CA2100163A1 - N-alkyl quinuclidinium salts - Google Patents
N-alkyl quinuclidinium saltsInfo
- Publication number
- CA2100163A1 CA2100163A1 CA002100163A CA2100163A CA2100163A1 CA 2100163 A1 CA2100163 A1 CA 2100163A1 CA 002100163 A CA002100163 A CA 002100163A CA 2100163 A CA2100163 A CA 2100163A CA 2100163 A1 CA2100163 A1 CA 2100163A1
- Authority
- CA
- Canada
- Prior art keywords
- compound
- alkyl
- formula
- pharmaceutically acceptable
- substance
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The present invention relates to novel N-alkyl quinuclidinium salts, pharmaceutical compositions comprising such compounds and the use of such compounds in the treatment and prevention inflammatory and gastrointestinal disorders, as well as several other disorders. The N-alkyl quinuclidinium salts of this invention have formula (I), wherein R1, R2, and X- are as defined below.
Description
~vo 92/121~1 2 i ~ O ~ g ~ PCT/~S91tO8836 N-ALKYL QUINIJCLIDINIUM SALTS
AS SUBSTANC FP ANTA~ISTS
Back~und o~ the Invention The present invention relat~s to novel N-alkyl quinuolidinium szlts, phannaceutical compositions comprising such cornpounds and the usa of such compounds in the treatment and prevention inflammatory and gastrointestinal disordars, as well as several other disorders. The pharmaceutically active compounds of this invention are substance P antagonists.
Substance P is a naturally occurring undecapeptide belonging to the tachykinin farnily of peptides, the latter bsing named because of their prornpt stimulatory action on smooth muscle tissue. Mora speci~ically, substance P is a pharm~cologically active neùropeptide that is produced in mammals (having originally been isolated from gut) and possesses a characteristic amino acid sequence that is illus.rated by D F. \/~ r et al. in U.S. Patent No. 4,680,283. The wide involvement of substance P and other tachykinins in the pathophysiology o~ numerous ciiseases has been amply dernonstrated in the art. For instance, substanoe P has recently been shewn to be involved in the transmission of pain or migraine (soe B.E.B. S~ndberg ~ al., Joumal of Vledicin~! Chemist , 25, iO09 (1982)~, a~ well as in central neNous system disorders such as anxiety and schizophrenia, in respiratory and inflammatory diseases such as asthma and rheumatoid arthritis, respectively, in rheumatic diseases such as fibrosi~is, and in gastrointestinai disorders and diseases of the G! tract ~uchas ulcerative colitis and Crohn's disease, etc. (see D. Regoli in 'Trends in Cluster Headache,' edited by F.
Sicuteri et al., Elsevier Scientific Publishers, Amsterdam, pp. 85-95 (~ 987)).
Quinuclidine derivatives and relatl3d compounds that exhib-lt activity as substance P receptor antagonists are referr0d to in PCT Patent Application PCT~JS
89/05338, fileci November 20, 1989 and United States Patent Application Seriai No.
557,442, filed ~)uly 23, 1990, both of which are assi~ned in common with the present application. Similar compounds are referrsd to in the PCT pa~ent applications Pntitled '3-Amino-2-Aryl Quinucliciines~ and ~Quinuclidine Derivatives' and filed on April 25, 1991 and May 15, 1991, respectivoiy. These applications are aiso assigned in common wilh the present application.
~ ~ ~ Piperidine deriva~ives and related heterocyclic nitrogen containing compounds that are useful as substance P ~ntagonists are referred to in United Stales Patent Application Seriai No. 619,361, filed Novernber 28, 1990 and United States Patent .
wo 9~/121~ ? ~. 5 ~ PCT/US91/0~3836 ,~
Application Serial No. 590,423, filed S~ptambar 28, 1990, both of which are assigned in common with .ha pr~siall; applic~tion.
Summarv of the Invention The prasent inv~n,icn r312t~s to compounds of the forrnula rR2 `' 1~` (1) wherein R' is (Cl-C4)alkyl, allyl, phenyl-(CI-C~)alkyl, HOOC~ C~O)alkyl or (C1-t 15 C4)alkoxy-OOC-(Cl-ClO)alkyl; R2 is selected from the group consisting of phenyl, thienyl, furyi and pyridyl, each of the forogoin~ R2 groups being optionally substituted with ~rom one to thr0e substituants indepandently sele~led trom tho group consisting ~ cyano, nltro, amino, N-mono-(C1-G3)alkylarnino, fluorine, chlorine, bromine, tr fluoromethyl, (C1-C3)ailkyl, (C1-C3~alkoxy, allyo~y, (Cl-C3)alkoxy~arbonyl, ~arboxr~nido and N,N~i-((~
C3)alkyl-carboxamido; and X is a pharmaceutically acceptable counterion, (e.g.
chloride, bromide, nuoride, iodide, mesylate, tosylats or trifluoromethanesulfonate).
Examples of pharrnaceutic~lly acceptable counterions are halides (e.g., tluoride, :1 chloride, bromide or iodide), (C1-t::3)alkyl-mono or di-carboxylates, mesylate, tosylate, arylcarboxylates, (Cl-C3)alkylsulfonates wherein the alkyl moiety may optionally be ¦ ~ ~ 25 substituted with one or more fluorine atoms, arylsulfonates, citrate, maleate, fumarate, lactata,~ malate, sulfates, phosphates, nitrates, tartrate, saccharate and pamoate.
Th~ term 'alkyl", as used herein, unless otherwise indicated, includes saturatedmonovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof.
; ~ Preferred- compounds of the forrnula I are those wherein R2 is 2-methoxyphenyl.
The prasant invention also ralates to a pharmaceutical composition 70r treating or preventing a conditi~n salected from the group consisting of inflarnmatory diseasas (e.g., arthntis, psoriasis, asthma and inflammatory bowel diseasa), colitis, pain, allergies , ~ .
1:~
~la~. & ~
- ,'0 92/121~ r/l.JS9~ 36 ., such as eczema and rhinitis, chronic obstructiv~ airways disease, hypersonsitivity disorders such as poi;.on i~l, vasospastic dissasas such as angina, migraine andRaynaud's disaasa, rloro~ing and coilay3n dis3~es such as sclaroderma and eosinophilic iascioliasis, n ~11 ex sym~i~hietic d~Jstrophy such as shouldsr/hand syndrorna, peripharal neuropalhy, disordars ralated to immune enhancernent or suppression such as systemic lupus erythsmatosus, and rhriumatic di~easQs such as fibrositis in amarnmal, includin5 a hurn2n, cornprising an amount oi ~ compound ot the formula 1, or a pharmaceui.,cally ac^3~ta;,la salt thsr30f, ~Xac~i~Je in trsating or preventing such condition, and a pharrnac3ut!cal!y acceptabl~i c~,er.
The prasent inYertion i~so r~!atss to ai msthod of trsating or preventing a condition sa'eo'3d l,om the SroU., _^ns'.s'inS 3~ ir.~.~r,mat3ry diseasas (e.g., arthritis, psoriasis, as~hrn~ _nci inilammatory oo~al ciisa~ ), colitis, pain, allerqies such 2s ~' eczerna anci rhinitis, chronic obstructive aint~ays dissass, hypersensitivrty disorders such as poison ivy, vasospastio disaases such as argina, migraine and Reynaud's disease, ^i5 fibrosin~ and collagen diseases such as solerodarrna and eosinophilic fascioiiasis, reflex syrnpathetic dystrophy such ~s shoulder/hand syndrome, peripharal neuropathy, di~orders related to immune ~nh~ncsment or suppression such as systamic lupus erythematosus, and rheum~tic diseases such as fibrositis in a mammal, including a human, comprising administ~ring to said mammal an amount of a compound of the formula 1, or a pharmac~uticaily acceptable salt theraof, effective in treating or ~ ~ pre~lenting such condition.
.; The present invention also relates to a pharrnaceutical composition ~or antagonizing the effects of substance P in a marnmal, including a human, comprising a substance P sntagonizing arnount of a compound of the forrnula 1, or a ~; 25 pharmaceuticaily acceptabl2 salt thareof, and a pharnacautic~Llly acceptable carrier.
The present invention aiso rel~tes to a method of antagonizin~ the effects of substance P in a marnmal, including a human, cornprising administerin~ to said mammal a substance P antagonizing amount cf a compound of the formula 1, or a pharmacautically acceptable satt thereof.
The presant invention also relates to a pharrnareuSical composition for troatingor prev~nting a disordar in a rnarnmal, inc!uding ~ human, r~su!ting from an ~xcPss of substanc~ P, comprising a .substarc~ P antagonizing ~rnount of a compound o~ the , ' , W0 ~/12~51 2 ~ 3 ~ PCl/US91/08836 ;
formula 1, or a pharmaceutically acceptable salt thersof, and a pharmac3uticall~J
acceptable carrisr.
The present invention also relates to a method of treating or preventing a disorder in a mammal, including a human, rssulting from an excess of substancQ P, 5 comprising administering to said mammal a substancP P antagonizlng ~mount of cornpound of the formula 1, or a pharmaceutically acceptable salt therso,.
The present invention also relates to a pharmaceutic~ composition ior tre2ting or preventing a condition selected from the ~roup consisting of inflarnmatonJ dise2s~s (e.g., arthritis, psoriasis, asthma and inflarnmatory bowel disaaseJ, coli~is, ~ain, ~IIQr~iss 10 such as eczPma and rhin~tis, chronic obs'ructiv~ air~;ays ~isaas~, h~e,s_ns,'.~
disorders such as poison ivy, vasospastic diseases ~uch as angina, ~Tli912iile ana Reynaud's disease, flbrosing and collagen diseases such as scleroderrna an~
eosinophilic~ascioliasis, reflex syrnpathetic dystrophy such as shoulder/hand syndrome, peripheral neuropathy, disorders related to immune enhancement or suppression such 15 as systemic lupus erythematosus, and rheumatic diseases such as fibrositis in a marnmal, including a hurnan, comprising an amount of a ccmpound of the formuia 1, or a pharmaceutically acceptable salt th~re~, effective in antagonizing the affect of substance P at its receptor site, and a phamlaceutically aceeptable ~urier.
