergic encephalomyelitis, glomerulonephritis, and the like; and further infectious diseases caused by pathogenic microorganisms. Further uses may include the treatment and prophylaxis of inflammatory and hyperproliferative skin diseases and cutaneous manifestations of immunologically-mediated illnesses, such as psoriasis, atopical dermatitis, contact dermatitis and further eczematous dermatitises, seborrhoeis dermatitis, Lichen planus, Pemphigus, bullous pemphigoid, Epidermolysis bullosa, urticaria, angioedemas, vasculitides, erythemas, cutaneous eosinophilias, Lupus erythematosus, acne and Alopecia areata; various eye diseases (autoimmune and otherwise) such as keratoconjunctivitis, vemal conjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, conical cornea, dystrophia epithelialis corneae, corneat leukoma, ocular pemphigus, Mooren's ulcer, Scleritis, Graves' opthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, etc.; reversible obstructive airway disease, which includes condition such as asthma (for example, bronchial asthma, allergic 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; intimation of mucosa and blood vessels such as gastric ulcers, vascular damage caused by ischemic diseases and thrombosis, 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 colitis; food-related allergic diseases which have symptomatic manifestation remote from the gastrointestinal 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; hematic diseases such as pure red cell aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia and anerythroplasia; bone diseases such as osteoporosis; respiratory diseases such as sarcoidosis, fibroid lung and idiopathic interstitial pneumonia; skin disease such as dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity and cutaneous T cell lymphoma; circulatory diseases such as arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa and myocardosis; collagen diseases such as scleroderma, Wegener's granuloma and Sjogren's syndrome; adiposis; eosinophilic fasciitis; periodontal disease such as lesions of gingiva, periodontium, alveolar bone and substantia ossea dentis; nephrotic syndrome such as glomerulonephritis; male pattern aleopecia or alopecia senilis by preventing epilation or providing hair germination and/or promoting hair generation and hair growth; muscular dystrophy; Pyoderma and Sezary's syndrome; Addison's disease; active oxygen-mediated diseases, as for example organ injury such as ischemia-reperfusion injury of organs (such as heart, liver, kidney and digestive tract) which occurs upon preservation, transplantation or ischemic disease (for example, thrombosis and cardiac infraction): intestinal diseases such as endotoxin-shock, pseudomembranous colitis and colitis caused by drug or radiation; renal diseases such as ischemic acute renal insufficiency and chronic renal insufficiency; pulmonary diseases such as toxinosis caused by lung-oxygen or drug (for example, paracort and bleomycins), lung cancer and pulmonary emphysema; ocular diseases such as cataracta, siderosis, retinitis, pigmentosa, senile macular degeneration, vitreal scarring and comeal alkali bum; dermatitis such as erythema multifonne, linear IgA ballous dermatitis and cement dermatitis; and others such as gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution (for example, air pollution), aging, carcinogenis, metastasis of carcinoma and hypobaropathy; disease caused by histamine or leukotriene-C4 release; Behcet's disease such as intestinal-, vasculo- or neuro-Behcet's disease, and also Behcet's which affects the oral cavity, skin, eye, vulva, articulation, epididymis, lung, kidney and so on. Furthermore, the compounds of the invention are useful for the treatment and prevention of hepatic disease such as immunogenic diseases (for example, chronic autoimmune liver diseases such as the group consisting of autoimmune hepatitis, primary biliary cirrhosis and sclerosing cholangitis), partial fiver resection, acute liver necrosis (e.g. necrosis caused by toxin, vital hepatitis, shock or anoxia), B-virus hepatitis, non-A/non-B hepatitis, cirrhosis (such as alcoholic cirrhosis) and hepatic failure such as fulminant hepatic failure, late-onset hepatic failure and "acute-on-chronic" liver failure (acute liver 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.\nAdditionally, some compounds appear to possess FK-506 antagonistic properties. The compounds of the present invention may thus be used in the treatment of immunodepression or a disorder involving immunodepression. Examples of disorders involving immunodepression include AIDS, cancer, senile dementia, trauma (including wound healing, surgery and shock) chronic bacterial infection, and certain central nervous system disorders. The immunodepression to be treated may be caused by an overdose of an immunosuppressive macrocyclic compound, for example derivatives of 12-(2-cyclohexyl-1-methylvinyl)-13, 19,21,27-tetramethyl- 11,28-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 realizing that they have forgotten to take their medication at the prescribed time and can lead to serious side effects.\nThe 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 compound 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) cells to chemotherapeutic agents. It is believed that the compounds of the invention may likewise be effective at overcoming resistance expressed to clinically useful antitumour drugs such as 5-fluorouracil, cisplatin, methotrexate, vincristine, vinblastine and adriamycin, colchicine and vincristine.\nA 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 acts as an inununosuppressive agent, and so antibodies are not produced by the body and immunity is not acquired. By introducing a compound of the invention into the body (as in a vaccine), the undesired immunosuppression may be overcome and immunity acquired.\nAqueous 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 comea, keratitis, dysophia epithelialis comeae, leukoma, Mooren's ulcer, sclevitis and Graves' ophthalmopathy) and rejection of comeal transplantation.\nWhen used in the above or other treatments, a therapeutically effective amount of one of the compounds of the present invention may be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt, ester or prodrug form. Alternatively, the compound may be administered as pharmaceutical compositions containing the compound of interest in combination with one or more pharmaceutically acceptable excipients. By a "therapeutically effective amount" of the compound of the invention is meant a sufficient amount of the compound to treat gastrointestinal disorders, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total dally 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 therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of 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 for to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.