1. A compound of Formula (II):
wherein:
R1 is an optionally substituted group selected from among C3-C9 cycloalkyl and \u2014C1-C4alkyl(C3-C9cycloalkyl), wherein any carbon of the R1 carbocyclic ring can be optionally substituted by both Y and Z;
R2 is H or an optionally substituted alkyl;
Y and Z are independently selected from among halogen or methyl; or
Y and Z taken together form an oxo (\u2550O);
one of A or B is -L-G and the other is selected from among H and an optionally substituted C1-C6 alkyl;
L is a bond, or an optionally substituted group selected from among C1-C6 alkylene, C1-C6 heteroalkylene, C1-C6 ketoalkylene, \u2014C(O)NR9\u2014(CH2)n\u2014, \u2014NR9\u2014C(O)\u2014(CH2)n\u2014, \u2014OC(O)O\u2014(CH2)n\u2014, \u2014NHC(O)O\u2014(CH2)n\u2014, \u2014O(O)CNH\u2014(CH2)n\u2014, \u2014C(O)O\u2014(CH2)n\u2014, or \u2014OC(O)\u2014(CH2)n\u2014, \u2014NR9C(O)N(R9)\u2014(CH2)n\u2014, \u2014S(O)\u2014(CH2)n\u2014, \u2014S(O)2\u2014(CH2)n\u2014, \u2014S(O)2NH\u2014(CH2)n\u2014, \u2014C(\u2550NR10)N(R9)\u2014(CH2)n\u2014, and \u2014NR9C(\u2550NR10)N(R9)\u2014(CH2)n\u2014;
G is tetrazolyl, \u2014NHS(\u2550O)2R8, \u2014S(\u2550O)2NHR9, \u2014OH, \u2014SH, \u2014N(R9)2, \u2014C(O)NHC(O)R8, \u2014C(O)NHS(\u2550O)2R8, \u2014S(\u2550O)2NHC(O)R1, \u2014S(\u2550O)2NHC(O)NHR8, \u2014C(\u2550NR10)N(R9)2, \u2014NR9C(\u2550NR10)N(R9)2, \u2014NR9C(\u2550NR10)NHC(\u2550NR10)N(R9)2, \u2014NR9C(\u2550CHR10)N(R9)2, \u2014C(O)NR9C(\u2550NR10)N(R9)2, \u2014C(O)NR9C(\u2550CHR10)N(R9)2, \u2014CO2H, a carboxylic acid bioisostere, \u2014(OP(\u2550O)OH)nOH, \u2014OP(\u2550O)OR8OH, \u2014OP(\u2550O)R8OH, \u2014NR9P(\u2550O)OR8OH, \u2014NR9P(\u2550O)R8OH, \u2014P(\u2550O)OR8OH; \u2014P(\u2550O)R8OH, \u2014S(O)yOH; \u2014OS(O)yOH; \u2014NR9S(O)yOH;
each R8 is independently a substituted or unsubstituted C1-C6 alkyl;
each R9 is independently H, a substituted C1-C6 alkyl or unsubstituted C1-C6 alkyl;
each R10 is independently selected from among H, \u2014S(\u2550O)2R8, \u2014S(\u2550O)2NH2, \u2014C(O)R8, \u2014CN, and \u2014NO2;
n is 1, 2, 3, or 4; x is 1, 2, or 3; y is 0, 1, or 2; and
pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs, or pharmaceutically acceptable solvates thereof.
2. The compound of claim 1, wherein one of A or B is -L-G and the other is H.
3. The compound of claim 1, wherein A is -L-G.
4. The compound of claim 1, wherein B is -L-G.
5. The compound of claim 1, wherein R2 is H.
6. The compound of claim 1, wherein:
L is a bond, or an optionally substituted group selected from among C1-C6 alkylene, C1-C6 ketoalkylene, \u2014C(O)NR9\u2014(CH2)n\u2014, \u2014NR9\u2014C(O)\u2014(CH2)n\u2014, \u2014S(O)2\u2014(CH2)n\u2014, and \u2014S(O)2NH\u2014(CH2)n\u2014.
7. The compound of claim 6, wherein L is a bond.
8. The compound of claim 1, wherein if L is not a bond, L taken together with A or B can form a carbocyclic ring.
9. The compound of claim 1, wherein:
G is \u2014N(R9)2, \u2014C(\u2550NR10)N(R9)2, \u2014NR9C(\u2550NR10)N(R9)2, \u2014NR9C(\u2550NR10)NHC(\u2550NR10)N(R9)2, NR9C(\u2550CHR10)N(R9)2, \u2014C(O)NR9C(\u2550NR10)N(R9)2, or \u2014C(O)NR9C(\u2550CHR10)N(R9)2.
10. The compound of claim 1, wherein:
each R10 is H.
