CA2070400A1 - Heterocyclic substituted naphthyridinones and methods and compositions employing them - Google Patents

Abstract

Nitrogen-containing heterocyclic substituted naphthyridinones of formula (I), effective in treating allergic reactions, inflammation, inflammatory bowel disease, pepticulcers and hyperproliferative skin disease, and pharmaceutical compositions employing them, are disclosed. Formula (I) or a pharmaceutically acceptable salt thereof, wherein: A is O or S; W represents (a) or (b); R
represents H or alkyl; R1 represents alkanediyl; R2 represents a covalent bond or -alkanediyl-O-; R3 represents alkyl, cycloalkyl, benzyl, substituted benzyl or hydroxyalkyl; Q represents phenyl, 1- or 2-naphthyl, 1-,2-,3-,4-,5-,6-, or 7-indenyl or 1-,2-,3-,4-,5-,6- or 7-indanyl, each of which may optionally be substituted with 1 to 3 Y groups as defined below; and each Y is independently selected from alkyl, halo, nitro, alkoxy, alkylthio, -CF3, -CN, cycloalkyl, alkylsulfinyl or alkylsulfonyl.

Description

~/0 91/08~8 ~qL'u~ PCl tUS90/06~73 .3~ 5 , ~T ~ ~ ~ ~ ! ~ L I ~ ~-J ~ s~ ) T u~ P ~T ~Y ~ N E s A P~ D
,i 'J '~C ~ C ~ ^l P L O Y l N, G T~l ~ M

. ~ .

Tha present invcntion relatesto certain heterocyclic 3~ substituted naphthyridinones and to methods and compositions using such compounds.
: I European published application No. 0 231 709 discloses phenyi naphthyridinones af the ~ormula:

~: ~ z 3 ~ wherein Z is, for example, ah amine functional ~roup and X and Y are, :tor; ~xampls, ~H, a halogen a~om, a lower alkyl group, a trifluoromethyl, an 25~ ~ àlkoxy, a methylthio, a nitro or a cyano. Among the amine functional ; : groups described~:are (C 2~N~

WO 91/08208 ~'7~ 3 PCT/US90/06&
.
: -2-where n is C to 5 and it is possible for R1 and R2 to 'orm a piparazin0 ring substituted by an alkyl or an aromatic nucleus which ma~ or may no, be substituted, or alternatively to form an imidazole ring. Thesa compounds are disclosed as ulcar-inhibiting drugs.
U.S. Patent NG. 4,684,727 disclosas zwi.terionic bicyclic compounds of the formula:

(~)n ~2 (R I F~ )m . Q

10 wherein the substitutents can be among ~hose exemplified below:
~ii W and X may be the sama or different and each independently represents -CHa or-N=;
Z1 and Z2 ara the same or different and ~ach independently represents -O- or-S-; : ::
R~, R2, R3, R4 and R5 are the same or different and each :
may be independen~ly s~l~cted from the group consisting of, for ~ example, H, alkyl having from 1 to 12 carbon atorns, alkenyl having from ~ 3 to 8 carbon atoms, alkynyl having from 3 to 8 carbon atoms, etc.;
'~ in addition, two of R1, R2 and R3 can be joined together to 20 represent a ring which oan contain from 2 to 8 carbon atoms, such as a pyrroie, piperidine or morpholine ring;
m is an intoger of from 0 to 3;
n is an integer of from 0 to 2;
Q repr~sents an aryl or an aromatic heterocyclic group 25 which can optionally be substituted with 1 to 3 substituents Y; and . ~ each Y substituent is independently selected from the I :~ group consisting of, for example, hydroxy, alkyl having from 1 to 6 ....
~: carbon atoms, halogen, NO2, alkoxy having from 1 to 6 carbon aloms, .,;` .
1: :

. WO91/08208 ~ qV~ PCI/US9O/06873 ` . i ,, : `' trifluorom~lhyl, cyano, ~tc. Thes~ compounds are disolosed ~s being anti-allergic, anti-inflammatory and/or cytoprotectiYe agant~.
l ' 5 i we have now surprisingly ~ound that compounds having the structural formul~ I
R
., I
i, 11 1 1 ~

~`i ~N~N~A
~3 ,.~ 10 :~ or a pharmaceutically acceptabls salt thereof have astivity useful in the treatment of allergy, inflammation, hyperproliferative s'.in disease and peptic ulcers, wher~in:
R is H or alkyl;
~; 15 AisOorS;
W repres~nts ~R1 r ~
N ~ or N+ );
R2 J - R3 ~ pl2 R9 represents alkanediyl;
R2 represents a covalent bond or-alkanediyl-O-;
. ~ R3 represents alkyl, cycloalkyl, benzyl, substituted benzyl or~hydroxyalkyl having 2 to 6 carbon atoms between the N atom and the OH group;
; ~: a represents phenyl, 1- or 2-naphthyl, l-, 2-, 3-, 4-, ~-, 6- or ~, ; ~ ~: 7~indenyl or l-, 2~, 3-, 4-, 5-, 6- or 7-indanyl, each of which may ~-, ~ optionally be substituted with 1 to 3 Y groups as defined below; and , ~
. ...

~ `' ~ fi WO 91/0820~ PClr/US90/06~,:
Z~ ~B~

each Y iS indep~ndently selected from alkyl, halo, nitro, :, ail~oxy, ~i~ylthio, -C, 3, -GN, cycloalkyl, al~ylsul~inyl or al5~ylsulfonyl.
Preferably, W is the group J
. 3 R2 A is p,a,arâi,!y O and Q is praf^rably ph_nyl or substitutad phanyl. W is pr~i~rabiy ~N~ , --N3, --N~) or - N/ \o 5 ,~ 10 ,`, .:
mora preferably ~N~ or --N~O ~ .
~ ~ . .

