What is claimed is:
1. A method of chemosensitization comprising administering a chemotherapeutically effective amount of at least one chemotherapeutic agent and a chemosensitizing effective amount of at least one 3-aryloxy-3-phenylpropylamine to a subject.
2. The method of claim 1, wherein the subject has a cancer.
3. The method of claim 1, wherein said cancer is selected from the group consisting of leukemia, lymphoma carcinoma and sarcoma.
4. The method of claim 1, wherein said at least one 3-aryloxy-3-phenylpropylamine is administered orally.
5. The method of claim 1, wherein said at least one 3-aryloxy-3-phenylpropylamine is of the formula:
5
wherein each R is independently hydrogen or methyl;
R is naphthyl or
6
R and R are halo, trifluoromethyl, C1-C4 alkyl, C1-C3 alkoxy or C3-C4 alkenyl; and
n and m are 0, 1 or 2; and acid addition salts thereof formed with pharmaceutically acceptable acids.
6. The method of claim 1, wherein said at least one 3-aryloxy-3-phenylpropylamine is selected from the group consisting of
3-(p-isopropoxyphenxoy)-3-phenylpropylamine methanesulfonate,
N,N-dimethyl 3-(3,4-dimethoxyphenoxy)-3-phenylpropylamine p-hydroxybenzoate,
N,N-dimethyl 3-(alpha-naphthoxy)-3-phenylpropylamine bromide,
N,N-dimethyl 3-(beta-naphthoxy)-3-phenyl-1-methylpropylamine iodide,
3-(2-methyl-4,5-dichlorophenoxy)-3-phenylpropylamine nitrate,
3-(p-t-butylphenoxy)-3-phenylpropylamine glutarate,
N-methyl 3-(2-chloro-p-tolyloxy)-3-phenyl-1-methylpropylamine lactate,
3-(2,4-dichlorophenoxy)-3-phenyl-2-methylpropylamine citrate,
N,N-dimethyl 3-(m-anisyloxy)-3-phenyl-1-methylpropylamine maleate,
N-methyl 3-(p-tolyloxy)-3-phenylpropylamine sulfate,
N,N-dimethyl 3-(2,4-difluorophenoxy)-3-phenylpropylamine 2,4-dinitrobenzoate,
3-(o-ethylphenoxy)-3-phenylpropylamine dihydrogen phosphate,
N-methyl-(2-chloro-4-isopropylphenoxy)-3-phenyl-2-methylpropylamine maleate,
N,N-dimethyl 3-(2-alkyl-4-fluorophenoxy)-3-phenylpropylamine succinate,
N,N-dimethyl 3-(o-isopropoxyphenoxy)-3-phenyl-propylamine phenylacetate,
N,N-dimethyl 3-(o-)bromophenoxy)-3-phenyl-propylamine beta-phenylpropionate,
N-methyl 3-(p-iodophenoxy)-3-phenyl-propylamine propiolate,
N-methyl 3-(3-n-propylphenoxy)-3-phenyl-propylamine decanoate, and
N-methyl 3-(p-trifluoromethylphenoxy)-3-phenylpropylamine.
7. The method of claim 1, wherein said at least one 3-aryloxy-3-phenylpropylamine is N-methyl 3-(p-trifluoromethylphenoxy)-3-phenylpropylamine or a pharmaceutically-acceptable salt therof.
8. The method of claim 1, wherein said at least one chemotherapeutic agent is selected from the group consisting of an alkylating agent, an antimetabolite, a natural product, a miscellaneous agent, a hormone and an antagonist.
9. A method of selecting a chemotherapeutic agent for which 3-aryloxy-3-phenylpropylamine is a chemosensitizer comprising:
assaying cytotoxicity of a candidate chemotherapeutic agent in the presence and in the absence of a 3-aryloxy-3-phenylpropylamine; and
selecting a candidate chemotherapeutic agent as a chemotherapeutic agent for which 3-aryloxy-3-phenylpropylamine is a chemosensitizer when the cytotoxicity of the candidate agent is greater in the presence of 3-aryloxy-3-phenylpropylamine than in the absence of 3-aryloxy-3-phenylpropylamine.