The pr~sent invsnffon also relates to ~ method of tr~ating or preventing a 20 condition selected from the group consisting of inflammatory diseases (e.g., arthritis, psoriasis, asthma and inflammatory bowel disease), col~tis, pain, ~lergies such as cczsma and rhinitis, chronic obstn~ctive ai~ays di~ease, hypersensitivity disorders such as poison ivy, vasospastic disoases such as angina, mi~ræne and ~eynaud's disease, fibrosing and colla~en diseases such as scleroderrna and eosinophilic fascioliasis, 25 reflex sympathetic dystrophy sueh as shoulder/hand syndrome, peripheral n~3uropathy, disorders related to immune enhancernent or suppression such as systemic lupus erythematosus, and rheumE~tic diseases such as fibros-r~is in a marnmal, including a human, comprising administering to said mammai an amount of a compound of the ~ormuia 1, or a pharrnaeeutically acceptable sait thereof, ~ffective in antagonizing the 30 effect of substance P at its r~eptor site.
The present invention aiso relates to a phamlaceutica~ composrtion for treating or preventing a disorder in a mammai, including a human, the tr0atment or pre~/ention of which is effected or facilita~ad by a decrease in substance P medi2ted ;~vo 92/12151 2 ~ Q ~ PCr/VS91/~8836 nsurotransmission, comprising an anount of a compound of the fonnula 1, or a pharmaceutically acceptable sait thereof, eMective in antagonizing the effect ofsubstance P at rts receptor site, and a pharmaceutically acceptable carrier.
The present invention also rslates to a msthod of treating or preventing a 5 disord~r in rnammal, including a hurnan, the treatment or prevention of which is effected or facilitated by a decrease in ~ubstance P mediated neurotransmission, comprising administering to said mamma, an, arnount of a compound of the formula 1, or a pharmaceutic~lly acceptable sait ther~,of, ~ffeçtiv2 in antagonizing the e~ect of substanca P at its receptor site.
The present inv2ntion ~so rel~t~s to a pharmaceutical composition for tr3--~.in~or preventing a disorder in a mammal, including a humar, the traatment or pr~ nt!on of which is effected or facilitated by a decrease in substance P media~d neurotransmission, comprising an arnount of a compound of the formula 1, or a pharm,aceuticaily acceptable sa,t thHreof, effective in treating or preventing such 15 disorder, and a pharrnacsLti~aily accaptable carrier.
The present invention aiso relates to a method of treating or prsventing a disorder in mamrna-i, including a human, thetrsatment or prevention of which is ~ected, or facilitated by a d,ecrease In substance P mediated ne~rotrar,smission, oomprising administering to said mammai an arnount ~ a compound of the forrr,uia 1, or a 20 pharrnaceuUcally acceptable salt thereo~, effective in treating or preventing such disorder.
The compounds ot the forrula I have chiral centers and therefore exist in diff~,rent enantiomeric ~orms. This invention relates to all optical isomers and all stcreoisomers of compounds of the formula 1, and mixtures thereof.
The opti~ally active compounds of tormula I are addltiorlally useful as intermediate in the synthesis of the corresponding racemic mixtures and oppositeenantiomers.
Formula I above includes compounds identical to those depicted but for the fact that one or more hydrogen or carbon atorns are replaced by radioactive 30 isotopes thereof, (e.~., triUum, carbon-14 or nitrogQn-15 isotop~s thereof). Such radiolabelled compounds ~r~ useful as reisearch and diagnostic tools in metabolism pharrnacokinetic studies ard in binding assays. Specific applications in research incilude radioligand binding assays, autoradiography studies and In ViYo bindlng ," ~
.
:
WO~2~12i~ r3 ` r .J pcr!ussa/o~36 -;
studies, while specinc applications in thP diagnostic area include studies of the substanca P racaptor in humans in in vi~/o binding in the relevant tissues for inflamrnation, c.g. immune-~ype cells or cells that are directly involvad in inflamm~tory bowel disorders ar,d -ha 1i~3.
Detailsd D~scriDtion of the Invention Com~ounds of the formula I may ba prepared by reacting the corresponding compound of the formula r~2 ~-o ,0 ~ ( I I ) wherein R2 j5 defined as above, with a compound of the formula R'X, wherain Rl is defined as abo~e ~nd X is chloro, fluoro, bromo, iodo, tosyloxy, mesyloxy, or trifluoromethanesulfonyloxy. Tha reaction is genoraliy carried out in a pol~r solvent such as ethanol, acetone, dim~thyHormamida or t~rahydrofuran, ~t atemperaSure from 20 about 0C to s.bout 150C, preferably at about the reflux temperature of the solvent.
Pres~ures from about û.5 atmospheras to about 5 atmospheres are generally acceptable, and arnbient pressure, i.e. about 1 atmosphere, is preferred as a matter of convenience.
The novel cornpounds of the formula I and the pharmaceuticaily acceptable salts 25 thereof are useful as substance P antagonists, i.e., they possess the ability to artagonize the effects of substance P at rts receptor site in mammals, and therefore they are able to function as therapeutic ager,ts in the treatment of th~ ~srementioned disorders and diseases in an afflictPd mammai.
The compounds of the ~ormula I which are basic in nature ar0 capable of 30 forming a wide variety ~ different salts with various inorganic and organic acids.
~: Although such salts must be pharmaceutically acceptabie for administration to animals, :~
X is o~ten desirable in pra~ice to inXially isolale a compound of tha Formula I ~rom the : ~ reaction mi~ure as a phannacautically unaccaptabla salt and then simply convert such ' . .
92J - 2 ~ ~, ~ ', .
~, 121~,1 PCT/US91/08836 sa,t to an aitarnata, phann~c~utic~Jly accsptable sa,t by standard ion exchange methods known to thos2 sl<illsd in ths ~t. In ~dditional, the acid addition salts of the compounds of this invention are raadily prapared by treatiny the appropriate compound of formula I ~/itil a substa~tially equiv~lsnt arnount of the chosen mineral or organic 5 acid in an aqueous soivent madium or in a sultable orsanic solvent, such as methanol or etharol. ~pon caraful evaporation of the solvsnt, the desired solid sait is readily obtained .
The coinpounds of ~ormula I ~nd th~ir pharmac3utically acceptable salts exhibit substanc.-~ D .ecc-~ptor-~irri~ c,.ivity ar,d, ~her3fora ~r0 of value in the tr,-~atment and 10 prevention OT i3 wida varia.! oi c,inical ~ci,diLiuns h3 r3atment or pr~v~ntion of which are effectad or tacilita;ad '~y ~ d~cr~as~ in sui~st~nce F ' rn~diated neurotransmission.
Such conditions inc!ude inflamrnatory dissases ~s.c,., arthritis, psoriasis, asthrna and inflamm. atory bowel dis3as~), e^litis, p2in, all rgiss such as ~czema and rhinitis, chronic o'Dstructive airways disease, hypersensitivity disorders such as poison ivy, vasGspastic 15 diseases such as angina, migraine and ~eynaud's disease, fibrosir,g and collagen diseases such ~s sclorodcrrna and eosirlophilio ~asciolias,is, OE,flex symp~hetic dystrophy such as shoulder/har,d syndro,ne, per;,pherai neuropathy, dlserders related to immune enhancement or suppressiorl such as, systemic lupus ery~hamatosus, andrheumatic diseases such 8s fibrositis. Hence, these compounds are readily adapted 20 to therapeutic use a~ substancs P antagonists for the control and/or treatment of any of the a~orasaid c!inical conditions in marnmals, including humans.
The compounds of the formula I and the pharmacautically acceptable salts thereof ca~ be administered via aither the oral, parenteral or topical routes. In generaJ, these compounds ara most desirably administered in dosages rarging from about 5.0 25 mg up to about 1500 mg per day, aithough Yariations will naeessarily occur dependin~
upon the weight and condition of the subject being lreated and the particular route of ~dministration chosen. However, a dosage level that is in the range of ~bout 0.07 mg to about 21 mg per kg of body weisht per day is most desirably ~mployed. Variations may nevertheless occur depending upon the species of animal being tre~ted and ~s30 individual res~onse to said medicament, a5 well as on the type of pharrnaceutical ~ormulation chosen and the time period and interval at which such administration is c~ried out. In eome instanc~s, do~aga Isvels bQIOW th_ lower lin~it ot the aforesaid rang~ may be mor3 than adequats, whil~ in other cases still larger doses rnay be wo 92/~2~1 2 ~ ~ `3 1 ~ ~ PCr/~Sgl/~8~.~6 employed without causing any harm~ul side effect, provided that such larger doses are first divided into several small doses for administration throughout th~ day.
The compounds of the invention may be administered aJone or in combination with pharmaceutic~lly acceptable carriers or diluents by aithPr of the threo rout3s previously indicated, rmd such administration may be carried out in single or rnultiple doses. More particularly, the novel therapeutic agents of this invention can b~
- administered in a wid~ variety of ditFer~nt dosag~ forms, i.e., they may be combined with various pharmaceutically ~cceptable inart c~rners in the torm o~ tabieta, ca?sulas, lozenges, troches, hard candies, powders, sprays, razrns, ~alY~s, suppositorios, 30!110s, gels, pastes, lotions, ointments, aqueous suspensions, injectable soiu~ions, ~ irs, syrups, and the like. Such carri~rs includ~ solid cliluents or flllars, st~riie aquaous media and various non-toxic organic solvents, etc. Moreover, oral pharmacauticalcompositions can be suitably sweetened and/or flavored. In g2neral, th~
therapeutically-effective compounds of this invention are present in such dosage forms at concentration leveis ranging from about 5.0% to about 70% by weight.
For orai aciministr~tion, tablets containing various Gxcipier~s such as rnicrocfystailine cellulose, sodium citrate, CaiGiUm carbonate, dicalcium phosphate and glyoine may be employsd along with various disintegrants such as starch (and ~, pr~er~bly corn, potato or tapioca s~arch), alginic acid nd certain complex silicates, together with granuiation binders like polyvinylpyrrolidone, sucrose, gelatin anci acacia.
