1. A compound of formula (I)
wherein,
A1 is selected from \u2014C\u2550O and \u2014NR5;
A2 is selected from \u2014O\u2014, \u2014C\u2550O and \u2014NR6;
R1 is \u2014H, \u2014OH or \u2014C1-3alkyl;
R2 is selected from phenyl, \u2014C5-8cycloalkyl, 5-6 membered heteroaryl, 6 to 9 membered heterocycle optionally and independently substituted with one or more R7;
R3 is \u2014H, \u2014C1-3alkyl or \u2014O\u2014C1-3alkyl;
R4 is \u2014H or \u2014C1-3alkyl;
R5 is \u2014H, \u2014C1-3alkyl or 6 membered heteroaryl;
R6 is \u2014C1-3alkyl, optionally substituted with \u2014N(\u2014C1-3alkyl)2, or R6 is 6 membered heterocycle;
or R1 and R6 taken together form a 5-6 membered heterocycloalkyl;
R7 is selected from halogen, \u2014O\u2014C1-3alkyl, \u2014C1-3 alkyl, which \u2014C1-3 alkyl can be optionally substituted with morpholine;
or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1, wherein A1 is \u2014C\u2550O and A2 is NR6, wherein R6 is \u2014CH3, \u2014CH(CH3)2, \u2014(CH2)2\u2014N(CH3)2, \u2014(CH2)3\u2014N(CH3)2\u2014N-methyl-piperidinyl.
3. The compound according to claim 1 wherein A1 is NR5 and A2 is \u2014C\u2550O, wherein R5 is \u2014H, \u2014CH3 or pyridyl.
4. The compound according to claim 1 wherein A1 is NR5 and A2 is \u2014O\u2014.
5. The compound according to claim 1, wherein R1 is \u2014H, \u2014OH, \u2014CH3.
6. The compound according to claim 1, wherein R2 is phenyl, optionally substituted with one or more independently selected halogen, \u2014CH3, \u2014O\u2014CH3 and \u2014CH2-morpholine.
7. The compound according to claim 1, wherein R2 is cyclopentyl, cyclohexyl or spiro3.5nonane.
8. The compound according to claim 1, wherein R2 is thiophenyl or pyridyl, optionally substituted with \u2014CH3 or tetrahydrofuran.
9. The compound according to claim 1, wherein R3 is \u2014CH3 or \u2014OCH3.
10. The compound according to claim 1, wherein R4 is \u2014H or \u2014CH3.
11. The compound according to claim 1, wherein R5 is \u2014H, \u2014CH3 or pyridyl.
12. The compound according claim 1, wherein A1 is \u2014C\u2550O and A2 is NR6, R6 and R1 taken together form a oxazolidine or 1,3oxazine.
13. A compound selected from
EX#
Structure
1
2
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5
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7
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10
11
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14
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34
and
35
or a pharmaceutically acceptable salt thereof.
14. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 optionally in combination with pharmaceutically acceptable excipients andor carriers.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
What is claimed is:
1. An instrument for treating surface layers of a patient’s skin, comprising:
a hand-held instrument having a working end that defines a working surface;
an abrasive fragment composition carried within the working surface for cutting skin surface layers;
wherein the working surface is of a partially floating flexible member that is capable of flexing proximally and distally; and
cooperating fluid inflow and fluid outflow apertures in the working surface.
2. The instrument of claim 1 further including a negative pressurization source in fluid communication with the outflow aperture.
3. The instrument of claim 1 further including a fluid source in fluid communication with the inflow aperture.
4. The working end of claim 1 wherein the abrasive fragment composition comprises diamond fragments.
5. The working end of claim 1 wherein the abrasive fragment composition comprises sharp-edged fragments having a cross-sectional dimension ranging from about 10 microns to 250 microns.
6. A system for treating surface layers of a patient’s skin, comprising:
(a) an instrument body with a distal working surface for engaging a skin surface;
(b) the working surface having partly a flexible floating wall member for conforming to skin topography;
(c ) an abrasive fragment composition carried in the working surface;
(d) at least one inflow aperture in said skin interface in fluid communication with a fluid reservoir; and
(e) at least one outflow aperture in said skin interface in communication with a negative pressurization source.
7. The system of claim 6 wherein the abrasive composition comprises diamond fragments.
8. The system of claim 6 wherein the at least one inflow apertures is located at a periphery of the working surface.
9. The system of claim 6 wherein the at least one outflow aperture is located generally centrally in the working surface.
10. A method for treating surface layers of a patient’s skin, comprising:
(a) providing an instrument with a partially floating working surface that carries an exposed abrasive fragment architecture;
(b) placing said floating working surface against a skin treatment site;
(c) actuating a negative pressurization source in fluid communication with at least one aperture in said working surface thereby drawing skin in contact with said abrasive fragment architecture;
(d) translating said floating working surface across the treatment site thereby cutting away surface layer portions; and
(e) wherein said working surface floatably maintains contact with the skin surface under the influence of negative pressurization between said working surface and the skin; and
11. The method of claim 10 wherein contemporaneous with steps (c) through (e) the additional step of flowing a fluid generally about the working surface between at least one inflow and outflow aperture therein the influence of said negative pressurization.
12. The method of claim 10 wherein in step (d), the removal of the skin surface layers induces neocollagenesis in the patient’s skin.
13. The method of claim 10 wherein neocollagenesis in the, patient’s skin reduces wrinkles.
14. The method of claim 10 wherein the flow of fluid hydrates the patient’s skin.
15. The method of claim 10 wherein the flow of fluid reduces pain.
16. The method of claim 10 wherein the flow of fluid removes skin debris from the treatment site.