\nThe pharmaceutical compositions of the present invention comprise a compound of the invention and a pharmaceutically acceptable carrier or excipient, which may be administered orally, rectally, parenterally, intracistemally, intravaginally, intraperitoneally, topically (as by powders, ointments, drops or transdermal patch), bucally, or as an oral or nasal spray. By "pharmaceutically acceptable carder" is meant a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. The term "parenteral" as used herein refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.\nPhannaceutical compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil, and injectable organic esters such as ethyl oleate. Proper fluidity can 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.\nLiquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the an such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.\nSuspensions, in addition to the active compounds, may contain" 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.\nA further form of topical administration is to the eye, as for the treatment of immune-mediated conditions of the eye such as autoimmune diseases, allergic or inflammatory conditions, and corneal transplants. The compound of the invention is delivered in a pharmaceutically 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/cilary, lens, choroid/retina and solera. The pharmaceutically acceptable ophthalmic vehicle may, for example, be an ointment, vegetable oil or an encapsulating material.\nCompounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono-- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are the phospholipids 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.\nThe compounds of the invention may be prepared using one or more of the processes which follow. The starting materials for use in these processes are preferably one of the macrolides isolated from culture media obtained in accordance with known methods by fermentation of microorganisms of the genus Streptomyces, which are disclosed in European Patent Application No. 0184162. Samples are available from the Fermentation Research Institute, Tsukuba, Ibaraki 305, Japan under the provisions of the Budapest Treaty, under deposit No. FERM BP-927. This strain has been redeposited on Apr. 27, 1989 with the Agricultural Research Culture Collection International Depository, Peoria, Ill. 61604, USA under the provisions of the Budapest Treaty, under deposit No. NRRL 18488. The macrolide FR-900520 (European Patent Application 0 184 162), 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(11), 1586-1591; (ii) H. Hatanaka, T. Kino, S. Miyata, N. Inamura, A. Kuroda, T. Goto, H. Tanaka and M. Okuhara, FR-900520 and FR-900523, Novel immunosuppressants isolated from A streptomyces. H. Fermentation, isolation and physico-chemical and biological characteristics. J. Antibiot., 1988. XLI(11), 1592-1601; (iii) T. Arai, Y. Koyama, T. Suenaga and H. Honda, Ascomycin, An Antifungal Antibiotic. J. Antibiot., 1962. 15(231-2); and (iv) T. Arai in U.S. Pat. No. 3,244,592. One or more of the processes discussed below may be then employed to produce the desired compound of the invention.\n(a) producing a compound of formula I, which contains bis(CH--OR) groups, in a corresponding compound wherein R is a protecting group.\n(b) producing a compound of formula I, which contains a mono(CH--OR) group, by selective deprotection in a corresponding compound wherein R is a protecting group.\n(c) producing a compound of formula I, which contains a CH--OR group, by selective activation of a selected CH--OH group in a corresponding compound wherein --OR is a leaving group which is easily displaced by nucleophilic attack.\n(d) producing a compound of formula I, which contains a CH--R100 group, by selective displacement of a selected CH--OR group in a corresponding compound wherein --R100 is a nucleophile.\n(e) producing a compound of formula I, which contains a CH--OH group, by selective and final deprotection in a corresponding compound.\nIn process (a), suitable protecting groups for hydroxyl include those groups well known in the art such as dimethylthexylsilyl, trisubstituted silyl such as tri(lower)alkylsilyl (e.g. trimethylsilyl, triethylsilyl, tributylsilyl, tri-i-propylsilyl, tert-butyl-dimethylsilyl, tri-tert-butylsilyl, triphenylmethyl-dimethylsilyl, etc.); lower alkyldiarylsilyl (e.g. methyl-diphenylsilyl, ethyl-diphenylsilyl, propyl-diphenylsilyl, tert-butyl-diphenylsilyl, etc.), and the like; triarysilyl (e.g. triphenylsilyl, tri-p-xylylsilyl, etc.); triarylalkylsilyl (e.g. tribenzylsilyl, etc.), and the like, in which the preferred one may be tri(C1 --to--C4)alkylsilyl and C1 --to--C4 alkyldiphenylsilyl, and the most preferred one may be tert-butyldimethylsilyl;\nSuitable o-silylations may be carried out using a wide variety of organosilicon reagents such as, but not limited to tert-butyldimethylsilyl chloride, N-(tert-butyldimethylsilyl)-N-methyltrifluoroacetamide (Mawhinney, T., and Madison, M. A. J. Org. Chem., 1982, 47, 3336), tert-butylchlorodiphenylsilane (Hanessian, S. and Lavallee, P Can. J. Chem., 1975, 63, 2975), tert-butyldimethylsilyl trifluoromethanesulfonate (Mander, L. N. and Sethi, S. P. Tetrahedron Lett., 1984, 25, 5953), dimethylthexylsilyl chloride or dimethylthexylsilyl trifluoromethanesulfonate (Wetter, H. and Oertle, K. Tetrahedron Lett., 1985, 26, 5515), 1-(tert-butyldimethylsilyl)-imidazole and the like.\nCarbonate hydroxy-protecting groups may be introduced using a wide variety of a haloformates such as methy, ethyl, 2,2,2-trichloroethyl, isobutyl, vinyl, allyl, 2-(trimethylsilyl)ethyl, 2-(benzenesulfonyl)ethyl, 2-(trimethylsilyl)ethoxy methyl, benzyl and substituted benzyl chloroformales, where benzyl substituents include p-methoxy, 3,4-dimethoxy and p-nitro, in the presence of tertiary base such as pyridine, triethylamine, imidazole, diisopropylethylamine and the like. (Tetrahedron Lett., 1980, 21, 3343; ibid., 1981, 22, 3667; ibid. 1981, 22,969; ibid. 1981, 22, 1933.)