MXPA96005030A - Antiemetic combination therapy using receptor antagonists n - Google Patents
Antiemetic combination therapy using receptor antagonists nInfo
- Publication number
- MXPA96005030A MXPA96005030A MXPA/A/1996/005030A MX9605030A MXPA96005030A MX PA96005030 A MXPA96005030 A MX PA96005030A MX 9605030 A MX9605030 A MX 9605030A MX PA96005030 A MXPA96005030 A MX PA96005030A
- Authority
- MX
- Mexico
- Prior art keywords
- azab
- phen
- octane
- clo
- benc
- Prior art date
Links
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Abstract
The present invention relates to methods of treating or preventing emesis in mammals, including humans, using an NK-1 antagonist in combination with one or more other active agents selected from (a) a glucocorticoid or corticosteroid, (b) a benzodiazepine, (c) metaclopramide and (d) an intracellular molecular debugger
Description
ANTIEMETIC COMBINATION THERAPY USING NK-1 RECEPTOR ANTAGONISTS The present invention relates to methods of treating or preventing emesis in mammals, including humans, using an NK-1 antagonist in combination with one or more other active agents selected from among (a) a glucocorticoid or corticosteroid, (b) a benzodiazepine, (c) rnetaclopramide and (d) an intracellular molecular debugger. U.S. Patent 5,393,762, "which was issued on February 28, 1995, relates to the use of NK-1 receptor antagonists for the treatment of emesis. The European Patent Applications 533280O1 and 615751FU, published on March 24, .1993 and September 21, 1994, respectively, also refer to the use of NK-1 receptor antagonists in the treatment of emesis. The application "Je Patent of the United States
08 / 353,049, filed December 9, 1994, relates to the use of NK-1 receptor antagonists in combination with 5HT3 receptor antagonists for the treatment of emesis.
SUMMARY OF THE INVENTION
The invention relates to a method for treating or preventing emesis in a mammal, including a human, "comprising administering to said mammal an NK-1 receptor antagonist in combination with one or more other active ingredients selected from (a) a glucocorticoid or corticosteroid, (b) a benzodiazepine, (c) metacloprarnide and (d) a molecular cell scavenger, in which the amount of the active ingredient in the combination is such that the combination produces an antiemetic effect synergistic This procedure is also referred to herein as "the synergistic process < 1e combination". An embodiment of this invention relates to the above smnergic combination procedure, in which there are five active ingredients in the combination and such active ingredients are, respectively, an NK-1 receptor antagonist, a henodiazepine, a glucocorticoid or corticosteroid, rnetacloprarnide. and an int ac 1 ular molecular debugger. Another embodiment of this invention relates to the above synergistic combination procedure, in «1 < There are four active ingredients in the combination and the active ingredients are an NK-1 receptor antagonist and three additional active ingredients selected from among (a) a gonococcal steroid or corticosteroid (b) an enzyme (c) ) rnetaclopramide and (d) a cellular molecular debugger. The embodiment of this invention relates to the above combination chemical procedure, in which there are three active ingredients in the combination and such active ingredients are an NK-1 receptor antagonist and two additional active ingredients selected from (a) a glucocorticoid of or corticosteroid, (b) a benzodiacepham, (c) rnetaclopramide and (d) an intracellular molecular cleanser. Another embodiment of this invention relates to the above 'synergistic combination procedure, in which there are two active ingredients in the combination and such active ingredients are an NK-1 receptor antagonist and an additional active ingredient selected from (a) a glucocorticoid of or corticosteroid, (b) a benzodiazepine, (c.) metacloprarnide, and (d) a molecular cell scavenger. Another embodiment of this invention relates to any of the above embodiments of the synergistic combination procedure, in which neither of the two active ingredients that are non-NK-1 receptor antagonists in the combination belong to the same of the following categories ( a) to (d): (a) a glucocorticoid or corticoest-eroid, (b) a benzo iacepma, (c) rnet cloprarnide and (d) a molecular cell scavenger. Another embodiment of this invention relates to any of the above embodiments of the synergistic combination procedure, in which one of the active ingredients in the combination is a benzodiazepine selected from lorazeμam, medazepa, alprazolam, temazeμam, quazeμarn, triazolarn, fl uni trazopam, chlordiazepoxide, chlordiazepoxide hydrochloride, dipotasic clorazepate, diazeparn, flurazeμarn, halazepain, oxazepam and prazeμam.
Another embodiment of this invention relates to any of the foregoing embodiments of the synergistic procedure of the combination, in which one of the active ingredients in the combination is a glucocorticoid or corticosteroid selected from "jexarnetasone, tria cinolone, betarnetasone, cortisone. , Llprednisolone and hydrocortione. Another embodiment of this invention relates to any of the foregoing embodiments of the smérgico procedure of the combination in which, one of the active ingredients in the combination is an intracellular molecular cleanser selected from acetylcysteine, glutathione, vitamin D, vitamin E, selenium and retmoids (eg, 13-cis-retinoic acid and isotret noin) The term "in combination with", as used in this application, means that the NK-1 receptor antagonist and the other or other mgredient * e / The active compound (s) in the combination are administered to the mammal in question as part of the same therapeutic program under an appropriate dosage regime prescribed by the attending physician, such that the therapeutic effects < If said ingredients are added, the active ingredients may be administered separately or as part of the same pharmaceutical formulation, depending on the particular dosage forms administered and the dosage regimen prescribed by the physician in charge of the treatment.
Another embodiment of this invention also relates to any of the foregoing embodiments of the synergistic procedure in which the NK-1 receptor antagonist administered to said mammal is selected from: (2S, 3S) ~ 3- [2-methoxy -5- (2-t-azolyl) benzyl-3-aminophenyl-2-f in 11-pi-di-nane, - (2S, 3S) -3-C5- (2-? Rn? Dazol? L) -2 -rnetox? benc? llarn? no-2-phenylpiperidine; (2S, 3) -3-C2-rnetox? -5- (2-oxopr? Rrol? D? N? L) benzyl 1] an? No-2-phen? L ??? ep din; (2S, 3S) -3- [2-? Netox? - 5- (4-rnet? L -2-t lazolyl) benzyl] -arn? No-2-femlp? P > er? dma; (2S, 3S) -3-r2-methox? -5- (1, 2,3-t? Ad? Azole-4?) Benzyl] -amino-2-phenylpiperidine; (2S, 3S) - (6-methox? -2-rnet? L-benzoth azol-5-lrne ii) - (2-phenylpi pepd? N -3? L) mine; (2S, 3S) -H5- (2,5-d? Rnet? J-pir rol-1-? L) -2 ~ rnetox? Bonc il] - (2-phen? L? Pep d? -3- ? l) m? na (2S ~ 3S) -3 ~ [2-? Net? -5- (5-oxazol yl) benzyl IJarní no -2 femylpiperidine; (25, 3S) - (5-methox? -2-rnethyl-benzoxazole-5? Lrnet? I) - (2-f in 11-p i e r i di n- 3 - 11) i na; (1 R, 2 E, R, R, R) - 3 - C 6 -meto i - 3 -rnet 11 benzylsoxazo 1 - 5 -113 rnet i larri i no- 2 - benz hydr 11 azano r -bo rna no; (2S, 3S) -N- (2-?? Netox? -5-met? Lsulfon? Lfen? L) -met 1-2-d? Phen? Lmet? Ii-azab? C? Clo C2.2.23 octan-3 -am? na;
