PH26104A - Aryl-substituted naphthyridine and pyrodopyrazine derivatives - Google Patents

Description

wy oo

PATENT

: » CASE 2408X 26104 1 sc 4B T : ARYL-SUBSTITUTED NAPHTHYRIDI E = 2 i AND PYRIDOPYRAZINE ony 2 0 2

J »

This invention relates to tricyclic = 2 naphthyridine and pyridopyrazine derivatives and to methods for their preparation.

One aspect of this invention comprises free ho bases and pharmaceutically acceptable salts thereof

I having the structural formula I

JN cor fC 1

N N A

(Rl-t-a2) a

Q wherein:

X represents CH or N; .

A represents O or S; : m is an integer of from 0 to 2; n is an integer of from 0 to 2; rl and R2? are the same or different and each is independently selected from H or alkyl:

W represents a covalent bond or a group selected from -0O-, -S(0) y=, ~NH-, -N(rRY)-, -N(cor%)-, and

BAD ORIGINAL 9

-N(s0,R%) {wherein p is an integer of from 0 to 2 and r4 i is alkyl}:

B represents alkylene having from 2 to 8 /carbon atoms, which alkylene may be optionally substituted with a group selected from -OH, -F, alkyl having from 1 to 4 carbon atoms, -CH,OH, -CHO, -CO,H, -COR3 {wherein R3 is selected from -NHRY, -N(rY), and -OorR%, and rR? is as defined above}, and -CN, with the proviso that OH or F is not on the carbon adjacent to W when W is -0-, AA -NH-, -N(rRY), -N(CORrR%)- or -N(s0,rY). B also may represent an unsubstituted alkylene having one or more double bonds.

Q represents an aryl or an aromatic heterocyclic group which can optionally be substituted with up to 3 substituents Y as defined below: and each Y substituent is independently selected from -OH, hydroxymethyl, alkyl, halo, -NO,, alkoxy, -CFj3, -CN, cycloalkyl, alkynyloxy, alkenyloxy, -S(0) -r4 {wherein r? and p are as defined above}, —co-R> {wherein

RS represents -OH, -NH,, -NHRY, N(R%), or -OR? in which rR? is as defined above}, -0-D-COR? {wherein D represents alkylene having from 1 to 4 carbon atoms and R3 is as defined above}, -NH,, -NHR?, -N(rY), { wherein rR? is as defined above} or -NHCOH.

Compounds of formula I in which W is oxygen or a covalent bond are preferred. Also, A is preferably oxygen, while X is preferably CH. The group -B-W- . preferably represents an alkylene or alkyleneoxy group, ratoranly/ (cy) ee, -(CHy)g~, ~(CH5)30- or -(CH;,)40-. . Other suitable -B-W- groups include -CH(OH)(CH,)3-. -CH,CH(OH) (CHy) 5-, —-(CHy)CH(OH)CHp-, -(CH;,)3CHOH-, ~CH(CH,OH) (CHy) 3=, —CH,CH(CH,OH)CH)=, ~(CH,)3CH(CH,OH) -, -CH(OH) (CHy) 4=, -CH,CH(OH)(CH,) 3-, =(CH,),-CH(OH) (CH,) ,-, -(CH,) 3CH(OH)CHy-, -(CH,)4CH(OH)-, -CH(CH,0H)(CHy)4-/ —CH,CH(CH,OH) (CHy) 3—, —(CHy),CH(CH,0H) (CH) 5—,

vo an ~-CH,CH (OH) CH,0-, -CH (CH,0H) (CH,) ,0-, ~CH,CH (CH,0H) CH,0-, : ~- (CH,) ,CH(CH,0H)O-, -CH (OH) (CH,)30~, -CH,CH (OH) (CH,) ,0-, - (CH,) ,CH (OH) CH,0~, ~CH(CH,OH) (CH,) 30-, / ~CH,CH (CH,0H) (CH,) ,0~-, -{CH,) ,CH(CH,0H)CH,0-, and -(CH,) 3CH (CH,0H) O~. The letter n preferably represents zero and m is preferably zero. Q is preferably phenyl or

Y-substituted phenyl, and in the latter case each Y substituent on the Q phenyl ring is preferably selected from chloro, nitro, methoxy or trifluoromethyl. The most preferred orientation for nitro, methoxy and trifluoromethyl substituents is in the meta position.

A preferred subgenus is represented by the formula II

BT \

Ww

XN

: XN NA orf)

IT wherein A, B, W, n and Y are as defined above and gq is 0 to 2.

When utilized herein, the terms below have’ the following scope: halo - represents fluoro, chloro, bromo and . iodo; alkyl (including the alkyl portion of alkoxy) and alkylene - represent straight and branched carbon chains and, unless otherwise specified, contain from 1 to 6 carbon atoms;

alkenyloxy - represents straight and branched carbon chains having at least one carbon to carbon double bond and, unless otherwise specified, contains from 3 to : 6 carbon atoms, the alkenyl group thereof being bonded to an adjacent structural element through an oxygen atom;

alkynyloxy - represents straight and branched carbon chains having at least one carbon to carbon triple bond and, unless otherwise specified, contains from 3 to 6 carbon atoms, the alkynyl group thereof being bonded to an adjacent structural element through an oxygen atom;

cycloalkyl - represents saturated carbocyclic rings having from 3 to 7 carbon atoms;

aryl - represents a carbocyclic group containing from 6 to 15 carbon atoms and having at least one benzene ring, with all available substitutable carbon atoms thereof being intended as possible points of attachment to the/ (CRIR?) group or to the N atom if m is zero.

More preferably, aryl is phenyl or Y-substituted phenyl.

Suitable aryl groups include, e.g., phenyl, naphthyl, indenyl, indanyl, 3-chlorophenyl, 4- chlorophenyl, 4-fluorophenyl, etc.;

aromatic heterocyclic - represents cyclic groups having at least one O, S and/or N in the ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character, with the aromatic heterocyclic groups preferably containing from 3 to 14 carbon atoms, e.g., 2-, 3- or 4-pyridyl, 2- or 3-

) furyl, 2- or 3-thienyl, 2-, 4- or 5-thiazolyl, 2-, 4- or 5-imidazolyl, 2-, 4-, 5- or 6-pyrimidinyl, 2- or 3- pyrazinyl, 3- or 4-pyridazinyl, 3-, 5- or 6- i1,2,4- triazinyl)}, 2-, 3-, 4-, 5-, 6- or 7-benzofuranyl, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 3-, 4- or S5-pyrazolyl, 2-, 4- or 5-oxazolyl, etc., with all available substitutable carbon atoms thereof being intended as a possible point of attachment to the (cR'R?) ny group or to the N atom if m is zero.

— TT _

Cm Co oAyody ok

Tre ag 26104 a

Dr

The invention in its pharmaceutical composi don 3! : aspect comprises a compound as described above in SE combination with a pharmaceutically acceptable carrie jz

The invention also includes a method Eo S 3d treating allergic reactions in a mammal which comprises 3g ti, administering an anti-allergic effective amount of the; : Se above-defined [pharmaceutical composition to the mammal. i

The invention in a second pharmaceutical method aspect is a method for treating inflammation in a mammal which comprises administering an anti-inflammatory effective amount of the above-defined pharmaceutical composition to the mammal.

The invention in a third pharmaceutical method . aspect is a method for treating peptic ulcers in a mammal {© which comprises administering a cytoprotective effective amount of the above defined pharmaceutical composition to the mammal.