10. The method of claim 9, wherein said 3-aryloxy-3-phenylpropylamine is of the formula:
7
wherein each R is independently hydrogen or methyl;
R is naphthyl or
8
R and R are halo, trifluoromethyl, C1-C4 alkyl, C1-C3 alkoxy or C3-C4 alkenyl; and
n and m are 0, 1 or 2; and acid addition salts thereof formed with pharmaceutically acceptable acids.
11. The method of claim 9, wherein said 3-aryloxy-3-phenylpropylamine is selected from the group consisting of
3-(p-isopropoxyphenxoy)-3-phenylpropylamine methanesulfonate,
N,N-dimethyl 3-(3,4-dimethoxyphenoxy)-3-phenylpropylamine p-hydroxybenzoate,
N,N-dimethyl 3-(alpha-naphthoxy)-3-phenylpropylamine bromide,
N,N-dimethyl 3-(beta-naphthoxy)-3-phenyl-1-methylpropylamine iodide,
3-(2-methyl-4,5-dichlorophenoxy)-3-phenylpropylamine nitrate,
3-(p-t-butylphenoxy)-3-phenylpropylamine glutarate,
N-methyl 3-(2-chloro-p-tolyloxy)-3-phenyl-1-methylpropylamine lactate,
3-(2,4-dichlorophenoxy)-3-phenyl-2-methylpropylamine citrate,
N,N-dimethyl 3-(m-anisyloxy)-3-phenyl-1-methylpropylamine maleate,
N-methyl 3-(p-tolyloxy)-3-phenylpropylamine sulfate,
N,N-dimethyl 3-(2,4-difluorophenoxy)-3-phenylpropylamine 2,4-dinitrobenzoate,
3-(o-ethylphenoxy)-3-phenylpropylamine dihydrogen phosphate,
N-methyl-(2-chloro-4-isopropylphenoxy)-3-phenyl-2-methylpropylamine maleate,
N,N-dimethyl 3-(2-alkyl-4-fluorophenoxy)-3-phenylpropylamine succinate,
N,N-dimethyl 3-(o-isopropoxyphenoxy)-3-phenyl-propylamine phenylacetate,
N,N-dimethyl 3-(o-)bromophenoxy)-3-phenyl-propylamine beta-phenylpropionate,
N-methyl 3-(p-iodophenoxy)-3-phenyl-propylamine propiolate,
N-methyl 3-(3-n-propylphenoxy)-3-phenyl-propylamine decanoate, and
N-methyl 3-(p-trifluoromethylphenoxy)-3-phenylpropylamine.
12. The method of claim 9, wherein said 3-aryloxy-3-phenylpropylamine is N-methyl 3-(p-trifluoromethylphenoxy)-3-phenylpropylamine or a pharmaceutically-acceptable salt thereof.
13. The method of claim 9, wherein said chemotherapeutic agent is selected from the group consisting of an alkylating agent, an antimetabolite, a natural product, a miscellaneous agent, a hormone and an antagonist.
14. A pharmaceutical composition comprising as a chemotherapeutically active ingredient at least one chemotherapeutic agent and as a chemosensitization active ingredient at least one 3-aryloxy-3-phenylpropylamine.
15. The pharmaceutical composition of claim 14, wherein said at least one 3-aryloxy-3-phenylpropylamine is of the formula:
9
wherein each R is independently hydrogen or methyl;
R is naphthyl or
10
R and R are halo, trifluoromethyl, C1-C4 alkyl, C1-C3 alkoxy or C3-C4 alkenyl; and
n and m are 0, 1 or 2; and acid addition salts thereof formed with pharmaceutically acceptable acids.