(2S, 3S) -N- (2-methox? -5-d? Met? Lam? Nofen? L) rnet? L-2-difeni lrnet? L-1-azab? C? CloC2.2.23octan-3 ~ ar? u na; and (2S, 3S) -N- (5-tr? fluoroacet? lam? no-2-rnetoxifinyl) ineethyl -2-d? femlmet? l -l-azab? c? cloC2.2.2] octan-3-arn? na (25,35) -3- (5-tert-but-l-2-rnetoxy? Benc? L) am? No-2 ~ 3-tr-i f luoromethoxyf eni Dpi pendin; (25,35) -3- (2-sopropox? -5-trifluorornetox? Benc? L) arn? No-2-fem-pipen dina; (25,35) -3- (2-etox? - 5- < p f luoroneto ibencí l) arn? no-2-phenyl-pipen dina; (2S, 35) -3- (2-methox? -5-tnfluorornetox ibencyl) arn? No-2-phen? Ip? Per? D? Na; (25,35) -3 - (- 5- erc-but? L-2 ~ tr? Luorornetox? Benc? L) arn? No-2-femlp? Er? D? Na; 2 ~ (di phenyl ethyl) -N- (2-rnetox? -5-tpfluoromei oxy -feml) rnet? I-azab? cycle T2.2.2] octan-3-arn? na; (2S, 35) -3- C5-chloro-2- (2, 2, 2 ~ r i luoroei x) benzyl amine-2-phenylpipenia; (25,35) -3 ~ (5- erc-but? L-2-tpfluoromethoxy? Benc? L) arn i no-2-f eni 1 pi pe pdina; (25,35) -3 - (0.-1 sopropoxy -5-p f luorornetox i boncí L) arnmo-2-phenylpipepdine; (25/35) - 3- (2- difluoro etox? -5- tp f luorornetox i ncil) - aini no - 2 - f em 1 μ i pe p d i na; (25, 5) -2-phen? L-3- [? - (2, 2, 2- * p luoroate and benzyl) -ammo iper-idine; and (25,35) -2-feml-3- (2-tnfluorometox? benc? l)] arn i no p i pe p d i na; c? s-3- (2-chlorobenzylamino) -2-phen? pipen dine; c? s-3- (2-tpfluorornet? lbenc? la? no) -2-femlpipendine; c? s-3 - (2- etox? benc? larn? no) -2- (2-fl uor-ofenyl) piperidm; ci -3 - (2 ~? netox? bencílamino) - 2- (2-chlorofeml) pi er ídi na; c? s-3 - (2-methoxybenzylamine) -2- (2-methyl? femi) pi in di na; c? s ~ 3- (2-methox? benc? larn? o) -2- (3-rnetox? feml) pipen di na; cis-3- (2-methobenzyl) -2- (3-fluorofeml) pipen di na; ci -3- (2-methobenzyl) -2- (3 -clo ofeni 1) μipendin; c? s-3- (2-methox? benc? lam? no) -2-femlp? dina; c? s-3- (2-methox? bencilarpine) -2- (3-? net? i eni 1) pipendine; c? s ~ 3 ~ (2-methox? benc? lammo) -2- (-fluorofenyl) μi pen í na; c? s-3- (2-methox? benc? lam? no) -2- (3- < leml) pipen < j na; ci 3- (2-? netox? benc? lam? no) -2- fem lazaciclohep-t ano; 3- (2-rnetox? Enc? La? N? No) - -mo il -2- feni lpi peri ma; 3- (2-methox-encylmethyl) -5-methox ~ 2 phenyl ipen dine;
3- (2-? Netox benzilarnmo) - 5-met? L ~ 2-fen? Lp? Pepd? na (25,35) -3- (2-? Netox? Benzylamino) -2-phen? L? Pepdma; (25,35) -l- (5-carboethoxy-ent-l-? L) -3- (2-rnetox? Benc? L-ino) -2-phen? Ipiper í na; (25,35) -l- (6-h? Drox? -hex-l-? L) -3- (2-? Netox? Benc? 1 a ino) -2-phenyl -ipepdine; (25,35) -l- (4-h? DroxL -? - phen? Lbut-l-? L) -3- (2- e < ox? -benzylamino) -2-phen? Lp? Per- ? ? na; (25,35) -l- (4 ~ oxo-4-phen? Lbut-l-? L) -3- (2-rnetoxi encí 1 a ino) -2 ~ fen? L ?? pep ina; (25,35) -l- (5,6-d? H? Drox? Hex-l -? L) -3- (2-? Ne ox? Benc? L? A mo) -2-phen? Lp? per? dina; c? s-3- (5-fluoro ~ 2-rnetox? benc? lam? no) ~? -f enil pipen dina; (25,35) -1- ~ (4-fluorofeml) ~ 4-oxobut-i-] -3- (2-? Netox? Benzylammo) -2-phenylpiperidine; (25,35) -1- U ~ (4-rluorofeml) - 4 -hydroxybut- J - j.1] J- (2-methox enlam) -2-feml piμepdi a; c? s-3- (2-metho? -5-rnet? lbenc? larn? no) 2-phenyl-1-pipen dine; (25.35 > -1- (4-benzene? Dobut-l-? L) -3- (2-methoxy? Benzyl L-amino) -2- feni 1 pipe ndi a; cis- 3- (2-eto) xi na ft -1-? l-rnet? larn? no) - 2 f eni 1 pi pen í na; (25, 35) -3- (2-methox? bencilarnino) -1- (5-N-rnet? l-ca rboxani dopent- 1 -i 1) -2- f em 1 pipen dina;
(25,35) -l- (4-c? Anobut-l-? L) -3- (2-methox? Benzylamino) 2 -phenyl pi in dyne; (25,35) -l-C4- (2-naphthalene) but-l-? L] -3- (2-rnetox? -benzylamine) -2-phen? Lp? Per? < ina; (25,35) -l- (5-benzzarn dopent-1-yl) -3- (2-methox? Benc? L-amino) -2-phen? L? Pepd? Na; (25,35) -l- (5-arn? Nopent-l-? I) ~ 3 ~ (2-rnetox? Benc? Lain? No) -2-feml? P r? D? Na; (25,35) -3 ~ (5-chloro-2-methox? Benc? Larn? No) -2-phenyl pipen di na; (25,35) -3- (2,5-d? Rneto? Enc? Larn? No) -2-phenylpipendine; c? s-3 - (3,5-d? fluoro-2-methox? benc? larn? no) -2-phenyl pipendine; c? s-3- (4,5-d? fluoro-2-rnetox? benc? ln? no) -2-f in 11 p i e p d a; c? s-3- (2,5-dimethoxybenzylamino) -1 -T 4 - (4- fl? oro fem L) -4-oxobut-l-? l] -2-feml ?? per? d? na cis -3- (5-chloro-2-me-oxo-benzyl-lane) -1- (5,5-dihydro-hexyl-1-yl) -2-femylpipepine; c? s-1- (5,5-d? h? drox? hex-l-? l) -3- (2, 5-dimethoxy-benzyl) -no-2-phenyl? piper-idine; c? s-2-feml-3- 22- (μr-op-2-? lox?) bencí lamí no] pipepdma; c? s ~ 3- (2,5-d? rnetox? benc? l írni hydrochloride o- 2- (3-rnetox i-feml) μiper-idina;
c-s-3- (5-chloro-2-r-methoxy-benzyl) arn-no-2- (3-ethoxy-phenyl) -pipehydrate dihydrochloride; d? clorh? dratodec? s-3- (5-chloro-2-methox? benc? l) arn? no-2- (-chloro-fem) ??? ep dina; 3- (-rnetox ibencí lamí no) - 2, 4 -di f em l i peri di na; c? s-3- (2-methox? benc? lamino) -2-phen? lp? rrol? d? na; (25,35) -3 ~ (5-et? L-2-methox? Benc? L) arn? No-2-phenylpiperidine; (25, 35) -3- (5-n-butyl-2-rnetox-benzyl) arn? No-phenylpiperidine; (25, 35) -3- (2-? Netox? -5-n-prop? Lbenc? L) arnino-2 f-phenylpenine; (25, 35) -3- (5-? Soprop? L-2-methox? Benc? L) am? No-2-t-enyl pipen dine; (25,35) -3- (5-s-but? L-2-rnetox? Benc? L) arn? No-2-phen l epepidine; (25,35) -3- (5-t-butyl-2-methox? Benc? L) arn? No-2-f-enyl pipen dine; (25, 35) -3- (2-methox? -5-phen? Lbenc? L) a? N? No ~ 2 phenylpipepdma; (2s, 3S) -N- (5 ~? Sopro? L-2 ~ methox? Phen?) Rnet? L-2-d? Phen? L? Net? Ll-azab? C? Clo C2 .2.23 octan -3-amma; (25, 35) -N- (5- »erc-but? L-2-rneto ?? feml) rnet 1-2 difeni l? Net? Li-azab? C? Clo C 2.2.23 octan-3-am ? to; (25.35) -N- (5-? Net? L -2-rnetox? Faith 11) methyl-2- "Jifenilinetil-l ~ azab? C? CloC2.2.23octan ~ 3-amma;
(25, 35) -N- (5-et? I-2-? Netox? Phen? L)? Net? L-2- «J? Phen? Lmet? L-1-azabicyclo C2 .2.23 octan- 3- am? na; (25,35) -N- (5-? So? Rop? L-2-methox? In? L)? Net? I -2-d? Femlmet? L-1-azabicyclo [2 .2 23 octan- 3 -amine; (25.35 > ~ N- (5-sec-but? L-2-methox? Phen? L) rnetH-2-d? Phen? Lmet? L-1-azab? C? Clo [2.2.23 octan -3-amin; and (25.35) -N- (5-n-prop? L-2-rnetox? Phen l) rnet? L-2-d? Phen? Lmet? L-1-azab? c? clo [2.2.23 octan-3-amine; [4-rnetox? -3- ((25,35) -2 -femlpipep dm-3-- 1-aminomethyl) phen? 3-rnetylamide of acid 2 , 4-d? Rnet? It? Azoi -5-sulfin; N- (4, 5-d? Met? Lt? Azol-2 ~? L) -N- [4-rnetox? -3 - ((25 , 35) -2-fem Ipi pep d? N-3-? Lammornet i 1) fen? L3 rnetanosu 1 f onarní; {. 5 [(4, 5-d? Rnet? Lt? Azol-2- íD etillan nol-2-? netox? benc? l. -. ((25, 35) -2- fen? lp? e? d? n-3 - 11) mine; . { 5- (4, 5 -d rnet-ilthiazole -2-? 1 -ary) -2-methoxy benzyl] ((25, 35) -2-feml?? Epep? N-3-alamine; rneti 1-T3- ( (25, 35) -2-phen? Ipipep din-3-ylan norneti 1) -4- tnf luorornetox? Eml-am? A of 4,5-dirnet-luthiazole-2 -suic acid; sopropoxy -3- ((25,35) -2- fe ilpiper-idm-3-amlammomethyl) feml3 -met lam of 2,4-d met i lt lazol-5-sulphonic acid; [4-? sopropox i -3- ((25, 35) -2-phen? Ipiperidm-) -i larninornetyl) phen? L3-? So? Trop? J 2, 4? Di et? It lazol-5-phonic sulphonic acid; [4-rnetox? -3- ((25, 35) -2- femlp? Per? D? - 3 ~ ilam nornetil) fen? L3-? Soprop? Lam? Of 2,4-d? Met acid? lt? azol-5-sulphonic co; [4-methox? -3- ((25, 35) -2- phen? Lp? Pepd? N-3-yla inonetii) feml3 -isobutylamide of 2, 4-d? Met? Lt? Azol-5 -sul acid phonic; [4 ~? Sopropox? -3- ((25,35) ~ 2 ~ phen? Lp? Per? Dm ~ 3 -ilarninornetyl) phen? L3-? Sobut? Lam? Of 2, 4-d? Net? Lt? Azol-5 - phonic sound; (3R, 45,55,55) -N, Nd? Et? L-5- (5-1 soprop? L-2-rnet ox i-benzylamino) -5-d? Femlrnet? Ll-azabi cycle [2.2 .23 octane-Be rboxarní da; (3R, 4S, 5S, 5S) -N, N-d? Et? L-5- (2,5-d? Rnetox? Benc? La? N? No) ~ 6-d? Phen? Lmet? 1-l-azab? C? Clo [2.2.23 octane-3-carboxam? gives; Acid (3R, 45,55,55) -5- (5-? op rop 11 - 2 -rnet oxybenzylamine) -6-d? femlrnet 1 -1 -azabí ciclo [2.2.2 oc no -3-carbox? l? co; Acid (3R, 45.55.6S) -5- (2-rneto ?? - 2 rnetiitiobencilami no) -6-d? in? lmet? l-l-azabí cycle [2.2.23 octane-3-carboxylic; acid (3R, 4S, 5S, 6S) ~ 5- (2, 5-d? rnetox? benc? la? n? no) -6-diphenyl-ethyl-l-azab? c? clo- [.2.23 oct non-carboxylic; aci or (3 R, 45, 55, 65) - 5- (2-e tox 1-5-rnet ilbencilaní no) -6-d? phen? lmet? 1-J-azabicyclo [2.2.23 octane-3-carboxyl i co; aci or (3R, 45,55,65) -5- (5- et? l-2 ~? netox? benc? lami) -6- diphenylmetal 1-1 -azaby cycle [2.2.2 octane-3- carboxylic; Acid (3R, 45.5S, 6S) -5- (2-rnetox? 1 -5-n-propylbenzyl) -6-d? femlmet? l-l-aza? c? cio [2.2.23 octane-3-carbox? l? co; Acid? (3R, 4S, 5555.6S) -5- (5-sec-but? 1-2-methox? benc? lam? no) -6-d? femlmet? l-i-azab? Cyclo [2.2.23 octane-carboxyl ico; acid (3R, 5,55,65) -5- (5-N-met? l-methanesul fon i lamino -2-methox? -benz? larn? no) -6 -difem lme il-1 -azabí ciclo [ 2, 2 octane-3-carboxylic; Acid (3R, 45.55.65) -5- (2-methox? -5-rnet? lsul finlbenben-1-amin) -6-d? phenolmet? i-azab? c? clo [2.2.23 octane-Be rboxylic; Acid (3R, 4S, 55.6S) ~ 5 ~ (2-rnetox -5-trifluorornei oxy benzyl-arnmo) -fi -difemlrneti l-1-azab? c? clo [2.2.23 octane-3-carboxylic acid; Acid (3R, 45,55,65) -5- (2 -rnetox? ~ 5-? net? 1 sul fon i 1 bencí 1 -amino) -6-d? feml et? i -1 -azabí cycle [2.2.2.3 oct no-3-carboyl; Acid (3R, 45,55,65) -5- (-d ?? net? lamino -2-rne ox? benc? lam? no) -6-d? faith? lmet? l-l-azab? cycle [2.2.2.3 octono-3 ~ c r ox? l ico; Acid (3R, 5,55,65) -5- (5-? soproμ? l- 2-mei x? benc? lam? no) -6-d? femmet? li-azab? c? clo [2.2 .2.3 octane -2-c rbo? L? Co; Acid (3R, 4S, 55.65) -5 ~ (2-methox? ~ 5-methyl-thiobenzylamino) -6-d? phenyi et? i-azab? c? clo [2.2. 