1. A compound of formula I or a pro-drug, or an ester or a pharmaceutically acceptable salt thereof:
and
A is of the formula:
Wherein:
Q is
where
i) X is selected from hydrogen, halogen, C1-C6 alkyl, or aryl;
ii) one of Y and Z is selected from: hydrogen, deuterium, halogen, or methyl and the other is independently selected from:
a) halogen;
b) R1, where R1 is selected from:
1) hydrogen;
2) deuterium;
3) C1-C6 alkyl, optionally substituted with halogen, TMS, aryl, heterocycloalkyl, or heteroaryl;
4) C2-C6 alkenyl, optionally substituted with halogen, TMS, aryl, heterocycloalkyl, or heteroaryl;
5) C2-C6 alkynyl, optionally substituted with halogen, TMS, aryl, heterocycloalkyl, or heteroaryl;
6) C3-C12 cycloalkyl;
7) substituted C3-C12 cycloalkyl;
8) aryl;
9) substituted aryl;
10) heterocycloalkyl;
11) substituted heterocycloalkyl;
12) heteroaryl; or
13) substituted heteroaryl;
c) \u2014C(O)OR1, where R1 is as previously defined;
d) \u2014C(O)OCH2\u2014V\u2014R1, where R1 is as previously defined and V is \u2014O\u2014 or \u2014S\u2014;
e) \u2014C(O)N(R3)(R4), where R3 and R4 are independently selected from R1 as previously defined;
f) \u2014C(O)SR1, where R1 is as previously defined;
g) \u2014C(O)OCH2OC(O)R1, where R1 is as previously defined;
h) \u2014C(S)OR1, where R1 is as previously defined;
i) \u2014C(S)SR1, where R1 is as previously defined;
j) R2, where R2 is selected from:
1) C1-C6 alkyl-M-R1, where R1 is as previously defined and M is absent or selected from:
i. \u2014NH\u2014;
ii. \u2014N(CH3)\u2014;
iii. \u2014S\u2014;
iv. \u2014S(O)n\u2014, where n=0, 1, or 2; or
v. \u2014O\u2014;
2) C2-C6 alkenyl-M-R1, where R1 and M are as previously defined; or
3) C2-C6 alkynyl-M-R1, where R1 and M are as previously defined;
k) Or in the alternative, Y and Z are taken together with the carbon atom to which they are attached to form a C3-C12 cycloalkyl moiety; and
iii) G is independently selected from halogen, TMS, R1 or R2 as previously defined;
B is selected from:
i) -\u03b1Abu-;
ii) -Val-;
iii) -Thr-; or
iv) -Nva-;
U is selected from:
i) -(D)Ala-;
ii) -(D)Ser-;
iii) -O-(2-hydroxyethyl)(D)Ser-;
iv) -O-(acyl)(D)Ser-; or
v) -O-(2-acyloxyethyl)(D)Ser-; and
W is selected from hydrogen or a hydroxy protecting group.
2. A compound of formula I according to claim 1, wherein A is of the formula A1:
where:
i) X is selected from hydrogen, halogen, or C1-C6 alkyl;
ii) one of Y and Z is selected from: hydrogen, deuterium, halogen, or methyl and the other is independently selected from:
a) halogen;
b) R1, where R1 is selected from:
1) hydrogen;
2) deuterium;
3) C1-C6 alkyl, optionally substituted with halogen;
4) C2-C6 alkenyl, optionally substituted with halogen; or
5) C2-C6 alkynyl, optionally substituted with halogen;
c) \u2014C(O)OR1, where R1 is as previously defined;
d) \u2014C(O)OCH2\u2014V\u2014R1, where R1 is as previously defined and V is \u2014O\u2014 or \u2014S\u2014;
e) \u2014C(O)N(R3)(R4), where R3 and R4 are independently selected from R1 as previously defined;
f) \u2014C(O)SR1, where R1 is as previously defined;
g) \u2014C(O)OCH2OC(O)R1, where R1 is as previously defined;
h) \u2014C(S)OR1, where R1 is as previously defined;
i) \u2014C(S)SR1, where R1 is as previously defined;
j) R2, where R2 is selected from:
1) C1-C6 alkyl-M-R1, where R1 is as previously defined and M is absent or selected from:
i. \u2014NH\u2014;
ii. \u2014N(CH3)\u2014;
iii. \u2014S\u2014;
iv. \u2014S(O)n\u2014, where n=0, 1, or 2; or
v. \u2014O\u2014;
2) C2-C6 alkenyl-M-R1, where R1 and M are as previously defined; or
3) C2-C6 alkynyl-M-R1, where R1 and M are as previously defined;
k) Or in the alternative, Y and Z are taken together with the carbon atom to which they are attached to form a C3-C12 cycloalkyl moiety; and
iii) G is independently selected from halogen, TMS, R1 or R2 as previously defined;
B is selected from:
v) -\u03b1Abu-;
vi) -Val-;
vii) -Thr-; or
viii) -Nva-;
U is selected from:
vi) -(D)Ala-;
vii) -(D)Ser-;
viii) -O-(2-hydroxyethyl)(D)Ser-;
ix) -O-(acyl)(D)Ser-; or
x) -O-(2-acyloxyethyl)(D)Ser-; and
W is selected from hydrogen or a hydroxy protecting group.
3. A compound of formula I according to claim 2, wherein A is of the formula A2:
where X, Y, and Z are as defined in claim 2.
4. A compound of formula I according to claim 2, wherein A is of the formula A3:
where Y and Z are as defined in claim 2.
5. A compound of formula I according to claim 1, wherein A is of the formula A4:
where W and G are as defined in claim 1.
6. A compound of formula I according to claim 1, wherein A is of the formula A5:
where G is as defined in claim 1.
7. A compound of formula I, according to claim 1, selected from:
Example 2: A compound of formula I, wherein Q is
W is Ac and X\u2550Y=Z=hydrogen;
Example 3: A compound of formula I, wherein Q is
W is H and X\u2550Y=Z=hydrogen;
Example 4: A compound of formula I, wherein Q is
Y is CH3, and W\u2550X=Z=hydrogen;
Example 5: A compound of formula I, wherein Q is
Y=Z=CH3, and W\u2550X=hydrogen;
Example 6: A compound of formula I, wherein Q is
Y is \u2014(CH2)3CH3, and W\u2550X=Z=hydrogen;
Example 7: A compound of formula I, wherein Q is
Y is \u2014(CH2)2Br, and W\u2550X=Z=hydrogen;
Example 10: A compound of formula I, wherein Q is
Y is \u2014CO2Me, and W\u2550X=Z=hydrogen;
Example 12: A compound of formula I, wherein Q is
Y is Et, and W\u2550X=Z=hydrogen;
Example 13: A compound of formula I, wherein Q is
Y is \u2014CH\u2550CHCH2TMS, and W\u2550X=Z=hydrogen;
Example 14: A compound of formula I, wherein Q is
G is H, and W is H;
Example 15: A compound of formula I, wherein Q is
Y is propyl, and W\u2550X=Z=hydrogen;
Example 16: A compound of formula I, wherein Q is
Y is cyclopropyl, and W\u2550X=Z=hydrogen;
Example 17: A compound of formula I, wherein Q is
Y is \u2014CH\u2550CHCH3, and W\u2550X=Z=hydrogen;
Example 18: A compound of formula I, wherein Q is
X\u2550Y=CH3, and W=Z=hydrogen;
Example 19: A compound of formula I, wherein Q is
W\u2550X=Y=hydrogen, and Z=CH3;
Example 21: A compound of formula I, wherein Q is
W\u2550X=Y=hydrogen, and Z=\u2014CH2CH\u2550CH2;
Example 22: A compound of formula I, wherein Q is
W\u2550X=Y=hydrogen, and Z is ethyl;
Example 23: A compound of formula I, wherein Q is
W\u2550X=Y=hydrogen, and Z=\u2014CH\u2550CHCH3;
Example 24: A compound of formula I, wherein Q is
W\u2550X=Y=hydrogen, and Z=\u2014CH2OCH3;
Example 25: A compound of formula I, wherein Q is
G=\u2014CH\u2550CHCH3 and W=hydrogen;
Example 26: A compound of formula I, wherein Q is
G=propyl and W=hydrogen; or
Example 27: A compound of formula I, wherein Q is
G=\u2014CH3 and W=hydrogen.
8. A pharmaceutical composition for the treatment of an immune disorder comprising a therapeutically effective amount of at least one compound of Formula (I) in claim 1, or a pharmaceutically acceptable salt, ester or prodrug thereof, in combination with a pharmaceutically acceptable carrier or excipient.
9. A method of treating organ transplantation rejection in a subject, which comprises administering to said subject a therapeutically effective amount of the pharmaceutical composition of claim 8.
10. A method of treating an immune disorder in a subject, which comprises administering to said subject a therapeutically effective amount of the pharmaceutical composition of claim 1.
11. The method of claim 10, wherein said immune disorder is selected from the group consisting of: rheumatoid arthritis, inflammatory bowel disease, psoriasis, asthma, atopic dermatitis, allergic rhinitis, and chronic obstructive pulmonary disease.
12. A method of treating an immune disorder in a subject, which comprises topically administering to said subject a therapeutically effective amount of the pharmaceutical composition of claim 1.
13. The method of claim 12, wherein said inflammatory or immune disorder is selected from the group consisting of psoriasis and eczema.
14. The method of claim 12, wherein said topically administering is achieved via inhalation.
15. The method of claim 14, wherein said inflammatory or immune disorder is an obstructive airways disease.
16. The method of claim 15, wherein said airways disease is selected from the group consisting of asthma, allergic rhinitis, bronchitis, cystic fibrosis, and chronic obstructive pulmonary disease.
17. The method of claim 16, wherein said chronic obstructive pulmonary disease is emphysema or chronic bronchitis.
18. A pharmaceutical composition comprising at least one compound of Formula (I) in claim 1, or a pharmaceutically acceptable salt, ester or prodrug thereof, in combination with a pharmaceutically acceptable carrier or excipient.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A dental composition comprising:
an addition-fragmentation agent of the formula:
wherein
R1, R2 and R3 are each independently Zm-Q-, a (hetero)alkyl group or a (hetero)aryl group with the proviso that at least one of R1, R2 and R3 is Zm-Q-;
Q is a linking group have a valence of m+1;
Z is an ethylenically unsaturated polymerizable group;
m is 1 to 6;
each X1 is independently \u2014O\u2014 or \u2014NR4\u2014, where R4 is H or C1-C4 alkyl; and
n is 0 or 1;
at least one monomer comprising at least two ethylenically unsaturated group; and
inorganic oxide filler.
2. The dental composition of claim 1 wherein the addition-fragmentation agent comprises at least two ethylenically unsaturated terminal groups.
3. The dental composition of claim 1 wherein the ethylenically unsaturated groups are (meth)acrylate groups.
4. The dental composition of claim 1 wherein Z comprises a vinyl, vinyloxy, (meth)acryloxy, (meth)acrylamido, styrenic and acetylenic functional groups.
5. The dental composition of claim 1 wherein Z is selected from:
wherein R4 is H or C1-C4 alkyl.
6. The dental composition of claim 1 wherein Q is selected from \u2014O\u2014, \u2014S\u2014, \u2014NR4\u2014, \u2014SO2\u2014, \u2014PO2\u2014, \u2014CO\u2014, \u2014OCO\u2014, \u2014R6\u2014, \u2014NR4\u2014CO\u2014NR4\u2014, NR4\u2014CO\u2014O\u2014, NR4\u2014CO\u2014NR4\u2014CO\u2014O\u2014R6\u2014, \u2014CO\u2014NR4\u2014R6\u2014, \u2014R6\u2014CO\u2014O\u2014R6\u2014, \u2014O\u2014R6\u2014, \u2014S\u2014R6\u2014, \u2014NR4\u2014R6\u2014, \u2014SO2\u2014R6\u2014, \u2014PO2\u2014R6\u2014, \u2014CO\u2014R6\u2014, \u2014OCO\u2014R6\u2014, \u2014NR4\u2014CO\u2014R6\u2014, NR4\u2014R6\u2014CO\u2014O\u2014, and NR4\u2014CO\u2014NR4\u2014,
wherein each R4 is hydrogen, a C1 to C4 alkyl group, or aryl group, each R6 is an alkylene group having 1 to 6 carbon atoms, a 5- or 6-membered cycloalkylene group having 5 to 10 carbon atoms, or a divalent arylene group having 6 to 16 carbon atoms, with the proviso that Q-Z does not contain peroxidic linkages.
7. The dental composition of claim 1 wherein Q is an alkylene or hydroxyl-substituted alkylene or aryloxy-substituted alkylene or alkoxy-substituted alkylene.