16. The pharmaceutical composition of claim 14, wherein said at least one 3-aryloxy-3-phenylpropylamine is selected from the group consisting of
3-(p-isopropoxyphenxoy)-3-phenylpropylamine methanesulfonate,
N,N-dimethyl 3-(3,4-dimethoxyphenoxy)-3-phenylpropylamine p-hydroxybenzoate,
N,N-dimethyl 3-(alpha-naphthoxy)-3-phenylpropylamine bromide,
N,N-dimethyl 3-(beta-naphthoxy)-3-phenyl-1-methylpropylamine iodide,
3-(2-methyl-4,5-dichlorophenoxy)-3-phenylpropylamine nitrate,
3-(p-t-butylphenoxy)-3-phenylpropylamine glutarate,
N-methyl 3-(2-chloro-p-tolyloxy)-3-phenyl-1-methylpropylamine lactate,
3-(2,4-dichlorophenoxy)-3-phenyl-2-methylpropylamine citrate,
N,N-dimethyl 3-(m-anisyloxy)-3-phenyl-1-methylpropylamine maleate,
N-methyl 3-(p-tolyloxy)-3-phenylpropylamine sulfate,
N,N-dimethyl 3-(2,4-difluorophenoxy)-3-phenylpropylamine 2,4-dinitrobenzoate,
3-(o-ethylphenoxy)-3-phenylpropylamine dihydrogen phosphate,
N-methyl-(2-chloro-4-isopropylphenoxy)-3-phenyl-2-methylpropylamine maleate,
N,N-dimethyl 3-(2-alkyl-4-fluorophenoxy)-3-phenylpropylamine succinate,
N,N-dimethyl 3-(o-isopropoxyphenoxy)-3-phenyl-propylamine phenylacetate,
N,N-dimethyl 3-(o-)bromophenoxy)-3-phenyl-propylamine beta-phenylpropionate,
N-methyl 3-(p-iodophenoxy)-3-phenyl-propylamine propiolate,
N-methyl 3-(3-n-propylphenoxy)-3-phenyl-propylamine decanoate, and
N-methyl 3-(p-trifluoromethylphenoxy)-3-phenylpropylamine.
17. The pharmaceutical composition of claim 14, wherein said at least one 3-aryloxy-3-phenylpropylamine is N-methyl 3-(p-trifluoromethylphenoxy)-3-phenylpropylamine or a pharmaceutically acceptable salt thereof.
18. The pharmaceutical composition of claim 14, wherein said at least one chemotherapeutic agent is selected from the group consisting of an alkylating agent, an antimetabolite, a natural product, a miscellaneous agent, a hormone and an antagonist.
19. A pharmaceutical kit comprising as a chemotherapeutically active ingredient at least one chemotherapeutic agent and as a chemosensitization active ingredient at least one 3-aryloxy-3-phenylpropylamine, wherein said at least one chemotherapeutic agent and said at least one 3-aryloxy-3-phenylpropylamine are individually packaged within the pharmaceutical kit.
20. The pharmaceutical kit of claim 19, wherein said at least one 3-aryloxy-3-phenylpropylamine is of the formula:
11
wherein each R is independently hydrogen or methyl;
R is naphthyl or
12
R and R are halo, trifluoromethyl, C1-C4 alkyl, C1-C3 alkoxy or C3-C4 alkenyl; and
n and m are 0, 1 or 2; and acid addition salts thereof formed with pharmaceutically acceptable acids.