3 octane-2-carboxylic; acid (3R, 45, 55, 65) -5- (2,5-dimethoxyibec i o) -6-d? phen? lmet? l-1-azabicyclo [2.2.23 octane-2-carboxyl; Acid (3R, 45.55.65) -5 ~ (2-rnetox? -5-rnet? lbencilam? no) -6-di phen? l? net? li-azab? c? clo [2.2. 23 octane-2-carhoxylic; Acid (3R, 4S, 55, 55) -5- (5 -eti 1-2 -meto xi encílamino) -6 -d? fen? lrnet? ii-azab? c? clo [2.2.23 octane- 2-carboxylic; acyl (3R, 4S, 5S, BS) -5- (2-methox? 1 -5-Sn-prOp? lbenc? la? n? no) -6 ~ d? phen? lrnet? l -1-azabic ? clo [2.2.2.3 octane- 2 -carbox ion; ac? (3R, 4S, 5S, 6S) -5 ~ (5-sec-but 11-2-rnetoxy benzylamine) -6-d? Fem lrne? Li-azab? C? Clo [2.2.23 octane-2 -car ox? l? co; Acid (3R, 45.55.6S) -5- (5 ~ N-rnet il meta nosul fom l mino - 2-rnetox? benc? l-am? no) - 6 -di feni line il -1 -azab? cycle [2.2.23 oc ano-2 ~ carbo? 11 co, ac? or (3R, 45, 55, 65) - 5- (2-rne oxy-5-methy1-su-1-benzyl-arnino) -6-d-phen? lmet? l-1 -azabí ciclo [2.2.23 octano-? -carboxilico; acid (3R, 45, 55, 65) -5- (2-rnet ox 1-5 -tp luorornetox ibenzyl-a ino) -6-d? phen lrnet? l-1-azabicyclo [2.2.23 octane-2 - carbo 11 ico; Acid (3R, 45.55, 65) -5- (2-ethoxy-5-rnet? lsul foml benzyl-ammo) -6-d? phen? Imet 1 - l-azab? cycle [2.2.23 octane-2-car * box? l ico;
Acid (3R, 4S 5S, 6S) -5- (5-? me? lam? no ~ 2-methoxybenzylamino) -6-d? phen? lrnet? l-1-azab? c? clo [2.2.23 octane-2-carboxyl; (3R, 45, 55.65) -N- carbamoyl-lmethyl-5- (5-isopropyl-1-2-rnetoxybenzyl-cinnamyl) -6-d? Femlrnet? I ~ 1-azab? C? Clo [2.2.23 octane-3-ca ro amid; (3R, 45,55,65) -N-carboxynet? L-5- (5-? Soprop? 1-2-netoxybenzylamino) -6-d? Femlmet? L-l-azab? cycle [2.2.23 octane-3-carboxy a; (3R, 45.55.6S) -3- (2-carbarno? Lp? Rrol? D? N-1- l) carbon? L-5- (5-? Soprop? L-2-methox? Benc? Larn ? no) - d -diphenylmethyl-1-azab? c? clo [2.2.23 octane; (3R *, 45 *, 55 *, 65 *) -N- (1-carbarnoilet 11) -5- (5 ~? So? Ro? L-2-methox? Bencilami) -6-d? Feml? net? i -? - azab? c? clo [2.2.23 octane-3-carboxarnide; (3R, 45.55.65) -N- (l-carbarnoi 1-3-metJlbutl) -5- (5-? Soμro? L-2-methoxy benzylamine) -6-d? ferulrnet il-l ~ azab? cic., io? 2 .2.23? ct non-3-carboxan? n? to; (3R, 4S, 55.6S) -N- (2-ca rbarnoi let 11) -5- (5-i sop i ~ op i L-2-rnetox ibencylarnino) -6 -difeni lrnetil-l-azat > ? c? c? o [2.2.23 octane-3-carboxam? da; (25,35) -N ~ (5-? Sopropen? L-2-? Netox? Feml) rnet i l -2- < J? fen? lmet? l-i-azab? c? [2.2.23 octan-3-amma; (25,35) -N- (2-methox? -5-v? N? Lfen? L) rnet ii -2-d? Phen? L? Net? I-1-azabicyclo [2.2.23 octan- 3 - amine; (25,35) -N- (2-rnetox? -4,5-d? Met ilfeniDinet? L-2-xfenilrnet il-l-azabicyclo [2.2.23 octan-3-arn? Na; (25, 35) -N- (5,6,7, 8-tetrahydro-3-rnetoxy? -2- na propyl) met? L-2-d? Phen? Lmet? Ll -zabicyclo [2.2.23 octan-3- amma; (25,35) -N- (5 ~ rnetox? ndan- 6-? 1) rnet? l ~ 6-d? phen? rneti ii-azabicyclo [2.2.23 octan-3-am? na; 25.35) -3- (2,4-d? Methox? -5-et? Lbenc? Lammo) -2-d? Phen? Lrnet? L-1-azab? C? Clo [2.2.2.3 octane; ( 25.35) -2- diphenyltrilethyl-N- [2-rnetox -5- (butyl phosphoryl) phen? 3-met? Ll-azab? C? Clo T2.2.23 octan-3-amine; (3R, 45, 55,65) -5- (5 ~? Sopropen? L-2-rnetox? Bene? L arnino) -6-d? Phen? Lmet? Li-azab? C? Clo [2.2.23 octane-Be rboxarní da; (3R, 45, 55, 65) -6 ~ d? Fem lmet? L ~ 5- (2-methox? -5-met? L? Ulfon? L ~ benc? Larn? No) -l-azab? C? clo [2.2.23 octane-3-carboxyam a; (3R, 45,55,65) -5- [5- (N-acet-il-N-rnetylamino) -7-met-ox-benzyl] n3 - 6-d? Phen? Lmet? L-1-azab? C? Clo [2.2.23 octane 3 ~ carboxam? A; (3R, 45.55.65) -6 ~ d? Femlrnet? L-5- [2 -rnetox? -5- (N-rnet il-N-rneti ls l fon i lamino) b encí lamí no 3 -1-aza? c? [2.2.23 oct o-3 -c r ox a id; 3R, 45,55,65) -6- di phenyl eti l-5- (2-methox? ~ 5-ethyl-sulphonylbenzylamino) -1-azab? c [2.2.23 octane -3 car-box Ll co; (25,35) -N- [5- (1-h? Drox? -l-met? Let 11) -2-rnetox? fen? l met? l-2-d? femlmet? l -1-azab? cycle [2.2.2 octan-3 -a ina; (2S, 35) -N- [2-rnetox? -5- (l-methox? -1-rnet? Let il) phen? 3 met? L-2-d? Phenylmet? L-1-azab? C? clo [2.2.23 octan-3-amma; acid (3R, 4S, 5S, 6S) -3- [5- (lh? drox? -l ~ rnet? let? l) -2-methox? phen? 3 met? iarnmo-6-di phenylrhenyl lazabicyclo [2.2 .23 octan-5- carboxylic; (25,35) -2-d? Phen? Lrnet? L-N- [5- (l? H? Drox? - 1-hydro irnet i letii) -2-methox? Fe? L? Net? 1-1-azab? cycle [2.2.23 octan-3 -amine; acetyl (3R, 4S, 55.65) -3 ~ [5- (l-rnetox? -l-rnet? let? i) -2-rneto ?? phen? 3met? lamino-6-d? phen? lmet? ll-azab? c? clo? 2 .2 23 octane-5-carbo-lico; acid (3R, 4S, 5S, 65) ~ 3- [5- (lh? drox? ~ l-met? lt? l) -2-rnetoxy phen? 3 methylamino-d-diflumethyl-i-azabicyclo [2.2. 23 octane-5-carboyl; acid (3R, 45.55.65) -3- [5- (l-et? lt? o- 1 -metí let il) -2-metho? phen? lmet et i lamino- d- if erulme? ll ~ azab ? cycle [2.2.71 octan -5-car box 111 co; (35.4R, 5S, 6S) -N-carbamo? Lmet? L-6-d? e? Irnet 11-5- (3,5-bistrifluoromethylD-benzyloxy) -l-azat > ? c? clo [2.2.23 octane-.! -c rbox a i a; (35.4R, 55.5S) -6-d? Phen? L? Net? L-5- (3,5-b? S (tpfluoromet il) -benzyloxy) -1-azab i cycle [2.2.23 octane -Sea rbo arm da; (35.4R, 55.65) -N, N- (3-? Xa-l, 5-pent? Len) -6-d? Phen? L? Net? L-5- (3, 5-bis ( tp luoromethyl) benzyl loxy) -1- azabicyclo [2.2.23 octane-3-carboxamide; acid (35, 4R, 55, 65) - 6-d? fen? lmet? l-5- (3,5- "Jirnetilbenzyloxy) -1-azab? sky [2.2.23 octane-3-carboxyl; (35.4R, 5S, 65) -N, Nd? And? L-6-di-femyl-phenyl -5- (3,5-bi s (tpfluoromet? L) benc? Lox?) - l-azab? C? Clo [2.2.23 octane-Be rboxami da; acid (35.4R, 55.65) -6-d? femlrnet? l-5- (3-f luoro-5-t n luoroethylbenzyloxy) -l-azab? c? clo [2.2.23 octane-Be rboxyl ICO; ac? «Jo (3S, 4R, 55,65) - 6-d t pheni lrnet? l-5- (3,5-b? s
(tp fluoromethyl) benzyloxy) -1-azab? e? [2.2.23 octane-3-carboxylic acid; (35, 4R, 55,65) -N, Nd rnet? L-6-d? Phen? Lmet? L-5- (3,5-b? S (tpfluoro and il) benzyloxy) -1-azab? c? clo [2,2.23 octane-3-carboxaini da; (2S *, 35 *, 4S *, 5R *) -4-carboxy? -3- [N- (-isopropyl-2-methoxybenzyl) am? No3 -5-rnet? ] -2-f n? L? Rrol idina; (25 *, 35 *, 55 *) -5-carbox? -3- [N- (- ethoxy-5-tp fluoromethoxybenzyl) am? No3 -2-phen? L? pendí na; (25, 35) -3- (6-netoxy-1-methyl-2-oxo-1,
2,3, 4-tetrah? Dro «ju? Nol? N-7-? L)? Pet? L-2-fon l? Μep« l? ~ 3- m? na (25,3S) -2-phenyl-N- [5- [2,2,2-tp f luoi or - 1 - t p fluoroinetiDet ii 3 -? ~ Rnetox i encí l3μ? μ ndi n-3 -a tu na, (25, 35) - 7 - di-ethyl-N- [2-netox-5 - (meulis oni 1) benzyl 13 -1-azab? c? clo [2.2 .23 octan-3 -amin; (25/35) -2-dLfem lmet íl N- (5-? Soμroμeml -2- ethoxybenzyl) -1-azabicyclo [2.2.23 octan-S -amine; and (2S, BS) -2-d? phen? lrnet? lN- [5- (lh? droxi "l-met? let? l) -2 ~? netox? benc? l3 -1-azab? c? clo [2.2.23 octan-3 -amine The former NK-1 receptor antagonists which are basic in nature are capable of forming a wide range of different salts with various inorganic and ganic acids. form pharmaceutically acceptable salts suitable for use in this invention are those which form non-toxic acid addition salts, ie, salts containing pharmacologically acceptable anions, such as hydrochloride salts, brornhydrate, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, etitrate, acidic acid, tartrate, bitartrate, sucemate, rnaleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulphonate, μ-toluenosui fonato and parnoate [ie-, 1, 1 '-inet i len- bi s- (2-h? «Lrox? -3 ~ naf t oat) 3. NK-l antagonists that are also naturally acidic are ca paces of forming base salts with various pharmacologically acceptable cations. The chemical bases that are used as reagents for preparing the pharmaceutically acceptable base salts of the therapeutic agents are those that form non-toxic base salts with the acid therapeutic agents. Such salts of non-toxic bases include those obtained from pharmacologically acceptable cations (such as sodium, potassium, calcium and magnesium, etc.).