: : Par~icularly preferred compounds include:

~0 91/0~208 ~ PCI/U~90/06X73 `l - 5-¢~ N'~

N N

~CF3 : /--\ ."' ",1 ~
~ ~ ~CI ~, XXN/~

~! " ~ N

::~ ` ~ : 5~ CN

WO 91/~)8208 pcT/ljs9o/û6~

~7~ 6-~I 3 ~CN ~ :
:1 '~` : : ~i ",~ : : hl .
~CN

. ~ 0 or 2@~ PCT/US90/06873 .

:' I I
~N~
~0 or a pharrnaceutically acceptable salt thereof.
.~ Other aspects of the invention involve a pharmacautical '~ 5 composition comprising a cornpound of formula I abcve in combination with a pharmaceutically acceptable carrier and methods of treatin~
allergic reactions, inflammation, inflammatory bowel disease, peptic ulcers and hyp~rprolifcratiYe skin dis0ase in a mammal c~mprising administering to said mammal an effective amount of a compound of : 1Q formula Iforsuch purpose.
. 3 ~
:: : D~LLED DES~RIPTI~N OFTHE INVENTION

Certain compounds of this invention may exist in isomeric forms. The invention contemplates all such isomers both in pure form and in admixture, including racemic rnixtures.
Certain compounds of the invention of formula I can exist in unsolvated as weil as solvated ~orms1 including hydrated forms, e.g., hqmihydrate. In g~noral, th~ solvated forms, with pharmaceutically 20:: acceptable soivonts such as water, ethanol and the lika, are equivalen~
. ~ :: to the: unsoivated forms for purposes of the invention.
Certain compounds of the invention e.g., those with a . ~ strongly basic amine group, also form pharmaceutically acceptable salts with organic and inorganic acids. Examples of suitable acids for such 2:5 salt formation:are hydrochloric, sulfuric, phosphcric, acetic, citric, oxalic, : maionic,~salicylic, malic, fumaric, succinic, ascorbic, maleic, ~ :
methanesulfonic ~and other mlneral,: sulfonic and carboxylic acids well ~:

WO 9 1 /08208 PCI / U~i90/0~.
, ,~,r~ fi~ f,;~

;~ known to those skilled in the art. The salts are prepared by contacting thv fras basa Form with a suffioient amount of the desired acid to prcduce a salt in the conventional manner. The free base forms may be regenerate~ by traating the salt with a suitable dilute aqueous base 5 solution such as dilute aqueous sodium hydroxide, potassium ca,~onâte, ~mmonia or sodiùm bicarbonate. The free base forms differ from thair respective salt torms somewhat in certain physical properties, such _s -^o!~hility in pe!ar solvents, but ths salts are otherwise eq~ivalent to Iheir respective free base forms for purposes of this 1 0 im~en.lion.
~:i The foilowing ~erms used in ~he present specification and claims have the meaninss given below, unless otherwise indicated: .
alkyl (including the alkyl portisnS of hydroxyalkyl, a.koxy, : ;:
f, alkylthio, alkylsulfinyl and alkylsulfonyl) - represents a straight or :~ ~fl 1~ branched, saturated hydrocarbon chain having from 1 to 10, preferably f from 1 to 6, carbon atoms; ~.
;~ alkanediyl - represents a dival~nt, saturated straight or :j branched hydrocarbon chain, having from 1 to 10, preferably from 1 to 6, :~ ~ carbon atoms;
20 ~ cyeloalkyl - represents a saturated carbocyclic ring having from 3 to 10, pre~erably from 3 to 6 carbon atoms;
halo - repr~sents fluoro, chloro, bromo or iodo;
- substituted phenyl (Including the substituted phenyl portion ~: of substitutad ~enzyl) - repr~santS a phenyl group in which 1 to 3 ~! 25 hydrogen atoms thereof are replaced by the same or dif~erent ~,, substituenls independently chosen frorn alkyl, halo, nitro, alkoxy, . il alkylthio, -CF3, -CN, cycloalkyl, alkylsulfinyl 9r alkylsulfonyl; and :
substituted benzyl - represents a benzyl group in which the phenyl ring is substituted as defined above.
The compounds of ~he invention can be made by the processes described below with reference to Scheme 1:

:

: ,:

