1. A compound according to structuial formula (I):
or a salt or N-oxide thereof, wherein:
R2 is selected from the group consisting of phenyl mono substituted at the 3- or 5-position with an R8 group, phenyl di- or tri-substituted with one or more of the same or different R8 groups and 5-15 membered heteroaryl optionally substituted with one or more of the same or different R8 groups;
R4 is selected from the group consisting of phenyl substituted with one or two of the same or different R8 groups and 5-15 membered heteroaryl optionally substituted with one or more of the same or different R8 groups;
R8 is selected from the group consisting of Ra, Rb, Rc substituted with one or more of the same or different Ra or Rb, \u2014ORa substituted with one or more of the same or Ra or Rb, \u2014B(ORa)2, \u2014B(NRcCRc)2, \u2014(CH2)mRb, \u2014(CHRa)m\u2014Rb; \u2014O\u2014(CH2)mRb, \u2014S\u2014(CH2)mRbk, \u2014O\u2014CHRaRb, \u2014O\u2014CRa(Rb)2, \u2014O\u2014(CHRa)m\u2014Rb, \u2014O\u2014(CH2)m\u2014CH(CH2)mRbRb, \u2014S\u2014(CHRa)m\u2014Rb, \u2014C(O)NH\u2014(CH2)mRb, \u2014C(O)NH\u2014(CHRa)m\u2014Rb, \u2014O\u2014(CH2)m\u2014C(O)NH\u2014(CH2)m\u2014Rb, \u2014S\u2014(CH2)m\u2014C(O)NH\u2014(CH2)mRb, \u2014O\u2014(CHRa)m\u2014C(O)NH\u2014(CHRa)m\u2014Rb, \u2014S\u2014(CHRa)m\u2014C(O)NH\u2014(CHRa)mRb, \u2014NH\u2014(CH2)mRb, \u2014NH\u2014(CHRa)m\u2014Rb, \u2014N(CH2)mRb2, \u2014NH\u2014C(O)\u2014NH\u2014(CH2)mRb, \u2014NH\u2014C(O)\u2014(CH2)m\u2014CHRbRb and \u2014NH\u2014(CH2)m\u2014C(O)\u2014NH\u2014(CH2)mRb;
each Ra is independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, (C4-C11) cycloalkylalkyl, (C1-C10) aryl, (C6-C16) arylalkyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16 membered heteroarylalkyl;
each Rb is a suitable group independently selected from the group consisting of \u2550O, \u2014ORd, (C1-C3) haloalkyloxy, \u2550S, \u2014SRd, \u2550NRd, \u2550NORd, \u2014NRcRc, halogen, \u2014CF3, \u2014CN, \u2014NC, \u2014OCN, \u2014SCN, \u2014NO, \u2014NO2, \u2550N2, \u2014N3, \u2014S(O)Rd, \u2014S(O)2Rd, \u2014S(O)2ORd, \u2014S(O)NRcRc, \u2014S(O)1NRcRc, \u2014OS(O)Rd, \u2014OS(O)2Rd, \u2014OS(O)2ORd, \u2014OS(O)2NRcRc, \u2014C(O)Rd, \u2014C(O)ORd, \u2014C(O)NRcRc, \u2014C(NH)NRcRc, \u2014C(NRa)NRcRc, \u2014-C(NOH)Ra, \u2014C(NOH)NRcRc, \u2014OC(O)Rd, \u2014OC(O)ORd, \u2014OC(O)NRcRc, \u2014OC(NH)NRcRc, \u2014OC(NRa)NRcRc, \u2014NHC(O)nRd, \u2014NRaC(O)nRd, \u2014NHC(O)nORd, \u2014NRaC(O)nORd\u2014NHC(O)nNRcRc, \u2014NRaC(O)nNRcRc, \u2014NHC(NH)nNRcRc and \u2014NRaC(NRa)nNRcRc;
each Rc is Ra, or, alternatively, two Rc are taken together with the nitrogen atom to which they are bonded to form a 5 to 8-membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which may optionally be substituted with one or more of the same or different Ra or suitable Rb groups;
each Rd is Ra;
each Rc is independently selected from the group consisting of(C1-C6) alkyl, (C3-C8) cycloalkyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, (C6-C16) arylalkyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16 membered heteroarylalkyl;
each m is independently an integer from 1 to 3; and
each n is independently an integer from 0 to 3;
wherein:
one or both of R2 and R4 are, independently of one another, a heteroaryl selected from the group consisting of:
wherein:
R35 is hydrogen or R8;
X is selected from the group consisting of CH, N and N\u2014O;
each Y is independently selected from the group consisting of O, S and NH;
each Y1 is independently selected from the group consisting of O, S, SO, SO2, SONR36, NH and NR37;
each Y2 is independently selected from the group consisting of CH, CH2, O, S, N, NH and NR37;
R36 is hydrogen or alkyl;
R37 is hydrogen,
R38 is selected from the group consisting of alkyl and aryl;
A is selected from the group consisting of O, NH and NR38;
R9, R10, R11 and R12 are each, independently of one another, selected from the group consisting of alkyl, alkoxy, halogen, haloalkoxy, aminoalkyl and hydroxyalkyl, or, alternatively, R9 and R10 or R11 and R12, or R9 and R10 and R11 and R12 are taken together form an oxo group;
each Z is selected from the group consisting of hydroxyl, alkoxy, aryloxy, ester, carbamate and sulfonyl;
Q is selected from the group consisting of \u2014OH, OR8, \u2014NRcRc, \u2014NHR39\u2014C(O)R8, \u2014NHR39\u2014C(O)OR8, \u2014NR39CHR40\u2014Rb, \u2014NR39\u2014(CH2)m\u2014Rb and \u2014NR39\u2014C(O)-CHR40\u2014NRcRc; and
R39 and R40 are each, independently of one another, selected from the group consisting of hydrogen, alkyl, aryl, alkylaryl, arylalkyl and NHR8.