The invention in a fourth pharmaceutical me thod aspect is a method for treating hyperproliferative skin : diseases, e.g. psoriasis, lichenified eczema or seborrhoeic dermatitis, in a mammal which comprises topically administering an effective amount of the above- identified pharmaceutical composition to the mammal. . . : £iEth pl fen] hod aspect—is-a—methed for Suppressing—theimmune response—in mammal which comprises—administering—to—a—mammal—in— . need—of such-treatment—an—immunosuppressing—effeetive- : Another aspect of the invention is a method for manufacturing a composition of formula I said method characterized by:

BAD ORIGiinaL o ..

a) treating a compound of formula IV

H OH

X B ) orf Ww

Nn

N N A é (Rl-c-Rr2) m

Q with a superacid having a Hammett activity function of less than minus 12; b) contacting a compound of the formula ( RlOglly cRl2«cpl3plé

Tt

OH

X RS

N ! 0 (Rl-c-a2) =

Q

XI. with a strong organic or inorganic acid to produce compound I; c) contacting a compound of the formula 0 eR Rte . \ R R ; v Ne

N ! 12

X C-R

Y

¢ —

N I 0 1. - 2 (R i R )a qQ

XIV.

FR, - ih # C . a ok “ds du A. Lo. i RRs

EVP ET }

with a strong base to form a compound of formula I; or : d) contacting a compound of the formula

X

»

N \ 0 2 (R-C—R

Q with a reducing agent to produce a compound of the formula ,

J ~

I

N N 0 2 (R=C—R ) 0 Q wherein X, A, m, n, W, B, OQ, Y, rl, Rr? are as previously defined and wherein R® is an alkyl group having from 2 to 8 carbon . atoms; r10, ril, R12, R13 ang r!4 independently are H or an alkyl having from 1 to 4 carbon atoms: r is 0 or 1.

The compounds of formula I contain a -(crIR?) - substituent wherein each Rl! group and each Rr? group may vary independently. Thus, for example, when m equals 2 the following patterns of substitution (wherein hydrogen and CH3 are used to represent any substituent, rl or RZ) are contemplated: -C(CH3) ,CHy~, =CH,C (CH3) 5, ~CH,CH(CH4)-, -CH(CH3)CH,%, -(C(CH3)H),- and the like.

As noted above, the compounds of the invention may include one or two Y substituents on the fused ring system. Also, the Q group may include up to three Y substituents depending upon the available sites for subst tution. In compounds where there is more than one such Y substituent, they may be the same or different.

Thus, compounds having combinations of different Y substituents are contemplated within the scope of the invention. Examples of suitable Y substituents include hydroxy, methyl, chloro, bromo, methoxy, cyclohexyl, allyloxy, 2-propynyloxy, methylthio, methylsulfonyl, carboxy, acetoxy, N-methylaminocarbonyl, acetoxymethoxy, acetylamino, methylsulfonylamino and the like.

Compounds of the invention of formulas I and II can exist in unsolvated as well as solvated forms, including hydrated forms, e.g., hemihydrate. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol and the like are equivalent to the unsolvated forms for purposes of this invention.

Certain compounds of the invention may exist in isomeric forms. The invention contemplates all such : isomers both in pure form and in admixture, including racemic mixtures.

Certain compounds of the invention also form : pharmaceutically acceptable salts with organic and inorganic acids, e.g., the pyrido- or pyrazino- nitrogen atoms may form salts with strong acid while compounds having basic Y substituents such as amino groups also form salts with weaker acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric,

phosphoric, acetic, citric, oxalic, malonic, salicylic, . malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids : well known to those in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium hydroxide, potassium carbonate, ammonia and sodium bicarbonate. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the salts are otherwise equivalent to their respective free base forms for purposes of the invention.

Also, some compounds of this invention are acidic, e.g., when Y is OH, and can form salts with inorganic and organic bases.

The compounds of this invention may be synthesized from the corresponding 3-spiro-4-keto analogues of formula III below, 0

I.

N } A I1I (Ri-c-rl),

Q which may be synthesized following the procedures . described in U.S. Patent No. 4,762,564 issued March 24, 1987 and in EPO Publication No. 0 144 996, published June 19, 1985. Alternative synthetic routes for the synthesis of these starting materials and substitutional variants thereof may be accomplished by those skilled in the art.

. in . This process involves a selective redyction of

Lé the 4-keto group of the compound of formula TTI! followed i by dehydration and rearrangement in the presence of a : \ strong organic or inorganic acid. In particular, the compound of formula III is selectively reduced at the 4 position using a reducing agent capable of reducing ketones in the presence of an amide function in an acidic medium, e.g., a hydride reducing agent, to produce a compound of formula IV

H_,OH 4X : or CL

Xn N A (l-t_s2

I m 0) iv.

Examples of suitable reducing agents for this step are sodium cyanoborohydride and tert-butylamine borane. For a discussion of such selective reducing agents, see, for example, Herbert C. Brown, Boranes in Organic Chemistry,

Cornell University Press, Ithaca and London, 1972. The reactions may be performed with cooling, with heating or at room temperature, as appropriate for the particular material being treated, e.g. at about 0%¢ to about 40%c. Typically, the reaction is essentially complete in several minutes, but some reactions take several days to obtain maximum yield.

Suitable solvents are those which are capable of dissolving the starting materials and which do not react with the reducing agent to make the solution basic, of which aqueous alcohol and aqueous tetrahydrofuran in combination with a weak mineral or carboxylic acid, such * as acetic acid, are examples.

The compounds according to structural formula . tv ore treated, either in their impure state or after suitable purification using techniques well known to : those versed in the art, e.g., chromatography, with a strong organic or inorganic acid such as H,S0y4, methanesulfonic acid, Eaton's reagent, polyphosphoric } acid, etc., or strongly acidic salts such as NaHSO,.

Superacids having a Hammett acidity function of less than about minus 12, i.e., minus 13, minus 14, etc., provide particularly advantageous results in this process.

Suitable superacids include trifluoromethanesulfonic acid, HF /BF 4, CH3SO03H/BF 3, etc. This measure of acidity is defined in Hammett, Louis P., and Deyup, Alden J.,

Journal of the American Chemical Society, Vol. 54, 1932,

P. 2721. The time and temperature of the reaction can vary depending on the acid employed. For example, with

CF3SO3H as the acid the temperature is generally in the range of from about room temperature (e.g., 25°C.) or below to about 150°C. Lower temperature (e.g., from about -78°C. to about 25°C.) may also be employed with for example HF /BF 3. The acid is also generally used in excess, e.g., in an amount of from about 1.5 to about 30 equivalents. While not wishing to be bound to a specific

Cy mechanism, it appears that this treatment causes : 4 rearrangement of the spiro ring to form the ring ®) <. - with the elimination of water, thus providing compounds of formula I. No diluent is required, but an inert co- solvent, such as a halohydrocarbon, e.g., methylene chloride, may be used.

Certain compounds of the invention can be prepared by an alternative reaction scheme employing as starting materials compounds of the formula Vv

OH

6 2X | XR (Ya . NE ¥ 0 (Rl-c-r?) . Q Vv wherein rl, RZ, Q, X, ¥, m and n are as defined above and

R® is an alkyl group having from 2 to 8 carbon atoms.

Such compounds can be prepared as described in U.S.

Patent No. 4,492,702 or by reaction of a compound of the formula VI with a compound of formula VII.

X ~, coon’ (Y) £ n > T + R6cu,co, RE —eee v

N NH

(cri?) vil

Q vi wherein rl, RZ, RS, Q, X, ¥Y, m and n are as defined above and R’ and R8® are the same or different and are alkyl of from 1 to 8 carbon atoms.