WO 91/08208 ~ PCr/liS90/06873 g ~iC:HE~P~I 1 .~
COOR~ CooR4 ¢~CH20H

, N L N NHQ N NHQ
-~ II III IV
~W

NHQ N N
~ ~ Q

;~ IE ~CH(OH)AIkyl ~(CO)Alkyl F ll ~
N NHQ N NHQ
V I V I I
AlkYI
~W
Ib (A=O) G N ~ N ~0 Q
; ~ .. ..
In the compound of Formula II, L represents a conventional leaving group such as chio!o~ bromo, iodo, tosyi, mesyl, 5 etc. and R4 can be H or alkyl. In Step A, the compound of Formula II
wh~rein R4 i~ H can be reacted with an amine of Formula QNH2 in aq~leous solution: with an acid catalyst such as para-toluene sulfonic : . .-acid.
In S~ep A, when R4 is alkyl (pre~era~1y not methyl), the . ~ : ;10 compound QNH2 can be reacted in excess (preferably more than 2 e~uivalents) ~ith the compound of Formula II and heated, preferably to about 1 25~C, for: a time sufficien~ to provide the desired reaction, e.g., by WO 91/08208 PCI~I~S90/068 `$ - 10 -following the reaction with thin iayer chromatography. This reac.ion can be run neat or in a suitable solvent such as tolu~n~ a, etc.
If R4 in Formula III is H, it is prefera~ly converted to an ester (i.e., R4 is a!kyl) by rsaction under standard esterif,câtion 5 conditions with, for example, potassium carbonate an~ cliethyl sulfate in dimethylformamide.
In Step B, ~he ester 3f Fermula ~ is reduce~ 'N,th 2 -I suitable reducing agent such as lithi~Jm al~minum hydr,d~, lit~ m borohydride or lithium triethylborohydrida ~"Super ~ydride~"). Wi~n 10 "Super llydride~", th~ naaction is preierably ocoled, e.~., to 3.
temperature CT from about -20C to aDou~ rool-n ~emperature. Wi[h lithium aluminum hydride, ~he reaction is normally pe~ormed in ~n ether .¦ such as ~iethylether under reflux. Wi~h li~hium borohydride, the reaction is run initially at room temperature, then heated at reflux (e.g., in 15 tatrahydrofuran) until the reaction is complete, e.g., as shown by thin ~'~ layerchromatography.
The compound of Formula I'V is oxidized in Step C with a suitable oxidizing agent such as ac~ivated manganese dioxide in a suitabl~ solvent, such as benzene, toluena, xylene, chloroform, etc., at 2a ~!evated temperaturo (e.~., abaut 50C to about 120C), preferably with :, ~ removal of water formed in the reaction.
7, ~ In Step D, ~he compound of Formula V is reacted with a ¦ compound of the Formula W-CH2-CO2alkyl in the presence of a catalytic amount of a suitable base. Exemplary bas~s includs potassium t-25 butoxide, sodiurn ethoxide, etc. The reaction can be performed in a : suitable solvent such as tetrahydrofuran (preferably containing a smallq quantity of a protic solvent such as t-butanol) or an alcohol solvent, preferably corresponding to the alcohol portion of the ester 3~ W-CH2-CO2alkyl. Other possible solvents include ether type solvents 30 such as dioxane, dimethoxyethane, etc. The reaction can be run at any :
suitable temperature, preferably at room temperature or below.
In Step E, the compound of Formula V is r~acted with a suitabie alkyl organometallic ag~nt MAlkyl, wherein M is, for example, a magnesium haiide or lithium. This reaction is run in a suitabl2 solvent ~'1: : .:

., ~ .

wo gl/08208 Pc~ S90/06873 .
~, such as an ether, e.g., diethylether or tetrahydrofuran. The reactiQn is preferably run at or below room temperaturs, e.5. from about 25~C .o about -20C. The reaction is neutralized with a mineral acid to provide the compound of Formula YI.
The conditions and reactants for Steps F and G are essentially Ihe same as those set fo~h a~ove ~cr ~iieos C and D
respectively.
The compounds of this inven~ion wnerein A is sulfur may be obtained by treating the purified 2-czrkonyl comDound of forrnula I
with thiating reagents well known in the a,~. Lawasson's P~Qasent ( .4-bis(4-melhoxyphenyl-1,3-dithia-2,4-dipnGsphetana-2,~-disu"ide~ o. ona of its analogues, in toluene, or phosphorus pentasulfide in pyridine are suitable for this purpose.
- ~ The compounds of formula I wherein W represents ,~ ~ 5 N+
R3 ~ R2 ~

can be prepared by reacting a compound of formula I wherein W ~: .
represents --N

20~ 2J
with a compound R3 L wherein L represents a suitable leaving group such as chloro, bromo, iodo, tosyl, mesyl, etc. The reaction is carried out 3 ~ ` in an inert solvent such as toluene or xylene at elevated temperatures, -e.g. from about 5ûC to about 1 ~0C. -~
The compounds of this invention may be employed as anti- :
allergy agents in the treatment of, for example, asthma, allergic or seasonal rhinitis, and/or chronic bronchitis. The anti-allergy method of ,1 ' ;~: : ' ~O 91/0820B PC~/US90/068 : - 12-this invvQntion is identified by tests which measure a compound's ability to inhibit IPU!~Otrjen~ rel9a~a.
In one such test procedure, the anti-allergy method of this invantion is idantified by tests which measure a compound's inhibition of `~ ~ leukotriene releas~v in s@nsitized guinea pigs. Male Hartley guinea pigs -~ (2~û-300 9) are sensitized with 5 mg ovalbumin injacted i.p. and 5 mg injected s.c. in 1 ml saline on day 1 and 5 mg ovalbumin injected i.p. on day 4. The sen~iti~Qd ~nimals are used 3-4 weeks later at which time they weigh 450-500 g. Sensitized guinea pigs are killea by a blow to the head and the lungs ramoved and cleaned of visible connective ~I tissue, trachea ana large blood vassels. Tha lungs from individual '~ animals are sliced into fragments approximately 1 mm in thickness using 2 Mcllwain tissue chopper and then washed with oxygenated Tyrode's buffer. WeisheQ' aliquots (approximately 400 mg wet weight) of lung are kS transferred into Yials containing 2 ml of fresh Tyrode's solution (containin~ 10 mM cysteine) and incubated in the pres@nc~ or absence of test compound for 12 rnin at 37G. Tha tissues are then challcnged with 20 1l~ ovalburnin/ml (final concentration) and incubated for 15 min.
~ To measure Iqukotriane rsieas~, an aliquot of superna~ant fluid is ; 20 extracted with 4 volumes of 100% ethanol. After removal of the precipitated protein, the leukotriene content is measured by a radioimmunoassay using [3H]LTC4 and antiserum obtained from New England Nuclear. The cross-reactivity of the antiserum for LTD4 is 55%.
Percent inhibition of lekotriene release is calculated by comparing for :~ ~ 25 each lung the release in the presence of the test compound to that in the absence of test compound. Representative compounds of the invention ~J: at a dos~ of 10 ~M are found to inhibit leukotriene releas~ in the test procedure as inclicated b~lsw in Table 1:

., ., 1.:

~ ~ .

WO 9~/0~208 PC~/IJ'~9~)/06873 ., .

, .