\nThe reaction may also be carried out using a starting material having an opposite configuration at a carbon center. In this situation, 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 corresponding ketone, (2) the obtained ketone is reduced under selective conditions. Both chiral centers having either [R]- or [S]-configuration can be obtained selectively and separately.\nIn process (b), suitable reagents for selective deprotection of a protecting group from C-32 may be carefully carried out using, but not limited to aqueous hydrogen fluoride in acetonitrile (Newton, R. F., Reynolds, D. P., Finch, M. A. W., Kelly, D. R. and Roberts, S. M. Tetrahedron Lett., 1979, 3891), tetraalkyl ammonium fluoride in tetrahydrofuran (Corey, E. J. and Snider, B. B. J. Am. Chem. Soc., 1972, 94, 2549, Corey, E. J. and Venkateswarlu, A. J. Am. Chem. Soc., 1972, 94, 6190) or tetraalkyl ammonium chloride-potassium fluoride in acetonitrile (Carpino, L. A. and Sau, A. C. J. Chem. Soc., Chem. Commun. 1979, 514) wherein an alkyl group as defined above, p-toluenesulfonic acid, potassium carbonate in anhydrous methanol (Hurst, D. T. and Malnnes, A. G. Can. J. Chem., 1965, 43, 2004), citric acid in methanol (Bundy, G. L. and Peterson, D.C. Tetrahedron Lett., 1978, 41), acetic acid: water (3:1) (Corey, E. J. and Varma, R. K. J. Am. Chem. Soc., 1971, 93, 7319), Dowex 50W-X8 in methanol (Corey, E. J., Ponder, J. W. and Ulrich, P. Tetrahedron Lett., 1980, 21, 137), boron trifluoride etherate in chloroform (Kelly, D. R., Roberts, M. S. and Newton, R. F. Synth. Commun. 1979, 9, 295), methanolic hydrogen fluoride (Hanessian, S. and Lavallee, P. Can. J. Chem., 1975, 53, 2975; ibid., 1977, 55, 562), and pyridinuim fluoride in tetrahydrofuran (Nicolaou, K. C., Seitz, S. P., Pavia, M. R. and Petasis, N. A. J. Org. Chem., 1979, 44, 4011), pyridinium p-toluenesulfonate in ethanol (Prakash, C., Saleh, S. and Blair, I. A. Tetrahedron Lett., 1989, 30, 19), N-bromo-succinimide in dimethylsulfoxide (Batten, R. J. et al., Synthesis, 1980, 234), and tetraethyldiboroxane in the presence of catalytic amounts of trimethylsilyl triflate (Dahlhoff, W. V. and Taba, K. M., Synthesis, 1986, 561).\nThe reaction is usually conducted under from cooling to heating, preferably from 0° C. to 50° C. The reaction may require 20 minutes to one day, depending on the reagent and temperature chosen.\nIn process (c), suitable reagents for activation of an alcohol include acetic anhydride, trifluoromethanesulfonic anhydride (triflic anhydride), fluorosulfonic anhydride, methane-sulfonyl chloride (mesyl chloride), p-toluenesulfonyl chloride (tosyl chloride), trifluoroacetic anhydride, trifluoroacetyl chloride, o-nitrobenzenesulfonyl chloride, 1-methyl-2-fluoropyridinium salt and the like.\nThe reaction is usually conducted under from cooling to heating, preferably from -70° C to 50° C. The reaction may require 20 minutes to one day, depend on the reagent and temperature chosen.\nIn process (d), a variety of compounds may be prepared from the displacement reactions. An activated hydroxyl group may be reacted with a primary or secondary amine (as defined above and below). The displacement reaction may be carried out in a solvent which does not adversely affect the reaction (e.g. chloroform, dichloromethane, tetrahydrofuran, pyridine, dimethylsulfoxide, N,N-dimethylformamide, hexamethylphosphoramide, etc. or a mixture thereof). The reaction may be conducted above, at, or below ambient temperature, preferably from 0° C. to 50° C. The reaction may require 20 minutes to one week, depend on the reagent chosen.\nIn process (e), a final deprotection of C-24 protecting group may be carried out according to the method described in process (c).\nExample 1: Formula I: R100 =H; R101 =ethyl; R102 =H; R103 =tert-butyldimethylsilyloxy; R104 =tert-butyldimethylsilyloxy; R105 =H.\nAscomycin (25 g, 0.032 mol, Formula I: R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =OH; R105 =H) was dissolved in a solution of imidazole (43.03 g, 0.64 mol) in dry N,N-dimethylformamide (500 mL) and tert-butyldimethylchlorosilane (47.64 g, 0.32 tool) was added in portions and stirred at room temperature for 24 hours. N,N-dimethyfformamide and excess tert-butyldimethylchlorosilane were removed by distillation (bath 35° C. ) under high vacuum. The solid residue was dissolved in 350 mL of ethylacetate, and the ethyl acetate layer was washed with saturated ammonium chloride aq. solution (200 mL×3), 10 %-NaHSO4 (200 mL×3), brine, saturated NaHCO3 (200 mL×3), and brine (200 mL×3). After dired over MgSO4, solvent was removed in vacuo and the solid residue was purified by silica gel chromatography, followed by HPLC eluting with 5% acetone in hexanes providing the title compound (27 g) in 84 % yield. MS (FAB) m/z: M+K=1058.\nExample 2: Formula I: R100 =H; R101 =ethyl: R102 =H; R103 =tert-butyldimethylsilyloxy; R104 =OH; R105 =H.\nTo a solution of 48% hydrofluoric acid (3 mL) was added Example 1 (32 g, 0.031 mol) in acetonitrile (500 mL), and the mixture was stirred at room temperature for 90 min. It was cooled to 0° C. in an ince bath, and solid NaHCO3 was added to the reaction mixture. It was stirred for 1 hr and solid was removed by filtration. Acetonirile was removed in vacuo and ethyl acetate (500 mL) was added to the residue, and the organic layer was washed with 10%-NaHCO3 (300 mL×3), brine (250 mL), 10%-NaHSO4 (300 mL×3), and brine (350 mL×3), and dried over anhydrous sodium sulfate. Evaporation of the solvent gave 35 g of crude title compound which was purified by silica gel column chromatography, followed by HPLC eluting with 25%-acetone in hexane. 24.28 g (85 %) of pure compound was obtained. MS (FAB) m/z: M+K=844;\nIn addition to the title compound, unreacted starting material (Example 1, 1.5 g) and ascomycin (500 mg) were isolated as a pure form.\nExample 3: Formula I: R100 =H; R101 =ethyl; R102 =H; R103 =tert-butyldimethylsilyloxy; R104 =O-trifluoromethanesulfonyl; R105 =H.\nThe product of Example 2 (4.0 g, 4.42 mmol) was dissolved in 20 mL of methylene chloride at 0° C. Pyridine (3.57 mL, 44.2 mmol), followed by trifluoromethanesulfonic acid anhydride (0.74 mL, 4.42 mmol) were carefully added to the reaction mixture. It was stirred at 0° C. for 20 min and the solvent was removed. Ethyl acetate (50 mL) was added to the residue. The organic layers were washed with brine, saturated NaHCO3 (20 mL×3), brine (20 mL), 10%-NaHSO4 (20 mL×3), brine (20 mL×3) and dried over anhydrous sodium sulfate. After the solvent was removed, the title compound was obtained in quantitative yield (4.2 g). This compound was used for the displacement reaction without further purification and characterization.