21. The pharmaceutical kit of claim 19, wherein said at least one 3-aryloxy-3-phenylpropylamine is selected from the group consisting of
3-(p-isopropoxyphenxoy)-3-phenylpropylamine methanesulfonate,
N,N-dimethyl 3-(3,4-dimethoxyphenoxy)-3-phenylpropylamine p-hydroxybenzoate,
N,N-dimethyl 3-(alpha-naphthoxy)-3-phenylpropylamine bromide,
N,N-dimethyl 3-(beta-naphthoxy)-3-phenyl-1-methylpropylamine iodide,
3-(2-methyl-4,5-dichlorophenoxy)-3-phenylpropylamine nitrate,
3-(p-t-butylphenoxy)-3-phenylpropylamine glutarate,
N-methyl 3-(2-chloro-p-tolyloxy)-3-phenyl-1-methylpropylamine lactate,
3-(2,4-dichlorophenoxy)-3-phenyl-2-methylpropylamine citrate,
N,N-dimethyl 3-(m-anisyloxy)-3-phenyl-1-methylpropylamine maleate,
N-methyl 3-(p-tolyloxy)-3-phenylpropylamine sulfate,
N,N-dimethyl 3-(2,4-difluorophenoxy)-3-phenylpropylamine 2,4-dinitrobenzoate,
3-(o-ethylphenoxy)-3-phenylpropylamine dihydrogen phosphate,
N-methyl-(2-chloro-4-isopropylphenoxy)-3-phenyl-2-methylpropylamine maleate,
N,N-dimethyl 3-(2-alkyl-4-fluorophenoxy)-3-phenylpropylamine succinate,
N,N-dimethyl 3-(o-isopropoxyphenoxy)-3-phenyl-propylamine phenylacetate,
N,N-dimethyl 3-(o-)bromophenoxy)-3-phenyl-propylamine beta-phenylpropionate,
N-methyl 3-(p-iodophenoxy)-3-phenyl-propylamine propiolate,
N-methyl 3-(3-n-propylphenoxy)-3-phenyl-propylamine decanoate, and
N-methyl 3-(p-trifluoromethylphenoxy)-3-phenylpropylamine.
22. The pharmaceutical kit of claim 19, wherein said at least one 3-aryloxy-3-phenylpropylamine is N-methyl 3-(p-trifluoromethylphenoxy)-3-phenylproplamine or a pharmaceutically-acceptable salt thereof.
23. The pharmaceutical kit of claim 19, wherein said at least one chemotherapeutic agent is selected from the group consisting of an alkylating agent, an antimetabolite, a natural product, a miscellaneous agent, a hormone and an antagonist.
24. A pharmaceutical composition comprising as an active ingredient at least one 3-aryloxy-3-phenylpropylamine, the pharmaceutical composition being packaged and indicated for use in chemosensitization, in combination with a chemotherapeutic agent andor in a medical condition for which chemosensitization is beneficial.
25. The pharmaceutical composition of claim 24, wherein said at least one 3-aryloxy-3-phenylpropylamine is of the formula:
13
wherein each R is independently hydrogen or methyl;
R is naphthyl or
14
R and R are halo, trifluoromethyl, C1-C4 alkyl, C1-C3 alkoxy or C3-C4 alkenyl; and
n and m are 0, 1 or 2; and acid addition salts thereof formed with pharmaceutically acceptable acids.
26. The pharmaceutical composition of claim 24, wherein said at least one 3-aryloxy-3-phenylpropylamine is selected from the group consisting of
3-(p-isopropoxyphenxoy)-3-phenylpropylamine methanesulfonate,
N,N-dimethyl 3-(3,4-dimethoxyphenoxy)-3-phenylpropylamine p-hydroxybenzoate,
N,N-dimethyl 3-(alpha-naphthoxy)-3-phenylpropylamine bromide,
N,N-dimethyl 3-(beta-naphthoxy)-3-phenyl-1-methylpropylamine iodide,
3-(2-methyl-4,5-dichlorophenoxy)-3-phenylpropylamine nitrate,
3-(p-t-butylphenoxy)-3-phenylpropylamine glutarate,
N-methyl 3-(2-chloro-p-tolyloxy)-3-phenyl-1-methylpropylamine lactate,
3-(2,4-dichlorophenoxy)-3-phenyl-2-methylpropylamine citrate,
N,N-dimethyl 3-(m-anisyloxy)-3-phenyl-1-methylpropylamine maleate,
N-methyl 3-(p-tolyloxy)-3-phenylpropylamine sulfate,
N,N-dimethyl 3-(2,4-difluorophenoxy)-3-phenylpropylamine 2,4-dinitrobenzoate,
3-(o-ethylphenoxy)-3-phenylpropylamine dihydrogen phosphate,
N-methyl-(2-chloro-4-isopropylphenoxy)-3-phenyl-2-methylpropylamine maleate,
N,N-dimethyl 3-(2-alkyl-4-fluorophenoxy)-3-phenylpropylamine succinate,
N,N-dimethyl 3-(o-isopropoxyphenoxy)-3-phenyl-propylamine phenylacetate,
N,N-dimethyl 3-(o-)bromophenoxy)-3-phenyl-propylamine beta-phenylpropionate,
N-methyl 3-(p-iodophenoxy)-3-phenyl-propylamine propiolate,
N-methyl 3-(3-n-propylphenoxy)-3-phenyl-propylamine decanoate, and
N-methyl 3-(p-trifluoromethylphenoxy)-3-phenylpropylamine.