~,~,~w ' Inhibition of SRS-A release . Q _ ~1 ,1, ,; phenyl --N~ 34%

m-CF3. phenyl~1 46%

~ m-CN phenyl-N~J 43% ;-,1::,~ r\ :
phenyl--N~--/o 65%

m-CN pnenyl--N~O 66%

m-CN-phenyl~ N~o 46%

, ~, :

.~ W~ 91/08208 PCT/US9~/06~
~; ' .~ .
:~ ' The anti-allergy activity of the compounds of ~he in\/ention may also be demonstrated by the following ~"otocol:
~1 Male Hartley guinea pigs (250-300 g) art~ sensitized ~ith 5 ,i mg ovaibumin injected i.p. and 5 mg inject3d s.c. in 1 ml salin ~ cn da~ 1 ! ~; and 5 mg ovalbumin injacted i.p. on day ,~. The sensitized animals ar~ ~:
used 3-4 weeks later at which time ~hey w~igh 4~0-500 ~3. Ths , sensitized guinea pigs ar~ fasted o~ernirtht ~nd tha fcllowing rnoming ' t are anesthetized with 0.9 ml/ks i.p. of diâllur~thGne~ u.1 g/ml diallybarbituric acid, 0.4 g/ml ethylur~a and 0.1 g/ml ur^~han5). The l O trachea are cannulated and the animals ars ~J~n~ilat tCI b~J 3 ~ r/ard@~
.' rodent respirator at 50 strokes/minute with a slroke voiume oi ~ ml. A
't side arm to the tracheal cannula is connected to 2 prassure transducer (Harvard) to obtain a continuous measurG~ of intratracheal press~re .~ which is recorded on a polygraph (Harvard). The jugular vein is cannulated for the i.v. administration of subs~ances~ The sensiti~ed ~t guinea plgs are injeeted i.v. with 1 mg/k~ propranclol, 5 mg/kg ;~ indomethacin and 2 mg/kg mepyramine given together in a volume of 1 mVkg. The animals are challenged with antigen (0.5% ovalbumin) as an aerosol generated from a DeVilbiss'l9 Model 65 ultrasonic nebulizer and .. ~ 20 deliver0d through the tracheal cannula for 30 seconds.
.~ Bronchoconstriction is measured as the peak increase in intratracheal pre sure occurring within 15 minutes after antigen challenge.
j Test compounds arGi administered orally 2 hours before ,'1 challenge with ovalbumin. Suppression of anaphylactic bronchospasm 2~ is expressed as a percent inhibition of the peak increase in intratrach~al j~ pressure by comparison to a vehicle-treated control group.
esults from the above procedure for two compounds of . ~ the inv~ntion are listed in Table 2 below.
~, , 1: ~: .
:$ ~
. .

:s:

WO 91/0~20$ Z~t~ PCT/~S90/06873 .

. Tablç 2 H
`` ~,i t ' 1 ':
~., .
3 inhibition of anaphylactic 3 bronchos~asm -m~g o,~O In',nl~ition phenyl --N~ 5 61 :i 'i~ . . r\ -phenyl --N~ ~O 5 93 The compounds of this invention are also usetul for the tr~atment of inflammation. Thus, they are useful in the trcatment of arthritis, bursitis, tendonitis, gout and other physical conditions tl 5 characterized by inflamrnation. The anti-inflammatory u~e of the compounds of this invention may b~ demonstrated by the Reversed -;f ~ Passiv~ Arthus Response Technique, as described below.
~: :
:: Rev~rsQ~P~ssive Arthu~ e~Qnse ~$~ 0 Animals~ Materi~ s ~n~Methods Male Lewis inbred albino rats weighing 180-200 grams obtained from Charles Riv~r Br~eding Laboratories are used in these experiments. The rats are housed 3 animals/cage and food and water are allowed ~ libitum. The animals are numbered 1-3 in each cage : .
15 ~ ~ and color marked for identification purposes.

~ :

~ WO 9110~20~ P~r/u~901068 .~ :
r~l - 16-, . .
:j All reagent~, and drugs are prepared just prior to the study.
Grystallized and ,yophilized bovine serum albumin (BSA), available `'3 from Sigma Chemical Company, is solubilized without shaking in cold, :~ 5 sterile, pyrogen-free saline (10 mg/ml). Lyophilized anti-bovine serum ', albumin (IgG fraction), obtained from Cappel Laboratories, is suspended in st ~ disLi,lsd ~ u. ~r and di!uted with eold, pyrogen-free saline (PFS) jus~ p,ior .o usa Thc lln_l c~ncantration of anti-bovine serum albumin is il 0.5 mg, ml of PFS. Bolh E~SA and anti-BSA solutions are iced during :;, 10 usc. Dr.,gs ar~ suspandad or solubili~ad in an aqueous solution ofmethyl cellulos2 (MC) with an homogenizer just prior to administration.
''~ . .
~r~3g Administrati~n and l~iQr, of Irfl~ n Groups of animals (6/~roup) are dosed with drug in MC by ~avage ono~ daily for 3 days. The last dose is administer~d one hour -~31~ prior to sensitization with BSA. Controls ar~ giYen MC alone and adrug-standard is usually included in sach assay for verification . purposes. Drugs are prepared and dilut~d so as to provide a dose for a 200 grarn animal which is equivalent ~o the mg/kg dosa for each i~ ~ 20 experiment. Thu,s each rat receives an oral dose in a volume of I approximately 2.0 cc. One hour after the last dose the animals are . ~ lightly anesthetizod with ether and l'sansitized" by injection of 0.2 ml of ;~ I PFS containing 1.0 mg of BSA into the penile vein. One hour ',ater, the animals are "challengedr in the right rear paw with subplantar injections of 0.2 ml of ml of PFS containing 0.1 mg of anti-BSA. Immediately after the subplantar injection, the right paw is dipped (up to the lateral malleoius) into the rnercury W811 of a plethysmo~raph. The volume of mercury displaced is converted to weight and recorded. This value is considered to be the control reading for the animal. Paw volumes are ; 30 subsequently recorded with a plethysmograph during the development ~ o~ the inilammation at 2 and 4 hours post-challenge.
.,, ~