\nExample 4; Formula I: R100 =H; R101 =ethyl: R102 =H; R103 =tert-butyldimethylsilyloxy; R104 =H; R1 =H; Z=(CH2)2 ; W=CH; X=-N=; R2 =H; m=1; p=2; q=0; Y=O.\nThe product of Example 3 (1.97 g, 1.90 mmol) was dissolved in 20 mL of freshly distilled methylene chloride, N-(2-aminoethyl)morpholine (0.70 mL, 7.6 mmol) and triethylamine (1.07 mL, 7.6 mmol) were added, and the reaction was then stirred at room temperature overnight. The reaction mixture was directly poured onto silica gel column and eluted to obtain title compound (1.7 mg) in 89% yield. MS (FAB) m/z: M+K=1056. M+H=1017.\nExample 5: Formula I; R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)2; W=CH; X=--N=; R2 =H; m=1; p=2; q=0; Y=O.\nThe product of Example 4 (1.7 g, 1.7 mmol) was dissolved in acetonitrile (10 mL), 48% hydrogen fluoride aqueous solution (48%-HF, 2.0 mL) in acetonitrile (10 mL) was added, and the reaction was then stirred at room temperature for 3 hours. It was cooled to 0° C. in an ice bath, and solid NaHCO3 was added to the reaction mixture. It was stirred for 0.5 hr and solid was removed by filtration. Acetonitrile was removed in vacuo and the residue was purified by RP-HPLC, eluting with acetonitrile-water-0.01% trifluoroacetic acid system. Recovered starting material (805 mg) and pure title compound (366 mg) were obtained. MS (FAB) m/z: M+H=904. Deprotection of C-24 protected C-32 adducts such as that obtained in example 4 can be performed under slightly different conditions to give less recovered starting materials: the C-24 protected C-32 adduct (500 mg) is dissolved in acetonitrile (5 mL), 48% hydrogen fluoride aqueous solution (48%-HF, 2.0 mL) in acetonitrile (3 mL) was added, and the reaction was then stirred at room temperature for 2 hours. It was cooled to 0° C. in an ice bath, and solid NaHCO3 was added to the reaction mixture. It was stirred for 0.5 hr and solid was removed by filtration. Acetonirile was removed in vacuo and the residue was purified by RP-HPLC, eluting with acetonitrile-water-0.01% trifluoroacetic acid system to give pure titled compound. MS (FAB) m/z: M+H=904. Anal. calc'd. for C49 H81 N3 O12 -2 TFA: C, 56.22; H, 7.38; N, 3.71. Found: C, 57.90; H, 7.67; N, 4.04.\nExample 6: Formula I: R100 =H: R101 =ethyl: R102 =H: R103 =OH: R104 =H; R1 =H; Z=(CH2)2 ; W=CH; X=--CH=; R2 =H; m=2; p=0; q=0: Y=NMe.\nFollowing the procedure of Example 4, but replacing N-(2-aminoethyl)morpholine with 2-(2-aminoethyl)-1-methylpyrrolidine provides the desired C-24 protected C-32 adduct.\nDeprotection of this material and purification is performed following the procedure of Example 5 to give the titled compound.\nExample 7: Formula I: R100 =H: R101 =ethyl: R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)3; W=CH: X=--N=; R2 =CH3; m=1: p=2: q=0: Y=CH2.\nFollowing the procedure of Example 4, but replacing N-(2-aminoethyl)morpholine with 1-(3-aminopropyl)-2-pipecoline provides the desired C-24 protected C-32 adduct. Deprotection of this material and purification is performed following the procedure of Example 5 to give the titled compound.\nExample 8: Formula I: R100 =H: R101 =ethyl: R102 =H: R103 =OH: R104 =H; R1 =H; Z=(CH2)0; W=CH: X=--CH=; R2 =H; m=1: p=2: q=0; Y=NBn.\nFollowing the procedure of Example 4, but replacing N-(2-aminoethyl)morpholine with 4-amino-1-benzylpiperidine provided the desired C-24 protected C-32 adduct. Deprotection of this material and purification was performed following the procedure of Example 5 to give the titled compound. MS (FAB) m/z: M+H=964, M+K=1002. Anal. calc'd. for C--55 H85N3 O11 --1.5 TFA: C, 56.08; H, 6.78; N, 3.21. Found: C, 55.68; H, 6.79; N, 3.19.\nExample 9: Formula I: R100 =H: R101 =ethyl: R102 =H: R103 =OH; R104 =H; R1 =H; Z=(CH2)3; W=CH; X=--N=: R2 =H; m=1; p=2; q=0; Y=CH2.\nFollowing the procedure of Example 4, but replacing N-(2-aminoethyl)morpholine with 3-piperidino-1-propylamine provided the desired C-24 protected C-32 adduct. Deprotection of this material and purification was performed following the procedure of Example 5 to give the titled compound. MS (FAB) m/z: M+H=916, M+K=954. Anal. calc'd. for C51 H85 N3 O11 -2 TFA: C, 57.73; H, 7.66; N, 3.67. Found: C, 57.71; H, 7.67; N, 3.63.\nExample 10: Formula I: R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)3; W=CH; X=--N=; R2 =H; m=2; p=2; q=0; Y=CH2.\nFollowing the procedure of Example 4, but replacing N-(2-aminoethyl)morpholine with 3-hexamethyleneimino-1-propylamine provides the desired C-24 protected C-32 adduct. Deprotection of this material and purification is performed following the procedure of Example 5 to give the titled compound.\nExample 11: Formula I; R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)3; W=CH; X=--N=; R2 =H; m=1; p=1: q=0; Y=CH2.\nFollowing the procedure of Example 4, but replacing N-(2-aminoethyl)morpholine with N-(3-aminopropyl)pyrrolidine provides the desired C-24 protected C-32 adduct. Deprotection of this material and purification is performed following the procedure of Example 5 to give the titled compound.\nExample 12: Formula I: R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)3; W=CH; X=--N=: R2 =H; m=1; p=2; q=0; Y=NCH3.\nFollowing the procedure of Example 4, but replacing N-(2-aminoethyl)morpholine with 3-(4-methylpiperazino)propylamine provided the desired C-24 protected C-32 adduct. Deprotection of this material and purification was performed following the procedure of Example 5 to give the titled compound. MS (FAB) m/z: M+H=931, M+K=969. Anal. calc'd. for C-51 H86 N4 O11 -1.75 TFA: C, 48.28; H, 6.01; N, 3.66. Found: C, 47.95; H, 6.87; N, 4.31.\nExample 13: Formula I: R100 =H: R101 =ethyl: R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2) 0; W=CH; X=--CH=; R2 =H; m=1; p=1; q=0; Y=NBn,\nFollowing the procedure of Example 4, but replacing N-(2-aminoethyl)morpholine with 1-benzyl-3-aminopyrrolidine provides the desired C-24 protected C-32 adduct. Deprotection of this material and purification is performed following the procedure of Example 5 to give the titled compound.\nExample 14; Formula I: R100 =H; R101 =ethyl; R102 H; R103 =OH; R104 =H; R1 =H; Z=(CH2)0; W=CH; X=--CH=; R2 and Y taken together=--N--CH2CH2--; m=2; p=1.\nFollowing the procedure of Example 4, but replacing N-(2-aminoethyl)morpholine with 3-aminoquinuclidine provides the desired C-24 protected C-32 adduct. Deprotection of this material and purification is performed following the procedure of Example 5 to give the titled compound.