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1. (WO2006018698) USE OF CELL-SPECIFIC CONJUGATES FOR TREATMENT OF INFLAMMATORY DISEASES OF THE GASTROINTESTINAL TRACT
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What Is Claimed Is:

1. A method for the maintenance treatment of an inflammatory disease, disorder or condition of the gastrointestinal tract or the delay or prevention of recurrence of said disease, disorder or condition comprising administering to a human or nonhuman mammalian subject in need thereof an effective amount of a low oral bioavailability conjugate compound of formula VII


VII

wherein

M is a macrolide subunit selected from the group consisting of 12-, 14-, 15-, 16-, 17-, and 18-membered lactonic ring molecules wherein "membered" refers to the number of carbon atoms or heteroatoms in the lactonic ring said macrolide having the property of accumulating within mammalian immune system cells that mediate inflammatory immune responses;

T is a steroidal or nonsteroidal anti-inflammatory subunit;

L is a linker molecule to which each of M and T are covalently linked,

and pharmaceutically acceptable salts, prodrugs, and solvates thereof in an oral dosage form;

wherein the conjugate of formula VII exhibits less than 10% oral bioavailability.

2. The method according to claim 1 , wherein the conjugate of formula VII exhibits less than 5 % oral bioavailability.

3. The method according to claim 1, wherein the conjugate of formula VII exhibits less than 2% oral bioavailability.

4. The method of claim 1 , where M has the property of accumulating within immune system cells that mediate inflammatory immune responses within the patient.

5. The method according to claim 1 , wherein M represents a group of Formula

VIII:


wherein

\ \ \ \
C=O CH2 CH-NR1R5 NRN
(i) Z and W independently are ' , ^ , / , /


, or a bond, wherein

Rt and Rs independently are hydrogen or alkyl;

RM is hydroxy, alkoxy, substituted alkoxy or ORP

RN is hydrogen, Rp, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, or -C( -X)-NRtR5; wherein X is =0 or =S;

C=O CH-NR1R5
provided that Z and W cannot both simultaneously be ' , / ,

\ \ \
CH9 NR ^MN C=NR M
/ or a bond,

(ii) U and Y are independently hydrogen, halogen, alkyl, or hydroxyalkyl;

(iii) R1 is hydroxy, ORP, -O-S2, or an = O;

(iv) S1 is hydrogen or a sugar moiety at position C/5 of the formula:


wherein

R8 and R9 are both hydrogen or together form a bond, or R9 is hydrogen and R8 is
-N(CH3)R51, wherein

Ry is Rp, Rz or -C(=O)RZ, wherein Rz is hydrogen or alkyl or alkenyl or alkynyl or cycloalkyl or aryl or heteroaryl or alkyl substituted with C2-C7-alkyl, C2-C7-alkenyl, C2-C7-alkynyl, aryl or heteroaryl;

R10 is hydrogen or Rp;

(v) S2 sugar moiety of the formula

wherein

R3 is hydrogen or methyl;

R11 is hydrogen, Rp, or O-R11 is a group that with R12 and with C/4" carbon atom forms a > C=O or epoxy group;

R12 is hydrogen, alkyl, alkyl-Rp, Rp or a group that with O-R" group and with C/4" carbon atom forms a > C=O or epoxy group;

(vi) R2 is hydrogen, hydroxy, ORP group, C1-C4 alkoxy or substituted alkoxy;
(vii) A is hydrogen or methyl;
(viii) B is methyl or epoxy;
(ix) E is hydrogen or halogen;

(x) R3 is hydroxy, ORP , alkoxy or R3 is a group that with R5 and with C/l 1 and C/ 12 carbon atoms forms a' cyclic carbonate or carbamate, or if W or Z is > N-RN R3 is a group that with W or Z forms a cyclic carbamate;;

(xi) R4 is C1-C4 alkyl;

(xii) R5 is hydrogen, hydroxy, ORP , C1-C4 alkoxy, or a group that with R3 and with C/ 11 and C/ 12 carbon atoms forms a cyclic carbonate or carbamate;

(xiii) R6 is hydrogen or Ci-Gi alkyl;

wherein M has a linkage site through which it is linked to the subunit T via the linking group L; provided that the linkage site being at one or more of the following: a) any reactive hydroxy, nitrogen, or epoxy group located on macrolide ring, sugar moiety S1, sugar moiety S2, or an aglycone oxygen or nitrogen when S1 and/or S2 is cleaved off;

/C=NRM
b) a reactive > N-RN or -NRLRS or ' group located on Z or W;

c) a reactive hydroxy group located at any one of R1 , R2, R3 and R5;

d) any other group that can be first derivatized to a hydroxy or -NRtRs group and

Rp is hydroxyl or amino protective group.

