1. A method for determining a batch size for aggregating data comprising the steps of:
estimating first costs, as a function of different sizes, for sending data to one of the following: a storage device and a computing node;
estimating second costs, as a function of different sizes, for losing said data; and
selecting said batch size based on said estimated first and second costs,
the steps of the estimating and selecting performed by an information logger executing on one or more processors, and receiving performance data of an application process executing on one or more of the processors, wherein the performance data is aggregated based on the selected batch size.
2. The method of claim 1 in wherein estimating said first costs comprises determining a cost function.
3. The method of claim 1 in wherein estimating said second costs comprises determining a cost function.
4. The method of claim 1 in which said batch size is determined by minimizing an aggregation of at least two of said estimated costs.
5. The method of claim 4, in which said aggregation comprises a sum.
6. The method of claim 1 further comprising the step of sending an amount of data corresponding to said batch size to at least one of said storage device and said computing node.
7. A program storage device readable by machine, tangibly embodying a program of instructions executable by the machine to perform method steps for determining a batch size for aggregating data, the method steps comprising:
estimating first costs, as a function of different sizes, for sending data to one of the following: a storage device and a computing node;
estimating second costs, as a function of different sizes, for losing said data; and
selecting said batch size based on said estimated first and second costs,
the method performed by an information logger executing on one or more processors, and receiving performance data of an application process executing on one or more of the processors, wherein the performance data is aggregated based on the selected batch size.
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 compound of the following formula:
34
and the salts thereof, wherein
A is hydrogen, halo, hydroxy, C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkoxy, oxo, OY wherein Y is a hydroxy protecting group, or absent;
the broken line represents an optional double bond with proviso that if the broken line is a double bond, then A is absent;
Ar1 is phenyl optionally substituted by one or more substituents selected from halo, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkoxy-C1-C4 alkoxy, CF3, carboxy-C1-C4 alkoxy and C1-C4 alkoxy-carbonyl-C1-C4 alkoxy;
Ar2 is aryl or heteroaryl selected from phenyl, naphthyl, pyridyl, thienyl, furyl, pyrrolyl and pyrimidyl, the aryl or heteroaryl being optionally substituted by one or more substituents selected from halo, hydroxy, amino, nitro, carboxy, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, di C1-C4 alkylamino, halo C1-C4 alkyl, C1-C4 alkylthio and sulfonyl methyl;
R1 is hydrogen, hydroxy, C1-C4 alkyl, C1-C4 alkoxy or OY wherein Y is a hydroxy protecting group; and
R2 and R3 are independently selected from hydrogen, hydroxy, C1-C7 alkyl optionally substituted by one or more hydroxy or halo, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C7 alkoxy, phenyl optionally substituted by halo, phenyl C1-C7 alkyl, halo substituted phenyl C1-C7 alkyl, and (CH2)nXR4 wherein n is one or two; X is O, NH or S and R4 is C1-C3 alkyl, or when Ar2 is phenyl, Ar2C(O)N(R2) is a phthalimide group and R3 is C1-C7 alkyl, or
R2 and R3, together with the nitrogen atom to which they are attached, form a pyrrolidine, piperidine or morpholine ring, optionally substituted by C1-C3 alkyl or halo.
2. A compound according to claim 1, wherein
A is hydrogen, halo, hydroxy, oxo or OY; or if the broken line is a double bond, then A is absent;
Ar1 is phenyl optionally substituted by one to three substituents selected from halo, hydroxy, C1-C4 alkoxy, carboxy C1-C4 alkoxy and C1-C4 alkoxy-carbonyl-C1-C4 alkoxy;
Ar2 is phenyl, pyridyl or thienyl, optionally substituted by one to two halo or C1-C4 alkoxy;
R1 is hydrogen, hydroxy or C1-C4 alkyl; and
R2 and R3 are independently selected from hydrogen, C1-C7 alkyl optionally substituted by one or more hydroxy or halo, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C4 alkoxy phenyl and halo substituted phenyl C1-C7 alkyl, when Ar2 is phenyl, Ar2C(O)N(R2) is a phthalimide group and R3 is C1-C7 alkyl, or
R2 and R3, together with the nitrogen atom to which they are attached, form a pyrrolidine or morpholine ring.