\nExample 15; Formula I: R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)2 ; W=CH; X=--N=; R2 =H; m=1; p=2; q=0; Y=CH2.\nFollowing the procedure of Example 4, but replacing N-(2-aminoethyl)morpholine with 1-(2-aminoethyl-piperidine provides the desired C-24 protected C-32 adduct. Deprotection of this material and purification is performed following the procedure of Example 5 to give the titled compound.\nExample 16; Formula I: R100 =H; R110 =ethyl; R102 =H; R103 =OH; R104 =OH; R104 =H; R1 =H; Z=(CH2)1; W=CH; X=--CH=; R2 =H; m=2; p=0; q=0; Y=NEt.\nFollowing the procedure of Example 4, but replacing N-(2-aminoethyl)morpholine with 2-(aminomethyl)-1-ethylpyrrolidine provides the desired C-24 protected C-32 adduct. Deprotection of this material and purification is performed following the procedure of Example 5 to give the titled compound.\nExample 17; Formula I: R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)3 ; W=CH; X=--N=; R2 =H; m=0; p=2; q=1; Y=O.\nFollowing the procedure of Example 4, but replacing N-(2-aminoethyl)morpholine with 4-(3-aminopropyl)morpholine provided the desired C-24 protected C-32 adduct. Deprotection of this material and purification was performed following the procedure of Example 5 to give the titled compound. MS (FAB) m/z; M+H=918, M+K=956.\nExample 18; Formula I: R101 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)2 ; W=CH; X=--N=; R2 =H; m=1; p=2; q=0; Y=NH.\nFollowing the procedure of Example 4, but replacing N-(2-aminoethyl)morpholine with 1-(2-aminoethyl)piperazine provided the desired C-24 protected C-32 adduct. Deprotection of this material and purification was performed following the procedure of Example 5 to give the titled compound. MS (FAB) m/z; M+H=903, M+K - 941. Anal. calc'd. for C49 H82 N4 O11 --1.5 TFA; C, 49.18; H, 6.15; N, 3.95. Found; C, 49.76; H, 6.88; N, 4.45.\nExample 19; Formula I: R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)2 ; W=CH; X=--N=; R2 =H; m=0; p=0; q=2; Y=CH2.\nFollowing the procedure of Example 4, but replacing N-(2-aminoethyl)morpholine with 1-(2-aminoethyl)pyrrolidine provided the desired C-24 protected C-32 adduct. Deprotection of this material and purification was performed following the procedure of Example 5 to give the titled compound. MS (FAB) m/z; M+H=888, M+K=926. Anal. calc'd. for C49 H81 N3 O11 --2 TFA; C, 57.20; H, 7.49; N, 3.76. Found; C, 57.34; H, 7.49; N, 3.75.\nExample 20; Formula I: R100 =H; R101 =ethyl; R102. =H; R103 =OH; R104 =H; R1 =H; Z=(CH2,)0; W=CH; X=--CH=; R2 =H; m=2; p=1; q=0; Y=NEt.\nFollowing the procedure of Example 4, but replacing N-(2-aminoethyl)morpholine with 3-amino-N-ethylpiperidine provides the desired C-24 protected C-32 adduct. Deprotection of this material and purification is performed following the procedure of Example 5 to give the titled compound.\nExample 21; Formula I: R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)2 ; W=CH; X=--N=; R2 =H; m=0; p=0; q=0; Y=CH2.\nFollowing the procedure of Example 4, but replacing N-(2-aminoethyl)morpholine with N-(2-aminoethyl)ethyleneimine provides the desired C-24 protected C-32 adduct. Deprotection of this material and purification is performed following the procedure of Example 5 to give the titled compound.\nExample 22; Formula I: R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)2 ; W=CH; X=--N=; R2 =H; m=2; p=2; q=0; Y=CH2\nFollowing the procedure of Example 4, but replacing N-(2-aminoethyl)morpholine with 2-(N-hexamethyleneimino)ethylamine provides the desired C-24 protected C-32 adduct. Deprotection of this material and purification is performed following the procedure of Example 5 to give the titled compound.\nExample 23; Formula I: R100 =H; R101 ; =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)2 ; W=CH; X=--NH--CH2CH2N=; R2 =H; m=1; p=1; q=0; Y=CH2.\nFollowing the procedure of Example 4, but replacing N-(2-aminoethyl)morpholine with 1-(2-[aminoethylamino]ethyl)pyrrolidine provides the desired C-24 protected C-32 adduct. Deprotection of this material and purification is performed following the procedure of Example 5 to give the titled compound.\nExample 24; Formula I: R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)2 ; W=CH; X=--NH--CH2CH2N=; R2 =H; m=1; p=2; q=0; Y=O.\nFollowing the procedure of Example 4, but replacing N-(2-aminoethyl)morpholine with N-(2-aminoethylamino)ethylmorpholine provides the desired C-24 protected C-32 adduct. Deprotection of this material and purification is performed following the procedure of Example 5 to give the titled compound.\nExample 25; Formula I: R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)2 ; W=CH; X=--NH--CH2CH2N=; R2 =H; m=1; p=2; q=0; Y=CH2.\nFollowing the procedure of Example 4, but replacing N-(2-aminoethyl)morpholine with N-(piperidinoethyl)ethylenediamine provides the desired C-24 protected C-32 adduct. Deprotection of this material and purification is performed following the procedure of Example 5 to give the titled compound.\nExample 26; Formula I: R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =Me; Z=(CH2)0; W=CH; X=--CH=; R2 =H; m=1; p=2; q=0; Y=NMe.\nThe product of Example 3 (2.1 g, 2.03 mmol) was dissolved in 10 mL of freshly distilled methylene chloride, 1-methyl-4-(methylamino)piperidine (10.15 mmol) and triethylamine (0.912 mL, 6.09 mmol) were added, and the reaction was then stirred at 50° C. for 5 hours and at room temperature for over night The reaction mixture was directly poured onto silica gel column and eluted to provide the desired C-24 protected C-32 adduct. Deprotection of this material and purification is performed following the procedure of Example 5 to give the titled compound.\nExample 27; Formula I: R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =Me; Z=(CH2)0; W=CH; X=--CH=; R2 =H; m=1; P=1; q=Q; Y=NMe.\nFollowing the procedure of Example 26, but replacing 1-methyl-4-(methylamino)piperidine with N,N'-dimethyl-3-aminopyrrolidine provides the desired C-24 protected C-32 adduct. Deprotection of this material and purification is performed following the procedure of Example 5 to give the titled compound.\nExample 28; Formula I: R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =Et; Z=(CH2)0; W=CH; X=--CH=; R2 =H; m=1; p=1; q=0; Y=NEt.\nExample 29; Formula I: R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =--CH2-(3-pyridyl); Z=(CH2)2 ; W=CH; X=--N=; R2 =H; m=1; p=2; q=0; Y=NH.\nFollowing the procedure of Example 26, but replacing 1-methyl-4-(methylamino)piperidine with 1-(2-[3-pyridylmethyl-Boc-amino]ethyl)piperazine provides the desired C-24 protected C-32 adduct. Deprotection of this material and purification is performed following the procedure of Example 5 to give the titled compound.