11. The compound of claim 1, wherein:
G is tetrazolyl, \u2014NHS(\u2550O)2R8, \u2014S(\u2550O)2NHR9, \u2014OH, \u2014SH, \u2014C(O)NHC(O)R8, \u2014C(O)NHS(\u2550O)2R8, \u2014S(\u2550O)2NHC(O)R8, \u2014S(\u2550O)2NHC(O)NHR8, \u2014CO2H, a carboxylic acid bioisostere, \u2014(OP(\u2550O)OH)xOH, \u2014OP(\u2550O)OR8OH, \u2014OP(\u2550O)R8OH, \u2014NR9P(\u2550O)OR8OH, \u2014NR9P(\u2550O)R8OH, \u2014P(\u2550O)OR8OH; \u2014P(\u2550O)R8OH, \u2014S(O)nOH; \u2014OS(O)yOH; or \u2014NR9S(O)yOH.
12. The compound of claim 1, wherein:
G is tetrazolyl, \u2014C(O)NHC(O)R8, \u2014C(O)NHS(\u2550O)2R8, \u2014S(\u2550O)2NHC(O)R8, \u2014S(\u2550O)2NHC(O)NHR8, \u2014CO2H, a carboxylic acid bioisostere, \u2014(OP(\u2550O)OH)xOH, \u2014OP(\u2550O)OR8OH, \u2014OP(\u2550O)R8OH, \u2014P(\u2550O)OR8OH; \u2014P(\u2550O)R8OH, or \u2014S(O)yOH.
13. The compound of claim 1, wherein:
G is tetrazolyl, \u2014C(O)NHC(O)R8, \u2014C(O)NHS(\u2550O)2R8, \u2014S(\u2550O)2NHC(O)R8, \u2014S(\u2550O)2NHC(O)NHR8, \u2014CO2H, carboxylic acid bioisosteres, \u2014(OP(\u2550O)OH)xOH, or \u2014S(O)yOH;
x is 1; and
y is 1 or 2.
14. The compound of claim 1, wherein:
R1 is selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclo-octyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl and cyclooctylmethyl.
15. The compound according to claim 15, wherein:
R1 is selected from among cyclohexyl and cyclohexylmethyl.
16. A compound of claim 1, wherein the compound is selected from among:
3-(cyclohexylcarbamoyloxy)benzoic acid (Compound 1);
3-(cyclohexylmethylcarbamoyloxy)benzoic acid (Compound 2);
4-(cyclohexylcarbamoyloxy)benzoic acid (Compound 3);
4-(cyclohexylmethylcarbamoyloxy)benzoic acid (Compound 4);
2-(3-((cyclohexylmethyl)carbamoyl)phenyl)acetic acid (Compound 7);
5-(3-(cyclohexylcarbamoyl)phenyl)-5-oxopentanoic acid (Compound 8);
5-(3-((cyclohexylmethyl)carbamoyl)phenyl)-5-oxopentanoic acid (Compound 9);
3-(1H-tetrazol-5-yl)phenyl cyclohexylcarbamate (Compound 10);
3-(1H-tetrazol-5-yl)phenyl cyclohexylmethylcarbamate (Compound 11);
4-(3-(cyclohexylcarbamoyl)phenyl)-4-oxobutanoic acid (Compound 12); and
4-(3-((cyclohexylmethyl)carbamoyl)phenyl)-4-oxobutanoic acid (Compound 13).
17. A pharmaceutical composition comprising a compound, pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate of claim 1 and a pharmaceutically acceptable diluent, excipient or binder.
18. A method of inhibiting the activity of fatty acid amide hydrolase or of treating a disease, disorder, or condition, which would benefit from inhibition of fatty acid amide hydrolase activity in a patient comprising administering to the patient a therapeutically effective amount of a compound, pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate of claim 1.
19. The method of claim 23, wherein the disease, disorder or condition is selected from among acute or chronic pain, eating disorders, cardiovascular diseases, metabolic diseases, disorders or conditions, renal ischemia, cancers, disorders of the immune system, allergic diseases, parasitic, viral or bacterial infectious diseases, inflammatory diseases, osteoporosis, ocular conditions, pulmonary conditions, gastrointestinal diseases and urinary incontinence.
20. The method of claim 19, wherein said compound is an irreversible inhibitor of fatty acid amide hydrolase.
21. The method of claim 21, wherein said compound does not substantially cross the blood-brain barrier.
22. Use of a compound of claim 1 for inhibiting the activity of fatty acid amide hydrolase activity or for the treatment of a disease, disorder, or condition, that would benefit from inhibition of fatty acid amide hydrolase activity.
23. Use of a compound of claim 1 for the formulation of a medicament for the inhibition of fatty acid amide hydrolase (FAAH).
24. An article of manufacture, comprising packaging material, a compound of claim 1, which is effective for inhibiting the activity of fatty acid amide hydrolase (FAAH), within the packaging material, and a label that indicates that the compound or composition, or pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, is used for inhibiting the activity of fatty acid amide hydrolase (FAAH).