: ~ :
1 ~:

. VV~ 91/1)8208 ~ PCI /US90/06873 ' ' E~illlI~
Results are expressed by the ehange in paw volume (~
paw volume) frorrZ the control reading for each animal to that recorded 2 and ~ hours post-challenge. All dZ~g iraated groups are compared to 5 the MC control for signiticarZt differences with an analysis of variance.
,~ The compounds of this invention are also useful in the treatment of peptic ulc~ors and strass ulcaration, and to promo~e healing Ot gastric and/or duod~nal ulcers. The antiulceZ activity of the :1 compounds of this i~Yention is identifled by standard tests which 10 measure ihs cyloprote~ive ei~ect in rats, e.g., by inducing ~`, gastrointestinal damage with ethanol prior to administering a cempound of the invention. The cempound,s may be used as conjunctive therapeutic agents for coadministration with such anti-;! inflammatory/analgesic agents as aspirin, indornethacin, i~ 15 phenylbutazone, ibuprofen, naproxen, tolmetin ~nd other agents. The :' compounds of this invention prevent the untoward side effects cf irritation and damage to the ga-~trointestinal tra~ caused by such agents.
-~ The compounds of formula I are usefui in tha treatment of iZ:~ : - hyperproliferative sk~ disease, e.g., psoriasis, which utility may be 20 demonstrated by the Arachidonic Acid Mouse Ear Test as described below.
1 ~

harles Rivsr, female, CD, (SD) BR mice, 6 weeks old, are ~ ~
caged 8igroups and allowed to acclimat0 1-3 weeks prior to use. ~:
Z,,~ Arachidonic acid (M) is dissolved in reagent grade ~ ., acetone (2 mg/.01 ml) and stored at -2Z.,n~C for a maximum of 1 week 30: prior to use. InflammatoZ~ reactions are induced by appiying 10 11 of AA
to both sur~aces of one ear (4 mg total).
Tsst drugs are dissolved in either reagent grade acetone or aqueous ethanol (only if insoluble in acetone~ at the same doses selected by Opas ~., , A~stract 2983, p. 1927 (1984) and ZZ
Z~

WO 91/OB208 PC~r/~'S90/06~

,`
Young ~al."L LcY~_~m~, pp. 367-371 (1984). These doses are ernployed to ensure maxirnum rasponses and to overco~,a any differenc~ in ~opical absorpticn which could occur with any drug applied .~ in an aqueous ethanol vehicle. Th~ t~st drug is appli~d 30 minutaâ prior 5 to challenge with M.
The s~verity ot the inflammation is mcasurc:~ 2S a function of increased sar weight. A 6 mrn punch biopsy is remoYed 1 hcl!r al~er M challenge and weighed to the near~st ~.1 ms ~ 2n _ st~c rd error and all possible comparisons are made via Duncan's ~lui~iple ` 10 Range Statistic.
As a result of the topical administration of a cornpound o 3~ formula I, a remission of the symptoms of the psoria~ic patient, in most cases, can be expected. Thus, on~ affected by psoriasiâ can expect a decrease in scaling, erythema, size of the plaques, pruritus and other .~ 15 syrnptoms associated with psoriasis. The dosag~ of medicament andtha l~ngth of time r~quir~d for successfully ~roating each individual ,~ ~ psoriatic patient may vary, but thos8 skiJled in the art of medicirle will be j~ abl0 to recognize these variations and adjust the course of therapy accordingly.
Tho activity against inflammatory bowel disease of the compounds of the invention can be demonstrated by the protocols : described in G.P. Msrris, L. Rebeiro, M. M. Herridge, M. Szewczuk, and . W. Eepew, 9B~Q~, ~, 1188 (1984) and J.L. Wallace, ~an. J.
~[~, ~, 422 (1988).
Administration of the dose can be intravenous, intranasal, `~ parenteral, oral, subcutaneous, intramuscular, topical, transdermal or any other acceptabie method. Th~ compounds of the present invention can be administered in any number of conventional dosage forms.
Solid dosag~ forms include capsules, tablets, pills, powders, 30 suspensions, solutions, cachets srsuppositories. Parenteral J~ ~ preparations include steril~ solutions or suspensions. Inhalationadministration can be in the form of a nasal or oral spray, or by insufflation. Topical dosage forms can be creams, ointrnents, lotions, ;:~

WO 91/0820~ ~7~ PCI/~S90/06873 ~`` 19_ .
transdermal devices (e.g., of ~he convsntional reservoir or matrix patch type) and ~he like.
~' The formulations and pharmaceutical compositions contemplated by the above dosage forms can be pr~par~d with conventional pharmaceutically accep~able excipients and additives, .i using conventional techniques. Such pharmacsutically accestable il excipients and additives include carriers, binder~. flavorinas. buffers, thickeners, color agents, dispersing agents, suspsnding asents perfumes, preservatives, lubricants, etc.
.~ 10 When used crally or parantsrally for the trea,ment of a!!~r3y, inflammation, peptic ulcsrs and/or hyperproliferalive skin disaasa~, the compounds of the invention can be administered in an amount ranging from about 0,1 mg/kg body weight to about 25 mg/kg body weight, pref~rably frorn about 0.1 mg/kg body weight to about 5 ms/kg body 15 weight p~r day. A typical recomm~nded dosag~ regimen is orai .. ~ ~ administration of from 10 mglday to 1~00 mg/day, preferably from 10 . : mg/day to 25û mg/day, in two to four divided doses to achieve relief of tha syrnptoms of inflammation.
Determination of the proper dosage of a compoun~ of the 20 invention for a particular situation is within the slcill of the art. Generally, treatment is initiated with smaller dosages that are less than the optimum dose of the compound, Thereafter, the dosage is increased by small incrernents until ~he optimum effect under the circumstances is rQached, For conv~ni~nce, the total daily dosage may be divided and 25 administered in portions during the day if desired.
The amount and frequency of administration of the c ompounds of formula I and the pharmaceutically acceptable salts thereof will be regulated according to the jud~ment of the attending `~ .
clinician considering such factors as age. condition and size of the 30 ~ pati~nt as well as saverity of the symptom beins treated.
The invention disciosed herein is exemplified by the foilowing examples, which should not be construed to limit the scope of `
the disclosure. Alternative meohanistic pathways and analogous 3~