\nExample 30; Formula I: R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =--(CH2)2--OH; Z=(CH2)2 ; W=CH; X=--N=; R2 =H; m=1; p=2; q=0; Y=O.\nFollowing the procedure of Example 26, but replacing 1-methyl-4-(methylamino)piperidine with 2-(2-morpholinoethylamino)-ethanol provided the desired C-24 protected C-32 adduct. Deprotection of this material and purification was performed following the procedure of Example 5 to give the titled compound. MS (FAB) m/z; M+H=948, M+K =986.\nExample 31; Formula I: R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =--(CH2)2--NH2; Z=(CH2)2 ; W=CH; X=--N=; R2 =H; m=1; p=1; q=0; Y=CH2.\nFollowing the procedure of Example 26, but replacing 1-methyl-4-(methylamino)piperidine with 1-(2-[Boc-aminoethylamino]ethyl)pyrrolidine provides the desired C-24 protected C-32 adduct. Deprotection of this material and purification is performed following the procedure of Example 5 to give the titled compound.\nExample 32; Formula I: R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =--(CH2)2--NH2; Z=(CH2)2 ; W=CH; X=--N=; R2 =H; m=1; p=2; q=0; Y=O.\nFollowing the procedure of Example 26, but replacing 1-methyl-4-(methylamino)piperidine with N-(2-Boc-aminoethylamino)ethylmorpholine provides the desired C-24 protected C-32 adduct. Deprotection of this material and purification is performed following the procedure of Example 5 to give the titled compound.\nExample 33; Formula I: R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =--(CH2)2--NH2; Z=(CH2)2 ; W=CH; X=--N=; R2 =H; m=1; p=2; q=0; Y=CH2.\nFollowing the procedure of Example 26, but replacing 1-methyl-4-(methylamino)piperidine with 1-(2-[Boc-aminoethylamino]ethyl)piperidine provides the desired C-24 protected C-32 adduct Deprotection of this material and purification is performed following the procedure of Example 5 to give the tired compound.\nExample 34; Formula I; R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =--CH2--CO2H; Z=(CH2)3; W=CH; X=--N=; R2= H; m=1; p=1; q=0; Y=CH2.\nFollowing the procedure of Example 26, but replacing 1-methyl-4-(methylamino)piperidine with N-(pyrrolidinopropyl)glycine provides the desired C-24 protected C-32 adduct. Deprotection of this material and purification is performed following the procedure of Example 5 to give the titled compound.\nExample 35; Formula I; R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)3; W=CH; X=--N=; R2 =CO2H; m=1; p=1; q=0; Y=CH2.\nFollowing the procedure of Example 4, but replacing N-(2-aminoethyl)morpholine with N-(3-aminopropyl)proline provides the desired C-24 protected C-32 adduct. Deprotection of this material and purification is performed following the procedure of Example 5 to give the titled compound.\nExample 36; Formula I: R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)2 ; W=CH; X=--CO--N=; R2 =H; m=1; p=1; q=0; Y=CH2.\nFollowing the procedure of Example 4, but replacing N-(2-aminoethyl)morpholine with 3-aminopropionic acid pyrrolidine amide provides the desired C-24 protected C-32 adduct. Deprotection of this material and purification is performed following the procedure of Example 5 to give the titled compound.\nExample 37; Formula I: R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)2 ; W=CH; X=--O--(CH2)2N=; R2 =H; m=1; p=1; q=0; Y=CH2.\nFollowing the procedure of Example 4, but replacing N-(2-aminoethyl)morpholine with O-(N-pyrrolidinoethyl)ethanolamine provides the desired C-24 protected C-32 adduct. Deprotection of this material and purification is performed following the procedure of Example 5 to give the titled compound.\nExample 38; Formula I: R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)3; W=CH; X=--N=; R2 =H; m=1; p=2; q=0; Y=NAc.\nFollowing the procedure of Example 4, but replacing N-(2-aminoethyl)morpholine with 3-(4-acetylpiperazino)propylamine provides the desired C-24 protected C-32 adduct. Deprotection of this material and purification is performed following the procedure of Example 5 to give the titled compound.\nExample 39; Formula I: R100 =H; R101 =ethyl; R102=H; R103 =OH; R104 =H; R1 =H; Z=(CH2)3; W=CH; X=--N=; R2 =H; m=1; p=2; q=0; Y=S.\nFollowing the procedure of Example 4, but replacing N-(2-aminoethyl)morpholine with N-(3-aminopropyl)thiomorpholine provides the desired C-24 protected C-32 adduct. Deprotection of this material and purification is performed following the procedure of Example 5 to give the titled compound.\nExample 40; Formula I: R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)0; W=CH; X=--CH=; R2 =H; m=1; p=2; q=0; Y=N--(CH2)3--NHBoc.\nFollowing the procedure of Example 4, but replacing N-(2-aminoethyl)morpholine with 4-amino- 1-(3-tert-butyloxycarbonylaminopropyl)-piperidine provides the desired C-24 protected C-32 adduct. Deprotection of this material is performed using Bu4 NF followed by purification by reverse phase HPLC to give the titled compound.\nExample 41; Formula I: R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)0; W=CH; X=--CH=; R2 =H; m=1; p=2; q=0; Y=N--(CH2)3--NH2.\nTreatment of the resultant compound of Example 40 with HF following the procedure of Example 5 gives the titled compound.\nExample 42; Formula I: R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)3; W=CH; X=--N=; R2 =H; m=1; p=2; q=0; Y=CH--NHBoc.\nFollowing the procedure of Example 4, but replacing N-(2-aminoethyl)morpholine with 4-tert-butyloxycarbonylamino-1-(3-aminopropyl)-piperidine provides the desired C-24 protected C-32 adduct. Deprotection of this material is performed using Bu4 NF followed by purification by reverse phase HPLC to give the titled compound.\nExample 43; Formula I: R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2);3; W=CH; X=--N=; R2 =H; m=1; p=2; q=0; Y=CH--NH2.\nTreatment of the resultant compound of Example 42 with HF following the procedure of Example 5 gives the titled compound.\nExample 44; Formula I: R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 and R105 taken together form an oxo group.\nMethylsulfide-chlorine complex was prepared by adding oxalyl chloride (0.32 g) into a stirred solution of dimethylsulfoxide (0.44 g) in methylene chloride (4 mL) and stirring at -70° C. for 0.5 hours. The solution of the complex was added in slow dropwise fashion into a stirring solution of ascomycin (1.6 g) in methylene chloride (5 mL) at -70° C. After stirring for 0.25 hours, triethylamine (1.4 g) was added at -70° C. Stirring was continued at -70° C. for 0.5 hours and then at room temperature for 1 hour. The reaction mixture was then diluted with ether (100 mL), washed with 1N HCl (aq) (2×30 mL), saturated brine (30 mL), dried over magnesium sulfate and solvent removed. The product was purified on silica gel (70 g) with ether elution. Yield; 0.95 g; MS (FAB) m/z; M+H=790.