6. The method according to claim 5 wherein S1 is H and R1 is OH.

7. The method according to claim 1 wherein L represents a group of Formula IXA or Formula IXB:



IXB X1-(CH2)m-Q-(CH2)n-X2

wherein

X1 is selected from the group consisting of -CH2-, -CH2NH-, -C(=O)-, -OC(=O)-, =N-O-, -0C(=0)NH- and -C(=O)NH-;

X2 is -NH-, -CH2-, -NHC(=0)-, -C(=O)-, -O- or -OC(=O)-;

Q is -NH- or -CH2-, wherein each -CH2- or -NH- group may be optionally substituted by Ci-C?-alkyl, C2-C7-alkenyl, C2-C7-alkynyl, C(=O)R\ C(=O)OR\
C(=O)NHR\ wherein Rx may be Ci-Ci-alkyl, aryl or heteroaryl;

m and n independently are a whole number from 0 to 8, with the proviso that if Q is NH, n cannot be 0.

8. The method according to claim 1 wherein T represents a steroid subunit of

Formula IX:


wherein

R\ R , independently represents hydrogen or halogen;

Rc is hydroxy, alkoxy, alkyl, thiocarbamoyl, carbamoyl or a valence-bond attached to X2 of chain L;

Rd and Re independently represent hydrogen, hydroxy, methyl or Ci-C4-alkoxy or are each a group that forms a 1 ,3-dioxolane ring with the other or a valence bond attached to X2 of chain L;

Rf is hydrogen, hydroxy, chloro, or forms a keto group with the carbon atom to which it is attached; and

Rj is hydrogen or halogen.

9. The method according to claims 1 wherein T represents a NSAID subunit selected from the group consisting of:

aceclofenac, acemetacin, acetaminophen, acetaminosalol, acetyl-salicylic acid, acetyl-salicylic-2-amino-4-picoline-acid, 5-aminoacetylsalicylic acid, alclofenac, amino-profen, amfenac, anileridine, azathioprine, bendazac, benoxaprofen, bermoprofen, α-bisabolol, bromfenac, 5-bromosalicylic acid acetate, bromosaligenin, bucloxic acid, butibufen, carprofen, CC 1088, CC 5013, CDC 801, celecoxib, chromoglycate, cinmetacin, cipamfylline, clindanac, clopirac, COX-189, cyclosporine, sodium diclofenac, diflunisal, ditazol, enfenamic acid, etodolac, etofenamate, etoricoxib, felbinac, fenbufen, fenclozic acid, fendosal, fenoprofen, fentiazac, fepradinol, FK-506, flufenamic acid, flunixin, flunoxaprofen, flurbiprofen, glutametacin, glycol salicylate, ibufenac, ibuprofen, ibuproxam, indomethacin, indoprofen, isofezolac, isoxepac, isoxicam, JTE-522, ketoprofen, ketorolac, L-745337, leflunomide, lornoxicam, loxoprofen, meclofenaniic acid, mefenamic acid, meloxicam, mesalamine, mesalazine, methotrexate, metiazinic acid, mofezolac, montelukast, mycophenolic acid, naproxen, niflumic acid, olsalazine, oxaceprol, oxaprozin, oxyphenbutazone, parsalmide, perisoxal, phenyl-acethyl-salicylate, phenylbutazone, phenylsalicylate, teophyline, pyrazolac, piroxicam, pirprofen, pranoprofen, protizinic acid, rapamycine, rofecoxib, salacetamide, salicylamide-O-acetyl acid, salicylsulphuric acid, salicin, salicylamide, salsalate, sulindac, sulfasalazine, suprofen, suxibutazone, tenoxicam, thalidomide, tetrafluorthalidomide, tiaprofenic acid, tiaramide, tinoridine, tolfenamic acid, tolmetin, tomoxiprol, tropesin, valdecoxib (Searle), xenbucin, ximoprofen, zaltoprofen, zomepirac, zafirlukast.

10. The method according to claim 1 whereby the compound of the formula VII has the structure:


11. The method according to claim 1 whereby compound of the formula VII has the structure:


12. The method according to claim 1 whereby compound of the formula VII has the structure:

13. The method according to claim 1 whereby compound of the formula VII has the structure:

14. The method according to claim 1 whereby compound of the formula VII has the structure:

15. The method according to claim 1 whereby compound of the formula VII has the structure:

16. The method according to claim 1 whereby compound of the formula VII has the structure:


17. The method according to claim 1 whereby compound of the formula VII has the structure:

18. The method according to claim 1 whereby the compound of the formula VII has the structure:


19. The method according to claim 1 whereby the compound of the formula VII has the structure:



20. The method according to claims 5 whereby the compound of the formula VII has the structure:


21. The method according to claim 1 whereby the compound of the formula VII has the structure:


22. The method according to claim 1 , whereby the inflammatory disease disorder or condition of the gastrointestinal tract is an inflammatory bowel disease.