wo gl/0820~ Pcr~ ;go/06 ~ 4 ~
.. - 20 -.
structuras within ~he scope of the invention may be apparent to those ~ skill~d in ;,,3 ~i .1~ ~Q~r~tive ~xamQle 1 il 5 Q~.?~~3-c~ç~ a~:lino-3-Q~ ç~ than~
,~ ,CO~Et ~, CH2OH
,,`~. I li li :~ ~N'--NH . - --D ~N~NH

.. ~CN ~CN
,, : ., .
, . . 10 A 1 L 3-neck flask was equipped with an addition funnel : ~ ~ with a glass stopper, a reflux condenser closed with a drying tuba, and a d~y N2 inlet. An excess of LiBH4 (3g) was added to dry tetrahydrofuran (THF; 35mL) contained in the fiask. The mixture was stirred : magn0tically. Ethyl 2-(3-cyanophenyl)aminonicotinate (30g) was ~ ~ 15 dissoived in dry THF ~2~0mL) in the droppin~ funnel, and then this : ~ solution was add~d dropwisQ to the solution in the flask. After all had :.:
i : been added, the mixture was heated gradually to the reflux point (ca.
70C). After heating at reflux for 2h an additional 1 .Og of reducing agent was added, and later, a further 0.5g. The reaction was followed by TLC
. ~ 20 until all the starting material had disappaared. The reactlon mixture was . ~ then allowed to cool and was stirred at room temperature overnight.
Soivent was removed under vacuum, and the product was poured over ic~ The pH of the~ solution was adjusted to oa. 2 and it was allowed to v ~ stand for 3h. The product was then extracted into ethyi acetate (3 x 25 ~ ~ 200mL).: The combinad ethyl acatata layers were washed with water (2 :x 300rr)L) then with:saturatcd NaCI solution (2 x 250mL). The separated organic layer~was dried (Na2SO4~, filtered and ~vaporated. The crude h 1~ : product wasl racrystaliized from isopropanol to yield the desired product, ` ~ ;; 18.99 (75%),: mp 132-133C.

~JO 91/08208 ~ P~TtUS9~)/06873 . .

... .
.j .
Found, C, 69.23; H, 5.06; N, 18.72.
Calcd. (f()r Cl3~1N30), C, 69.32; H, 4.92; N, 18.66.

L;~CGqi=r ~CH2OH
;~ N''NH N N H
:: j ~
~.~ , ~
. ~ ~CF3 ~CF3 :, . '.
`:, , i ~ 10 In a 3-neck 1 L ~iask, 0quipped with a reflux condenser clossd by a drying tubej a dropping funnal with a s~ptum cap on top, and a dry N2 inl~, was placad ethyl i~-(3-trifluornmethylphanyl)amino-nicotinate (30g) and dry tetrahydrofuran ~THF) ~150mL). The solution was stirred rnagnetically in an ics-salt bath for 2û minutes after which 15 ~ time th~ insid~ tempera~ure had reached about -5C. A solution nf Sup~r HydridarM (lithium triathylborohydride; 250mL of a 1 M solution in THF) was transferred in the absence of air, using a double-ended ` ~ needle, into th~ dropping funnei. This solution was added to the flask ,~i ~ dropwis~, keeping th0 tempera~ure around 0C. After all had been 20 added the reaction mixture was allowed to warrn to room temperature and was stirred overnight. Thin layer chromatography was used to ` ~ o!low the course of the reaction. Reaction was completed by the . ~ addition cf a further 1 00mL of the Super-Hydride~d solution at room temperature. The total product was pour~d over ice (4009), with stirring, . ~ ;2~5 ~ andi~the pH;;was adjusted ~o 5 with conc. HCI Solid NaCI was added to salt out the arganic layer which was s~parated. The aqueous layer was extracte~with~ ethyi~aGetate (2 x ~1OOmL) and the organic laysrs were `;~h~ co~mbined. ~ Tha combined org~anic layer was washed with saturated ~ NaCl~so!ution (2 x 1O~mL), dried (Na2SO4), filtered, and evaporated to a ~ 30 ~ ~ ~yeliow~:oi!. A~small quantity of this crude product was purified by flash WO ~1/08208 ` PCI /l~S90/06E
:

chromatography over silica gel eluting with hexane:ethyl ace~ate (80:20 ~ 67:33). Fractions containing the desired product ~Ycr~ comb,"ed aln~
evaporated to a light yellow solid, mp 105.5 - 1 07C
'~,`
.~ 5 Found, C, 5~.26; H, 4.24; N, 10.17.
Calcd. (for Cl3H1~N20F3), C, ~8.21; H, ~.13; i~ 10 -' .
!
Prpa~iv~ ~ar~le 10Pr~pa~atiQn Qf ~-cv~ henvl)anlirLQ-~Y-pyri~1in~^a~ Ye~
., 1 ~CH2OH ~GHO
¦ N NH ~ N NH -~CN ~CN
:
2-~3-trifluoromethylphenyl)amino 3-pyridinemethanol (19) 15 was dissolved in toiuone (50mL) contained in a flask. The flask was attached to a Dean and Stark water-separator and a re~lux condenser.
To the reaction flask was added activated MnO2 (4g) and it was heatad, ~i with magnetic stirring, to about 80C. The reaction was foilowed by thin !~ layer chromatography and was complete after about l .5h. The product20 was filter~d through-a bed of celit6 which was washed with fresh ethyl acetate. The clear solution was cvaporated to a yellow solid. The crude .1 product was purified by running it through a flash column sf silica gel, 1~ eluting with CH2(::12:ethyl acetate ~90:1 O) to yield the desired product, 0.~69 (57%), m.p. 152-154(: .
Found, C, 69.5B; H, 3.90; N, 18.96.
Calcd. (for Cl3HgN~O), C, 69.94; H, 4.06; N, 18.83.
~1 "';1:
.~ .