The treatment of emesis includes the treatment of nausea, retching and vomiting. Emesis includes acute emesis, delayed emesis and predicted emesis. Substance P receptor antagonists are useful in the treatment of emesis, independently of its cause. For example, emesis because it is induced by drugs such as agents for cancer chemotherapy (eg cyclophosphamide, car-nustma, lomustma and chlorambucil), cytotoxic antibiotics (eg dac + nom ciña, doxorubicma, rnitornicina-C and bleornicma), opioid analgesics (eg morphine), antimetabolites (eg, cytarabine, methotrexate and 5-fluorouracil), vinca alkaloids (eg etoposide, vmblastine and vincristine) and other drugs such as cisplatin, Dacarbacma, procarbazine and hydroxyurea. Emesis may also be induced by radiation sickness, radiation therapy, poisons, toxins such as those caused by metabolic disorders or by infection (eg gastritis), pregnancy, vestibular disorders such as motion sickness, postoperative disease, gastrointestinal obstruction, reduced gastrointestinal notoriety, visceral pain (eg myocardial infarction or peritonitis), migraine, elevated intercranial pressure or reduced metaterranal pressure (eg, altitude sickness). The methods of this invention can also be used to treat or prevent emesis induced by the ipecac drug.
DETAILED DESCRIPTION OF THE INVENTION
The following references refer, as a whole, to derivatives of quinuclidma, pipen dina, ethylene diarnma, pyrrolidine and azanorbornane and to related compounds which exhibit activity as NK-1 receptor antagonists and which can be used in combination with one to four additional active ingredients , as described above, in the pharmaceutical compositions and methods of this invention and processes for preparing the same: U.S. Patent 5,162,339, which was issued on November 11, 1992; U.S. Patent 5,232,929, < That was granted on August 3, 1993; International Patent Application UO 92/20676, published on November 26 «je 1992; U.S. Patent Application UO 93/00331, published January 7, 1993; International Patent Application UO 92/21677, published on December 10 «le 1992; U.S. Patent Application UO 93/00330, published January 7, 1993; International Patent Application UO 93/06099, published on April 1, 1993; International Patent Application UO 93/10073, published that of ayo of 1993; Application «he International Patent UO 92/06079, published on April 16, 1992; International Patent Application UO 92/12151, published July 23, 1992; International Patent Application UO 92/15585, published on September 17, 1992; Application «Je International Patent UO 00
93/10073, published May 27, 1993; International Patent Application UO 93/19064, published on "Je September" Je 1993; International Patent Application UO 94/08997, published on April 28, 1994; International Patent Application UO 94/04496, published on March 3, 1994; International Patent Application UO 94/13663, publLca < Ja on June 23, 1994; Application «he International Patent UO 94/20500, published on September 15, 1994; International Patent Application PCT / 1B94 / 00221, which designates the United States and was issued on July 18, 1994; Application "International Patent PCT / JP94 / 00781," which designates the United States and was filed on May 13, 1994; International Patent Application PCT / 3P94 / 01092, designating the United States and filed on July 5, 1994 and International Patent Document 5 PCT / 3P94 / 01514, "} It designates the United States and was submitted on September 13, 1994. All previous international patent applications designate the United States as the national state in which it will be processed. The above patents and patent applications are hereby added in their entirety as background. The NK-1 receptor antagonists listed in the summary of the invention can be prepared by methods described in the patents and patent applications previously cited therein and in the scientific literature. Other NK-1 receptor antagonists that can be used in the combination therapies of this invention are described in the following background: European Patent Application EP 499,313, published "the 19th" on August, 1992, Patent Application. European EP 520,555, published on 30 December 1992; Application "European Patent EP 522,808, published on January 13" Je 1993, European Patent Application EP 528,495, published on February 24, 1993, PCT Patent Application UO 93/14084, published on July 22"Je July" 1993, Application of Patent PCT UO 93/01169, published January 21, 1993, Application "Patent PCT UO 93/01165, published January 21," 1993, PCT Patent Application U 93/01159, publ. Ca "Ja January 21, 1993, 5ol? c" l "Patent PCT UO 92/20661, published on November 26" je 1992, European Patent Application EP 517,589, published on December 12, 1992, Application of European Patent EP 428,434, published May 22, 1991, European Patent Application EP 360. S90, published on 28 < March 1 «Je L990, Patent Application PCT UO 95/04042, published on February 9« Je 1995, Patent Application PCT UO 95/08549, published on March 30, 1995, Patent Application PCT UO 95 / 193- , published July 20, 1995, PCT Patent Application UO 95/23810, published on September 8, 1995 and PCT Patent Application UO 95/20575, published on August 3, 1995. All these publications are also add to < ]or? or background in its totality. This invention relates both to methods of treating emesis in which the NK-1 receptor antagonist and one or more other active ingredients are administered together, as part of the same pharmaceutical composition, as well as to processes in which they are administered. administered separately as part of an adequate dosing regimen designed to obtain the benefits of combination therapy. The regime of "appropriate Josification, the amount of each dose administered and the specific intervals between doses of each active agent will depend on the specific combination of active agents used, the disorder of the patient being treated, the emetogen and the severity." Jel disorder. The active agents used in the synergistic process of the combination of this invention will be administered in amounts such that the combination of active agents produces a synergistic effect. These will usually be administered in amounts less than, or equal to, those that are effective as sole agents for the treatment or prevention of emesis and, active agents that have not been used as antiemetic agents, those to which they are "attached" to mammals for any therapeutic purpose. The certifications approved by the TOA will entrust the active ingredients used in the smergic process of the invention that have received the approval of the FDO for administration to humans are available to the public (see, for example, Rernmgton's Pharrnaceutical Sciences, 18 »Edition , Macl-Publishing Co. Easton, PR, 1990 and Physician's Desk Reference, 49 »Edition, Medical Economics Data Production Co., Montvale, N3, 1995). Similarly, the dosing regimen for each of the active ingredients in the combination will be prescribed by the attending physician, taking into account the factors cited above. Such regimens will generally be similar to those known to be effective for the same active agents when used as the sole antiemetic agent or as unique components in combination antiemetic therapy. The following are examples of the dosages of unique antiemetic agents that have been described in the literature for certain active agents that can be used in the methods of this invention: dexamethasone: 4-20 g per dose (po / iv), once daily or every 4-6 hours lorazeparn: 1.0-3.0 rng / m2 per dose (? .v.), once a day or every 6 hours metacloprarnuJa: 1-3 ing / kg (iv) per dose , ca «the 2 hours for 2-5« josis (see Pisters et al. "Management of Nausea and Voinitmg Caused by finticancer Drugs: State of the Art", Oncology, 6, pages 107-112, 1992). The following articles also refer to antiemetic dosages of some of the active agents that can be used in the synergistic combination procedure of this invention: Shor-t, R., "fintiernetic Clsums for Glutathione Bacl-ed by Phase III Tria!" , INPHfiRMA, January 21 <; Je 1995; Borgeat et al., "Prelirninary Cornmumcation: Rdjuvant Propofol Enables Better Control of Nausea and Emesis ..." Canadian Oournal of flnesthes a, 1994, 41 (11), pages 1117-9; "Drugs for Vorniting Caused by Cancer- Chernotherapy", The Medical Letter,
, pages 124-6, 1993, The Medical Letter, Inc. New Roehelle, NY; Cerosirno et al., "Adrenal Corticostero?" Js as Antiernetics dupng Cancer Chernother-apy ", Pharmacotherapy, 6, 1986, pages 118-127; Tpozzi et al., "Opt nun Management of Nausea and Vorn ting in Cancer Chemotherapy", Drugs, 34, pages