In this alternative method, the compound of formula V is first reacted with an electrophilic halogenating agent, e.g., Bry, I, + KI, ICl, etc., to produce a compound of formula VIII: 0 6

X

Z | 2 aE l_c.p (R i R )a

Q

VIII wherein 2 represents halo. This reaction can be . performed in an inert solvent and at any suitable temperature, preferably, at room temperature or below. . The compound of formula VIII is subjected to a nucleophilic displacement with an alcohol, e.g., an alkdnol such as methanol or an aralkanol such as benzyl alcohol. For example, the compound of formula VIII may be reacted with 1,8-diazobicyclo[5.4.0}undec-7-ene [DBU] and an alcohol, with the alcohol group replacing the halide group to produce a compound of formula IX 0

Ré oo 1 on . wg N 0 (Rlobetd) { qQ

IX wherein R? is the residue of the alcohol, e.g. alkyl group such as methyl or aralkyl group such as benzyl.

This reaction may be conducted in an inert solvent and at any suitable temperature, again preferably at room temperature or below.

The compound of formula IX is reacted with a compound of the formula M-(CcrIORL1) crl2=crl3gl4 {wherein M is an alkali metal such as Li or is Mg-Z where

Z is a halo group: r10, rll, R12, R13 and r!4 may be the same or different and each is selected from B or alkyl having from 1 to 4 carbon atoms: and r is 0 or 1} to . produce a compound of formula X / (culOnlly cplZecaldnl® x OH RS 9 mE | OR

N I 0 l.c-rl (R : R )a

Q

X.

This reaction is performed under conventional conditions, e.g., in an inert solvent such as THF or diethyl ether } and at any suitable temperature up to reflux.

The R? group is then removed with an ether cleaving reagent, e.g., CF3SO3H, BBrj, C,oHgSH and AlClj,

K*C,HgS™ in DMF, Na'C,HgS™ in DMF, etc., under conventional reaction conditions for such reactions to produce a compound of formula XI ( RlOglly crl2acrl3nl® r } H ma oH l.c-n? (R i R )a

Q

XI.

~15~-

The R® alkyl group is eliminated and a . cyclizafion dehydration is effected by use of a strong organic or inorganic acid, such as CF3503H, . polyphosphoric acid, Eaton's reagent, P,0¢ in CHCl, . etc., to produce an alkene from the r® group and a compound of formula XII 2

X x 0 wag

NN N N 0 (R1-c-rY)

Q

XII.

When r is 1, the following isomer may also result: 3glé a R

X XN 0 ‘ wa

Nn " 0 (rl-c-nd)

Q

XIla.

This reaction can be performed neat or with an inert solvent and at any suitable temperature, preferably at room temperature or below. /

In another method similar to that described in . C. Keneko, T. Naito and M. Somei, J.C.S. Chem. Comm., 804 (1979), a compound of formula XIII (crlOplly—cnl2acrlipls . i r } Xx x8 (r)

N I 0 l.c-np? (R | R Ya

Q

XIII

{wherein R}, RZ, r10, rll, R12 R13 R14 oo, x, v, m, n and r are as defined above} can be irradiated with ultraviolet radiation, e.g., about 3000A, to produce a compound of formula XIV 0 ————(cr}%) ¢ vy 13 ald) \ R_ 7 ! ! \ Cl fall x C-R mw. nN

N I 0 (rl-c-rd) : X1v.

The compound of formula XIII is preferably in an inert solvent, 9. an alcohol such as methanol, or methanol/CH,Cl,, and the reaction mixture may be cooled during irradiation, if necessary. The starting compounds of formula XIII can be prepared by the methods described - in U.S. Patent No. 4,492,702.

The compound of formula XIV is reacted with a strong base such as a salt of an alcohol, e.g., a sodium or potassium alkoxide such as NaOCH3, to produce a compound of formula XV all Ale ~ CRORE oR ——R wo. TL, (Rl-t-ad).

Q

Xv.

This last reaction can be conducted in an inert solvent, e.g., an alcohol such as methanol, and at any suitable temperature, preferably at about 75° to about 125°C.

The compounds of this invention wherein A is - sulfur may be obtained by treating the purified 2- carbonyl compound of formula I with thiating reagents well known in the art. Lawesson's Reagent {2,4-bis(4- methoxyphenyl-1,3~-dithia-2,4-diphosphetane-2,4-disulfide} or one of its analogs, in toluene, or phosphorus pentasulfide in pyridine/is suitable for this purpose. } For preparing pharmaceutical compositions from the compounds described by this invention, inert, . pharmaceutically acceptable carriers are admixed with the active compounds. The pharmaceutically acceptable carriers may be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. A solid carrier can be one or more substances which may also act

§ 26104 -18- as diluents, flavoring agents, solubilizers, lubricants, . suspending agents, binders or tablet disintegrating agents; it may also be an encapsulating material. : Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for . parenteral injection. Liquid preparations can also be formulated in solution or suspension in aqueous polyethylene glycol solution.

Formulations for topical application may include creams, aerosols, sprays, dusts,. powders, lotions and ointments which are prepared by combining an active ingredient according to this invention with conventional pharmaceutical diluents and carriers commonly used in topical dry, liquid, cream and aerosol formulations.

Ointments and creams may, for example, be formulated with an aqueous or oily base’ with the addition of suitable thickening and/or gelling agents.

Lotions may be formulations with an aqueous or oily base and will, in general, also include one or more of the following, namely, stabilizing agents, emulsifying agents, dispersing agents, suspending agents, thickening agents, coloring agents, perfumes and the like.

Powders may be formed with the aid of any suitable powder base, e.g. talc, lactose, starch, etc.

Drops may be formulated with an aqueous base or non- aqueous base also comprising one or more dispersing ] agents, suspending agents, solubilizing agents, etc.

The topical pharmaceutical compositions according to the invention may also include one or more preservatives or bacteriostatic agents, e.g., methyl hydroxybenzoate, propyl hydroxybenzoate, chlorocresol, benzalkonium chlorides, etc.

The topical pharmaceutical compositions according to the invention may also contain other active ingredients such as antimicrobial agents, particularly . antibiotics, anesthetics, analgesics and antipruritic agents.

Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral } administration. Such liquid forms include solutions, suspensions/and emulsions.

The compounds of the invention may also be deliverable transdermally for systemic distribution. The transdermal compositions can take the form of creams, lotions and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.

Preferably, the pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active components.

The compounds of this invention may be employed as anti-allergy agents in the treatment of, for example, 7 asthma, allergic or seasonal rhinitis, and/or chronic

Ld bronchitis. The anti-allergy method of this invention is identified by tests which measure a compound's inhibition of anaphylactic bronchospasm in sensitized guinea pigs having antigen induced broncho-constriction.

In one such test procedure, male Hartley guinea pigs (250-300 g) are sensitized with 5 mg ovalbumin . injected 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 - sensitized animals are used 3-4 weeks later at which time they weigh 450-500 g.

The sensitized guinea pigs are fasted overnight and{ the following morning are anesthetized with 0.9 ml/kg i.p. of dialurethane (0.1 g/ml diallybarbituric acid, 0.4 g/ml ethylurea and 0.4 g/ml urethane). The trachea are cannulated and the animals are ventilated by a Harvard® . rodent respirator at 50 strokes/minute with a stroke volume of 5 ml. A side arm to the tracheal cannula is - connected to a pressure transducer (Harvard) to obtain a continuous measure of intratracheal pressure which is recorded on a polygraph (Harvard). The jugular vein is cannulated for the i.v. administration of substances.