Additionally, lubricating agents suoh as rnagnesium stearate, sodium lauryi sulfate and . ~.
talc are often very us~ful for tabletting purposes. Solid cornpositions of a similar type may also b~ ~mployed as fillers in gelatin capsules; preferred m~tarials in thisconnection also include lactos~ or rnilk sug~ ll as high molecular weight polyethylene glycols. When aqusous suspensions and/or atixirs are ~esired for oral '' administration, the active ingredient may be combined with various sweetening or flavorirlg agents, coloring matter or dyes, and, If so desired, emulsi~ying ~ndlor suspending agents as well, together with such diiuents as water, ethanol, propylene glycol, glyeerin and various I ~ combinations ther~f.
For parenteral adminlstration, solution~ of ~ therapeutic compound of ~he present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed. The aqueous solutions should be suitably buHered (prefPraDly pH
greater than 8) if necessary and the liquid diluent flrst rendered isotonio. These aqueous ~, :
~ ~ Q ~
~O ~ 2151 P~r/US91/0~836 solutions ~re suitable for intravenous injection purposes. The oily solutions are suit~bla ~or intraarticular, intrarnuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily aecomplished by stzndard pharrnaceutical techniques well known to those skilled in the art.
Additionally, it is al50 possible to administer the compounds of the present invention topically when treating inflammatory conditions of the skin and this may preferably be done by way of creams, jellies, gels, pastes, ointments and the like, in accordance with standard pharmaceutical practice.
The acti~Aty of the compounds of th~ present invention as substance P
anta~onists is determined by their abil;ty to inhibit the binding of subst3ncs P zt ~t~
raceptor s~es in bovine caùdate tissue, employing radioac~ive ligands to visu~ th~
tachykinin receptors by rneans of auto-radiograFhy. The substance P antagonizingactivty of the harein described compounds may be evaluated by using the standardassay procedure described by Ivl. A. Cascieri et al., as reported in the Journal of Biolo~ical Chemistrv, Vol. 258, p. 5158 (1983). This rnethod essentially involves determining the concentration o~ the individual compound required to reduce by 50%
the amoumt of radiolabellod substance P ligands at their rec~ptor sites in said isolated cow tissues, theraby affording characteristic IC50 values for eaoh cornpound testsd.
In this procedure, bovine caudate tissue is removed from a -701: freezer asld homogenizad in 50 volumes (w.h.) o~ an ice cold ~0 mM Tris (i.e., trimethamine which is 2-amino 2-hydroxymethyl-1,~propanediol) hydrochloride b-rffer having a pH of 7.7.
The homogenate is centrifuged ~t 30,000 x G for a period of 20 minutes. The pellet is resuspended in 50 volumes of Tris buffer, rehomogenized and then recentri~uged at 30,000 x G for anothar twenty- minute period. The pallet is then resuspended in 40 volurnes of ice~cold 60 mM Tris buffer (pH 7.7) containing 2 rnM of calcium chloride, 2 ~nM of magn~siurn chloride, 40 g/mi of bacitracin, 4,ug/ml o~ leup~ptin, 2,ug of chymostatin and 200 g/ml of bovine serum aJbumin. This step completes the production of the tissua preparation.
Tha radioligand binding procedure is then carri~d out in the following manner, vi2., by initiating the reaction via ~he addition of 100 ,ul of the test cornpound made up to e~ conGentration of 1 ~M, followed by the addition of 100 ,ul o~ radioaetiva ligand mads up to a final concentration 0.5 mM and then finaliy by thP addltion o~ 800 ,ul of the tissue preparation produced as dascrib~d above. The final volume is thus 1.û ml, .
2 ~
WO 92/12151 P~/IJS91/OB836 -`~
-1~
.
and the reaction mixture is n2~t vor~exed and incubated at roo~ temperature (~3. 20C) for a period of 20 minu~as. Th~ tubas ~r~ thar~ filt~r_d using a coll harvester, and the glass fiber filtars (Whatman GF/B) are washed four times with 50 mM of Tris buffer (pH
7.7), with th~ ,lltsrs ~avi,lg ~r~/io~sl~J ~esn ~r~soa~d ~or a period of t~o hours prior 5 to the filtering proc~durs. Radioactivity is than dat~rmined in a Beta counter at 53%
counting ~ici nc~J, and tha IC~G Y~luas ars caicul~te~ by using standard statistical methods .
The sres~n; ir.~J~ntio~ is illustra~ed by th3 follo~ving axarnple. It will be understood, ~ic7v--v_r, ~n t ~.he In~lsn.~.ior~ is ,~ot !imi~ed to the specific details of this 1 0 exarnple.
E,~A~.PL~ 1 (2~.3S)-c~s-l-Ms'h~/1-2-(di~hsnvlmeth~ N-((2-methox~Dhenvi)methvl)-1-aza-bicycloI2.2.210ctarl-3-_mina iodid~: To ~ ~0 mL round-bottomed flask equipped with condenser and N2 inlet wer~ added 500 m~ (1.21 mmol) (2S,3S)~is-2-(diphenylmethyl)-15 N-t(2-methoxyphenyl)methyl)-1-~abicyclo[2.2.2]octan-3-amine and 6 mL ethanol. The solution was heated to near boiling, and 207 mg (1.46 mmol) methyt iodide was added.
Hea~ing was continued tor 10 min, then the sotution was cooled to afford a precip-~ate, which was filtered ~nd dried. The resùltin~ solid gave mp 2~244C, 328 mg (49%
yield).
'tl NMR (~, CDCI3): 1.8-2.0 ~m, 2H), 2.1-2.3 (m, 2H), 2.47 (S, 3H), 2.59 (m, 1H), 3.04 (dd, J=13,84, 2H) (m, 1H), 3.50 tm, 1H), 3.63 ~5, 3H), 3.67 (S, 1H), 3.95 (m, 1H~, :
AS SUBSTANC FP ANTA~ISTS
Back~und o~ the Invention The present invention relat~s to novel N-alkyl quinuolidinium szlts, phannaceutical compositions comprising such cornpounds and the usa of such compounds in the treatment and prevention inflammatory and gastrointestinal disordars, as well as several other disorders. The pharmaceutically active compounds of this invention are substance P antagonists.
Substance P is a naturally occurring undecapeptide belonging to the tachykinin farnily of peptides, the latter bsing named because of their prornpt stimulatory action on smooth muscle tissue. Mora speci~ically, substance P is a pharm~cologically active neùropeptide that is produced in mammals (having originally been isolated from gut) and possesses a characteristic amino acid sequence that is illus.rated by D F. \/~ r et al. in U.S. Patent No. 4,680,283. The wide involvement of substance P and other tachykinins in the pathophysiology o~ numerous ciiseases has been amply dernonstrated in the art. For instance, substanoe P has recently been shewn to be involved in the transmission of pain or migraine (soe B.E.B. S~ndberg ~ al., Joumal of Vledicin~! Chemist , 25, iO09 (1982)~, a~ well as in central neNous system disorders such as anxiety and schizophrenia, in respiratory and inflammatory diseases such as asthma and rheumatoid arthritis, respectively, in rheumatic diseases such as fibrosi~is, and in gastrointestinai disorders and diseases of the G! tract ~uchas ulcerative colitis and Crohn's disease, etc. (see D. Regoli in 'Trends in Cluster Headache,' edited by F.
Sicuteri et al., Elsevier Scientific Publishers, Amsterdam, pp. 85-95 (~ 987)).
Quinuclidine derivatives and relatl3d compounds that exhib-lt activity as substance P receptor antagonists are referr0d to in PCT Patent Application PCT~JS
89/05338, fileci November 20, 1989 and United States Patent Application Seriai No.
557,442, filed ~)uly 23, 1990, both of which are assi~ned in common with the present application. Similar compounds are referrsd to in the PCT pa~ent applications Pntitled '3-Amino-2-Aryl Quinucliciines~ and ~Quinuclidine Derivatives' and filed on April 25, 1991 and May 15, 1991, respectivoiy. These applications are aiso assigned in common wilh the present application.
~ ~ ~ Piperidine deriva~ives and related heterocyclic nitrogen containing compounds that are useful as substance P ~ntagonists are referred to in United Stales Patent Application Seriai No. 619,361, filed Novernber 28, 1990 and United States Patent .
wo 9~/121~ ? ~. 5 ~ PCT/US91/0~3836 ,~
Application Serial No. 590,423, filed S~ptambar 28, 1990, both of which are assigned in common with .ha pr~siall; applic~tion.
Summarv of the Invention The prasent inv~n,icn r312t~s to compounds of the forrnula rR2 `' 1~` (1) wherein R' is (Cl-C4)alkyl, allyl, phenyl-(CI-C~)alkyl, HOOC~ C~O)alkyl or (C1-t 15 C4)alkoxy-OOC-(Cl-ClO)alkyl; R2 is selected from the group consisting of phenyl, thienyl, furyi and pyridyl, each of the forogoin~ R2 groups being optionally substituted with ~rom one to thr0e substituants indepandently sele~led trom tho group consisting ~ cyano, nltro, amino, N-mono-(C1-G3)alkylarnino, fluorine, chlorine, bromine, tr fluoromethyl, (C1-C3)ailkyl, (C1-C3~alkoxy, allyo~y, (Cl-C3)alkoxy~arbonyl, ~arboxr~nido and N,N~i-((~
C3)alkyl-carboxamido; and X is a pharmaceutically acceptable counterion, (e.g.
chloride, bromide, nuoride, iodide, mesylate, tosylats or trifluoromethanesulfonate).
Examples of pharrnaceutic~lly acceptable counterions are halides (e.g., tluoride, :1 chloride, bromide or iodide), (C1-t::3)alkyl-mono or di-carboxylates, mesylate, tosylate, arylcarboxylates, (Cl-C3)alkylsulfonates wherein the alkyl moiety may optionally be ¦ ~ ~ 25 substituted with one or more fluorine atoms, arylsulfonates, citrate, maleate, fumarate, lactata,~ malate, sulfates, phosphates, nitrates, tartrate, saccharate and pamoate.