3. A compound according to claim 2, wherein
A is hydrogen, fluorine, chlorine, hydroxy or OY wherein Y is methoxymethyl or tetrahydropyranyl; or if the broken line is a double bond, then A is absent;
Ar1 is phenyl optionally substituted by chlorine, hydroxy, methoxy or carboxymethoxy;
Ar2 is phenyl, pyridyl or thienyl, optionally substituted by chlorine, fluorine or methoxy;
R1 is C1-C4 alkyl;
R2 is C1-C7 alkyl optionally substituted by hydroxy or fluorine, C2-C6 alkenyl, halo substituted phenylmethyl or phenyl; and
R3 is hydrogen or methyl; or
R2 and R3, together with the nitrogen atom to which they are attached, form a pyrrolidine or morpholine ring.
4. A compound according to claim 3, wherein
A is hydroxy, fluorine or chlorine; or if the broken line is a double bond, then A is absent; Ar1 is phenyl optionally substituted by carboxymethoxy; Ar2 is phenyl optionally substituted by methoxy or pyridyl; R1 is C1-C4 alkyl; R2 is C1-C7 alkyl optionally substitute by hydroxy; and R3 is hydrogen.
5. A compound according to claim 4 selected from
4-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino-N-propylbenzamide;
4-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino-2-methoxy-N-propylbenzamide;
6-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino-N-propylnicotinamide;
4-N-1-(S)-(3-carboxymethoxyphenyl)-2-(3-(S)-hydroxypyrrolidin-1-yl)-ethyl-N-methylamino-N-propylbenzamide;
4-N-2-(3-(S)-fluoropyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino-N-propylbenzamide;
4-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino-N-(2-(S)-hydroxypropyl)benzamide;
5-N-2-(3-(S)-fluoropyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino-N-propylpicolinamide;
4-N-methylamino-N-2-(3-pyrrolin-1-yl)-1-(S)-phenylethyl-N-propylbenzamide; and
4-N-2-(3-(S)-chloropyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino-N-(2-(S)-hydroxypropyl)benzamide.
6. A compound according to claim 3 selected from
4-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino-N-isopropylbenzamide;
3-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino-N-propylbenzamide;
2-chloro-4-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino-N-propylbenzamide;
4-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino-3-methoxy-N-propylbenzamide;
3-chloro-4-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino-N-propylbenzamide;
4-N-1-(S)-(3-hydroxyphenyl)-2-(3-(S)-hydroxypyrrolidin-1-yl)-ethyl-N-methylamino-N-propylbenzamide;
4-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-(3-methoxyphenyl)-ethyl-N-methylamino-N-propylbenzamide;
4-N-1-(S)-phenyl-2-(pyrrolidin-1-yl)ethyl-N-methylamino-N-propylbenzamide;
4-N-1-(S)-(3-chlorophenyl)-2-(3-(S)-hydroxypyrrolidin-1-yl)-ethyl-N-methylamino-N-propylbenzamide;
4-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(R)-phenylethyl-N-methylamino-N-propylbenzamide;
4-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino-pyrrolidinebenzamide;
4-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino-morpholinebenzamide;
4-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino-N-(2-(R)-hydroxypropyl)benzamide;
4-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino-N-isobutylbenzamide;
4-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino-N-allylbenzamide;
4-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino-N-(3,3,3,-trifluoropropyl)benzamide;
3-fluoro-4-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino-N-propylbenzamide;
4-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino-N-(2,2,3,3,3,-pentafluoropropyl)benzamide;
4-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino-N-tert-amylbenzamide;
5-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino-N-propylpicolinamide;
4-N-2-(3-(S)-fluoropyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino-N-(2-(S)-hydroxypropyl)benzamide;
2-chloro-4-N-2-(3-(S)-fluoropyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino-N-propylbenzamide; and
4-N-2-(3-(S)-chloropyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino-N-propylbenzamide.