The animals are challenged with antigen (0.5% ovalbumin) as an aerosol generated from a DeVilbiss® Model 65 ultrasonic nebulizer and delivered through the tracheal cannula for 30 seconds. Bronchoconstriction is measured as the peak increase in intratracheal pressure occurring within 5 minutes after antigen challenge.

The sensitized guinea pigs are injected i.v. with 1 mg/kg propranolol, 5 mg/kg indomethacin and 2 mg/kg mepyramine given together in a volume of 1 ml/kg.

Fifteen minutes later the animals are challenged with nebulized ovalbumin. Test compounds are administered ’ orally 2 hours before challenge with ovalbumin.

Suppression of anaphylactic bronchospasm is expressed as a percent inhibition of the peak increase in intratracheal pressure by comparison to a vehicle-treated control group.

Four compounds of the invention tested in the above procedure were found to inhibit anaphylactic brochospasm as indicated in Table I below:

Table I 3 \

Ww

Xx -. A

EDg {(p.o.)~in

Compound Y -B~-W- anaphylactic

No. bronchospasm test 1 m-Cl —(CHp) 4- 2 mg/kg . (hemihydrate) H -(CHy) 4- 2 mg/kg

These compounds were also found to inhibit allergen- induced histamine release from guinea pig and human sensitized tissue.

The compounds are effective non-adrenergic, non-anticholinergic, antianaphylactic agents. When administered orally they are active at doses from about 0.5 to 25 mg/kg of body weight, preferably 0.5 to 10 ' . mg/kg; whens administered parenterally, e.qg., intravenously, the compounds are active at dosages of from about 0.1 to 5 mg/kg body weight preferably 0.1 to 2.5, and when administered by inhalation (aerosol or nebulizer) the compounds are active at dosages of about 0.1 to 5 mg per puff, one to four puffs may be taken every 4 hours.

The compounds of this invention are also useful . for the treatment of inflammation. Thus, they are useful in the treatment of arthritis, bursitis, tendonitis, gout : and other physical conditions characterized by inflammation. The anti-inflammatory use of the compounds of this invention may be demonstrated by the Reversed . Passive Arthus Response Technique, as described below.

Reversed Passive Arthus Response (RPAR)

Animals, Materials and Methods

Male Lewis inbred albino rats weighing 180-200 grams obtained from Charles River Breeding Laboratories are used in these experiments. The rats are housed 3 animals/cage and food and water are allowed ad libitum.

The animals are numbered 1-3 in each cage and color marked for identification purposes.

Drug and Reagent Preparation

All reagents and drugs are prepared just prior to the study. Crystallized and lyophilized bovine serum albumin (BSA), available from Sigma Chemical Company, is solubilized without shaking in cold, sterile, pyrogen- free saline (10 mg/ml). Lyophilized anti-bovine serum albumin (IgG fraction), obtained from Cappel

Laboratories, is suspended in sterile distilled water and diluted with cold, pyrogen-free saline (PFS) just prior to use. The final concentration of anti-bovine serum . albumin is 0.5. mg/ml of PFS. Both BSA and anti-BSA solutions are iced during use. Drugs are suspended or - solubilized in an aqueous solution of methyl cellulose : (MC) with an homogenizer just prior to administration.

Drug Administration and Induction of Inflammation

Groups of animals (6/group) are dosed with drug in MC by gavage once daily for 3 days. The last dose is . administered one hour prior to sensitization with BSA.

Controls are given MC alone and a drug-standard is usually included in each assay for verification } purposes. Drugs are prepared and diluted so as to provide a dose for a 200 gram animal which is equivalent to the mg/kg dose for each experiment. Thus each rat : receives an oral dose in a volume of approximately 2.0 cc. One hour after the last dose the animals are lightly anesthetized with ether and "sensitized" by injection of 0.2 ml of PFS containing 1.0 mg of BSA into the penile vein. One hour later, the animals are "challenged" in 7 the right rear paw with subplantar injections fof 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 maleolus) into the mercury well of a ) plethysmograph. 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 subsequently recorded with a plethysmograph during the development of the inflammation at 2 and 4 hours post-challenge.

Results

Results are expressed by the change in paw volume (A paw volume) from the control reading for each animal to that recorded 2 and 4 hours post-challenge. : All drug treated groups are compared to the MC control for significant differences with an analysis of variance. Differences from control in drug-treated groups are expressed as percent change from control in

Table II.

TABLE II

3 \ -W

I

XN 0

Compound Percent Inhibition

No. x -B-W- Dose(p.o0) vs. Control at 2 hrs. at 4 hrs. 1 mCl -(CHj) 4~ 25 mg/kg 64 30 2 H -(CHy) 4~ 25 mg/kg 75 29 (hemihydrate) 4 H -(CHy40- 25 mg/kg 74 25

On the basis of the test results, an oral dosage range of from about 5 mg/kg of body weight per day to about 50 mg/kg of body weight per day in divided doses taken at about 4 hour intervals is recommended. The dosage to be administered and the route of administration depends upon the particular compound used, the age and general health of the patient and the severity of the inflammatory condition. Thus, the dose ultimately decided upon must be left to the judgment of a trained - health-care practitioner./

The compounds of this invention are also useful ¢ in the treatment of peptic ulcers. They display chemotherapeutic activity which enables them to relieve the symptoms of peptic ulcer disease and stress ulceration, and to promote healing of gastric and/or duodenal ulcers. The antiulcer activity of the compounds of this invention is identified by standard tests which

261.0 measure the cytoprotective effect in rats, e.g., by . inducing gastrointestinal damage with ethanol prior to administering a compound of the invention. The compounds : may be used as conjunctive therapeutic agents for coadministration with such anti-inflammatory/analgesic agents as aspirin, indomethacin, phenylbutazone, ] ibuprofen, naproxen, tolmetin and other agents. The compounds of this invention prevent the untoward side effects of irritation and damage to the gastrointestinal tract caused by such agents.

In the treatment of peptic ulcer disease, and the prevention and treatment of drug-induced gastric ulceration, the active compounds of this invention can be administered in unit dosage forms such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, suppositories, mechanical delivery devices, e.g. transdermal, and the like. The compounds of this invention may be administered at doses of about 0.05 - 50 mg/kg of body weight per day.

Preferably the total dosages ar¢/ administered in 2-4 divided doses per day. :

The compounds of formula I are useful in the treatment of hyperproliferative skin disease, e.g., psoriasis, which utility may be demonstrated by the

Arachidonic Acid Mouse Ear Test as described below.

Arachidonic Acid

Mouse Ear Test,

Materials and Methods

Charles River, female, CD, (SD) BR mice, 6 weeks old, are caged 8/group and allowed to acclimate 1-3 weeks prior to use.

Arachidonic acid (AA) is dissolved in reagent grade acetone (2 mg/.01 ml) and stored at -20°C for a maximum of 1 week prior to use. Inflammatory reactions : are induced by applying 10 ul of AA to both surfaces of one ear (4 mg total). ’ Test drugs are dissolved in either reagent . grade acetone or aqueous ethanol (only if insoluble in acetone) at the same doses selected by Opas et al., Fed.

Proc. 43, Abstract 2983, p. 1927 (1984) and Young et al.,

J. Invest. Dermatol. 82, pp 367-371 (1984). These doses are employed to ensure maximum responses and to overcome any difference in topical absorption which could occur with any drug applied in an aqueous ethanol vehicle. The test drug is applied 30 minutes prior to challenge with

AA. /

The severity of the inflammation is measured as a function of increased ear weight. A 6 mm punch biopsy is removed 1 hour after AA challenge and weighed to the nearest 0.1 mg. Mean % standard error and all possible comparisons are made via Duncan's Multiple Range

Statistic.