\nExample 45; Formula I: R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R105 =OH.\nLithium tri-t-butoxyaluminum hydride (0.2 mL, 1 M in THF) was added slowly into a stirred solution of the product of Example 44 (0.056 g) in dry THF (1 mL) at -70° C. under nitrogen. After stirring at -70° C. for 3 hours, it was partitioned between ether (50 mL) and 1N HCl (10 mL). The organic phase was dried over magnesium sulfate, the solvent was removed and the product purified by prep TLC (35% acetone in hexanes). Yield; 0.025 g; MS (FAB) m/z; M+K=830.\nExample 46; Formula I: R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R105 =O-trifluoromethanesulfonyl .\nThe product of Example 45 (4.0 g, 4.42 mmol) is dissolved in 20 mL of methylene chloride at 0° C. pyridine (3.57 mL, 44.2 mmol), followed by trifluoromethanesulfonic acid anhydride (0.74 mL, 4.42 mmol) are carefully added to the reaction mixture. It is stirred at 0° C. for 20 minutes and the solvent is removed. Ethyl acetate (50 mL) is added to the residue. The organic layers are washed with brine, saturated NaHCO3 (20 mL×3), brine (20 mL), 10%-NaHSO4 (20 mL×3), brine (20 mL×3) and dried over anhydrous sodium sulfate. After the solvent is removed, the title compound is obtained. This compound is used for the displacement reaction without further purification and characterization.\nExample 47; Formula I: R100 =H; R101 =ethyl; R102 =H; R103 =OH; R105 =H; R1 =H; Z=(CH2)3; W=CH; X=--N=; R2 =H; m=1; p=2; q=0; Y=CH2.\nFollowing the procedure of Example 4, but replacing N-(2-aminoethyl)morpholine with 3-piperidino-1-propylamine and the resultant compound of Example 3 with the resultant compound of Example 46 provided the desired C-24 protected C-32 adduct. Deprotection of this material and purification was performed following the procedure of Example 5 to give the titled compound. MS (FAB) m/z; M+H=916, M+K=954.\nExample 48; Formula I: R100 =H; R101 =ethyl; R102 and R103 taken together form a bond; R104 =OH; R105 =H.\nAscomycin (10 g, 12.6 mmol) and pyridinium p-toluene sulfonate (1 g, 3.98 mmol) were dissolved in 200 mL of toluene and stirred at 70° C. over night. Solvent was removed, and the residue was purified by silica gel column chromatography, eluting with 5-10% acetone in hexane. The title compound (8.89 g) was isolated in 91% yield. MS (FAB) m/z; M+K=812.\nExample 49; Formula I: R100 =H; R101 =ethyl; R102 =H; R103 =H; R104 =OH; R105 =H.\nThe product of Example 48 (2.2 g, 2.8 mmol) was hydrogenated in the presence of 5% rhodium on alumina (220 mg) in 100 mL of ethanol at room temperature for 1 hour. After filtered, the filtrate was concentrated in vacuo to obtain the title compound in quantitative yield. The obtained product was then loaded on silica gel column, and eluted with 5-10% acetone in hexane to obtain the pure title compound in 75-80 yield. MS (FAB) m/z; M+K=814.\nExample 50; Formula I: R100 =H; R101 =n-propyl; R102 =H; R103 =OH; R104 =OH; R105 =H.\nFK-506 (150 mg, 0.2 mmol) was dissolved in 6 mL of ethyl acetate and 30 mg of 10%-palladium on charcoal was added. It was hydrogenated at room temperature for 20 minutes under one atmosphere pressure. After filtration of the catalyst, the solvent was evaporated to dryness to yield 150 mg of crude product, which was then purified by silica gel column chromatography, eluting with a chloroform; acetone (5:1) mixture. The pure tired compound (114 mg) was isolated in 76% yield. MS (FAB) m/z; M+K=844.\nExample 51; Formula I: R100 =H; R101 =ethyl; R102 and R103 taken together form a bond; R104 =O-trifluoromethanesulfonyl; R105 =H.\nFollowing the procedure of Example 3, but replacing the resultant compound of Example 2 with the resultant compound of Example 48 gives the titled compound.\nExample 52; Formula I: R100 =H; R101 =ethyl; R102 =H; R103 =H; R104 =O-trifluoromethanesulfonyl; R105 =H.\nFollowing the procedure of Example 3, but replacing the resultant compound of Example 2 with the resultant compound of Example 49 gives the titled compound.\nExample 53; Formula I: R100 =H; R101 =n-propyl; R102 =H; R103 =OH; R104 =O-trifluoromethanesulfonyl; R105 =H.\nFollowing the procedures of Examples 1-3, but replacing ascomycin with the resultant compound of Example 50, the titled compound is obtained.\nExample 54; Formula I: R100 =H; R101 =ethyl; R102 and R103 taken together form a bond; R104 =H; R1 =H; Z=(CH2)3; W=CH; X=--N=; R2 =H; m=1; p=2; q=0; Y=CH2.\nThe product of Example 51 (2.03 mmol) is dissolved in 10 mL of freshly distilled methylene chloride, 3-piperidino-1-propylamine (10.15 mmol) and triethylamine (6.09 mmol) are added, and the reaction is then stirred at room temperature overnight. The reaction mixture is directly poured onto silica gel column and eluted to obtain pure title compound.\nExample 55; Formula I: R100 =H; R101 =ethyl; R102 =H; R103 =H; R104 =H; R1 =H; Z=(CH2)3; W=CH; X=--N=; R2 =H; m=1; p=2; q=0; Y=CH2.\nThe product of Example 52 (2.03 mmol) is dissolved in 10 mL of freshly distilled methylene chloride, 3-piperidino-1-propylamine (10.15 mmol) and triethylamine (6.09 mmol) are added, and the reaction is then stirred at room temperature overnight. The reaction mixture is directly poured onto silica gel column and eluted to obtain pure title compound.\nExample 56; Formula I: R100 =H; R101 =propyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)3; W=CH; X=--N=; R2 =H; m=1; p=2; q=0; Y=CH2.\nFollowing the procedure of Example 9, but replacing ascomycin (Formula I: R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =OH; R105 =H) with the resultant compound of Example 53 provides the titled compound.\nExample 57; Formula I: R100 =H; R101 =methyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)3; W=CH; X=--N=; R2 =H; m=1; p=2; q=0; Y=CH2.\nFollowing the procedure of Example 9, but replacing ascomycin (Formula I: R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =OH; R105 =H) with FK-523 (Formula I: R100 =H; R101 =methyl; R102 =H; R103 =OH; R104 =OH; R105 =H) provides the titled compound.\nExample 58; Formula I: R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 H; Z=(CH2)1; W=N; X=--CH=; R2 =benzyl; m=2; p=0; q=1; Y=O.