:. WO 91/08208 z~7~Z~ 3 PCr/lu'S90/06873 - 23 ~

By essentially the same procedures dascribed in Preparative Examples 1, 2 and/or 3 above, tha compoundv listed below l were also prepared:
. Z
2-(3-trifluoromethyl phanyl) amino-3-pyridine-` carboxaldehyde, mp 75-77.5C; and `~ 2-phenylamino-3-pyridineZcarl~oxaldehyde.
. Z

.ZPr~Qar~l~n o~-(1-syr2~ v~ fdn~ -naDhthvrldin-2(1H~-onf~

¢~NH + CN CHZ COZE ~ ¢~ ~ ~ ~

~: 2-Phenylamino-3-pyridinecarboxaldehyde (2.0g) and ethyl 2-pyrrolidinylacetate (1.659) were mixed together in dry t~Ztrahydrofuran (THF) [5mL) and t-butanol (1 mL) un~er N2. To the mixtur~ was added ~: : 2û fresh potassium t-butoxide (KOt~Bu; 0.1g). After 24hr. a further 0.19 of I ~ KOt-Bu was adcied, th~n at 25hr and 48hr. additional amounts of 0.1g . `~ ; were added. A~ter a ~otal of 2.5 days an additional 0.4369 of KOt-Bu was ~ ~: ~ added and the mixture was allowed to stir for a further 2.5 days. The .. ~ solvent was removed and the residue was dissolved in CH2CI2. Wa~er 25 ~ was added and the pH of th~ aqueous layer waS adjusted to aZbout 7 with ~1 N H2SO4. The organic layer was separated and chromatographed on silica gel. Fractions corZtaining the product were . ~ ccmbined and:evaporated to an off-white cniZ3e product which was .
: ~ ::

:

;

wo 9~/08208 . ~ Pcr/~,s90/o . .
recrystallized from isoprop~nol to yield the desired product, m.p. 201.5-202.5C.
`I Foun~, C, 74.23; H, 5.8~; N, 14.30.
~, Calcd. (for C18H17N3O), C, 74.20; H, 5.88; N, 14.42 ;~. 5 ~m~

Pr~aration of 3~ Yrrolidinvl~ if!u~rom~thylQhenyl)-1.~:
hthyridin-~1 H!-QnQ
, ., ¢~NH ~ N-CH2-COzE~ lo 2-(3-Tri~luoromethylphenyl)amino 3-pyridin0-carboxaldehyde (19) and ~thyl 2-pyrrolidinyl-ac~tate ~0.69) wer~
.l ~ dissolv~d in a mixture of THF (1 OmL) and t-BuOH (2mL). Th~ solution : ~i 15 was stirred under N~ and to it was added fresh KOt-Bu ~0.429). After 3hr an additional 0.19 of KOt-Bu was added, thon after 4hr the solvents were r~moved under vacuum. Watar (1 OmL) was added and the pH was ~; . adjusted to about 7 with 1 N-H2SO4. The product was extracted with 2 x 10mL of CH2C12. The organic layer was washed with saturated NaC;I
3,~ ~ 20 solution ~2 x 1 0mL), dri~d (Na2S04), and evaporated under vacuum.
~,~ The product was purified by chromatography on silica gel and the light yeilow product was then recrystallized from methanol to yield the desired product, mp 168.5-170C, after drying overnight under vacuum.
Found, C, 63.32; H, 4.22; N, 11.60; F, 16.28.
:: 25 (~alcd- (forc19Hl6N3c~F3)~ ~,63.50;H,4.49;N,11.69;F,15.86.

ii .

' WO 91/082U8 ~g~ - PCI`/US90/06873 - 2~-.
By ~asically the same procedures as described above in Exampl~ l and 2, the following cornpounds were also prepared:
3-~1 -Pyrrolidinyl)-1 -(3-cyanoph~nyl~-1 ,8-naphthyridin-2-` (1 H )-one; mp >250C.
..; ~ ' ~/

~CN

Found, C, 72.13; H, 5.06; N, 17.81. ~: -Calcd. ~for C19H16N4)' C, 72.13; H, 5.10; N, 17.71.
;,:
3-(4-Morpholinyl)-1-phenyi-1,8-naphthyridin-2(1H)-one;
mp 167-1 68C.
'.' ~ ` O ' :', :~ ~NXNJ :

Found, C, 70.32; H, 5.55; N, 13.70.
Calcd. (for C1.8H17N3O2), C, 70.34; H, ~.5~; N, 13.67.

2~ 26-3-[3-(Hexahydro-1 H-azepin-1 -yl)-1 ,2-dihydro-2-oxo-1,8-naphthyri~in-1-ylj-b~n-o-nit,ile; mp 19~!-196''C

N J
N ~ ~ O

'~ `~C~I .