As a result of the topical administration of a compound of formula I, a remission of the symptoms of the psoriatic patient, in most cases, can be expected. Thus, one affected by psoriasis can expect a decrease in scaling, erythema, size of the plagues, pruritus and other symptoms associated with psoriasis. The dosage of . medicament and the length of time required for } successfully treating each individual psoriatic patient v may vary, but those skilled in the art of medicine will be able to recognize these variations and adjust the course of therapy accordingly.

Included within the invention are preparation for topical application to the skin whereby the compounds having structural formula I are effective in the

— Ayo gy x 26104 -27- treatment and control of skin diseases characterized by rapid rates of cell proliferation and/or abnormal cell proliferation, e.g. psoriasis. . In a preferred method of carrying out the invention, a pharmaceutical formulation comprising a ’ compound of formula I together with a non-toxic, pharmaceutically /cceptable topical carrier, usually in concentrations in the range of from about 0.001 percent to about 10 percent, preferably from about 0.1 percent to about 5 percent, is applied several times daily to the affected skin until the condition has improved. Topical applications may then be continued at less frequent intervals (e.g. once a day) to control mitosis in order to prevent return of severe disease conditions.

As mentioned in Serial No. 851,068, filed April 11, 1986, the subject compounds possess anti-allergy and anti-inflammatory activities. For example, Compound A

By has an ED35 value of about 0.5 mg/kg p.o. in tests rw! oe measuring the inhibition of anaphylactic bronchospasm in ; . sensitized guinea pigs having antigen-induced i bronchoconstriction and an EDg, value of about 4.5 mg/kg { p.0. in tests measuring the reverse passive Arthus ‘ - reaction in the pleural cavity of rats (as described by © Myers et al., Inflammation, Vol. 9, No.l, 1985, pp. 91- ‘ In all of the above modes of treatment, the dosage to be administered and the route of administration depends upon the particular compound selected, the age and general health of the subject, and the severity and type of condition to be controlled. Thus, the dose ultimately provided must be left to the judgment of a trained health-care practitioner.

The quantity of active compound in a unit dose ’ preparation may be varied or adjusted from 1 mg to 100 mg according to the particular application and the potency ) of the active ingredient and the intended treatment. The . composition may, if desired, also contain other therapeutic agents. - When administered parenterally, e.g. intra- venously, the compounds are administered at a dosage range of about 0.1 to 5 mg/kg of body weight in single or multiple daily doses.

The invention disclosed ‘herein is exemplified by the following preparative examples, which should not be construed to limit the scope of the disclosure.

Alternative mechanistic pathways and analogous structures within the scope of applicants invention, may be apparent to those skilled in the art. . Preparative Example 1 1'-(3-Chlorophenyl)-1',4'-dihydro-4'-hydroxy-spiro[cyclo- pentane-1,3'(2'H)-[1,8]-naphthyridin]-2'-one

To a solution of 2.2 g (6.73 mmol.) of 1'-(3- chlorophenyl)-spiro{cyclopentane-1,3'-[1,8]- naphthyridin)-2',4'-(1'H)dione in 176 mL of (1:1) THF:

EtOH (abs.) was added 2.54 g (40 mmol.) of NaBH3CN and 3.0 mL of acetic acid. The solution was stirred at room - temperature. Af additional 0.2 g (3.2 mmol.) of NaBH;CN and 0.3 mL of acetic acid were added on the fourth day. ’ After 9 days the reaction was stopped by slow addition of mL of water. After concentration, the residue was purified by column chromatography, eluting with CHC14-

CH30H (95:5) to yield a colorless solid, 1.82 g. (5.53 mmol. 82%).

Recrystallization from CHCl3 and diethyl ether . (Et,0) yielded the product, m.p. 144-146°C.

Preparative Example 2 (SR,RS)-1-(3-Chlorophenyl)-4-hydroxy=1,3',4,4',5',6"'- ; hexahydro-spiro[l,8-naphthyridine-3(2H),2' [2H] -pyran}-2- one (Compound A) and (RS,RS)-1-(3-Chlorophenyl)-4- hydroxy-1,3',4,4',5',6'-hexahydro-spiro(1,8,- naphthyridine-3 (2H) ,2'[2H]-pyran]-2-one (Compound B)

To a solution of 1.0 g (2.92 mmol.) of 1-(4- chlorophenyl)-3',4',5',6'-tetrahydro-spiro(1,8- naphthyridine-3,2'-[2H]-pyran]-2,4-dione in 80 mL of (1:1) THF /C,HgOH (abs.) was added 0.734 g (11.66 mmol.) of NaBH3CN and 0.6 mL of acetic acid. The solution was stirred at room temperature for 5 days, then it was quenched by the addition of 5 mL of water. After concentration, the residue was purified by column chromatography over silica gel, eluting with CHC13-CH;O0H (95:5), to yield 1.06 g (95%) of a mixture /of the diastereomers, Compounds A and B. These were separated by preparative reversed-phase HPLC, eluting with CH3CN-

H,0-CH3COOH (30:70:1) to yield 0.52 g (54%) of Compound

A, m.,p. 183-184.5°C, and 0.12 g (12%) of Compound B, m.p. 186.5-188.5°C. . Preparative Example 3 } 4-Hydroxy-1,3',4,4',5',6'-hexahydro-1-phenyl-spiro[1,8- naphthyridine-3(2H),2'[2H]-pyran]-2-one (mixture of diastereomers)

In a stirred mixture of tetrahydrofuran (THF) (200 mL) and CyH.0H (200 mL) was suspended l-phenyl-

3',4',5',6'-tetrahydro-spiro(1,8-naphthyridin-3,2'-[2H]- ’ pyran}-2,4-dione (6.2 g) at room temperature. To the suspension was added acetic acid (2.6 mL) and tert- ) butylamine~borane (3.24 g). . After stirring for about 1 hour, water (ca. 200 mL) was added and the mixture was concentrated under . vacuum to a volume of about 100 mL Additional water (400 mL) was added and the mixture was extracted with methylene chloride. The methylene chloride extract was separated, dried over sodium sulfate, filtered and concentrated. Ether was then added and the mixture was cooled. The resulting solid was removed by filtration, washed with fresh ether and dried to yield the desired product as a mixture of /diastereomers, m.p. 211-213°C.

By the methods described in Preparative

Examples 1-3, the following compounds were prepared: . 1',4'-Dihydro-4'-hydroxy-1'-phenyl-spiro[cyclopentane- 1,3'-(2'H)[1,8)-naphthyridin]}-2'-one, m.p. 148-150°C; and p 1',4'~-dihydro-4"'-hydroxy-1'-phenyl-spirol[ furan-2,3- (2'H)[1,8]-naphythridin}-2'-one, mixture of diastereomers, m.p. 220-222°C.

Example 1 . . 7,8,9,10-Tetrahydro-5-phenyl-benzo[c] [1,8] -naphthyridin- 6- (5H) —one

A solution containing 1.2 g (4.07 mmol.) of : 1',4'-dihydro-4'-hydroxy-1'-phenyl-spiro[cyclopentane- 1,3'(2'H)-[1,8]-naphthyridin]-2'-one in 5.0 mL of trifluoromethanesulfonic acid was stirred at room temperature for 1.75 hours.

To this solution was added 100 mL of water and the resulting solution was adjusted to pH 5.0 with 2N

NaOH. The precipitate was collected by filtration,

Co washed with water, and redissolved in 200 mL of CH,C1,.