\nFollowing the procedure of Example 4, but replacing N-(2-aminoethyl)morpholine with 2-aminomethyl-4-benzylmorpholine (J. Med. Chem. 1993, 36, 1356) provides the desired C-24 protected C-32 adduct. Deprotection of this material and purification is performed following the procedure of Example 5 to give the titled compound.\nExample 59; Formula I: R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)1; W=N; X=--CH=; R2 =benzyl; m=3; p=0; q=1; Y=O.\nFollowing the procedure of Example 4, but replacing N-(2-aminoethyl)morpholine with 2-aminomethyl-4-benzyl-hexahydro-1,4-oxazepine (J. Med. Chem. 1993, 36, 1356) provides the desired C-24 protected C-32 adduct. Deprotection of this material and purification is performed following the procedure of Example 5 to give the titled compound.\nExample 60; Formula I: R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)0; W=CH; X=--CH=; R2 and Y taken together are --(CH2)3 --N--; m=1; p=1; q=0 (exo isomer).\nFollowing the procedure of Example 4, but replacing N-(2-aminoethyl)morpholine with exo-1-azabicyclo[3.2.1]nonan-6-amine (J. Med. Chem. 1993, 36, 683) provides the desired C-24 protected C-32 adduct. Deprotection of this material and purification is performed following the procedure of Example 5 to give the titled compound.\nExample 61; Formula I: R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)0; W=CH; X=--CH=; R2 and Y taken together are --(CH2)3 --N--; m=1; p=1; q=0 (endo isomer).\nFollowing the procedure of Example 4, but replacing N-(2-aminoethyl)morpholine with endo-1-azabicyclo[3.2.1]nonan-6-amine (J. Med. Chem. 1993, 36, 683) provides the desired C-24 protected C-32 adduct. Deprotection of this material and purification is performed following the procedure of Example 5 to give the titled compound.\nExample 62; Formula I: R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)0; W=CH; X=--CH=; R2 and Y taken together are --O--(CH2)2 --N--; m=1; p=2; q=0 (endo isomer).\nFollowing the procedure of Example 4, but replacing N-(2-aminoethyl)morpholine with endo-1-aza-4-oxabicyclo[3.3.1]nonan-6-amine (J. Med. Chem. 1993, 36, 683) provides the desired C-24 protected C-32 adduct. Deprotection of this material and purification is performed following the procedure of Example 5 to give the titled compound.\nExample 63; Formula I: R100 =OH; R101 =ethyl; R102 =H; R103 =H; R104 =H; R1 =H; Z=(CH2)3; W=CH; X=--N=; R2 =H; m=1; p=2; q=0; Y=CH2.\nThe product of Example 55 (5 mmol) is dissolved in 25 mL of methylene chloride. This is added to a solution of 5 mL of methylene chloride containing tert-butyl hydroperoxide in 2,2,4-trimethylpentane (6.65 mL, 20 mmol) and selenium oxide (830 rag, 7.5 mmol). The reaction is monitored by thin layer chromatography. The mixture is stirred at room temperature until the starting material is disappeared. Solvents are removed and an approximately 100 mL of ethyl acetate is added to the residue. The ethyl acetate layer is washed with brine, dried over anhydrous sodium sulfate. Purification of the title compound is carried out by high performance liquid chromatography.\nExample 64; Formula I: R100 =F; R101 =ethyl; R102 =H; R103 =H; R104=H; R1 =H; Z=(CH2)3; W=CH; X=--N=; R2 =H; m=1; p=2; q=0; Y=CH2.\nA solution of the product of example 63 (100 mg) in 1 mL of methylene chloride is cooled to -78° C. in a dry ice/isopropanol bath. To this stirred solution, diethylaminosulfur trifluoride (10 mL) is added. After 3 minutes, saturated sodium bicarbonate (1 mL) is added followed by 5 mL of ethyl acetate and the mixture is warmed to room temperature. Extraction from ethyl acetate, drying over anhydrous magnesium sulfate and purification by high performance liquid chromatography gives the pure title compound.\nExample 65; Formula I: R100 =OC(O)CH3 ; R101 =ethyl; R102 =H; R103 =H; R104 =H; R1 =H; Z=(CH2)3; W=CH; X=--N=; R2 =H; m=1; p=2; q=0; Y=CH2.\nA solution of the product of example 63 (100 mg) in 1 mL of pyridine is cooled to 0° C. in an ice bath. To this stirred solution, N,N-dimethylaminopyridine (3 mg), followed by acetic acid anhydride (20 ml) are added. After stirred at 0° C. for 5 hours, it is stirred at room temperature for one over night. Extraction from ethyl acetate, drying over anhydrous magnesium sulfate and purification by high performance liquid chromatography gives the pure title compound.\nExample 66; Formula I: R100 =H; R101 =ethyl; R102 =H; R103 =tert-butyldimethylsilyloxy; R104 =O-fluorosulfonyl; R105 =H.\nTo a stirred solution of the product of Example 2 (0.5 g, 0.6 mmol) in CH2 Cl2 (5 mL) at -70° C. was added 2,6-lutidine (0.26 mL, 2.2 mmol), followed by fluorosulfonyl anhydride (0.12 mL, 1.1 mmol). The reaction mixture was warmed to 0° C., and stirred for 0.5 hr. The reaction was partitioned between ether, ice cold 0.1N HCl and brine. The organic layer was dried over Na2 SO4, faltered and evaporated to give 0.53 g of the crude tittle compound in 97% yield. FAB-MS (m/z)1026 (M+K)\nExample 67; Formula I: R100 =H; R101 =ethyl; R102 =H; R103 =OH; R104 =H; R1 =H; Z=(CH2)3; W=CH; X=--N=; R2 =H; m=1; p=2; q=0; Y=CH2.\nTo a stirred solution of the product of Example 66 (0.20 g, 0.2 mmol) in CH3 CN (1.5 mL) at 0° C. was added 3-piperidino-1-propylamine (0.06 g, 0.4 mmol). The reaction was stirred at room temperature overnight. The product was isolated by RP-HPLC (41.4 mm ID, Dynamax-60A, C18 column) to obtain the C-24 protected product in 58% yield. FAB-MS (m/z)1030 (M+H), 1068 (M+K). To a stirred solution of the above product (0.11 g, 0.1 mmol) in CH3 CN (2 mL) was added 48% aqueous HF (0.4 mL) in CH3 CN (1 mL). After stirring at room temperature for 1.5 hr, the product was purified by RP-HPLC to give the titled compound in 66% yield. FAB-MS (m/z) 915 (M+H), 954 (M+K)\nExample 68; In Vitro Assay of Biological Activity\nThe immunosuppressant activity of the compounds of the present invention was determined using the human mixed lymphocyte reaction (MLR) assay described by Kino, T. et al. in Transplantation Proceedings XIX(5);36-39, Suppl. 6 (1987), incorporated herein by reference. The results of the assay, shown below in Table 1, demonstrate that the compounds tested are effective immunomodulators at sub-micromolar concentrations.\nTABLE 1______________________________________  Ex. # IC.sub.50 (M)______________________________________  5     <1 × 10.sup.-6  8     <1 × 10.sup.-6  9     <1 × 10.sup.-6  12    <1 × 10.sup.-6  17    <1 × 10.sup.-6  18    <1 × 10.sup.-6  19    <1 × 10.sup.-6  30    <1 × 10.sup.-6  47    <1 × 10.sup.-6______________________________________\nClasificación de EE.UU. 514/291, 514/63, 540/452, 540/456