2. The compound of claim 1 in which R2 and R4 are the same.
3. The compound of claim \u2018in which each R35 is independently selected from the group consisting of hydrogen, \u2014ORd, \u2014NRcRc, \u2014C(O)NRcRc, \u2014(CH2)mRb where Rb is selected from the group consisting of \u2014NRcRc, \u2014C(O)NRcRc, \u2014C(O)ORd, and \u2014ORd, and \u2014C(O)ORd, where Rc and Rd are as defined in claim .
4. The compound of claim 1 in which R4 is an optionally substituted heteroaryl which is attached to the remainder of the molecule via a ring carbon atom.
5. The compound of claim 1 which R4 is an optionally substituted heteroaryl which is attached to the remainder of the molecule via a ring carbon atom.
6. The compound of claim 1 in which one of R2 and R4 is, a phenyl mono substituted at the 3- or 5-position with an R8 group for R2, a phenyl di- or tri-substituted with one or more of the same or different R8 groups for R2 or a phenyl substituted with one or two of the same or different R8 groups for R4.
7. The compound of claim 6 in which the substituted R4 phenyl group is mono substituted with R8.
8. The compound of claim 7 in which R8 is selected from the group consisting of (C1-C6) alkyl, ORd, \u2014O\u2014(CH2)mRb where Rb is selected from the group consisting of \u2014NRcRc, \u2014C(O)NRcRc, \u2014C(O)ORd, and \u2014(NH)RcRc, \u2014O\u2014C(O)NRcRc, \u2014O\u2014C(O)ORd, \u2014O\u2014C(NH)NRcRc, \u2014NH\u2014(CH2)mRb where Rb is selected from the group consisting of \u2014NRcNRc, and \u2014NHC(O)nNRcRc.
9. The compound of claim 6 in which the substituted R2 or R4 phenyl group is disubstituted with R8.
10. The compound of claim 9 in which each R8 is independently selected from the group consisting of (C1-C6) alkyl, \u2014ORa substituted with one or more of the same or different Ra or Rb, \u2014O\u2014(CH2)mRb where Rb is selected from the group consisting of \u2014NRcRc, \u2014C(O)NRc,Rc, \u2014C(O)ORd, and \u2014(NH)RcRc, \u2014O\u2014C(O)NRcRc, \u2014O\u2014C(O)ORd, \u2014O\u2014C(NH)NRcRc, \u2014NH\u2014(CH2)mRb where Rb is selected from the group consisting of \u2014NRcNRc, and \u2014NHC(O)nNRcRc.
11. The compound of claim 1 in which the R2 phenyl group is trisubstituted with R8.
12. The compound of claim 11 in which each R8 is independently selected from the group consisting of (C1-C6) alkyl, \u2014ORa substituted with one or more of the same or different Ra or Rb, \u2014O\u2014(CH2)mRb where Rb is selected from the group consisting of \u2014NRcRc, \u2014C(O)NRcRc, \u2014C(O)ORd, and \u2014(NH)RcRc, \u2014O\u2014C(O)NRcRc, \u2014O\u2014C(O)ORd, \u2014O\u2014C(NH)NRcRc, \u2014NH\u2014(CH2)mRb where Rb is selected from the group consisting of \u2014NRcNRc, and \u2014NHC(O)nNRcRc.
13. The, compound of claim 11 in which the phenyl has the formula:
wherein: R31 is methyl or (C1-C6) alkyl; R32 is hydrogen or (C1-C6) alkyl; and R33 is a halo group.