The organic solution was washed twice with 50 mL of saturated NaHCO3 solution, then with 100 mL of H,0, dried

Co with Mgs0y,, filtered, and concentrated in vacuo to yield 0.62 g (55%) of material, which was recrystallized from ‘ CHC143/Et,0 to yield/the desired product, m.p. 160-162°C.

Example 2 2,3-Dihydro-6-phenyl-1H-pyrano[2,3,-c} [1,8] -naphthyridin- 5(6H) -one, La H,0

To trifluoromethanesulfonic acid (5.0 mL) was added slowly, in portions, 1',4'-dihydro-4'-hydroxy-1'- phenylspiro[furan-2,3-(2'H)-[1,8]-naphythyridin]-2'-one (1.09) using a solid powder addition funnel, under N, at . room temperature. The reaction was followed by HPLC and

TLC which showed that one diastereomer rearranged faster than the other but that both eventually disappeared, after a total of about 24 hours.

The resulting solution was poured into ice- water (200 mL) containing NaOH (2.26 g). The pH was then adjusted to 4 with 1 N HCl. The precipitate which formed on standing was collected, washed with water and purified by chromatography on silica gel (100 g), eluting with

CHCl, containing 2.5% of methanol, to yield the desired - product, m.p. 250-252°C.

In a similar manner, except for the length of ) time for which the reaction is run (progress followed by

TLC), the following compounds were prepared: 5-(3-Chlorophenyl)-7,8,9,10-tetrahydro-benzofc] [1,8] - naphthyridin-6 (5H) -one, m.p. 133-135°C.; /

7-Phenyl-1,2,3,4-tetrahydro-oxepino[2,3-c][1,8]- : naphthyridin-6 (7H) -one, m.p. 191-193°C.; and 7- (3-Chlorophenyl)-1,2,3,4-tetrahydro-oxepino(2,3- . cl [1,8)}-naphthyridin-6 (7H) -one, m.p. 215-217°C. . Example 3 2,3-Dihydro-6-phenyl-1H-pyrano[2,3-c] {1,8]- naphythyridin-5(6H)-thione.

A suspension of 2,3-dihydro-6-phenyl-1H- pyrano[2,3-c] [1,8] -naphythyridin-5(6H)-one in dry toluene is stirred and heated in an N, atmosphere with a slight excess of Lawesson's Reagent [2,4-bis(4-methoxyphenyl)- 1,3-dithia-2,4-diphosphetane~-2,4-disulfide] at 50°C then at gradually increasing temperatures (15°C intervals, up to the reflux temperature) until TLC shows that reaction } is occurring. Heating is continued until essentially no starting material remains; then the mixture is cooled, filtered, evaporated and purified by chromatography to yield the desired product.

By following the procedure of Example 3, or modifications well known to one skilled in the art, other sulfur-containing analogs of the invention may be produced./

Example 4 “ 1,2-Dihydro-5-phenylfuro(2,3-c] [1,8] naphthyridin- 4 (5H) -one

Dissolve 3-n-butyl-4-hydroxy-l-phenyl-1,8- naphthyridin-2 (1H) -one (10 g) in CHCl, (1 L). Add a solution of Br, (1.74 mL, 5.43 g) in CH,Cl, (30 mL) slowly. Stir briefly after the addition, then wash with water and evaporate. Recrystallize the intermediate bromo-compound (3-bromo-3-n-butyl-1l-phenyl-1,8- naphthyridin-2,4 (1H) -dione) from CH,Cl,/diethyl ether/hexane and redissolve it in CH,Cl, (200 mL) and

CH4OH (75 mL). Add DBU (12 mL, about 3 equiv.) and stir : at room temperature. Evaporate off the solvents after about 1 hour and redissolve the residue in CH,Cl, (750 ’ mL). Add H,0 and adjust the aqueous layer to pH of about 4 with IN HCl. Dry with Mgs04 and evaporate.

Recrystallize the product (3-n-butyl-3-methoxy-l-phenyl- 1,8-naphthyridin-2,4 (1H) -dione) from diethyl ether /CH,C1, and purify, if necessary, by chromatography over silica gel, eluting with CH,Cl, containing 5% ethyl acetate.

Dissolve the purified product (5 g) in dry tetrahydrofuran (THF) (50 mL) and cool to below 0°C. Add a slight excess of vinyl magnesium bromide (1M in THF) and allow to react for 1 hour, then warm to room temperature. = Add aqueous NH4Cl solution (50 mL), . evaporate off the THF and extract into CH,C1, (2x50 mL). Wash with H,0 (2x50 mL), dry fwith Na,S0, and : evaporate to yield a mixture of diastereomeric alcohols (diastereomers of 3-n-butyl-4-ethenyl-4-hydroxy-3- ; methoxy-1l-phenyl-1,8-naphthyridin-2(1H)-one). oo Dissolve the mixture in CH,Cl, (50 mL) and cool to -78°C. Add a slight excess of BBrj in CH,Cl, (10 mL) and stir for 1 hour. Allow to warm to room temperature, add H,0 (25 mL) and adjust the pH of the aqueous layer to 4. Separate the organic layer, wash with water (2x25 - “ mL) , ary faith Na5504, and evaporate. Dissolve the crude . 1% product (3-n-butyl-4-ethenyl-3,4-dihydroxy-l-phenyl-1,8- ot naphthyridin-2(1H)-one) in cold CF4SO3H (below 0°C) (20 mL) and stir until reaction is complete, as shown by HPLC analysis of a small sample. Allow to warm to room temperature, then pour into ice-water, adjust the pH to 4 and extract with CHpClp (2x50 mL). Wash the organic layer with H,O0 (2x25 mL), dry with MgSO4, evaporate and

261,04 -36- purify by column chromatography over silica gel, eluting . with increasing concentrations of ethyl acetate in

CH,Cl,. Evaporate the fractions containing the product : and recrystallize to yield the desired product.

Example 5 1,2-Dihydro-2-(hydroxymethyl)-4~phenyl- cyclobuta(c)[1,8]naphthyridin-3(4H)-one

A solution of 4-(2-propenyloxy)-l-phenyl-1,8- naphthyridin-2(1H)-one (1.0 g) in methanol (350 mL) under an atmosphere of nitrogen was irradiated at 3000A for 34 days. Solvent was removed under vacuum and the reaction product purified by chromatography on silica gel in

CH,C1, containing 10% ethyl acetate. The fractions containing the product were combined and evaporated to yield 3(S R),9b(R S)-3,3a-dihydro-5-phenyl-3,9b-methano- 2H-furo[3,2-c] [1,8] naphthyridin-4(5H)~one, which was recrystallized from CH,Cl,/diethyl ether, m.p. 198- 199.5°C.

This compound (1.5 g) was dissolved in CH30H (100 mL). To the solution was added sodium methoxide (320 mg) and the mixture was heated at 90°C under a nitrogen atmosphere for about 2.5 hours. Solvent was removed under vacuum, the residue suspended in water, and the pH adjusted to 4 with IN HCl. The product was . extracted with CH,Cl, (3x100 mL) and the combined extracts washed with water (100 mL), dried with MgSOy. . and partially evaporated before separation on a silica gel chromatography column. The column was first eluted with CH,C1, containing 10% ethyl acetate, followed by

CH,Cl, containing 5% CH;0H, and the product isolated from the relevant fractions, m.p. 204-206°C.