Found, C" 3.08; H, 5.57; N 1~.36.
Calcd. (for C21H20N4)' C, 73.23; H, 5.85; N, 16.27.
1 : .
. :, 3-~1,2-Dihydro-3-(4-morpholinyi)-2-oxo-1,8-naphthyridin~
yl]b~nzonitril~, mp 215-217C.
.~1, .1~ ~ .;
~ CN

;~ 15 Found, C, 68.63; H, 4.73; N, 16.74.
alcd. C, 68.67; H, 4.85: N, 16.85.

he following formulations exemplify some of the dosage : forms:of the compositions of:this invention. In each, the term "active : 20 compound" refers to 3-(4-morpholinyl)-1-phenyl-1,8-naphthyridin~ H)-one. However, this compoun~ may be replaced by equally effective amounts of other~ompounds of formula I. ~:

Wo 9~/~820~ PCI/U~90/06873 `
. ~7 -; :
~ ,~A M PLE ~
.. ~ ,.

;:~ . 1. Acti~/s compound ~5 100 2. L~ctose I~S~ 122 113 3. Corn Starch, F~ca G,_~e, 3C 40 . as a 10% pasle in Purified Water 4. Corn Starch, Food Grade 45 40 11 5. Magnesium Stearate 3 7 Total 22~ 300 ... .

.~l Mix Item Nos. 1 and 2 in a sui~able mixer for 10minute~. Granulateth~ mi~ure with Item No. 3. Millthe damp granules :
through a coarse screen (e.g., 1/4", 0.63 cm) if necessary. :)~ the damp A: granules~ Screen the dried granules ii necessary and mix with Item No.
4 and mix for 10-15 minutes. Add !tern No. 5 and mix for 1-3 minutes.
ompress ~he mixture tc appropriate si~e and w~igh on a suitable tablet machine.

.
.
, WO 91/08tO~ PCr/~S90/06 r~ f ~.
E~AMPL~

~ 9L~nL m~/tablet m~!~

s 1. ActiYe compound 25 loo 2. Lactose USP 122 113 3. Corn Starch, Food Grade, 30 40 `~j asa10%pastein Purified Water 4. Corn Starch, Food Grade45 40 Jlagnesium S~earate _~ . 7 ~ 15 To~al 2~h 30û ~ -:`~ ....

:: Mix Item Nos. 1 and 2 in a suitable mixer ~or 10-15 20 minutes. Granulateth~ mixture with Item No. 3. Millthe damp granules through a coarse screen (e.g., 1/4", 0.63 cm) if necessary. Dry the damp granules. Scr@erl the dried granules if necessary and mix with Item No.
~: : 4 and mix for 10~15 minutes. Add Item No. 5 and mix for 1-3 minutes.
Compress the mixture to appropriat~ siza and weigh on a suitabls tablet 25 maohine W~ 91/0~208 PCT/US90/~6g.

EX~PLE

.! 5 !~!~ 1~

`1 :
'J
, 1. Active compound 2~ 100 .l 2. Lactsse USP 106 123 3. Corn Starch, Food Grade 40 70 ~YI 4. Magnesium Stearate NF 4 7 .i, Total 175 300 .

'; 15 l~h~~
:-, Mix Item Nos. 1, ~ and 3 in a suitablf~ blender for 10-15 minutes. Add Item No. 4 and mix for 1-3 minutes. Fiil the mixture into ~: .
suitabl~ two piecs hard gelatin capsules on a suitabls encapsulating ~ machine.
: ~ 20 --~
`.: While the present invention has been described in - .
~: ~ conjunction with the specific embodiments set forth above, many i~ alternatives, modifications and variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications and ~: :
2~5 vanations are intended to fall within the spirit and scope of the present : - ~ inY~ention. :: . .

Claims (14)

WO 91/08208 PCT/US90/068??

CLAIMS:

1. A compound having the structural formula I

I
or a pharmaceutically acceptable salt thereof, wherein:
A is O or S;
W represents or ;
R represents H or alkyl;
R1 represents alkanediyl;
R2 represents a covalent bond or -alkanediyl-O-;
R3 represents alkyl, cycloalkyl, benzyl, substituted benzyl or hydroxyalkyl having 2 to 6 carbon atoms between the N atom and the OH group;
Q represents phenyl, 1- or 2-naphthyl, 1-,2-,3-,4-,5-,6- or 7-indenyl or 1-,2-,3-,4-,5-,6- or 7-indanyl, each of which may optionally be substituted with 1 to 3 Y groups as defined below; and each Y is independently selected from alkyl, halo, nitro, alkoxy, alkylthio, -CF3, -CN, cycloalkyl, alkysulfinyl or alkylsulfonyl.

2. A compound according to claim 1, wherein W is the group .

WO 91/08208 PCT/US90/068?

3. A compound according to claim 2, wherein A is O.

4. A compound according to claim 3, wherein R is H.

5. A compound according to claim 4, wherein Q is phenyl or substituted phenyl.

6. A compound according to claim 5, wherein W is , , or .

7. A compound according to claim 5, wherein W
is or .

8. A compound according to claim 1, having the following structural formula:

WO 91/08208 PCT/US90/0687?

WO 91/08208 PCT/US90/068?

or or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising a compound of formula I as defined in claim 1 in combination with a pharmaceutically acceptable carrier.

WO 91/08208 PCT/US90/0687?

10. A method of treating allergic reaction in a mammal comprising administering to said mammal an antiallergic effective.
amount of a compound of formula I as defined in claim 1.

11. A method of treating inflammation in a mammal comprising administering to said mammal an antiinflammatory effective amount of a compound of formula I as defined in claim 1.

12. A method of treating hyperproliferative skin disease in a mammal comprising administering to said mammal an effective amount of a compound of formula I as defined in claim 1.

13. A method of treating peptic ulcers in a mammal comprising administering to said mammal a cytoprotective amount of a compound of formula I as defined in claim 1.

14. A method of treating inflammatory bowel disease in a mammal comprising administering to said mammal an effective amount of a compound of formula I as defined in claim 1.