136-149 (1987); and Grunberg et al., "Control of Chemotherapy Induced Emesis," New England 3ournal of Medicine, December 9, 1993, pages 1790-1796. The above articles are added here as bibliographic references in their entirety. In general, in carrying out the synergistic combination procedure of this invention, the NK-1 receptor antagonist is administered to an average adult human "Je 70 k in an amount ranging from about 0.36 to about 8. , 6 rng per kilogram of body weight of the patient being treated per day, in single or divided doses, preferably from about 0.36 to about 4/3 rng / kg. However, variations will occur depending on the animal species being treated and its individual response to said drug, as well as the type of pharmaceutical formulation chosen and the period of time and interval at which said medication is carried out. ? n? strac? on. In some cases, dosage levels lower than the lower limit will be more suitable, while in other cases even higher doses may be employed without causing any harmful side effects, provided such higher doses are first divided into several lower doses for administration to along «Jel day. The combination of active agents used in the synergistic procedure The combination of this invention can also be used for the treatment of emesis in further combination with a 5HT3 receptor antagonist (eg ordansetron, granisetron or tropiset on) " NK-1 receptor antagonist and the other active ingredients that are employed in the synergistic combination method of this invention will be referred to as "therapeutic agents" hereinafter. The therapeutic agents can be administered either orally or parenterally. These will usually be administered orally or parenterally daily in single or divided doses, so that the total amount of each active agent is within the above instructions. The therapeutic agents can be administered alone or in combination with pharmaceutically acceptable carriers or diluents by any of the routes indicated above, and such administration can be carried out in single or divided doses. More particularly, the therapeutic agents of this invention can be administered in a wide range of different dosage forms, that is, they can be combined with various inert pharmaceutically acceptable carriers in the form of "tablets", capsules, tablets. , tablets to dissolve in the mouth, hard candies, aqueous suspensions, injectable solutions, elixirs, syrups and the like. Such carriers include diluents or solid fillers, sterile aqueous media and various non-toxic organic solvents, etc. On the other hand, oral pharmaceutical compositions can be sweetened and / or flavored appropriately. In general, the therapeutic compounds of this invention, when administered in a targeted manner (ie, not in the same pharmaceutical composition) are present in said dosage forms at concentration levels ranging from about 5, 0% to about 70% by weight. For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine, together with various disintegrants such as starch, can be used. preferably, corn starch, potato or tapioca), algimco acid and certain complex silicates, together with granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and rubber ar giga. In addition, they are often very useful for the preparation of lubricating agent tablets such as magnesium stearate, sodium lauryl sulfate and talc. Solvent compositions of a similar type can also be used as fillers in gelatin capsules; Preferred materials in this regard also include lactose or milk sugar, as well as high molecular weight polyethylene glycols. When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring materials or dyes and, if desired, also emulsifying and / or suspending agents, together with diluents. such as water, ethanol, propylene glycol, glycepine and various combinations thereof. For parenteral administration, solutions of a compound of the present invention in sesame or peanut oil or in aqueous propylene glycol can be employed. The aqueous solutions will be suitably buffered if necessary and the liquid diluent will become isotonic initially. These aqueous solutions are "Jeweled for the purposes of intravenous injection. Oily solutions are suitable for the purposes of intraarticular, intramuscular and subcutaneous injection. The preparation of all these solutions under sterile conditions is easily carried out by conventional pharmaceutical techniques well known to those skilled in the art. The activity of certain compounds of the present invention, or receptor antagonists, of substance P, can be determined by its ability to inhibit the binding of substance P at its receptor sites in cells of bovine caudate tissue, using radioactive ligands to visualize the tachykinin receptor by means of autoradiography. The antagonizing activity of substance P of the compounds described herein can be analyzed using the conventional assay method described by M. 0. Casciep et al., As described in Journal of Biological Chemistry, Vol. 258, page 5158 (1983 ). This method essentially involves determining the individual compound concentration required to reduce to 50% the amount of substance P ligands radioactively labeled at their receptor sites in said isolated bovine tissues, thereby providing the characteristic IC 50 values for each compound rehearsed In this procedure, the bovine tissue is removed from a freezer at -70 ° C and is ovenified at 50 volts (w / v) from a Tris tapon (ie, trimetamma which is 2-arn? no-2-hydroxymethyl, 3-pro? anodol) ice-cooled hydrochloride 50 rnlvl having a pH of 7.7. The fertilizer is centrifuged at 30,000 x G for a period of 20 minutes. The sediment is resuspended in 50 volumes of Tr s buffer, homogenized and centrifuged again at 30,000 x G for another 20 minute period. The pellet is then resuspended in 40 volumes of ice-cold 50 mM Tris buffer (|) H 7.7) containing 2 mM calcium chloride, 2 mM Magnesium chloride, 4 jjg / ml bacitracin, 4 μg / ml of leupeptma, 2 μg of quirnostatma and 200 μg / ml of bovine serum albumin. This stage completes the production of the fabric preparation. The process for binding to a radioactive compound is then carried out in the following manner, namely by initiating the reaction by adding 100 μl of the compound to the assay carried to a concentration of 1 μM, followed by the addition of 100 μl of radioactive ligand brought to a final concentration of 0.5 mM and finally by the addition of 800 μl of the tissue preparation produced as described above. The final volume is therefore 1.0 ml and the reaction mixture is then stirred and incubated at room temperature (about 20 ° O for a period of 20 minutes.) The tubes are then filtered using a collector. and the glass fiber filters (Uhatrnan GF / B) are washed four times with 50 mM of tarnpon Tris (pH 7.7), the filters having previously been soaked for a period of two hours before the "filtered" process. The radioactivity is then determined in a Beta counter with a count efficiency of 53%, and IC50 values are calculated using conventional statistical procedures.
Claims (10)
1. The use of an NK-1 receptor antagonist in combination with one or more different active idients selected from (a) a glucocorticoid or corticoid, (b) a benzodiacephem, (c) rnetacloprarnide and (d) a molecular-debugger- intracellular, in the preparation of compositions for treating or alleviating emesis in a mammal.
2. The use of an NK-1 receptor antagonist, according to claim 1, characterized in that it is used in combination with a benzodiacephem, a glucocorticoid or corticosteroid, rnetaolopramide and a molecular debugger i nt r'aeel ular.
3. A proceeding according to the claim 1, wherein there are four active idients in the combination and such active idients are an NK-1 receptor antagonist and three additional active idients selected from (a) a glycocorticoid or corticosteroid gone, (b) a benzodiazepine, (c) ) metaelopra ida and (d) an intracellular molecular debugger.
4. A method according to claim 1, in the < There are three active idients in the combination and such active idients are an NK-1 receptor antagonist and two active idients added to them selected from (a) a glucocorticoid or corticosteroid i, (b) a benzodiacephem, (c) metaclopramide and (d) a molecular-molecular debugger.
5. A method according to claim 1, wherein there are two active idients in the combination and such active idients are an NK-1 receptor antagonist and an additional active idient selected from re (a) a glucocorticoid or corticosteroid, ( b) a benzo «Jiacepina, (c) rnetaeloprarnide and (d) a molecular-molecular-tracer.