’ Example 6 5-phenyl-8,9-dihydro-7H-cyclopentalc] [1,8] naphthyridin-6- (5H)-one 1/4 H,0 6a To a stirred mixture of the product of Example ’ 5, 1,2-dihydro-2-(hydroxymethyl)-4-phenyl- cyclobuta(c) (1,8) naphthyridin-3(4H)-one and triethylamine (0.2 mL) in CH,Cl, (5 mL) was added methanesulfonic anhydride (0.l14g) at room temperature. After 2 hours at room temperature an additional quantity of methanesulfonic anhydride (65 mg) was added. The reaction/was followed by TLC (silica gel/CH,Cl,:5%

MeOH). When the reaction was complete, the reaction . mixture was evaporated to dryness, redissolved in fresh

CH,Cl,, washed with 50 ml of H,0 adjusted to a pH of about 8, dried (MgSO4), and evaporated. . The crude mesylate (0.22) was dissolved in

CF3S03H (1 mL) at room temperature (in an No atmosphere). After 2 days at room temperature the solution was heated at 80°C for about 20 hours. After cooling, dilute NaOH solution was added and the mixture was adjusted to pH 4.5 with aqueous HCl solution. The product was extracted with CH,Cl, and this extract was washed with H,0, dried (MgSO), and evaporated to yield a mixture of the positonal double bond isomers. - 6b The mixture of double bond positional isomers from 6a (50 mg) was dissolved in MeOH (10 mL) containing ) AcOH (0.1 mL). To the solution was added ammonium formate (36 mg) and 5% Pd/C (25 mg). The mixture was stirred (in an N, atmosphere) at room temperature and was followed by TLC (silica gel/CH,Cl,:5% MeOH). Additional quantities (x2) of ammonium formate (36 mg) were added after stirring had progressed for 0.5 hours and 4 hours. After 25 hours the solution was diluted with

MeOH, filtered through Celite which was/washed with more

MeOH, and evaporated. The crude product was purified by chromatography (silica gel/CH,Cl,:5% MeOH) to yield the desired product, which was recrystallized from

Et,0/CH,Cl,, m.p. 230~232°C; yield 75%.

By the methods of Examples 1-5 using suitably substituted reagents, the compounds according to Table

III may be prepared.

39a

TABLE III

= cor fC i N N-NA (Rl-t-r2) : | 2

Q

Xx ny» n rR ga BW °

CH 0 - 0 - =- 0 ~CH,CH,CH,0- CgHg~ cH 0 - 0 - - 0 ~CH,CH,O- CgHg-

N 0 - 0 - =- 0 ~CH,CH,CH,CH,~ CgHg-

N 0 - 0 - - 0 ~CH,CH,CH,CHy~ 3-Cl-CgHy-

N 0 - 0 - =- 0 -CHpCH,CHpCHyO- CgHg—

N 0 - 0 - =- 0 ~CH,CH,CH,0- CgHs—

N 0 - o - =~ 0 -CH,CH,0- CgHsg-

CH 0 - 0 - =- s ~CHyCH,CH,CH)O- CgHg- : . CH 0 - 0 - - s ~CH,CH,CH,CHy- CeHs~

CH 1 7-CH; 0 - - © ~CHoCH,CH,0~ 4-CH30-CgHy-

CH 0 - 0 - - 0 ~CHyCH(OH)CHyO- ~~ CgHg-

CH 0 - 0 - - © —CH,CH(CH,0H)CHy~ CgHg-

CH 0 - 0 - - 0° ~CH,CH,CH(CH,0H)O- CgHg—

CH 0 - 0 - =- 0 ~CHCHyCH,CH,0~ 3-CH3S-CgH,-

CH 0 - 0 - - 0 ~CH,CH,CH,CHy~ 3-NO,~CgHy=

CH 0 - 0 - =~ 0 ~CH,CH,CHy= 3-Br-CgHy-

CH 0 - 1 H H 0 —CHyCH,CHyN(CH3)= 3-CF3-CgHy- ” CH 0 - 1 CH; H © ~CH,CH,CH- J \)

S

: CH 1 6Cl 1 H H 0 ~CH,CH,CH,~S* (0) CgHs-

CH 0 - 2 H H oO ~CH,CH,CH,0- 4-F-CgHy-

CH 0 - 1 H H © ~CH,CH,CH,CH,~

CH 0 - 1 H H O ~CH,CH,CH,0- 2

N

*Numbering based on 1,8-naphthyridine.

} The following formulations exemplify some of the dosage forms of the compositions of this invention.

In each, the term "active compound" designates 7-phenyl- 1,2,3,4-tetrahydro-oxepino(2,3-c}[1,8]-naphthyridin- - 6 (7H) -one. It is contemplated, however, that this compound may be replaced by equally effective amounts of } other compounds of formula I.

Pharmaceutical Dosage Form Examples

Example A

Tablets

No. Ingredient mg/tablet mg/tablet 1. Active compound 100 500 2. Lactose USP 122 113 3. Corn Starch, Food Grade, 30 40 as a 10% paste in

Purified Water 4. Corn Starch, Food Grade 45 40 - 5. Magnesium Stearate _3 _1

Total 300 700

Method of Manufacture

Mix Item Nos. 1 and 2 in a suitable mixer for 10-15 minutes. Granulate the mixture with Item No. 3. Mill the damp granules through a coarse screen (e.g., 1/4") if \ needed. Dry the damp granules. Screen the dried granules if needed 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 appropriate size and weight on a suitable tablet machine.

LF

Example B

Capsules : No. Ingredient mg/capsule mg/capsule . 1. Active compound 100 500 2. Lactose USP 106 123 3. Corn Starch, Food Grade 40 70 . 4, Magnesium Stearate NF 4 7

Total 250 700

Method of Manufacture

Mix Item Nos. 1, 2 and 3 in a suitable blender for 10-15 minutes. Add Item No. 4 and mix for 1-3 minutes. Fill the mixture into suitable two-piece hard gelatin capsules on a suitable encapsulating machine.

Example C

Parenteral } Ingredient ’ mg/vial mg/vial :

Active Compound Sterile Powder 100 500

Add sterile water for injection or bacteriostatic water for injection, for reconstitution. - Example D

Injectable

Ingredient mg/vial - Active Compound 100

Methyl p-hydroxybenzoate 1.8

Propyl p-hydroxybenzoate 0.2 ” Sodium Bisulfite 3.2

Disodium Edetate 0.1

Sodium Sulfate 2.6

Water for Injection g.s. ad 1,0 ml

Method of Manufacture (for 1000 vials) 1. Dissolve p-hydroxybenzoate compounds in a portion (85% of the final volume) of the water for injection at 65-70°C. ji 2, Cool to 25-35°C. Charge and dissolve the sodium bisulfite, disodium edetate and sodium sulfate. . 3. Charge and dissolve active compound. 4, Bring the solution to final volume by added water for injection. 5S. Filter the solution through 0.22, membrane and fill into appropriate containers. 6. Finally sterilize the units by autoclaving.

Example E

Nasal Spray mg/ml

Active Compound 10.0

Phenyl Mercuric Acetate 0.02 : Aminoacetic Acid USP 3.7

Sorbitol Solution, USP 57.0

Benzalkonium Chloride Solution 0.2 ’ Sodium Hydroxide 1N Solution to ————— adjust pH

Water Purified USP to make 1.0 ml

The following formulations exemplify some of the dosage forms in which the anti-psoriatic agents of the invention may be employed. : Example F ’ Ointment ’ Formula mg/g

Active Compound 1.0-20.0

Benzyl Alcohol, NF 20.0

Mineral Oil, USP 50.0

White Petrolatum, USP to make 1.0 g

Method of Manufacture . Disperse active compound in a portion of the mineral oil. Mix and heat to 65°C, a weighed quantity of white petrolatum, the remaining mineral 0il/and benzyl } alcohol, and cool to 50°-55°C. with stirring. Add the dispersed active compound to the above mixture with stirring. Cool to room temperature.