7. A compound according to claim 2 selected from
4-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino-N-methylbenzamide;
4-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino-N-ethylbenzamide;
4-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino-N-butylbenzamide;
4-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino-N-pentylbenzamide;
4-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino-N-phenylbenzamide;
4-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino-N-(2-chlorobenzyl)benzamide;
4-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino-N,N-dimethylbenzamide;
4-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino-N-methyl-N-propylbenzamide;
5-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino-N-propyl-2-thiophenecarboxamide;
4-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethylamino-N-propylbenzamide;
4-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino-N-propylphthalimide;
4-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino-N-ethoxybenzamide;
4-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino-N-(3-hydroxypropyl)benzamide,
4-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino-N-cyclopropylbenzamide;
4-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino-N-(S)-sec-butylbenzamide;
4-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino-N-(R)-sec-butylbenzamide;
4-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino-N-propargylbenzamide;
4-N-1-(R)-(3-carboxymethoxyphenyl)-2-(3-(S)-hydroxypyrrolidin-1-yl)-ethyl-N-methylamino-N-propylbenzamide;
4-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino-N-tert-butylbenzamide;
4-N-hydroxy-N-2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethylamino-N-propylbenzamide;
4-N-2-(3-(S)-fluoropyrrolidin-1-yl)-1-(S)-phenylethyl-N-hydroxyamino-N-propylbenzamide;
4-N-2-(3-(R)-fluoropyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino-N-propylbenzamide;
4-N-2-(3-(S)-fluoropyrrolidin-1-yl)-1-(R)-phenylethyl-N-methylamino-N-propylbenzamide;
4-N-2-(3-(S)-chloropyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino-N-(2-(R)-hydroxypropyl)benzamide; and
4-N-2-(3-oxopyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino-N-propylbenzamide.
8. A pharmaceutical composition for the prevention or treatment of a medical condition for which agonist activity toward opioid kappa receptor is needed, in a mammalian subject, which comprises a therapeutically effective amount of a compound according to claim 1, and a pharmaceutically inert carrier.
9. A pharmaceutical composition according to claim 8, which is useful as an analgesic, anesthetic, anti-inflammatory or neuroprotective agent, or useful in the treatment of arthritis, stroke or functional bowel disease.
10. A method for the treatment of a medical condition for which agonist activity toward opioid kappa receptor is needed, in a mammalian subject, which comprises administering to said subject a therapeutically effective amount of a compound according to claim 1.
11. A compound of the following formula:
35
wherein
Ar2a is phenyl, pyridyl or thienyl;
X is hydrogen, halo or C1-C7 alkoxy;
R1 is hydrogen, optionally protected hydroxy or C1-C4 alkyl; and
R2 and R3 are independently hydrogen or C1-C7 alkyl optionally substituted by hydroxy or halo.
12. A compound according to claim 11 selected from
4-methylamino-N-propylbenzamide;
5-N-methylamino-N-propylpicolinamide;
2-chloro-4-methylamino-N-propylbenzamide;
4-methylamino-N-(2-(S)-hydroxypropyl)benzamide;
4-methylamino-N-(2-(R)-hydroxypropyl)benzamide;
4-methylamino-N-(2,2,3,3,3-pentafluoropropyl)benzamide; and
4-methylamino-N-tert-amylbenzamide.
13. A compound selected from
2-(3-(S)-fluoropyrrolidin-1-yl)-1-(S)-phenylethanol;
2-(3-(S)-fluoropyrrolidin-1-yl)-2-(R)-phenylethanol;
2-(R)-phenyl-2-(3-pyrroline-1-yl)ethanol;
2-(3-(R)-fluoropyrrolidin-1-yl)-1-(S)-phenylethanol;
2-(3-(R)-fluoropyrrolidin-1-yl)-2-(R)-phenylethanol;
2-(3-(S)-fluoropyrrolidin-1-yl)-1-(R)-phenylethanol,
2-(3-(S)-fluoropyrrolidin-1-yl)-2-(S)-phenylethanol
2-(3-(S)-chloropyrrolidin-1-yl)-1-(S)-phenylethanol; and
2-(3-(S)-chloropyrrolidin-1-yl)-2-(R)-phenylethanol.
14. A process for producing a compound of formula (I), which comprises reacting an amide compound of the formula (VId):
36
with an ethanol compound selected from compounds (Va), (Vb) and (Vc), and a mixture of compounds (Va) and (Vb):
37
in the absence or presence of a base in a reaction inert solvent.