6. A method according to the claim 1, in which none of the two active idients that are not NK-1 receptor antagonists in the combination belong to the same category as the following categories (a) to (d): (a) a glucocorticoid or corticosteroid, ( b) a benzodiacepham, (c) rnetaclopramide and (d) an intracellular molecular debugger.
7. A method according to claim 1, in the < One of the active idients in the combination is a benzodiazepine selected from lorazepa, edazepam, aiprazolain, ternazepam, quazepam, triazolam, flunit razepam, chlordiazepoxide, chlordiazepoxide hydrochloride, dipotasic clorazepate, diazepam, flurazeparn, halazepa, oxazeam and prazeparn.
8. A procedure in accordance with the claim 1, in which one of the active idients in the combination is a glucocorticoid or corticosteroid selected from dexarnethasone, tnarncinolone, betarnetasone, cortisone, ethylprednisolone and hydrocortisone.
9. A method according to claim 1, in which one of the active idients in the combination is a molecular molecule selected from acetyl chloride, vitamin D, vitamin E, selenium and retinoids (eg. , acid 13-c? s-ret? no? co ei sotretmom).
10. A procedure of agreement with the claim 1, wherein the NK-1 receptor antagonist ad? N? N? Stra «Jo said mammal is selected entr-e: (2S, 3S) -3- [2-metho? -5- (2-t lazolyl) benzyl 3 amin-2-phenyl im pennyl; (25.3S) -3 ~ [5- (2-?? n? Dazol? L) -2-methox? Benc l3arn? No-2-f-enylpyridom; (25,35) -3- [2-? Ne ox? -5- (2-oxopyrrolidinyl) benzyl an? No-7-phenolipidin; (25,35) -3- [2-rneto? -5- (4-rnet? 1-2-t? Zol il) benc? L -arn? No-2-phenylpyribine; (25, 35) - 3 - [2-met oxy-5 - (1, 2, 3-t-lazol-11) benzyl-1-ino-2-phen? L? -er -? «J na; (25, 35) - (6-methox? -2-rnet? L-hennot? Azole-5-ylmethyl) (2-f in 11 p i pe n < 1? N-3 - 11) an i na; (25.35) - [5- (7,5-d? Rnet? L -? Rrol-l-? I) -2-m tox? bencí 13 - (2 - f em 1 p i pe r i d i n- 3 - 11) am i n; (25-35) -3- [2-methox? -5- (5-oxazole? L) benz? 3am? No-2-f em 1 p i pe r-i d i na; (25, 35) - (6-? Netox? -2-rnet? L ~ benzoxazol-5-lrnethyl) - (2-f em 1 - p i pe n di n - 3 - 11) ami n; (15R, 25R, 3SR, 4SR) - 3- [6-rnetox? -3-met? Lbenc? Soxazol -5-? L met? lam? no-2-benzh? dr? zanorbornane; (25,35) -N- (2-? Netox? -5-methylsulfonylfeml) -? Net? L-2-d? Phen? L? Netii-l-azab? C? Clo [2.2.23 octan-3- am? na; (25,35) -N- (2-? Netox? - 5- < J? Rnet? Larn? Nofen? L) met i] ~ 2 -d? Femlmet? L-1 -azab? C? Clo [2.2 .23octan-3 ~ arn? Na; and (25, 35) -N- (5-tpfluoroacet? iam? no-2-?? netox? f? rul) met? l-2 ~ d? fen? lmet i -l-azab? c? clo [2.2.2 octan-3-arn? na; (25,35) -3- (5-terc-but.?l-2- methoxybenz? 1) am.?no-2-3-t rifluoromethoxy fem 1) pipen dina; (25, 35) -3- (2-? Sopro? Ox? - 5-t rifluorornotoxy benzyl) am? No-2-feml -pipen di na; (25.3S) -3- (2-ethoxy -5- 1 pf 1 uo onetoxi ene L1) arn? No-2-phenyl-pi endin; (25, 35) -3- (2-? Netox? ~ 5-t pfl uorornetoxy benn 1) arnmo-2-phenylpyripine; (25, 35) - 3 - (- 5 - 1 e r c - b ut 11 - 2 - 1 r i f 1 uor rorne t i x i be n c 11) arn? No-2 phenyl pepdina; 2- (diflumethylmethyl) -N- (2-rnetox? 5- tp t luoro et oxy phenyl) rnet? L-l-azab? C? Clo [2.2.23 octan-3-arn? Na; (25, 3S) -3- [5-chloro-2- (2, 2, -t rif luoroethoxy) benzyl ammo-2-phenylpipepine; (2S, S5) -3- (5-tert-butyl-2-tpfluoromethoxybenzyl) ammo-2-phenylpiperidine; (25,35) -3- (2-? Sopropox? -5-tpfluoromethoxy? Benc? L) arn? No-2-femlpiperuJina; (2S, 35) - 3- (2-d? Fluorometox? -5-tp luorornetox ibencil ) -arn? no-2-fen? l ?? per? d? na; (2S, 35) -2-feml-3- 2- (2, 2, 2-tnf 1 uoroethoxybenzyl 1) -aminopipepdine; and (2S, 35) -2-phenol-3- (2-tpfluoromethoxybenzyl) 3 aminopiperidma; c? s-3- (2-chlorobenzylamine) -2-phen? lp? er-? di na; c? s-3- (2-tr? fluorornet? lbenc? lam? no) ~ 2-f em 1 p i pe p d i na; c? s-3- (2-methox? benc? larn? no) -2- (2-fl uorophenyl) pi pendin; ci s-3- (2-methoxy? benzylamino) -2- (2-chlorophen? l) pipen di na; c? s-3- (2-methoxybenzylamino) -2- (2-methylphenyl) pipen di na; c? s-3- (2-methox? benc? lam? no) -2- (3-rnetoxy phenyl) pipepd na; c? e-3- (2-rnetox? benc? larn? no) -2- (3-f luor-ofeml) piμepdine; c? s-3- (2-rnetoxy? benzylamino) -2- (3-chloro phenyl) μ pe -i dine; c? s-3- (2-methoxybenzylamino) -2-phenylpiperidine; c? s-3- (2-rnetox? benc? lam? no) -2- (3-et ilphenyl) piperidm; c? s-3- (2-methox? benc? larnino) -2- (4? fluorophen?) piperidma; c? s-3- (2-methox? benc? larn? no) -2- (3-t? in? l) p? per'i «J? na; cis -3- (2-methoxy? benzylamine) -2- phenylazacycloheptane; 3- (2-rnetox? Benc? Larn? No) -4-met? L-2-phen? Lp? Pend? Na; 3- (2-met oxybenzylamine) - 5-met? 1-2- enylpiperi dina; 3- (2-? Netox? Benc? Lar? No) -6-rne? -2- fen? L? Pe -? ? na (2S, 3S) -3- (2-rnetox? Benc? Larn? No) -2-fen? L ?? per-? dyne; (25,35) -l- (5-carboethoxy? Pent-l-? L) -3- (2-methox? Benc? L -arnmo) -2- femlp per-i dina; (25,35) -l- (6-hydrox? -hex-l-? L) -3- (2-rnetox? Benc? L arrimo) -2-phenylpipepd a; (25,35) -l- (4-h? Dro? -4-phen? Lbut-l-? L) -3- (2-me «ox? -benzylam) -2-phen? L ??? er? d? na (25,35) -l- (4-oxo-4-phen lbut-1-yl) -3- (2-rnetoxy benzyl • ami no) -2- f em 1 ?? pe pd i na; (25.35) ~ l- (5,6-d? H? Drox? HeX "l-? L) -3- (2-? Netox? Enc? L amino) -2-fen lpiperi dina; c? S -3 ~ (5- fluoro-2-methox? Benc? Larn? No) -2 -f in 11 pi na n di na; (25.35) -1- [4- (4-fluorofeml) - 4 ~ oxobut - l-113 -3- (2-methox? benc? lammo) -2-femlpipepdine; (25,35) -1- [4- (- fluorofe 1) - -h? rox? but-1 -i 13 3- (2-? Netox? Benc? Larn? No) -2-feml ?? per? D? na cis- 3- (2-rnetox? -5-? net ilbenei lamino) -2-feml pipen di na; (25.35 > ~ l- (4-benzarn? Dobut-l-? L) -3- (2-methobenzyl-amino) -2-phen? Lp? Pepdma; c? S-3 ~ (2-rnetox? Naft-l-? L-met? Larn? No) -2 -fn 11 pi pe pdi na; (25, 3S) -3- (2-methox? Benc? Larn? No) -l - (5-N-rnet? L-carboxam? Dopent-1-? L) -2- phenylpiperidy; (25,35) ~ l- (4 ~ c? Anobut- 1 -? L) -3- (2 - rnetoxi bencí lami o) -2- fenilpí pendí na; (2S, 35) -l- [4- (2-naftarn? «Jo) but- 1-113-3- (2 ~ rne ox? -bencilarnino) -2 - phenyl penicillin (25,35) -1- (5-benzardn? dopent-i -yl) -3- (2-rnet oxibe cil-ami no) - 2 - f in 11 pi pe ndi na; (25, 35) ~ 1- (5-arn? Nopent-1-yl) -3- (2-nitroxybenzyl) no-2-pi.-dine piper (25.35) -3- (5-chloro-2-? nt oxib ncí Lamino) -2 -fen 11 piperidine; (25,35) -3- (2, 5-d? rnetox? benc? Lamino) -2 phenylpí pendí na; e? s-3 - (3, 5- d? f luoro-2-? netox? benc? lamino) 2-phenylpipendine; c? s-3 ~ (4, 5-d? f luoro-2-? netox? benc? l mino) - 2-phenylpi peri dina; c? s-3- (2,5-d? me or? benc? lamino) -l- [i - (4- fl uoro feml) 4-oxobut-l-? L] -2-phenyl ipep ma; cis-3- (5-chloro-2-methoxybenzylamine) -1- (5,6-d? h? drox? hex-1-? l) -2-phen? lp? pepdma; c? sl- (5,6-d? h? drox? hex-l-? l) ~ 3- (2,5-d? meto? -benc? larn? no > -2-femlp? pepdma; c? s-2-phen? l-3- [2- (pr-o? -2-? lox?) benc? lam? no3 pi pendin; cs-3- hydrochloride (2, 5-d) ? methox? benc?) ammo-2- (3-rnetox? -fen? l) pipendine; c? s-3- (5-chloro-2-rnetoxybenzyl) arn? no-2- (3-rnetoxy) dihydrochloride phenyl) pipepdina; d? clorh? dratodec? s-3- (5-chloro-2-meto? benc? l) m? no-2 - (3-chloro-phen? l) pipen dina; 3- (2 -rnetox? bencí lamí no) -2, 4-d? fe l ??? ep dina; c? s-3- (2-methox? benc? lam? no) -2-fer lpyrrolidma; (25,35) -3- (5-et? L-2-rnetox? Benc? Ll mi o- 2 -teni pipen dine; (25, 35) -3- (5-n-but? L-2-rnetox? Bene 1 ) ammono-2-phenylpipe di (25, 3S) -3- (2-rnetox? -5-n-prop? lbenc? 1) am? no-2-phe-pipen dine; , 35) -3- (5-? Sopr-op? 1 -2-rnet oxybenzyl) a? N? No-7-p-enyl pipen dina; (25,35) -3- (5-s-but? L -2-methox? Benc? L) arn? No-2-phenyl pipen dina; (25,35) -3- (5-t-but? 1-2-rnetox? Benz 1) arn? No-2 f in 11 pi pe ridi na; (25, 3S) -3- (2-rnetox? -5-femlbenc? L) am? No-2-fe n 11 p i pe r i «J i na; (2s, 35) -N- (5 ~? Soprop? L-2-methox? Phen? 1) rnet? 1-2-d? Phen? Lnet? L-l-azab? C? Cl [2 .2.23 octan-3-am? Na; (2S, 35) -N- (5-tert-butyl-2-rnetox? Phen?) Rnet? 1-2 d? Phen? Lmet? I-azab? C? Clo [2.2.23 octan-3-amine; (25,35) -N- (5-met? L-2-methox? Feml) met? L ~ 2-di phenylrneti l-l-azab? C? Clo [2.2.23octan-3-amine; (25, 35) -N- (5-et? L-2 ~ methox? Phen?) Rnet? 1-2 diphenylmethyl-1-azabicyclo [2 .2.23 octan-3-arnine; (25,35) -N- (5-? Soprop? L-2-rnetox? Phen? L) rnet? L-2-diphenylmethi-i-azabicyclo? 2 .2 23 octan-3 ~ arn? na (25.35 > -N- (5-sec-but? L-2-methox? Phen?) Rnet? I-2-di-phenyl-1-azabylcyclo [2.2.23 octan-3-arnma; and (25,35) -N- (5-n-prop? l-2-methox? phen? l) rnet? i-2-di phen? lmet? li-azab? c? clo [2.2.23 octan- 3 ~ a? N? Na; [4-rnetox? -3- ((25,35) -2-phen? 1 pj? Er? Dm-3- 11 -aminorneti 1) phen? 3-methylarnide of acid 2, 4-dimethylol-5-sulphonic acid; N- (4,5-d? Rnet? Lt? Azole-2? L) -N- [4-methox? -3- ((25.35) ) -? • femlpí pep «1? N-3-? Lam? Nomet il) fen? L3 -metanosul fonami da; { 5 [(4, 5-d? Rnet? Lt? Azol-2-? L) methamphenol-2-nitroxylbenzyl} - ((2S, 35) -2-phenolyl-3-ene-3-yl) amine; 4,5-d? Rnet? Lt? Azol -2-? L-arnmo) -2-rnetox? Benc? L] - ((25,35) -2 f epil? R? -3 ~? L; rnet? l- [3- ((25,35) -2-phen? l? per? d? n-3-? larn? nomet il) 4-t ri fluorometox? fen? l -arn? 4,5-d? rnet? lt? azol -2-sulphonic acid; [4 ~? sopropo? -3- ((2S, 3S) -2-phenylepipepd? n-3-aminomethyl). of 2,4-d? met? lt? aolol ~ 5-sulphonic acid; [4-? so? ropox? -3- ((25,35) -2-phen? lp? pe r? d? n ~ 3-ilarninornetii) fen? l3-? soprop? lam? of 2, 4-d? met? i thiazol-5-phonic sulphonic acid; [4-rne tox? -3 - ((2S, 35) -2- f em 1 pi pep di n- 3 -larninometii) phen? L3-? So? Rop? Lar? N of the acid 2,4-d? met? it? azol-5-sulphonic; [4-rnetox? -3- ((25, 3S) -2-phen? Ipipendi n-3-amlammornethyl) pheni-1-diisobutyia 2, 4-d? Met? Lt? Azol-5-sulphonic acid; [4 ~? So? Ropox? -3- ((2S, 3S) -2- phenylpiperid -3-i the inornetyl) pheni 13-? Sobutyl lamide of 2,4-d? Et? Lt lazole -sulphonic acid; (3R, 5, 55, 65) -N, N-dieL 11-5- (5 ~? Op op? L-2-? Net? Benei l mino) -6 -di fe lmet? L ~ l -azabi cycle [2.2.23 octane-3-carboxarni a; (SR, 45.55.65) -N, Nd? Et? L ~ 5- (2,5-d? Methox? Benc? La? Pno) -6-d? Fem 1 rnet? L-1-azab C ict [2.2.23 octane-3-carbox id; Acid (3R, 4S, 5S, 6S) -5- (5-? o? ro? 1- 2-methoxybenzylamine) -6-d? fe lmet? l-1-azab? c? clo [2.2 .23 octane-3-carboxylic acid; Aci «Jo (3R, 4S, 5S, 6S) -5- (2-inetox? -2- metí ítiobencí lamí no) -6-d? phen? lrnet? i -? - aza? c? clo [2.2.23 octane-3-carboxylic; 3R, 45, 5S, 65) -5- (2,5-d? methox? benc? lam? no) -6 ~ di phen? l-meth? azab? c? clo- [2.2.23 octane] - 3 -carbo Ilic; (3R, 45,55,65) -5 ~ (2-rnetox? -5-met? lbenc? lammo) -6? d? phen? lme? ll-azab? c? clo [2.2.23 octane- 3 -Ilbox; acid (3R, 45, 55, 65) -5- (5-et? l-2-rnetoxy? benzylamino) -6-diffene eti 1-l-azab? c? clo [2.2.23 octane -3-car -Il-box; acid (3R, 45,55,65) -5- (2-rnetoxil-5-n-prop? lbenc? larn? no) -6-d? fe lrnet ll ~ azab? c? clo [2.2. 23 octane-3-carboxylic acid; acid «Jo (3R, 45, 5555.65) -5- (5-sec-butyl-2-rnetoxy benzylimide) -6-d? femlmet? l-l-azab? cycle [2.2.23 octane-3-carboyl; Acid (3R, 4S, 5S, 65) -5- (5-N-rnet? l-rnetanosul fon i lamino - 2-rnetox? - enc? lammo) -6-d? fem linet 1-1-azab? cycle [2.2.23 oct no 3 -carboxylic; aci do (3R, 45, 55, 65) -5- (2-methox? -5-rnet? Isul finyl benzyl-ammo) -6-d? phen? lmet? li-azab? c? clo [7.2. 23 octane-3-carboxylyl; ae? or (3R, 45.55.6S) -5- (-met or 1-5-t-rifluorOrnetoxybenzyl-arnino) -6-d? phenylmethyl-1-azabicyclic or [2.2.23 octane-3-carboxylic acid; acid (3R, 45, 55, 65) - 5- (2-rnetox? -5-metilol or l enc il -am? no) -5-d? phen? lrnet? l-l ~ a ab? c? clo [2.2.2.3 octane-3-carboxyl i eo; Acid (3R, 4S, 5S, 65) -5- (5-dimet? lam? no-2-methoxybenzylamine) -6-d? femlrnet? 1-1 -azabí cycle [2.2.2.3 octono-3-carbox? L? Co; Acid (3R, 4S, 55.65) -5- (5-? soprop? l-2-methox? benc? lammo) -6-d? phen? met? ll-azab? c? clo [2.2. 2.3 octane-2-carboxylic acid; ac? «Jo (3R, 45.5S, 65) -5- (2-methox? -5-methylthiobenzylamino) -6-d? phen? lmet? -1-azab? cycle [2.2.23 octane - 2- car-box i lico; (3R, 4S, 55, 65) -5- (2, 5-d? rnetox becilarnmo) -6-difenmlrnet 1-1-azab? cycle [2.2.23 octane-2-carboxylic acid; acid (3R, 45, 55, 65) - 5- (2-rnetoxy-5-rnet-yl-benzyl-amino) -6-d-fe-lmet-l-1-azab-cyclo [2.2.23 octane-2-carbo] íl ico; Acid (3R, 45.5S, 65) -5- (5 ~ et? l-2-rnetoxy encylamide) -6-d? phen? lmethyl-l-azab? c? clo [2.2.23 octane -2-carbox 1 i co; Acid (SR, 4S, 5S, 6S) -5- (2-ethoxy-l-5-5-n-propylbenzylamino) -6-d? and lrnet? ll-azab? c? clo [2.2.2.3 octane-2-carboxylic acid: (3R, 4S, 5S, 6S) ~ 5- (5-sec-but i 1-2-methox ? benzyl? no) -6-d? femlrnet? li -zabicyclo [2.2.23 octane-2-carboxylic acid; (3R, 45, 55, 65) -5- (5-N-methylrnetanosul foni lamí no-2 - methox? benc? l-am? no) - 5- l? fe lme? i -l-azab? cycle [2.2.21 oethane-2-car-box 1 ico; (3R, 45,55,65) - 5- (2-rnetox? -5-rnet-il-1-benzyl-1 -ammo) -6-d-femmethyl-ii-azab? C? Clo [2.2.23? ~ 2- carboyl, acid (3R, 4S, 55,65) -5- (2-rnetox? ~ 5-t -ifluoro-ethoxybenzyl-ano) -6-d? Fe lmet? Ll ~ azab? C? clo [2.2.23 octane-2-carboxylic acid] (3R, 4S, 5S, 6S) -5- (2 ~ rneto-5-rnet? lsulfomlbenc? l ~ arn? no) -6-d ? femlmet? 