Example G

Cream

Formula mg/g

Active Compound 1.0-20.0

Stearic Acid, USP 60.0

Glyceryl Monostearate 100.0

Propylene Glycol, USP 50.0

Polyethylene Sorbitan Monopalmitate 50.0

Sorbitol Solution, USP 30.0 ) Benzyl Alcohol, NF 10.0 : Purified Water, USP to make 1.0 g

Method of Manufacture

Heat the stearic acid, glyceryl monostearate and polyethylene sorbitan monopalmitate to 70°C. In a

Separate vessel, dissolve sorbital solution, benzyl alcohol, water, and half quantity of propylene glycol and heat to 70°C. Add the aqueous phase to oil phase with high speed stirring. Dissolve the active compound in remaining quantity of propylene glycol and add to the above emulsion when the temperature of emulsion is 37°- ’ 40°C. Mix uniformly with/stirring and cool to room . temperature.

Example H

Gel

Formula mg./g

Active Compound 1.0-20.0 : Propylene Glycol, USp 300.0

Butylated Hydroxytoluene 5.0

Carbomer 940 5.0

Sodium Hydroxide (added as a 1% w/w solution in propylene glycol) 0.7

Polyethylene Glycol 400, USP 669.3~-688.

Method of Manufacture

Prepare a 1% solution of the sodium hydroxide in propylene glycol. Add approximately one-half the remaining propylene glycol and the polyethylene glycol . 400 to a suitable vessel and mix. Dissolve the butylated hydroxytoluene in this mixture. Disperse Carbomer 940, a polymer of acrylic acid crosslinked with a polyfunctional agent, in the above mixture with vigorous agitation. add the solution of sodium hydroxide with high speed agitation to bring pH up to 7 and mix until a thick gel forms. Dissolve the active compound in the remaining propylene glycol and add to the gel slowly as the gel is continuously mixed./

Example I , Lotion . Formula mg/g

Active Compound 1.0-20.0

Carbomer 940 3.0

Sodium hydroxide (charged as 4% w/w 0.05 aqueous solution)

Isopropyl Alcohol 40.00

Purified Water, USP to make 1.0 g

Method of Manufacture

Prepare a 4% solution of sodium hydroxide in water. Heat the purified water to 60°C. Add Carbomer 940 and mix at high speed until dispersed. Cool the above mixture to room temperature and slowly charge . sodium hydroxide solution until uniform. Add 80% of isopropyl alcohol to the above with mixing. Dissolve the active compound in remaining isopropyl alcohol. Add this to the mixture with stirring. Adjust PH to 5.0 to 5.5 with sodium hydroxide, if necessary./

Example J

Topical Aerosol

Formula mg/g

Active Compound 1.0-20.0 ’ Caprylic/Capric Triglyceride 50.00

Mineral 0il 20.00

Denatured Alcohol 150.00

Hydrocarbon Aerosol Propellant d.s. ad. 1.0 g

Method of Manufacture

Add and mix the caprylic/capric triglyceride mineral oil and specially denatured alcohol in a suitable compounding tank. Add the active compound and continue mixing until the active compound is dissolved or . dispersed uniformly. Fill the concentrate into cans and then fill the required amount of hydrocarbon aerosol propellant.

-46—~

While the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and variations thereof will be apparent to those of ordinary skill in . the art. All such alternatives, modifications and variations are intended to fall within the spirit and : scope of the present invention. ‘

. . , « ' -53-

ABSTRACT OF THE DISCLOSURE

! Aryl-substituted naphthyridines and pyrido- pyrazines are disclosed which are useful in treating allergic reactions, inflammation, peptic ulcers, hyperproliferative skin disease and/or suppressing immune responses in mammals. Pharmaceutical compositions and methods of treatment employing such compounds are also disclosed. ~ \

CN

. ih

P/PASP1030

Claims (13)

1. CLAIMS! 1, A compound having the atructural formula I B 0

   (x). | i I UN A “A (==, Q and pharmaceutically acceptable salts thereof, where in: X represents CH or Nj A represents O or 53% m is an integer of from O to 2% n ia an integer of from O to 2; rR! and rR? are the same or different and each : is independently selected from H and alkylj W represents a covalent bond or a group selected from -O-, ~8(0) - and -N(RY)- (wherein p is an integer of from O to 2 and g is alkyl having 1 to 4 carbon atoms); B is selected from alkylene having from 2 to 8 carbon atoms, which alkylene may be optionally

   1 —————————— ——— + — substituted with a group selected from -OH, ~F, and ~CH, 0H, with the proviso that OH or F is not on the carbon adjacent to W when W is selected from -Oe -8(0) - and -N(RY)-, and unsubstituted alkylene have ing from 2 to 8 carbon atoms and one or more double bonds Q represents an aryl group selected from phenyl and naphthyl or an aromatic monocyclic heterocyclic group selected from pyridyl and thienyl, each of which can optionally be substituted with one substi- tuent Y as defined below; and each Y substituent is independently selected from ~OH, hydroxymethyl, alkyl having 1 to 4 carbon atoms, halo, =NO,, alkoxy having 1 to 4 carbon atoms, ~CF, and -s-g" wherein Rg? is as defined above.
2. 2. The compound of Claim 1 having the formula SB { \ ; vw a. Prd ' PN 3 (0, | ] | 11 Sa ~~ nN N | A w=} — l
3. 2. wherein A, B, W, Y and n are as defined in Claim 1 and q is 0 or 1, and wherein, if n + q is greater than 1, the Y groups may be the same or different, 3e The compound of Claim 2 wherein: -B-W- represents an alkylene group or an al- kylenoxy group either of which may be substituted; said alkylene and alkylenoxy group having from 2 to 8 carbon atoms and the substituents thereof are as defined in Claim 1.
4. 4, The compound of Claim 2 wherein B~-W represents =(CH,) =o -(CH,) c= -(CH,),~0= or -(CH,) 4-0; and n is zero.
5. Se The compound of Claim 2 wherein: A is oxygen and the Y substituent on the phenyl ring is selected from independently chloro, nitro and trifluoromethyl.
6. 6. A compound according to Claim 1, namely 5-phenyl-7,8,9,10-tetrahydro-benzo/c 7/T,8/~ naphthyridin-6(5H)~one.
7. Te A compound according to Claim 1, namely S=(3-chlorophenyl)-7,8,9,10=tetrahydro~benzo- [<_7/1,8/-naphthyridin-6(5i)=-one.
8. 8. A compound according to Claim 1, namely
9. 7-phenyl-1,2,3,4=tetrahydro-oxepino/2, 3-c/= /1:8/-naphthyridin-6(7H)-one. LS A compound according to Claim 1, namely 7-(3-chlorophenyl)=-1,2,3,4=-tetrahydro-oxepino- [2+3-c//T,8/-naphthyridin-6-(7H)=one.
10. 10. A pharmaceuticel composition which comprises a compound as defined ih Claim 1 in combination with a pharmaceutically acceptable carrier.
11. 11. A method for treating allergic reactions in a mammal which comprises administering an anti-allergic effective amount of the pharmaceutical composition defined in Claim 10 to said mammal.
12. 12. A method for treating inflammation in a mammal which comprises administering an anti-inflammatory effective amount of the pharmaceutical composition defined in Claim 10 to said mammal,
13. 13. A method for treating hyperproliferative skin diseases in a mammal which comprises topically ad- ministering an effective amount of a pharmaceutical composition defined in Claim 10 to said mammal. DAVID J. BLYTHIN MARVIN I. SIEGEL HO=~JANE SHUE SIDNEY R. SMITH Inventors