Th~ term 'alkyl", as used herein, unless otherwise indicated, includes saturatedmonovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof.
; ~ Preferred- compounds of the forrnula I are those wherein R2 is 2-methoxyphenyl.
The prasant invention also ralates to a pharmaceutical composition 70r treating or preventing a conditi~n salected from the group consisting of inflarnmatory diseasas (e.g., arthntis, psoriasis, asthma and inflammatory bowel diseasa), colitis, pain, allergies , ~ .
1:~
~la~. & ~
- ,'0 92/121~ r/l.JS9~ 36 ., such as eczema and rhinitis, chronic obstructiv~ airways disease, hypersonsitivity disorders such as poi;.on i~l, vasospastic dissasas such as angina, migraine andRaynaud's disaasa, rloro~ing and coilay3n dis3~es such as sclaroderma and eosinophilic iascioliasis, n ~11 ex sym~i~hietic d~Jstrophy such as shouldsr/hand syndrorna, peripharal neuropalhy, disordars ralated to immune enhancernent or suppression such as systemic lupus erythsmatosus, and rhriumatic di~easQs such as fibrositis in amarnmal, includin5 a hurn2n, cornprising an amount oi ~ compound ot the formula 1, or a pharmaceui.,cally ac^3~ta;,la salt thsr30f, ~Xac~i~Je in trsating or preventing such condition, and a pharrnac3ut!cal!y acceptabl~i c~,er.
The prasent inYertion i~so r~!atss to ai msthod of trsating or preventing a condition sa'eo'3d l,om the SroU., _^ns'.s'inS 3~ ir.~.~r,mat3ry diseasas (e.g., arthritis, psoriasis, as~hrn~ _nci inilammatory oo~al ciisa~ ), colitis, pain, allerqies such 2s ~' eczerna anci rhinitis, chronic obstructive aint~ays dissass, hypersensitivrty disorders such as poison ivy, vasospastio disaases such as argina, migraine and Reynaud's disease, ^i5 fibrosin~ and collagen diseases such as solerodarrna and eosinophilic fascioiiasis, reflex syrnpathetic dystrophy such ~s shoulder/hand syndrome, peripharal neuropathy, di~orders related to immune ~nh~ncsment or suppression such as systamic lupus erythematosus, and rheum~tic diseases such as fibrositis in a mammal, including a human, comprising administ~ring to said mammal an amount of a compound of the formula 1, or a pharmac~uticaily acceptable salt theraof, effective in treating or ~ ~ pre~lenting such condition.
.; The present invention also relates to a pharrnaceutical composition ~or antagonizing the effects of substance P in a marnmal, including a human, comprising a substance P sntagonizing arnount of a compound of the forrnula 1, or a ~; 25 pharmaceuticaily acceptabl2 salt thareof, and a pharnacautic~Llly acceptable carrier.
The present invention aiso rel~tes to a method of antagonizin~ the effects of substance P in a marnmal, including a human, cornprising administerin~ to said mammal a substance P antagonizing amount cf a compound of the formula 1, or a pharmacautically acceptable satt thereof.
The presant invention also relates to a pharrnareuSical composition for troatingor prev~nting a disordar in a rnarnmal, inc!uding ~ human, r~su!ting from an ~xcPss of substanc~ P, comprising a .substarc~ P antagonizing ~rnount of a compound o~ the , ' , W0 ~/12~51 2 ~ 3 ~ PCl/US91/08836 ;
formula 1, or a pharmaceutically acceptable salt thersof, and a pharmac3uticall~J
acceptable carrisr.
The present invention also relates to a method of treating or preventing a disorder in a mammal, including a human, rssulting from an excess of substancQ P, 5 comprising administering to said mammal a substancP P antagonizlng ~mount of cornpound of the formula 1, or a pharmaceutically acceptable salt therso,.
The present invention also relates to a pharmaceutic~ composition ior tre2ting or preventing a condition selected from the ~roup consisting of inflarnmatonJ dise2s~s (e.g., arthritis, psoriasis, asthma and inflarnmatory bowel disaaseJ, coli~is, ~ain, ~IIQr~iss 10 such as eczPma and rhin~tis, chronic obs'ructiv~ air~;ays ~isaas~, h~e,s_ns,'.~
disorders such as poison ivy, vasospastic diseases ~uch as angina, ~Tli912iile ana Reynaud's disease, flbrosing and collagen diseases such as scleroderrna an~
eosinophilic~ascioliasis, reflex syrnpathetic dystrophy such as shoulder/hand syndrome, peripheral neuropathy, disorders related to immune enhancement or suppression such 15 as systemic lupus erythematosus, and rheumatic diseases such as fibrositis in a marnmal, including a hurnan, comprising an amount of a ccmpound of the formuia 1, or a pharmaceutically acceptable salt th~re~, effective in antagonizing the affect of substance P at its receptor site, and a phamlaceutically aceeptable ~urier.
The pr~sent invsnffon also relates to ~ method of tr~ating or preventing a 20 condition selected from the group consisting of inflammatory diseases (e.g., arthritis, psoriasis, asthma and inflammatory bowel disease), col~tis, pain, ~lergies such as cczsma and rhinitis, chronic obstn~ctive ai~ays di~ease, hypersensitivity disorders such as poison ivy, vasospastic disoases such as angina, mi~ræne and ~eynaud's disease, fibrosing and colla~en diseases such as scleroderrna and eosinophilic fascioliasis, 25 reflex sympathetic dystrophy sueh as shoulder/hand syndrome, peripheral n~3uropathy, disorders related to immune enhancernent or suppression such as systemic lupus erythematosus, and rheumE~tic diseases such as fibros-r~is in a marnmal, including a human, comprising administering to said mammai an amount of a compound of the ~ormuia 1, or a pharrnaeeutically acceptable sait thereof, ~ffective in antagonizing the 30 effect of substance P at its r~eptor site.
The present invention aiso relates to a phamlaceutica~ composrtion for treating or preventing a disorder in a mammai, including a human, the tr0atment or pre~/ention of which is effected or facilita~ad by a decrease in substance P medi2ted ;~vo 92/12151 2 ~ Q ~ PCr/VS91/~8836 nsurotransmission, comprising an anount of a compound of the fonnula 1, or a pharmaceutically acceptable sait thereof, eMective in antagonizing the effect ofsubstance P at rts receptor site, and a pharmaceutically acceptable carrier.
The present invention also rslates to a msthod of treating or preventing a 5 disord~r in rnammal, including a hurnan, the treatment or prevention of which is effected or facilitated by a decrease in ~ubstance P mediated neurotransmission, comprising administering to said mamma, an, arnount of a compound of the formula 1, or a pharmaceutic~lly acceptable sait ther~,of, ~ffeçtiv2 in antagonizing the e~ect of substanca P at its receptor site.
The present inv2ntion ~so rel~t~s to a pharmaceutical composition for tr3--~.in~or preventing a disorder in a mammal, including a humar, the traatment or pr~ nt!on of which is effected or facilitated by a decrease in substance P media~d neurotransmission, comprising an arnount of a compound of the formula 1, or a pharm,aceuticaily acceptable sa,t thHreof, effective in treating or preventing such 15 disorder, and a pharrnacsLti~aily accaptable carrier.
The present invention aiso relates to a method of treating or prsventing a disorder in mamrna-i, including a human, thetrsatment or prevention of which is ~ected, or facilitated by a d,ecrease In substance P mediated ne~rotrar,smission, oomprising administering to said mammai an arnount ~ a compound of the forrr,uia 1, or a 20 pharrnaceuUcally acceptable salt thereo~, effective in treating or preventing such disorder.
The compounds ot the forrula I have chiral centers and therefore exist in diff~,rent enantiomeric ~orms. This invention relates to all optical isomers and all stcreoisomers of compounds of the formula 1, and mixtures thereof.
The opti~ally active compounds of tormula I are addltiorlally useful as intermediate in the synthesis of the corresponding racemic mixtures and oppositeenantiomers.
Formula I above includes compounds identical to those depicted but for the fact that one or more hydrogen or carbon atorns are replaced by radioactive 30 isotopes thereof, (e.~., triUum, carbon-14 or nitrogQn-15 isotop~s thereof). Such radiolabelled compounds ~r~ useful as reisearch and diagnostic tools in metabolism pharrnacokinetic studies ard in binding assays. Specific applications in research incilude radioligand binding assays, autoradiography studies and In ViYo bindlng ," ~
.
:
WO~2~12i~ r3 ` r .J pcr!ussa/o~36 -;
studies, while specinc applications in thP diagnostic area include studies of the substanca P racaptor in humans in in vi~/o binding in the relevant tissues for inflamrnation, c.g. immune-~ype cells or cells that are directly involvad in inflamm~tory bowel disorders ar,d -ha 1i~3.
Detailsd D~scriDtion of the Invention Com~ounds of the formula I may ba prepared by reacting the corresponding compound of the formula r~2 ~-o ,0 ~ ( I I ) wherein R2 j5 defined as above, with a compound of the formula R'X, wherain Rl is defined as abo~e ~nd X is chloro, fluoro, bromo, iodo, tosyloxy, mesyloxy, or trifluoromethanesulfonyloxy. Tha reaction is genoraliy carried out in a pol~r solvent such as ethanol, acetone, dim~thyHormamida or t~rahydrofuran, ~t atemperaSure from 20 about 0C to s.bout 150C, preferably at about the reflux temperature of the solvent.
Pres~ures from about û.5 atmospheras to about 5 atmospheres are generally acceptable, and arnbient pressure, i.e. about 1 atmosphere, is preferred as a matter of convenience.
The novel cornpounds of the formula I and the pharmaceuticaily acceptable salts 25 thereof are useful as substance P antagonists, i.e., they possess the ability to artagonize the effects of substance P at rts receptor site in mammals, and therefore they are able to function as therapeutic ager,ts in the treatment of th~ ~srementioned disorders and diseases in an afflictPd mammai.
The compounds of the ~ormula I which are basic in nature ar0 capable of 30 forming a wide variety ~ different salts with various inorganic and organic acids.