23. The method according to claim 22, wherein the inflammatory bowel disease is Crohn's disease, ulcerative colitis or celiac disease.

24. A pharmaceutical composition comprising an amount of a conjugate compound of formula VII or a pharmaceutically acceptable salt, prodrug or solvates thereof


VII

wherein

M is a macrolide subunit selected from the group consisting of 12-, 14-, 15-, 16-, 17-, and 18-membered lactonic ring molecules wherein "membered" refers to the number of carbon atoms or heteroatoms in the lactonic ring said macrolide having the property of accumulating within mammalian immune system cells that mediate inflammatory immune responses;

T is a steroidal or nonsteroidal anti-inflammatory subunit;

L is a linker molecule to which each of M and T are covalently linked,

wherein the conjugate of formula VII exhibits oral bioavailability of less than 10%, said amount being effective in treating a disease, disorder or condition of the gastrointestinal tract characterized by inflammation during a partial or total remission phase of said disease, disorder or condition.

25. The method of claim 1 wherein the subject has been previously determined to be responsive to treatment with an active ingredient comprising as its active moiety the subunit T.

26. A method for the maintenance treatment of an inflammatory disease, disorder or condition of the gastrointestinal tract or the delay or prevention of recurrence of said disease, disorder or condition comprising administering to a human or nonhuman mammalian subject in need thereof an effective amount of a low oral bioavailability conjugate compound of formula VII


VII

wherein M represents a group of Formula XIV:

wherein
R

(0 Z and W are, together,
, wherein
RM is hydroxy, alkoxy, substituted alkoxy or ORP;
RN is hydrogen, Rp, or alkyl;
(ii) R1 is hydroxy, ORP or -O-S2;
(iii) S1 is hydrogen or a sugar moiety at position C/5 of the formula:



wherein Ry is H, alkyl, or Rp (iv) S2 is a sugar moiety of the formula:


wherein

R12 is hydrogen, alkyl, alkyl-Rp, or Rp; and

Rp is hydroxy 1 or amino protective group;

wherein M has a linkage site through which it is linked to the subunit T via the linking group L; provided that the linkage site being at one or more of the following:

a) any reactive hydroxy, nitrogen, or epoxy group located on macrolide ring, sugar moiety S1, sugar moiety S2, or an aglycone oxygen or nitrogen when S1 and/or S2 is cleaved off;

/C=NRM
b) a reactive > N-RN or ' group located on Z and W; and

T is a steroidal or nonsteroidal anti-inflammatory subunit;

L is a linker molecule to which each of M and T are covalently linked, wherein L represents a group of Formula IXA or Formula IXB:



IXB X1-(CH2)m-Q-(CH2)n-X2

wherein X1 is selected from the group consisting of -CH2-, -CH2NH-, -C(=O)-, -OC(=O)-, =N-O-, -OC(=O)NH- and -C(=O)NH-;

X2 is -NH-, -CH2-, -NHC(=O)-, -C(=O)-, -O- or -OC(=O)-;

Q is -NH- or -CH2-, wherein each -CH2- or -NH- group may be optionally substituted by Ci-C7-alkyl, C2-C?-alkenyl, Ca-Cy-alkynyl, C( = O)RX, C( = O)OR\
C(= O)NHR", wherein Rx may be Ci-C7-alkyl, aryl or heteroaryl;

m and n independently are a whole number from 0 to 8, with the proviso that if Q is NH, n cannot be 0;

and pharmaceutically acceptable salts, prodrugs, and solvates thereof in an oral dosage form; and

wherein the conjugate of formula VII exhibits less than 10% oral bioavailability.

27. The method of claim 26, wherein

wherein M represents a group of Formula XV:



wherein
(i) RN is hydrogen, Rp, or alkyl;
(ii) R1 is hydroxy or -O-S2;
(iv) S1 is hydrogen or a sugar moiety at position C/5 of the formula:



(v) S2 is a sugar moiety of the formula:

wherein Rp amino protective group; and

wherein M has a linkage site through which it is linked to the subunit T via the linking group L; provided that the linkage site is the reactive > N-RN via the linking group L.