14. The compound of claim 1 which inhibits mast cell or basophil cell degranulation as measured in an in vitro assay.
15. The compound of claim 14 which has an IC50 of about 20 \u03bcM or less.
16. A pharmaceutical composition comprising a pyrimidinediamine compound and a pharmaceutically acceptable excipient, carrier or dilutent, said pyrimidinediamine compound being a compound according to structural formula (I):
or a salt or N-oxide thereof, wherein:
R2 is selected from the group consisting of phenyl mono substituted at the 3- or 5-position with an R8 group, phenyl di- or tn-substituted with one or more of the same or different R8 groups and 5-15 membered heteroaryl optionally substituted with one or more of the same or different R8 groups;
R4 is selected from the group consisting of phenyl substituted with one or two of the same or different R8 groups and 5-15 membered heteroaryl optionally substituted with one or more of the same or different R8 groups;
R8 is selected from the group consisting of Ra, Rb, Rc substituted with one or more of the same or different Ra or Rb, \u2014ORa substituted with one or more of the same or Ra or Rb, \u2014B(ORa)2, \u2014B(NRcCRc)2, \u2014(CH2)mRb, \u2014(CHRa)m\u2014Rb, \u2014O\u2014(CH2)mRb, \u2014S\u2014(CH2)mRb, \u2014O\u2014CHRaRb, \u2014O\u2014CRa(Rb)2, \u2014O\u2014(CHRa)m\u2014Rb, \u2014O\u2014(CH2)m\u2014CH(CH2)mRbRb, \u2014S\u2014(CHRa)m\u2014Rb, \u2014C(O)NH\u2014(CH2)mRb, \u2014C(O)NH\u2014(CHRa)m\u2014Rb, \u2014O\u2014(CH2)m\u2014C(O)NH\u2014(CH2)m\u2014Rb, \u2014S\u2014(CH2)m\u2014C(O)NH\u2014(CH2)mRb, \u2014O\u2014(CHRa)m\u2014C(O)NH\u2014(CHRa)m\u2014Rb, \u2014S\u2014(CHRa)m\u2014C(O)NH\u2014(CHRa)mRb, \u2014NH\u2014(CH2)mRb, \u2014NH\u2014(CHRa)m\u2014Rb, \u2014N(CH2)mRb2, \u2014NH\u2014C(O)\u2014NH\u2014(CH2)mRb, \u2014NH\u2014C(O)\u2014(CH2)m\u2014CHRbRb and \u2014NH\u2014(CH2)m\u2014C(O)\u2014NH\u2014(CH2)mRb;
each Ra is independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, (C4-C11) cycloalkylalkyl, (C1-C10) aryl, (C6-C16) arylalkyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16 membered heteroarylalkyl;
each Rb is a suitable group independently selected from the group consisting of \u03b1O, \u2014ORd, (C1-C3) haloalkyloxy, \u2550S, \u2014SRd, \u2550NRd, \u2550NORd, \u2014NRcRc, halogen, \u2014CF3, \u2014CN, \u2014NC, \u2014OCN, \u2014SCN, \u2014NO, \u2014NO2, \u2550N2, \u2014N3, \u2014S(O)Rd, \u2014S(O)2Rd, \u2014S(O)2ORd, \u2014S(O)NRcRc, \u2014S(O)1NRcRc, \u2014OS(O)Rd, \u2014OS(O)2Rd, \u2014OS(O)2ORd, \u2014OS(O)2NRcRc, \u2014C(O)Rd, \u2014C(O)ORd, \u2014C(O)NRcRc, \u2014C(NH)NRcRc, \u2014C(NRa)NRcRc, \u2014-C(NOH)Ra, \u2014C(NOH)NRcRc, \u2014OC(O)Rd, \u2014OC(O)ORd, \u2014OC(O)NRcRc, \u2014OC(NH)NRcRc, \u2014OC(NRa)NRcRc, \u2014NHC(O)nRd, \u2014NRaC(O)nRd, \u2014NHC(O)nORd, \u2014NRaC(O)nORd\u2014NHC(O)nNRcRc, \u2014NRaC(O)nNRcRc, \u2014NHC(NH)nNRcRc and \u2014NRaC(NRa)nNRcRc;
each Rc is Ra, or, alternatively, two Rc are taken together with the nitrogen atom to which they are bonded to form a 5 to 8-membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which may optionally be substituted with one or more of the same or different Ra or suitable Rb groups;
each Rd is Ra;
each Rc is independently selected from the group consisting of (C1-C6) alkyl, (C3-C8) cycloalkyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, (C6-C16) arylalkyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16 membered heteroarylalkyl;
each m is independently an integer from 1 to 3; and
each n is independently an integer from 0 to 3;
wherein:
one or both of R2 and R4 are, independently of one another, a heteroaryl selected from the group consisting of:
wherein:
R35 is hydrogen or R8;
X is selected from the group consisting of CH, N and N-O;
each Y is independently selected from the group consisting of O, S and NH;
each Y1 is independently selected from the group consisting of O, S, SO, SO2, SONR36, ,NH and NR37;
each Y2 is independently selected from the group consisting of CH, CH2, O, S, N, NH and NR37;
R36 is hydrogen or alkyl;
R37 is hydrogen,
R38 is selected from the group consisting of alkyl and aryl;
A is selected from the group consisting of O, NH and NR38;