~: Although such salts must be pharmaceutically acceptabie for administration to animals, :~
X is o~ten desirable in pra~ice to inXially isolale a compound of tha Formula I ~rom the : ~ reaction mi~ure as a phannacautically unaccaptabla salt and then simply convert such ' . .
92J - 2 ~ ~, ~ ', .
~, 121~,1 PCT/US91/08836 sa,t to an aitarnata, phann~c~utic~Jly accsptable sa,t by standard ion exchange methods known to thos2 sl<illsd in ths ~t. In ~dditional, the acid addition salts of the compounds of this invention are raadily prapared by treatiny the appropriate compound of formula I ~/itil a substa~tially equiv~lsnt arnount of the chosen mineral or organic 5 acid in an aqueous soivent madium or in a sultable orsanic solvent, such as methanol or etharol. ~pon caraful evaporation of the solvsnt, the desired solid sait is readily obtained .
The coinpounds of ~ormula I ~nd th~ir pharmac3utically acceptable salts exhibit substanc.-~ D .ecc-~ptor-~irri~ c,.ivity ar,d, ~her3fora ~r0 of value in the tr,-~atment and 10 prevention OT i3 wida varia.! oi c,inical ~ci,diLiuns h3 r3atment or pr~v~ntion of which are effectad or tacilita;ad '~y ~ d~cr~as~ in sui~st~nce F ' rn~diated neurotransmission.
Such conditions inc!ude inflamrnatory dissases ~s.c,., arthritis, psoriasis, asthrna and inflamm. atory bowel dis3as~), e^litis, p2in, all rgiss such as ~czema and rhinitis, chronic o'Dstructive airways disease, hypersensitivity disorders such as poison ivy, vasGspastic 15 diseases such as angina, migraine and ~eynaud's disease, fibrosir,g and collagen diseases such ~s sclorodcrrna and eosirlophilio ~asciolias,is, OE,flex symp~hetic dystrophy such as shoulder/har,d syndro,ne, per;,pherai neuropathy, dlserders related to immune enhancement or suppressiorl such as, systemic lupus ery~hamatosus, andrheumatic diseases such 8s fibrositis. Hence, these compounds are readily adapted 20 to therapeutic use a~ substancs P antagonists for the control and/or treatment of any of the a~orasaid c!inical conditions in marnmals, including humans.
The compounds of the formula I and the pharmacautically acceptable salts thereof ca~ be administered via aither the oral, parenteral or topical routes. In generaJ, these compounds ara most desirably administered in dosages rarging from about 5.0 25 mg up to about 1500 mg per day, aithough Yariations will naeessarily occur dependin~
upon the weight and condition of the subject being lreated and the particular route of ~dministration chosen. However, a dosage level that is in the range of ~bout 0.07 mg to about 21 mg per kg of body weisht per day is most desirably ~mployed. Variations may nevertheless occur depending upon the species of animal being tre~ted and ~s30 individual res~onse to said medicament, a5 well as on the type of pharrnaceutical ~ormulation chosen and the time period and interval at which such administration is c~ried out. In eome instanc~s, do~aga Isvels bQIOW th_ lower lin~it ot the aforesaid rang~ may be mor3 than adequats, whil~ in other cases still larger doses rnay be wo 92/~2~1 2 ~ ~ `3 1 ~ ~ PCr/~Sgl/~8~.~6 employed without causing any harm~ul side effect, provided that such larger doses are first divided into several small doses for administration throughout th~ day.
The compounds of the invention may be administered aJone or in combination with pharmaceutic~lly acceptable carriers or diluents by aithPr of the threo rout3s previously indicated, rmd such administration may be carried out in single or rnultiple doses. More particularly, the novel therapeutic agents of this invention can b~
- administered in a wid~ variety of ditFer~nt dosag~ forms, i.e., they may be combined with various pharmaceutically ~cceptable inart c~rners in the torm o~ tabieta, ca?sulas, lozenges, troches, hard candies, powders, sprays, razrns, ~alY~s, suppositorios, 30!110s, gels, pastes, lotions, ointments, aqueous suspensions, injectable soiu~ions, ~ irs, syrups, and the like. Such carri~rs includ~ solid cliluents or flllars, st~riie aquaous media and various non-toxic organic solvents, etc. Moreover, oral pharmacauticalcompositions can be suitably sweetened and/or flavored. In g2neral, th~
therapeutically-effective compounds of this invention are present in such dosage forms at concentration leveis ranging from about 5.0% to about 70% by weight.
For orai aciministr~tion, tablets containing various Gxcipier~s such as rnicrocfystailine cellulose, sodium citrate, CaiGiUm carbonate, dicalcium phosphate and glyoine may be employsd along with various disintegrants such as starch (and ~, pr~er~bly corn, potato or tapioca s~arch), alginic acid nd certain complex silicates, together with granuiation binders like polyvinylpyrrolidone, sucrose, gelatin anci acacia.
Additionally, lubricating agents suoh as rnagnesium stearate, sodium lauryi sulfate and . ~.
talc are often very us~ful for tabletting purposes. Solid cornpositions of a similar type may also b~ ~mployed as fillers in gelatin capsules; preferred m~tarials in thisconnection also include lactos~ or rnilk sug~ ll as high molecular weight polyethylene glycols. When aqusous suspensions and/or atixirs are ~esired for oral '' administration, the active ingredient may be combined with various sweetening or flavorirlg agents, coloring matter or dyes, and, If so desired, emulsi~ying ~ndlor suspending agents as well, together with such diiuents as water, ethanol, propylene glycol, glyeerin and various I ~ combinations ther~f.
For parenteral adminlstration, solution~ of ~ therapeutic compound of ~he present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed. The aqueous solutions should be suitably buHered (prefPraDly pH
greater than 8) if necessary and the liquid diluent flrst rendered isotonio. These aqueous ~, :
~ ~ Q ~
~O ~ 2151 P~r/US91/0~836 solutions ~re suitable for intravenous injection purposes. The oily solutions are suit~bla ~or intraarticular, intrarnuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily aecomplished by stzndard pharrnaceutical techniques well known to those skilled in the art.
Additionally, it is al50 possible to administer the compounds of the present invention topically when treating inflammatory conditions of the skin and this may preferably be done by way of creams, jellies, gels, pastes, ointments and the like, in accordance with standard pharmaceutical practice.
The acti~Aty of the compounds of th~ present invention as substance P
anta~onists is determined by their abil;ty to inhibit the binding of subst3ncs P zt ~t~
raceptor s~es in bovine caùdate tissue, employing radioac~ive ligands to visu~ th~
tachykinin receptors by rneans of auto-radiograFhy. The substance P antagonizingactivty of the harein described compounds may be evaluated by using the standardassay procedure described by Ivl. A. Cascieri et al., as reported in the Journal of Biolo~ical Chemistrv, Vol. 258, p. 5158 (1983). This rnethod essentially involves determining the concentration o~ the individual compound required to reduce by 50%
the amoumt of radiolabellod substance P ligands at their rec~ptor sites in said isolated cow tissues, theraby affording characteristic IC50 values for eaoh cornpound testsd.
In this procedure, bovine caudate tissue is removed from a -701: freezer asld homogenizad in 50 volumes (w.h.) o~ an ice cold ~0 mM Tris (i.e., trimethamine which is 2-amino 2-hydroxymethyl-1,~propanediol) hydrochloride b-rffer having a pH of 7.7.
The homogenate is centrifuged ~t 30,000 x G for a period of 20 minutes. The pellet is resuspended in 50 volumes of Tris buffer, rehomogenized and then recentri~uged at 30,000 x G for anothar twenty- minute period. The pallet is then resuspended in 40 volurnes of ice~cold 60 mM Tris buffer (pH 7.7) containing 2 rnM of calcium chloride, 2 ~nM of magn~siurn chloride, 40 g/mi of bacitracin, 4,ug/ml o~ leup~ptin, 2,ug of chymostatin and 200 g/ml of bovine serum aJbumin. This step completes the production of the tissua preparation.
Tha radioligand binding procedure is then carri~d out in the following manner, vi2., by initiating the reaction via ~he addition of 100 ,ul of the test cornpound made up to e~ conGentration of 1 ~M, followed by the addition of 100 ,ul o~ radioaetiva ligand mads up to a final concentration 0.5 mM and then finaliy by thP addltion o~ 800 ,ul of the tissue preparation produced as dascrib~d above. The final volume is thus 1.û ml, .
2 ~
WO 92/12151 P~/IJS91/OB836 -`~
-1~
.
and the reaction mixture is n2~t vor~exed and incubated at roo~ temperature (~3. 20C) for a period of 20 minu~as. Th~ tubas ~r~ thar~ filt~r_d using a coll harvester, and the glass fiber filtars (Whatman GF/B) are washed four times with 50 mM of Tris buffer (pH
7.7), with th~ ,lltsrs ~avi,lg ~r~/io~sl~J ~esn ~r~soa~d ~or a period of t~o hours prior 5 to the filtering proc~durs. Radioactivity is than dat~rmined in a Beta counter at 53%
counting ~ici nc~J, and tha IC~G Y~luas ars caicul~te~ by using standard statistical methods .
The sres~n; ir.~J~ntio~ is illustra~ed by th3 follo~ving axarnple. It will be understood, ~ic7v--v_r, ~n t ~.he In~lsn.~.ior~ is ,~ot !imi~ed to the specific details of this 1 0 exarnple.
E,~A~.PL~ 1 (2~.3S)-c~s-l-Ms'h~/1-2-(di~hsnvlmeth~ N-((2-methox~Dhenvi)methvl)-1-aza-bicycloI2.2.210ctarl-3-_mina iodid~: To ~ ~0 mL round-bottomed flask equipped with condenser and N2 inlet wer~ added 500 m~ (1.21 mmol) (2S,3S)~is-2-(diphenylmethyl)-15 N-t(2-methoxyphenyl)methyl)-1-~abicyclo[2.2.2]octan-3-amine and 6 mL ethanol. The solution was heated to near boiling, and 207 mg (1.46 mmol) methyt iodide was added.