25. A compound having the structure of Formula (I):
wherein:
R1 is an optionally substituted group selected from among C1-C6 alkyl, C3-C9 cycloalkyl and \u2014C1-C4alkyl(C3-C9cycloalkyl);
R2 is H or an optionally substituted alkyl;
if R1 is an optionally substituted C3-C9 cycloalkyl or an optionally substituted \u2014C1-C4alkyl(C3-C9cycloalkyl), then any carbon of the R1 carbocyclic ring can be optionally substituted by both Y and Z;
Y and Z are independently selected from among halogen or methyl; or
Y and Z taken together form an oxo (\u2550O);
one of A or B is -L-G and the other is selected from among H and an optionally substituted C1-C6 alkyl; or
A and B are each independently selected from among H and an optionally substituted C1-C6 alkyl provided that at least one X is N;
L is a bond, or an optionally substituted group selected from among C1-C6 alkylene, C1-C6 heteroalkylene, C1-C6 ketoalkylene, \u2014C(O)NR9\u2014(CH2)n\u2014, \u2014NR9\u2014C(O)\u2014(CH2)n\u2014, \u2014OC(O)O\u2014(CH2)n\u2014, \u2014NHC(O)O\u2014(CH2)n\u2014, \u2014O(O)CNH\u2014(CH2)n\u2014, \u2014C(O)O\u2014(CH2)n\u2014, or \u2014OC(O)\u2014(CH2)n\u2014, \u2014NR9C(O)N(R9)\u2014(CH2)n\u2014, \u2014S(O)\u2014(CH2)n, \u2014S(O)2\u2014(CH2)n\u2014, \u2014S(O)2NH\u2014(CH2)n\u2014, \u2014C(\u2550NR10)N(R9)\u2014(CH2)n\u2014, and \u2014NR9C(\u2550NR10)N(R9)\u2014(CH2)n\u2014;
G is tetrazolyl, \u2014NHS(\u2550O)2R8, \u2014S(\u2550O)2NHR9, \u2014OH, \u2014SH, \u2014N(R9)2, \u2014C(O)NHC(O)R8, \u2014C(O)NHS(\u2550O)2R8, \u2014S(\u2550O)2NHC(O)R8, \u2014S(\u2550O)2NHC(O)NHR8, \u2014C(\u2550NR10)N(R9)2, \u2014NR9C(\u2550NR10)N(R9)2, \u2014NR9C(\u2550NR10)NHC(\u2550NR10)N(R9)2, \u2014NR9C(\u2550CHR10)N(R9)2, \u2014C(O)NR9C(\u2550NR10)N(R)2, \u2014C(O)NR9C(\u2550CHR10)N(R9)2, \u2014CO2H, a carboxylic acid bioisostere, \u2014(OP(\u2550O)OH)xOH, \u2014OP(\u2550O)OR8OH, \u2014OP(\u2550O)R8OH, \u2014NR9P(\u2550O)OR8OH, \u2014NR9P(\u2550O)R8OH, \u2014P(\u2550O)OR8OH; \u2014P(\u2550O)R8OH, \u2014S(O)yOH; \u2014OS(O)yOH; or \u2014NR9S(O)yOH;
each R8 is independently a substituted or unsubstituted C1-C6 alkyl;
each R9 is independently H, a substituted C1-C6 alkyl or unsubstituted C1-C6 alkyl;
each R10 is independently selected from among H, \u2014S(\u2550O)2R8, \u2014S(\u2550O)2NH2, \u2014C(O)R8, \u2014CN, and \u2014NO2;
n is 1, 2, 3, or 4; x is 1, 2, or 3; y is 0, 1, or 2; and
pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs, or pharmaceutically acceptable solvates thereof.
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. An apparatus for calibrating a hollow chamber sheet extruded line formed out of thermoplastic resin, comprising:
a vacuum housing;
a planar intake area at a first end of said vacuum housing, said planar intake area being configured to receive an extruded line;
support rollers within said vacuum housing configured to support said extruded line; and
a planar outlet area through which said extruded line exits said vacuum housing, said planar outlet area being located at a second end of said vacuum housing opposite said first end.
2. The apparatus according to claim 1, wherein said support rollers are configured to be adjustable in height relative to the vacuum housing.
3. The apparatus according to claim 1, further comprising:
means for cooling the support rollers.
4. The apparatus according to claim 1, further comprising:
a drive configured to turn said support rollers.
5. The apparatus according to claim 1, wherein the planar outlet area 4 comprises:
flexible sealant strips formed of a thermally resistant resin.
6. A method for calibrating a hollow chamber sheet extruded line formed out of thermoplastic resin, comprising the steps of:
receiving an extruded line in a planar intake area of a vacuum housing, said planar intake area being located at a first end of said vacuum housing;
supporting said extruded line with support rollers within said vacuum housing;
pulling said extruded line through a planar outlet area at a second end of said vacuum housing through which said extruded line exits said vacuum housing, said second end being opposite said first end.
7. The method of claim 6, further comprising the step of:
adjusting the height of said support rollers relative to the vacuum housing.
8. The method of claim 6, further comprising the step of:
cooling the support rollers.
9. The method of claim 6, further comprising the step of:
turning said support roller with a drive.
10. The method of claim 6, wherein the planar outlet area comprises flexible sealant strips formed of a thermally resistant resin, and the method further comprises the step of:
pulling the extruded line through said flexible sealant strips.