1-1-azab? c? clo [2.2.23 octane-2-carboxylic acid: acid (3R, 4S, 55.65) -5- (5-d? rnet? lam? no-2- rnetoxibencila ino) -6-d? fem lmet? l-1-azab? c? clo [2.2.23 octane-2-carboxylic; (3R, 45.55,65) ~ N-carbamo? lmet? l-5 - (5-? Soprop 1 -2-methoxybenzylamino) -6-d? Phen lmet? L-azab? Cycle [2.2.23 octane -3-carbo amide; (3 R, 45.55, 6 5) -N-carboxymethyl-5- (5-? -propy-l-2-nitroxybenzylamino) -6-d? Phen-lrnet 1-1-azab? C? Clo [2.2.23 octane-3-carboxamide; (3R, 45.55.65) -3- (2-C-rbarno-1-pyrrolidyl-1-yl) carbonyl-5- (5'-soprop? 1-2-methox? Benc? Lam? No) - 6-diphenylmethyl 1-azab? C? Clo [2.2.23 octane; (3R *, 4S *, 55 *, 65 *) -N- (1 -carbarnoilet 11) -5- (5-? Sopro? L-2-methox? Benc? Larn? No) -6-d? Fe lmet? i -1-azab? c? clo [2.2.23 octane-3-carboxarnide; (3R, 4S, 5S, 6S) -N ~ (1-car'bamoi 1-3-rnet i lbut i 1) -5- (5-isopropyl 1-2-rnetox? Benc? Lami) -6 - « Jifenilmetil -l ~ azab? cycle [2 .2.23 octane-3-carboxarnide; (3R, 45,55,65) -N- (2 ~ carbarno? Let? L) -5- (5-? SoprOp? 1-2- rnetoxibencilammo) -6-d? Femlrnet? Li-azab? C? C o [2.2.23 octane-3 -carbox ami a, - (25,35) -N- (5-? so? ropen? l-2-rnetox? feml) rneta 1 -2-d? fen? lmet? il-azab? c? cl [2.7.23 octan-3-amma; (2S, 3S) -N- (2-rnetox? -5 ~ v? N? Lfeml) rnet? L -2-d? Phen? Lmet? I-1-azab? C? Clo [2.2.23 octan-3 -am? na; (25,35) -N- (2-rnetox? -4,5-d? Met? Lfen? L) rnet? L -2-d? Phen? Lmet? Il-azab? C? Clo [2.2.23 octan -3-am? Na; (2S, 35) -N- (5,6,7,8-te rah? Dro-3-rnetox? -2-naft? I) rnet? L-2- d? Phen? Lrnet? L-1-azab ? c? clo [2.2.23 octan-3-arn? na; (2S, 3S) -N- (5-methoxy? Jan-6-? L) met 1-6-d? Fe lmet? L-l-azabicyclo [2.2.23 octan-3-amine; (25,35) -3- (2,4-d? Methox? -5-et? Lbenc? Larnmo) -2-d? Fe lrnet? L-1-azab? C? Clo [2.2.2.3 octane; (25,35) -2- d? Phen? Lrnet? LN ~ [2 ~ methox? -5- (diethyl phosphoyl) phen? L3-met 11-l-azab? C? Clo [2.2.23 octan-3- arní na; (3R, 4S, 55.6S) -5- (5-? Sopropeml-2-rnetox? Boncil • arnino) -6-d? Phen? Lrnet 1-i-azab? C? Clo [2.2.23 octane-3 -car box gone; (3R, 45, 55, 65) -6 -di fen? Lrnet? I-5- (2-rnetox? ~ 5-rnetisulphomethyl-benzylamino) -1-azab? C? Elo [2.2.23 octane-Sea r ox gone; (3R, 45,55,65) -5- [5- (N-acet? LN-met? Lam? No) -2-methox? Benc? Larn? No3 -6-d? Phen? Lrnet? Ll-azab ? cycle [2.2.23 octane-3-carboxy ida; (3R, 45.5S, 65) ~ 6-d? Phen? L? Netil-5- [2-methox? -5- (N-metLl-N ~ rnet? Isulfon? Lamino) benzyl lar 3-l-azab ? cycle [2.2.23 octane-3-carboxamide; Acid (3R, 45.5S, 65) -6-d? phen? lnet? l-5- (2-methox? -5-met? l-sulfomlbenc? lam? no) -l-azab? c? clo [2.2.23 octane-3-carboxylic; (2S, 35) -N- [5- (1-hydrox? -l-rnet? Let? L) -2-methox? -fen? L rnet? L-2-d? Phen? Lmet? Ll-azab? c? clo [2.2.23 octan -3-amine; (25,35) -N- [2-? Netox? ~ 5- (1-methox? -l-? Net ilet íl) feml3? Net? L-2-d? Femlmet? L-l-azab? C? [2.2.23 octan-3-a? n? na acid (3R, 4S, 5S, 6S) -3- [5- (lh? drox? -l ~ met? iet? i) -2-rnetoxifeni 13 metí lamí no- 6 -difemlrnetil-lazabicyclo [2.2.23 octan- 5-carboxyl; (25,35) -2-d? Phen? L? Net? LN- [5- (1-hydroxy? -1- hydroxyethyl ethyl) -2-methox? Feml3rnet? Ll-azab? C? Clo [2.2.23 octan-3-amine; acid (3R, 5, 5,65) -3- [5- (1-rnetox? -l-rnet? let? l) »2-? netox? phen? l3rnet? lam? no-6-d? femlmet? ll-azab? c? cl [2 .2 23 octan-5-c rbox? li co; (3R, 45,55,65) -3-C5- (1-h? drox? -l-methylethyl) -2 -rnetox? phen? 3 metiiapuno-6-diphenylrnet i- i - azabicielo [2.2.23] octan-5-carbo 1 ico; acid (3R, 4S, 5S, 65) -3- [5- (l-et? lt? o-1-? net? let? l) -7-rnetox? feml3met? iam? no-6- < J? erulmet? l-l-d? ab? c? clo [2.2.23 octan- 5 -carboxy 1 ico; (35.4R, 55.55) -N-carbamo? Lmet i 1 -6-di fen i lrnet 1 - (3, 5- bis (tpfluoropiiethyl) benzyloxy) -1-azab? cycle [2.2.2 octane-3-c rboxarm da; (3S, 4R, 5S, 6S) -6-d? Femlp? Et? L-5- (3,5-b? S (tpfluorometii) -benzyloxy) -1-azab? C? Clo [2.2.23 octane- 3-carboxarnide; (3S, 4R, 5S, 65) -N, N- (3-oxa-l, 5-pen? Len) -6-d? Phenylmethyl-5- (3,5-b? S (tnfluorornet? L) benz ? lox?) -1-azabí cycle [2.2.23 octane-3-carboxy ida; acid (35.4R, 5S, fiS) -6- «1? feni lrnet i 1 -5- (3,5-dirnethylbenzyloxy) -1-azab? c? clo [2.2.23 octane-3-carboxylic acid; (3?, 4R, 5S, 6S) -N, N-d? Et? L -6-d? fen? lrne il-5- (3,5-bisítrif luoromethyl) bencí loxi) - 1-azab? cycle [2.2.23 oct no-3-carboxamide; acid (35, < ÍR, 5S, 6S) ~ 6- «J? phen? lmet 11-5- (3-f luor-o-5-tpfluoromethylbenzyloxy) -l-azab? c? clo [2.2.23 octane -3-earbox íl ico; acid (35, 4R, 55.65) -6-d? femlrnet? i ~ 5- (3,5-b? s (tnfluoro eti l) benzyloxy) -1-azab? cycle [2.2.23 octane-3-carboxylic; (35, 4R, 55, 65) -N, N-dimet? L-6-d? en-lmet? l-5- (3,5-b? s (tp fluoromethydebenzyloxy) -1-azab? c? clo [2.2.23 octane-3-earboxarnide; (2S?, 35 *, 45 *, 5R *) -4-earbox? -3- [N ~ (5-? So? Rop? L -2-methoxybenzyl) am? -5-met? 1 -2- fen 11 pi r ol id; (25 *, 35 * , 55 *) -5-carboxy? -3 - [N ~ (-? Netox? -5-tpf luoro-ethoxy-benzyl) amino-3-p-yl-piperapdine; (25, 35) -3- (6-methoxy-1-methyl-2-oxo-1, 2,3,4-tetrahydroquinol-7-yl) rnetyl-2-phenylpiperidin-3-arn.ina; (2?, 3?) -2-phenyl-N- [5- [2,2,2-trifluoro-l-tri fluoromethyl) et.yl-3-oxo-benzyl-3-piperidin-3-amino; (25, 35) -2-diphenyl-phenyl-N-2-rnetoxy. - 5 - (ritylsulfonyl) benzyl 3 -1-azabicyclo [2.2.23 octan-3-amine; (2S, 35) -2-difenilrnet.il-N- (5-isopro-enyl-2-methoxybenzyl) -1-azab.cycle [2.2.23 octan-3-arnin; and (2S, BS) -2-diphenylmethyl-N- [5 - (l-hydroxy-l-rnetiiet.-yl) -2-rnetoxybenzyl-3-azabicyclo [2.2.23 octan-3-arnin.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US572895P | 1995-10-20 | 1995-10-20 | |
| US005728 | 1995-10-20 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| MX9605030A MX9605030A (en) | 1997-09-30 |
| MXPA96005030A true MXPA96005030A (en) | 1998-07-03 |
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