Hea~ing was continued tor 10 min, then the sotution was cooled to afford a precip-~ate, which was filtered ~nd dried. The resùltin~ solid gave mp 2~244C, 328 mg (49%
yield).
'tl NMR (~, CDCI3): 1.8-2.0 ~m, 2H), 2.1-2.3 (m, 2H), 2.47 (S, 3H), 2.59 (m, 1H), 3.04 (dd, J=13,84, 2H) (m, 1H), 3.50 tm, 1H), 3.63 ~5, 3H), 3.67 (S, 1H), 3.95 (m, 1H~, :
4.12 (m, 1H), 4.46 (d, J=11.5, 1H), 5.42 (dd, J=6.6, 11.5, 1H), 6.33, 6.68, and 7.07-7.2 (mUIt;PIetS~ 14H), 7.7-7.9 (brOad m, 2H~.
'3C-NMR (~, CDCI3): ~0.0, 22.4, 23,8, 46.1, 4g.4, 53.g, 54.6, 55.3, 55.6, 61.2, 71.6, 110.2, 120.4, 126.9, 127.2, 127.9, 1~8.5, 129.6, 141.7, 143.5, 157.1.
Mass Spec. (%): 426 (1"~arent), 2-9 (31), 246 (46), 142 (45),121 (100), 91 ', ~ (62).
: ` ~
1 .
W0 92~12151 ;~ PC~/lLJS91/~ 36 Tha title compounds of Examples 2-8 were prepared by a procedure similar to that of Exarnpia 1.
t2s 3s)-cls-l-(4-carb~thoxvbutvl~-2-(di~henvlmethvl)-N-((2-me1h 5 phenyl)methyl~ 7abicvclo~2.2.210ctan-3-amine iodide:
Prapar~d in 13/o yield, m.p. ~5C.
Mass Spac.: 5~1 (1, parent), 373 (89), 359 (56),121 (100), 91 (45).
~XAMI_E 3 (2S 3s)-cis-~ -rar~o~thox\l~henv!mathv~ dir~henvlmelhv!)-N-((2-meth 10 phenyl~me(hvl)-1--~7 .bic~,c!o~2.2.'~'1cctan-3-~nnin3 iodid3:
Prepared in 1~% ~Jis!d, m r 1'10-1~S~C.
Anai. Calc'd ~or C~3H 3N2031~1/3H~0: C ~.40, H 6.21, N 3.96. Found: C 64.05, H ~.16, N 3.~8.
(2S.3S!-cis~ L~carbomethoxvpentvl)-2-(dlphenvlmethvl~N-lL2-meth Prepared (using acetQnitrila instead ot ethanol as solvent3 in 5% yield, as an oil.
Ana~. Calc'd for C3aH45N2O~SF3-HClo1l2H2o C 57.32, H 6.65, N 3.71. Found:
C 57.29, H 6.48, N 3.68. Found: C 57.29, H 6.48, N 3.68 (2S.3S)~is-1-(5-Carboxy~entYI)-2-1di~henylmethvl)-N-(12 rnetho~methvl)-1-azabicvclo~2.2.2~ ;~-amine trHiate:
Prepared by hydrolysis of the above compound with potassium hydroxide in ethanol.
High Res. Mass Sp~c: Calc'dforC3,H,.3N203: ~27.3278. Found: 527.3268.
3~ EXAMPLE 6 2S,3S~-cis-l-AllYI-2-(diPhenv!methvll-N-U2-methoxyPhenvl~methyl)-1-aza-bicvclo~2.2.210ctan-3-arrline bromipe:
Prepared in 58% yield, m.p. 15~160C.
~ Anai. Calc'd for C3lH37N20Br-1.25H20: C 66.96, H 7.16, N 5.04. Found: C
66.95, H 7.06, N 4.97.
~, .
~VO 92/11~1~1 21 Q ('~ , PCI/US91/0883fi E~MPLE 7 ~S,3S~is-1-Benzyl-2-(diphenvlm~y~ ~oxyDhenvllmethvl)-1-aza-bicyclo ~2 .2 .21 octan-3-amlne bromide:
Prepared in 53% yield, m.p. 206-208aC.
Anal. Calc'd~orC35H33N20BroH20: C 69.87, H 6.87, N 4.66. Found: C 69.48, H 6.34, N 4.52.
(2S 3S) cis-1-(Carboethvoxymeth~ ~i~henvlmethvl)-N-((2-methox~/- -phenyl~methvl~-1-azabicycloL2.2.21Oct n-3-amine bromide:
10 Prepared in 17~ yield, m.p. 12~135C.
Anal. Calc'd for C32H39N2O38r4H2O: C 64.32, H 6.92, N ~.69. Found: C 64.1 '.
H 6.88, N 4.62.
.
.
'3C-NMR (~, CDCI3): ~0.0, 22.4, 23,8, 46.1, 4g.4, 53.g, 54.6, 55.3, 55.6, 61.2, 71.6, 110.2, 120.4, 126.9, 127.2, 127.9, 1~8.5, 129.6, 141.7, 143.5, 157.1.
Mass Spec. (%): 426 (1"~arent), 2-9 (31), 246 (46), 142 (45),121 (100), 91 ', ~ (62).
: ` ~
1 .
W0 92~12151 ;~ PC~/lLJS91/~ 36 Tha title compounds of Examples 2-8 were prepared by a procedure similar to that of Exarnpia 1.
t2s 3s)-cls-l-(4-carb~thoxvbutvl~-2-(di~henvlmethvl)-N-((2-me1h 5 phenyl)methyl~ 7abicvclo~2.2.210ctan-3-amine iodide:
Prapar~d in 13/o yield, m.p. ~5C.
Mass Spac.: 5~1 (1, parent), 373 (89), 359 (56),121 (100), 91 (45).
~XAMI_E 3 (2S 3s)-cis-~ -rar~o~thox\l~henv!mathv~ dir~henvlmelhv!)-N-((2-meth 10 phenyl~me(hvl)-1--~7 .bic~,c!o~2.2.'~'1cctan-3-~nnin3 iodid3:
Prepared in 1~% ~Jis!d, m r 1'10-1~S~C.
Anai. Calc'd ~or C~3H 3N2031~1/3H~0: C ~.40, H 6.21, N 3.96. Found: C 64.05, H ~.16, N 3.~8.
(2S.3S!-cis~ L~carbomethoxvpentvl)-2-(dlphenvlmethvl~N-lL2-meth Prepared (using acetQnitrila instead ot ethanol as solvent3 in 5% yield, as an oil.
Ana~. Calc'd for C3aH45N2O~SF3-HClo1l2H2o C 57.32, H 6.65, N 3.71. Found:
C 57.29, H 6.48, N 3.68. Found: C 57.29, H 6.48, N 3.68 (2S.3S)~is-1-(5-Carboxy~entYI)-2-1di~henylmethvl)-N-(12 rnetho~methvl)-1-azabicvclo~2.2.2~ ;~-amine trHiate:
Prepared by hydrolysis of the above compound with potassium hydroxide in ethanol.
High Res. Mass Sp~c: Calc'dforC3,H,.3N203: ~27.3278. Found: 527.3268.
3~ EXAMPLE 6 2S,3S~-cis-l-AllYI-2-(diPhenv!methvll-N-U2-methoxyPhenvl~methyl)-1-aza-bicvclo~2.2.210ctan-3-arrline bromipe:
Prepared in 58% yield, m.p. 15~160C.
~ Anai. Calc'd for C3lH37N20Br-1.25H20: C 66.96, H 7.16, N 5.04. Found: C
66.95, H 7.06, N 4.97.
~, .
~VO 92/11~1~1 21 Q ('~ , PCI/US91/0883fi E~MPLE 7 ~S,3S~is-1-Benzyl-2-(diphenvlm~y~ ~oxyDhenvllmethvl)-1-aza-bicyclo ~2 .2 .21 octan-3-amlne bromide:
Prepared in 53% yield, m.p. 206-208aC.
Anal. Calc'd~orC35H33N20BroH20: C 69.87, H 6.87, N 4.66. Found: C 69.48, H 6.34, N 4.52.
(2S 3S) cis-1-(Carboethvoxymeth~ ~i~henvlmethvl)-N-((2-methox~/- -phenyl~methvl~-1-azabicycloL2.2.21Oct n-3-amine bromide:
10 Prepared in 17~ yield, m.p. 12~135C.
Anal. Calc'd for C32H39N2O38r4H2O: C 64.32, H 6.92, N ~.69. Found: C 64.1 '.
H 6.88, N 4.62.
.
.
Claims (13)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A compound of the formula (I) wherein R1 is (C1-C4)alkyl, allyl, phenyl-(C1-C3)alkyl, HOOC-(C1-C10)alkyl or (C1-C4)alkoxy-OOC-(C1-C10)alkyl; R2 is selected from the group consisting of phenyl, thienyl, furyl and pyridyl, each of the foregoing R2 groups being optionally substituted with from one to three substituents independently selected from the group consisting of cyano, nitro, amino, N-mono-(C1-C3) alkylamino, fluorine, chlorine, bromine, trifluoromethyl, (C1-C3)alkyl, (C1-C3)alkoxy, allyoxy, (C1-C3)alkoxy-carbonyl, carboxamido and N,N-di-(C1-C3)alkyl-carboxamido; and X is a pharmaceutically acceptable counterion, or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 wherein R2 is 2-methoxyphenyl.
3. A compound according to claim 2 wherein R1 is methyl.
4. A compound according to claim 3 wherein X is iodide.
5. A pharmaceutical composition for treating or preventing a condition selected from the group consisting of inflammatory diseases, arthritis, colitls, pain, allergies, chronic obstructive airways disease, hypersensitivity disorders, vasospastic diseases, fibrosing and collagen diseases, reflex sympathetic dystrophy, peripheral neuropathy, disorders related to immune enhancement or suppression and rheumatic diseases in a mammal, comprising an amount of a compound according to claim 1 effective in preventing or treating such condition and a pharmaceutically acceptable carrier.
6. A pharmaceutical composition for antagonizing the effects of substance P in a mammal, comprising a substance P
antagonizing effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier.
antagonizing effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier.