27. The pharmaceutical composition of claim 24, wherein said at least one 3-aryloxy-3-phenylpropylamine is N-methyl 3-(p-trifluoromethylphenoxy)-3-phenylpropylamine or a pharmaceutically acceptable salt thereof.
28. The pharmaceutical composition of claim 24, wherein said at least one chemotherapeutic agent is selected from the group consisting of an alkylating agent, an antimetabolite, a natural product, a miscellaneous agent, a hormone and an antagonist.
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. Household appliance comprising a heat pump arrangement with a heat pump adapted to transfer heat to an operating medium of the appliance, with a closed storage tank adapted to receive a phase change substance and being heat exchangeably coupled with a process side of the heat pump, with at least one sensor adapted and arranged to detect an actual phase state of the phase change substance, and with a recovery unit adapted and operable to actively recover the phase change substance in dependence of a signal of the sensor.
2. Household appliance according to claim 1, wherein the storage tank is coupled to an evaporator side of the heat pump such that the phase change substance functions as a heat reservoir for the heat pump.
3. Household appliance according to claim 1, wherein the at least one sensor is configured to sense at least one parameter indicative of a state of the phase change substance and selected from the group temperature, level, volume, transparency, acoustical dispersion, optical dispersion, conductivity, speed of sound and pressure.
4. Household appliance according to claim 1, wherein the heat pump arrangement is adapted to activate the recovery unit in case that a sensor signal indicates a critical phase state.
5. Household appliance according to claim 1, wherein the recovery unit comprises at least one of a ventilator adapted to impinge the storage tank with ambient air, and a heating element for actively heating the phase change substance.
6. Household appliance according to claim 1, wherein the recovery unit comprises a valve assembly adapted and arranged such that the heat pump is operable in reversed mode to recover the phase change substance.
7. Household appliance according to claim 1, selected from the group washing machine, dishwasher, water heater, chiller.
8. Method of operating a household appliance which comprises a heat pump arrangement with a heat pump adapted to transfer heat to an operating medium of the appliance, with a closed storage tank adapted to receive a phase change substance and being heat exchangeably coupled with a process side of the heat pump, with a sensor adapted and arranged to detect an actual phase state of the phase change substance, and with a recovery unit adapted and operable to actively recover the phase change substance in dependence of a signal of the sensor, wherein the method comprises the steps of detecting an actual phase state of the phase change substance and operating the recovery unit if a sensor signal is indicative of a predefined critical phase state of the phase change substance.
9. Method according to claim 8, wherein activating the recovery unit comprises activating a ventilator to impinge the storage tank, thus indirectly the phase change substance, with ambient air.
10. Method according to claim 8, wherein activating the recovery unit comprises activating a heating element to actively apply heat to the phase change substance.
11. Method according to claim 8, wherein activating the recovery unit comprises operating the heat pump in reversed mode to thereby transfer heat energy to the phase change substance.