8. The dental composition of claim 1 wherein Q is an alkylene of the formula \u2014CrH2r\u2014, where r is 1 to 10.
9. The dental composition of claim 1 wherein Q is a hydroxyl-substituted alkylene.
10. The dental composition of claim 1 wherein Q is \u2014CH2\u2014CH(OH)\u2014CH2\u2014.
11. The dental composition of claim 1 wherein Q is an aryloxy-substituted alkylene.
12. The dental composition of claim 1 wherein R5 is an alkoxy-substituted alkylene.
13. The dental composition of claim 1 wherein R1\u2014X1\u2014 groups (and optionally R2\u2014X2\u2014 groups) is selected from H2C\u2550C(CH3)C(O)\u2014O\u2014CH2\u2014CH(OH)\u2014CH2\u2014O\u2014, H2C\u2550C(CH3)C(O)\u2014O\u2014CH2\u2014CH(O\u2014(O)C(CH3)\u2550CH2)\u2014CH2\u2014O\u2014, H2C\u2550C(CH3)C(O)\u2014O\u2014CH(CH2OPh)\u2014CH2\u2014O\u2014, H2C\u2550C(CH3)C(O)\u2014O\u2014CH2CH2\u2014N(H)\u2014C(O)\u2014O\u2014CH(CH2OPh)\u2014CH2\u2014O\u2014, H2C\u2550C(CH3)C(O)\u2014O\u2014CH2\u2014CH(O\u2014(O)C\u2014N(H)\u2014CH2CH2\u2014O\u2014(O)C(CH3)C\u2550CH2)\u2014CH2\u2014O\u2014, H2C\u2550C(H)C(O)\u2014O\u2014(CH2)4\u2014O\u2014CH2\u2014CH(OH)\u2014CH2\u2014O\u2014, H2C\u2550C(CH3)C(O)\u2014O\u2014CH2\u2014CH(O\u2014(O)C\u2014N(H)\u2014CH2CH2\u2014O\u2014(O)C(CH3)C\u2550CH2)\u2014CH2\u2014O\u2014, CH3\u2014(CH2)7\u2014CH(O\u2014(O)C\u2014N(H)\u2014CH2CH2\u2014O\u2014(O)C(CH3)C\u2550CH2)\u2014CH2\u2014O\u2014, H2C\u2550C(H)C(O)\u2014O\u2014(CH2)4\u2014O\u2014CH2\u2014CH(\u2014O\u2014(O)C(H)\u2550CH2)\u2014CH2\u2014O\u2014 and H2C\u2550C(H)C(O)\u2014O\u2014CH2\u2014CH(OH)\u2014CH2\u2014O\u2014, H2C\u2550C(H)C(O)\u2014O\u2014(CH2)4\u2014O\u2014CH2\u2014CH(\u2014O\u2014(O)C(H)\u2550CH2)\u2014CH2\u2014O\u2014, and CH3\u2014(CH2)7\u2014CH(O\u2014(O)C\u2014N(H)\u2014CH2CH2\u2014O\u2014(O)C(CH3)C\u2550CH2)\u2014CH2\u2014O\u2014.
14. The dental composition of claim 1 wherein the ethylenically unsaturated groups of the monomer are (meth)acrylate groups.
15. The dental composition of claim 1 wherein the monomer is an aromatic monomer having a refractive index of at least 1.50.
16. The dental composition of claim 1 wherein the monomer is a low volume shrinkage monomer.
17. The dental composition of claim 1 wherein the monomer is an isocyanurate monomer, a tricyclodecane monomer, or a mixture thereof.
18. The dental composition of claim 1 wherein the hardened dental composition exhibits a stress deflection no greater than 2.0.
19. The dental composition of claim 1 wherein the dental composition comprises at least one (meth)acrylate monomer selected from ethoxylated bisphenol A dimethacrylate (BisEMA6), 2-hydroxyethyl methacrylate (HEMA), bisphenol A diglycidyl dimethacrylate (bisGMA), urethane dimethacrylate (UDMA), triethlyene glycol dimethacrylate (TEGDMA), glycerol dimethacrylate (GDMA), ethylenegylcol dimethacrylate, neopentylglycol dimethacrylate (NPGDMA), polyethyleneglycol dimethacrylate (PEGDMMA), and mixtures thereof.
20. The dental composition of claim 1 wherein the filler inorganic oxide filler comprises nanoparticles.
21. The dental composition of claim 20 wherein the inorganic nanoparticles comprise silica, zirconia, or mixtures thereof.
22. The dental composition of claim 20 wherein the inorganic nanoparticles are in the form of nanoclusters.
23. A method of treating a tooth surface, the method comprising
providing a hardenable dental composition of claim 1 comprising an addition-fragmentation agent,
placing the dental composition on a tooth surface; and
hardening the hardenable dental composition.
24. The method of claim 23 wherein the dental composition further comprises at least one ethylenically unsaturated monomer with acid functionality.
25. A dental article comprising the hardenable dental composition of claim 22 at least partially hardened.
26. A method of treating a tooth surface, the method comprising providing an at least partially hardened dental article according to claim 25, adhering the dental article on a tooth surface in the mouth of a subject.
27. The dental composition of claim 1 further comprising a redox hardening agent.