7. A pharmaceutical composition for treating or preventing a condition in mammal, the treatment or prevention of which is effected or facilitated by a decrease in substance P mediated neurotransmission, comprising an claim 1 effective in antagonizing the effect of substance P at its receptor site and a pharmaceutically acceptable carrier.
8. A pharmaceutical composition for treating or preventing a condition in a mammal, the treatment or prevention of which is effected or facilitated by a decrease in substance P mediated neurotransmission, comprising an amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, effective in treating or preventing such condition and a pharmaceutically acceptable carrier.
9. A process for preparing a compound of the formula (I) wherein R1 is (C1-C4)alkyl, allyl, phenyl-(C1-C3)alkyl, HOOC-(C1-C10)alkyl or (C1-C4)alkoxy-OOC-(C1-C10)alkyl; R2 is selected from the group consisting of phenyl, thienyl, furyl and pyridyl, each of the foregoing R2 groups being optionally substituted with from one to three substituents independently selected from the group consisting of cyano, nitro, amino, N-mono-(C1-C3)alkylamino, fluorine, chlorine, bromine, trifluoromethyl, (C1-C3)alkyl, (C1-C3)alkoxy, allyoxy, (C1-C3)alkoxy-carbonyl, carboxamido and N,N-di-(C1-C3)alkyl-carboxamido; and X is a pharmaceutically acceptable counterion;
comprising reacting a compound of the formula (II) wherein R2 is defined as above, with a compound of the formula R1X, wherein R1 is defined as above and X is chloro, fluoro, bromo, lodo, tosyloxy, mesyloxy or trifluoromethanesulfonyl.
comprising reacting a compound of the formula (II) wherein R2 is defined as above, with a compound of the formula R1X, wherein R1 is defined as above and X is chloro, fluoro, bromo, lodo, tosyloxy, mesyloxy or trifluoromethanesulfonyl.
10. A process according to claim 9, wherein the compound of formula 1 prepared by said process is a compound wherein R2 is 2-methoxyphenyl.
11. A process according to claim 9, wherein the compound of formula 1 prepared by said process is a compound wherein R1 is methyl.
12. A process according to claim 9, wherein the compound of formula 1 prepared by said process is a compound wherein X is iodide.
13. A process according to claim 9, wherein the compound of formula 1 prepared by said process is a compound wherein R1 is selected from carboethoxybutyl, carboethoxyphenylmethyl, carbomethoxypenyl, carboxypentyl, benzyl, allyl, and carboethoxymethyl.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US63964491A | 1991-01-10 | 1991-01-10 | |
| US639,644 | 1991-01-10 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2100163A1 true CA2100163A1 (en) | 1992-07-11 |
Family
ID=24564973
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002100163A Abandoned CA2100163A1 (en) | 1991-01-10 | 1991-12-04 | N-alkyl quinuclidinium salts |
Country Status (14)
| Country | Link |
|---|---|
| EP (1) | EP0566589A1 (en) |
| JP (1) | JPH0733385B2 (en) |
| KR (1) | KR930703311A (en) |
| AU (1) | AU652407B2 (en) |
| CA (1) | CA2100163A1 (en) |
| FI (1) | FI933167A0 (en) |
| HU (1) | HUT65612A (en) |
| IE (1) | IE920071A1 (en) |
| IL (1) | IL100584A (en) |
| MX (1) | MX9200057A (en) |
| NZ (1) | NZ241261A (en) |
| PT (1) | PT100003A (en) |
| WO (1) | WO1992012151A1 (en) |
| ZA (1) | ZA92148B (en) |
Families Citing this family (59)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5364943A (en) * | 1991-11-27 | 1994-11-15 | Pfizer Inc. | Preparation of substituted piperidines |
| CA2084193C (en) * | 1990-06-01 | 1998-04-07 | John A. Lowe, Iii | 3-amino-2-aryl quinuclidines |
| DK0613458T3 (en) * | 1991-11-12 | 1998-02-09 | Pfizer | Acyclic ethylenediamine derivatives as substance P receptor antagonists |
| DE69331190T2 (en) * | 1992-05-18 | 2002-04-18 | Pfizer | BRIDGED AZABICYCLIC DERIVATIVES AS SUBSTANCE P ANTAGONISTS |
| US5637699A (en) * | 1992-06-29 | 1997-06-10 | Merck & Co., Inc. | Process for preparing morpholine tachykinin receptor antagonists |
| US6048859A (en) * | 1992-06-29 | 2000-04-11 | Merck & Co., Inc. | Morpholine and thiomorpholine tachykinin receptor antagonists |
| US5719147A (en) * | 1992-06-29 | 1998-02-17 | Merck & Co., Inc. | Morpholine and thiomorpholine tachykinin receptor antagonists |
| EP0654029A1 (en) * | 1992-08-04 | 1995-05-24 | Pfizer Inc. | 3-benzylamino-2-phenyl-piperidine derivatives as substance p receptor antagonists |
| GB9216911D0 (en) * | 1992-08-10 | 1992-09-23 | Merck Sharp & Dohme | Therapeutic agents |
| US5387595A (en) * | 1992-08-26 | 1995-02-07 | Merck & Co., Inc. | Alicyclic compounds as tachykinin receptor antagonists |
| US5393762A (en) * | 1993-06-04 | 1995-02-28 | Pfizer Inc. | Pharmaceutical agents for treatment of emesis |
| TW385308B (en) * | 1994-03-04 | 2000-03-21 | Merck & Co Inc | Prodrugs of morpholine tachykinin receptor antagonists |
| IL116249A (en) * | 1994-12-12 | 2003-07-06 | Pfizer | Nk-1 receptor antagonists for the treatment of neuronal damage and stroke |
| FR2728165A1 (en) | 1994-12-19 | 1996-06-21 | Oreal | USE OF AN ANTAGONIST OF SUBSTANCE P FOR THE TREATMENT OF SKIN REDNESS OF NEUROGENIC ORIGIN |
| FR2728169A1 (en) | 1994-12-19 | 1996-06-21 | Oreal | USE OF A SUBSTANCE P ANTAGONIST FOR THE TREATMENT OF PRURITUS AND EYE OR PALPEBRAL DYSESTHESIA |
| FR2728166A1 (en) | 1994-12-19 | 1996-06-21 | Oreal | TOPICAL COMPOSITION CONTAINING AN ANTAGONIST OF SUBSTANCE P |
| TW458774B (en) | 1995-10-20 | 2001-10-11 | Pfizer | Antiemetic pharmaceutical compositions |
| FR2741262B1 (en) | 1995-11-20 | 1999-03-05 | Oreal | USE OF A TNF-ALPHA ANTAGONIST FOR THE TREATMENT OF CUTANEOUS REDNESS OF NEUROGENIC ORIGIN |
| US7163949B1 (en) | 1999-11-03 | 2007-01-16 | Amr Technology, Inc. | 4-phenyl substituted tetrahydroisoquinolines and use thereof |
| AU781179B2 (en) | 1999-11-03 | 2005-05-12 | Albany Molecular Research, Inc. | Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine and serotonin |
| RU2301808C2 (en) | 2000-07-11 | 2007-06-27 | Эймр Текнолоджи, Инк. | 4-phenyl-substituted tetrahydroisoquinolines, pharmaceutical composition and method for treatment based on thereof |
| RU2388751C2 (en) | 2004-07-15 | 2010-05-10 | Амр Текнолоджи, Инк. | Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof for inhibiting norepinephrine, dopamine and serotonin reuptake |
| ES2382814T3 (en) | 2005-05-17 | 2012-06-13 | Merck Sharp & Dohme Ltd. | Cis-4 - [(4-chlorophenyl) sulfonyl] -4- (2,5-difluorophenyl) cyclohexanopropanoic acid for cancer treatment |
| KR20080044840A (en) | 2005-07-15 | 2008-05-21 | 에이엠알 테크놀로지, 인크. | Aryl-and heteroaryl-substituted tetrahydrobenzazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin |
| BRPI0616463A2 (en) | 2005-09-29 | 2011-06-21 | Merck & Co Inc | compound, pharmaceutical composition, and use of a compound |
| GB0603041D0 (en) | 2006-02-15 | 2006-03-29 | Angeletti P Ist Richerche Bio | Therapeutic compounds |
| WO2008039327A2 (en) | 2006-09-22 | 2008-04-03 | Merck & Co., Inc. | Method of treatment using fatty acid synthesis inhibitors |
| US20110218176A1 (en) | 2006-11-01 | 2011-09-08 | Barbara Brooke Jennings-Spring | Compounds, methods, and treatments for abnormal signaling pathways for prenatal and postnatal development |
| KR101591656B1 (en) | 2007-01-10 | 2016-02-19 | 엠에스디 이탈리아 에스.알.엘. | - Amide substituted indazoles as polyADP-ribosepolymerasePARP inhibitors |
| CA2682727C (en) | 2007-04-02 | 2016-03-22 | Banyu Pharmaceutical Co., Ltd. | Indoledione derivative |
| CA2690191C (en) | 2007-06-27 | 2015-07-28 | Merck Sharp & Dohme Corp. | 4-carboxybenzylamino derivatives as histone deacetylase inhibitors |
| EP2247185B1 (en) | 2008-03-03 | 2014-04-16 | Tiger Pharmatech | Tyrosine kinase inhibitors |
| AR071997A1 (en) | 2008-06-04 | 2010-07-28 | Bristol Myers Squibb Co | CRYSTAL FORM OF 6 - ((4S) -2-METHYL-4- (2-NAFTIL) -1,2,3,4-TETRAHYDROISOQUINOLIN-7-IL) PIRIDAZIN-3-AMINA |
| US9156812B2 (en) | 2008-06-04 | 2015-10-13 | Bristol-Myers Squibb Company | Crystalline form of 6-[(4S)-2-methyl-4-(2-naphthyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyridazin-3-amine |