R9, R10, R11 and R12 are each, independently of one another, selected from the group consisting of alkyl, alkoxy, halogen, haloalkoxy, aminoalkyl and hydroxyalkyl, or, alternatively, R9 and R10 or R11 and R12, or R9 and R10 and R11 and R12 are taken together form an oxo group;
each Z is selected from the group consisting of hydroxyl, alkoxy, aryloxy, ester, carbamate and sulfonyl;
Q is selected from the group consisting of \u2014OH, OR8, \u2014NRcRc, \u2014NHR39\u2014C(O)R8, \u2014NHR39\u2014C(O)OR8, \u2014NR39CHR40\u2014Rb, \u2014NR39\u2014(CH2)m\u2014Rb and \u2014NR39\u2014C(O)-CHR40\u2014NRcRc; and
R39 and R40 are each, independently of one another, selected from the group consisting of hydrogen, alkyl, aryl, alkylaryl, arylalkyl and NHR8.
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 topical skin care composition comprising:
a) a safe and effective amount of a sugar amine;
b) a safe and effective amount of a retinoid;
c) a safe and effective amount of a peptide; and
d) a dermatologically acceptable carrier for the sugar amine, retinoid, and peptide.
2. A composition according to claim 1 wherein the composition comprises from about 0.001% to about 20% of the sugar amine.
3. A composition according to claim 2 wherein the composition comprises from about 0.05% to about 10% of the sugar amine.
4. A composition according to claim 1 wherein the composition comprises from about 0.001% to 10% of the retinoid.
5. A composition according to claim 4 wherein the composition comprises from about 0.01% to about 0.5% of the retinoid.
6. A composition according to claim 1 wherein the composition comprises from about 1\xd710\u22126% to about 20% of the peptide.
7. A composition according to claim 6 wherein the composition comprises from about 1\xd710\u22125% to about 5% of the peptide.
8. A composition according to claim 1 wherein the composition contains from about 1% to about 10% of the sugar amine, from about 0.1% to about 10% of the retinoid, and from about 1\xd710\u22125% to about 5% of the peptide.
9. A composition according to claim 1 wherein the sugar amine is selected from the group consisting of glucosamine, derivatives of glucosamine, mannosamine, derivatives of mannosamine, galactosamine, derivatives of galactosamine, and mixtures thereof.
10. A composition according to claim 9 wherein the sugar amine is selected from the group consisting of glucosamine, N-acetyl glucosamine, galactosamine, N-acetyl galactosamine, mannosamine, N-acetyl mannosamine, and mixtures thereof.
11. A composition according to claim 10 wherein the sugar amine is glucosamine.
12. A composition according to claim 1 wherein the retinoid is retinyl propionate.
13. A composition according to claim 1 wherein the peptide is a palmitoyl peptide derivative.
14. A composition according to claim 1 wherein the sugar amine is glucosamine, the retinoid is retinyl propionate, and the peptide is a palmitoyl peptide derivative.
15. A composition according to claim 1 wherein the composition further comprises an additional skin care active selected from the group consisting of desquamatory actives, anti-acne actives, vitamin B3 compounds, hydroxy acids, anti-oxidants, radical scavengers, chelators, anti-inflammatory agents, topical anesthetics, tanning actives, skin lightening agents, anti-cellulite agents, flavonoids, antimicrobial actives, skin soothing agents, skin healing agents, antifungal actives, sunscreen actives, conditioning agents, structuring agents, thickening agents, and mixtures thereof.
16. A composition according to claim 15 wherein the additional skin care active is selected from the group consisting of allantoin, bisabolol, tocopherol nicotinate, niacinamide, tocopherol, tocopherol esters, phytosterol, isoflavone, dexpanthenol, panthenol, salicylic acid, farnesol, phytantriol, and mixtures thereof.
17. A composition according to claim 16 wherein the composition further comprises niacinamide.
18. A method of regulating the condition of skin, said method comprising the step of
a) topically applying a safe and effective amount of the composition of claim 1 to the skin of a mammal in need of treatment.
19. A method according to claim 18 wherein the sugar amine is glucosamine.