| UA105182C2 (en) | 2008-07-03 | 2014-04-25 | Ньюрексон, Інк. | Benzoxazines, benzothiazines, and related compounds having nos inhibitory activity |
| WO2010114780A1 (en) | 2009-04-01 | 2010-10-07 | Merck Sharp & Dohme Corp. | Inhibitors of akt activity |
| PE20120373A1 (en) | 2009-05-12 | 2012-05-17 | Albany Molecular Res Inc | 7 - ([1,2,4] TRIAZOLO [1,5-A] PYRIDIN-6-IL) -4- (3,4-DICHLOROPHENYL) -1,2,3,4-TETRAHYDROISOQUINOLINE |
| AU2010247735B2 (en) | 2009-05-12 | 2015-07-16 | Albany Molecular Research, Inc. | Crystalline forms of (S)-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)- 1,2,3,4-tetrahydroisoquinoline and use thereof |
| AU2010247849B2 (en) | 2009-05-12 | 2015-11-19 | Albany Molecular Research, Inc. | Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof |
| CN102638981B (en) | 2009-10-14 | 2015-07-22 | 默沙东公司 | Substituted piperidines that increase p53 activity and the uses thereof |
| WO2011163330A1 (en) | 2010-06-24 | 2011-12-29 | Merck Sharp & Dohme Corp. | Novel heterocyclic compounds as erk inhibitors |
| CN107090456B (en) | 2010-08-02 | 2022-01-18 | 瑟纳治疗公司 | Inhibition of beta 1 gene expression using short interfering nucleic acids mediated by RNA interference of catenin (cadherin-associated protein) |
| HUE044815T2 (en) | 2010-08-17 | 2019-11-28 | Sirna Therapeutics Inc | RNA INTERFERENCE MEDIATED INHIBITION OF HEPATITIS B VIRUS (HBV) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA) |
| US8883801B2 (en) | 2010-08-23 | 2014-11-11 | Merck Sharp & Dohme Corp. | Substituted pyrazolo[1,5-a]pyrimidines as mTOR inhibitors |
| EP2613782B1 (en) | 2010-09-01 | 2016-11-02 | Merck Sharp & Dohme Corp. | Indazole derivatives useful as erk inhibitors |
| EP2615916B1 (en) | 2010-09-16 | 2017-01-04 | Merck Sharp & Dohme Corp. | Fused pyrazole derivatives as novel erk inhibitors |
| EP3766975A1 (en) | 2010-10-29 | 2021-01-20 | Sirna Therapeutics, Inc. | Rna interference mediated inhibition of gene expression using short interfering nucleic acid (sina) |
| US9351965B2 (en) | 2010-12-21 | 2016-05-31 | Merck Sharp & Dohme Corp. | Indazole derivatives useful as ERK inhibitors |
| US20140045847A1 (en) | 2011-04-21 | 2014-02-13 | Piramal Enterprises Limited | Crystalline form of a salt of a morpholino sulfonyl indole derivative and a process for its preparation |
| EP2770987B1 (en) | 2011-10-27 | 2018-04-04 | Merck Sharp & Dohme Corp. | Novel compounds that are erk inhibitors |
| WO2013165816A2 (en) | 2012-05-02 | 2013-11-07 | Merck Sharp & Dohme Corp. | SHORT INTERFERING NUCLEIC ACID (siNA) COMPOSITIONS |
| RU2660429C2 (en) | 2012-09-28 | 2018-07-06 | Мерк Шарп И Доум Корп. | Novel compounds that are erk inhibitors |
| US9655899B2 (en) | 2012-11-28 | 2017-05-23 | Merck Sharp & Dohme Corp. | Compositions and methods for treating cancer |
| TW201429969A (en) | 2012-12-20 | 2014-08-01 | Merck Sharp & Dohme | Substituted imidazopyridines as HDM2 inhibitors |
| EP2951180B1 (en) | 2013-01-30 | 2018-05-02 | Merck Sharp & Dohme Corp. | 2,6,7,8 substituted purines as hdm2 inhibitors |
| WO2015034925A1 (en) | 2013-09-03 | 2015-03-12 | Moderna Therapeutics, Inc. | Circular polynucleotides |
| US10947234B2 (en) | 2017-11-08 | 2021-03-16 | Merck Sharp & Dohme Corp. | PRMT5 inhibitors |
| EP3833668A4 (en) | 2018-08-07 | 2022-05-11 | Merck Sharp & Dohme Corp. | Prmt5 inhibitors |
| WO2020033284A1 (en) | 2018-08-07 | 2020-02-13 | Merck Sharp & Dohme Corp. | Prmt5 inhibitors |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1173445B (en) * | 1984-03-16 | 1987-06-24 | Guidotti & C Spa Labor | AGENTS WITH ANTIBRONCOSPASTIC ACTIVITY AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM |
| MX18467A (en) * | 1988-11-23 | 1993-07-01 | Pfizer | THERAPEUTIC AGENTS OF QUINUCLIDINES |
| IT1230881B (en) * | 1989-06-20 | 1991-11-08 | Angeli Inst Spa | DERIVATIVES OF R (-) 3-QUINUCLIDINOL |
-
1991
- 1991-12-04 EP EP92901108A patent/EP0566589A1/en not_active Withdrawn
- 1991-12-04 HU HU9301988A patent/HUT65612A/en unknown
- 1991-12-04 CA CA002100163A patent/CA2100163A1/en not_active Abandoned
- 1991-12-04 JP JP4501342A patent/JPH0733385B2/en not_active Expired - Lifetime
- 1991-12-04 WO PCT/US1991/008836 patent/WO1992012151A1/en not_active Application Discontinuation
- 1991-12-04 AU AU90947/91A patent/AU652407B2/en not_active Ceased
-
1992
- 1992-01-08 MX MX9200057A patent/MX9200057A/en unknown
- 1992-01-09 NZ NZ241261A patent/NZ241261A/en unknown
- 1992-01-09 PT PT100003A patent/PT100003A/en not_active Application Discontinuation
- 1992-01-09 ZA ZA92148A patent/ZA92148B/en unknown
- 1992-01-09 IE IE007192A patent/IE920071A1/en not_active Application Discontinuation
- 1992-10-05 IL IL10058492A patent/IL100584A/en not_active IP Right Cessation
-
1993
- 1993-06-30 KR KR1019930701985A patent/KR930703311A/en not_active Application Discontinuation
- 1993-07-09 FI FI933167A patent/FI933167A0/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| JPH05508866A (en) | 1993-12-09 |
| NZ241261A (en) | 1994-05-26 |
| IL100584A0 (en) | 1992-09-06 |
| HUT65612A (en) | 1994-07-28 |
| IE920071A1 (en) | 1992-07-15 |
| KR930703311A (en) | 1993-11-29 |
| EP0566589A1 (en) | 1993-10-27 |
| WO1992012151A1 (en) | 1992-07-23 |
| PT100003A (en) | 1993-02-26 |
| ZA92148B (en) | 1993-07-09 |
| MX9200057A (en) | 1992-07-01 |
| IL100584A (en) | 1995-10-31 |
| FI933167A (en) | 1993-07-09 |
| AU652407B2 (en) | 1994-08-25 |
| HU9301988D0 (en) | 1993-12-28 |
| JPH0733385B2 (en) | 1995-04-12 |
| FI933167A0 (en) | 1993-07-09 |
| AU9094791A (en) | 1992-08-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2100163A1 (en) | N-alkyl quinuclidinium salts | |
| EP0613458B1 (en) | Acyclic ethylenediamine derivatives as substance p receptor antagonists | |
| US11180490B2 (en) | Cyclopropyl urea formyl peptide 2 receptor and formyl peptide 1 receptor agonists | |
| JP4616971B2 (en) | 1-azabicycloalkane compounds and pharmaceutical uses thereof | |
| JPH0647586B2 (en) | 1-Heteroaryl-4-[(2.5-pyrrolidindione-1-yl) alkyl] piperazine derivative | |
| JPH082901B2 (en) | 1-azabicyclo [3.2.2 nonane-3-amine derivatives | |
| CA2133077A1 (en) | Azacyclic compounds | |
| PL170516B1 (en) | Method of obtaining novel derivatives of fluoroalkoxy benzylaminic compounds of piperidine | |
| UA59379C2 (en) | 6-phenyl-pyridin-2-amine derivatives having an activity of nitric oxide synthase inhibitors | |
| US4971969A (en) | Pharmaceutical composition containing 1-(mono- or bis(trifluoromethyl)-2-pyridinyl)piperazines | |
| KR960009570B1 (en) | Imidazoline derivative and preparation thereof | |
| JPS60255764A (en) | (r)-alpha-ethyl-2-oxo-1-pyridineacetamide, manufacture and pharmaceutical composition | |
| JPS5830314B2 (en) | Production method of guanidine compound | |
| JPS61155377A (en) | Tetrahydro-benzthiazole compound and manufacture | |
| CA2403264A1 (en) | Chiral fluoroquinolizinone arginine salt forms | |
| HU187673B (en) | Process for preparing 2-piperazino-pyrimidine derivatives | |
| AU679115B2 (en) | Imidazolidinone derivative, acid-addition salt thereof, and remedy for senile dementia | |
| SK45196A3 (en) | 4-indolylpiperazinyl derivatives | |
| WO2008142623A2 (en) | Tumor necrosis factor - alpha inhibitors | |
| CA2072598A1 (en) | Pharmaceutical compositions | |
| AU697553B2 (en) | Resolution of 1-azabicyclo{2.2.2}octan-3-amine, 2-(diphenylmethyl)-n -{{2-methoxy-5-(1-methylethyl)phenyl}methyl} | |
| US20050080120A1 (en) | 4-[3,5-bis-(2-hydroxy-phenyl)-[1,2,4]triazol-1-yl]-benzoic acid derivatives for treating an excess of metal in the body | |
| HU197738B (en) | Process for producing quinolin carboxylic acid derivatives and pharmaceutical compositions containing them as active components | |
| US4843085A (en) | Pyridine derivatives, process for production thereof and pharmaceutical compositions useful as anti-arhytmics | |
| US6303608B1 (en) | 2-{4-[4-(4,5-dichloro-2-methylimidazol-1-yl)butyl]-1-piperazinyl}-5-fluoropyrimidine, its preparation and its therapeutic use |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |