Abstract:
Compounds of the formula ##STR1## wherein the broken line represents an optional double bond; X is O, S, CH 2  or CH 2  CH 2  ; R 1  is selected from the group consisting of hydrogen, halogen, C 1  -C 6  alkoxy, C 1  -C 6  alkanoyl, C 1  -C 6  alkyl, and C 1  -C 6  alkyl substituted with 1, 2 or 3 halogen atoms; R 2  is selected from the group consisting of phenyl, substituted phenyl, heterocyclic groups, and substituted heterocyclic groups, said substituted phenyl and substituted heterocyclic groups being substituted with 1 or 2 substituents independently selected from the group consisting of C 1  -C 6  alkyl, trifuluoromethyl, and halogen; R 3  and R 4  are independently selected from the group consisting of hydrogen, halogen, C 1  -C 6  alkyl, or trifluoromethyl, or R 3  and R 4 , taken together with the carbon atoms to which they are attached, form a six-membered carbocyclic aromatic ring, said aromatic ring being optionally substituted with one or two substituents selected from the group consisting of halogen, C 1  -C 6  alkyl, and C 1  -C 6  alkyl substituted with 1, 2 or 3 halogen atoms; and the pharmaceutically acceptable salts thereof. The compounds are useful in treating inflammation or other prostaglandin or leukotriene mediated diseases.

Description:
This is a division, of application Ser. No. 08/357,615, filed on Dec. 14, 1994, now abandoned, which was a division of application Ser. No. 07/438,469 filed on Nov. 13, 1989, now U.S. Pat. No. 5,403,839, which in turn, is the National Phase of PCT/US88/00781, filed Mar. 11, 1988. 
    
    
     BACKGROUND OF THE INVENTION 
     The present invention relates to pyrroloquinoline and pyrrolophenothiazine carboxamides and related compounds, methods of preparing such compounds, pharmaceutical compositions comprising such compounds and the use of such compounds in treating inflammation (e.g., arthritis) or other prostaglandin or leukotriene mediated diseases. 
     Oxindole-carboxamides useful as antiinflammatory agents and analgesics are referred to in U.S. Pat. Nos. 4,556,672, 4,569,942, 4,644,005, 4,678,802, and 4,686,224, and in U.S. Ser. No. 670,697, filed Nov. 13, 1984, and U.S. Ser. No. 821,296, filed Jan. 22, 1986. 
     U.S. Pat. No. 4,695,571 refers to tricyclic oxidoles as antiinflammatory agents. 
     U.S. Pat. No. 4,690,943 refers to 1,3-diacyl-2-oxindoles as antiinflammatory agents and analgesics. 
     U.S. Pat. No. 4,658,037 and U.S. Ser. No. 670,697, filed Nov. 13, 1984, refer to intermediates for preparing oxindole carboxamides. 
     SUMMARY OF THE INVENTION 
     The present invention relates to compounds of the formula ##STR2## wherein the broken line represents an optional double bond; X is O, S, CH 2  or CH 2  CH 2  ; R 1  is selected from the group consisting of hydrogen, halogen (e.g., fluorine, chlorine, bromine and iodine), C 1  -C 6  alkoxy (e.g., OCH 3 ), C 1  -C 6  alkanoyl, C 1  -C 6  alkyl, and trifluoromethyl; R 2  is selected from the group consisting of phenyl, substituted phenyl, heterocyclic groups, and substituted heterocyclic groups, said substituted phenyl and substituted heterocyclic groups being substituted with 1 or 2 substituents independently selected from the group consisting of C 1  -C 6  alkyl, trifluoromethyl, and halogen (e.g. fluorine, chlorine, bromine and iodine); R 3  and R 4  are independently selected from the group consisting of hydrogen, halogen (e.g., fluorine, chlorine, bromine and iodine), C 1  -C 6  alkyl, and trifluoromethyl, or R 3  and R 4 , taken together with the carbon atoms to which they are attached, form a six-membered carbocyclic aromatic ring, said aromatic ring being optionally substituted with one or two substituents selected from the group consisting of halogen (e.g., fluorine, chlorine, bromine or iodine), C 1  -C 6  alkyl, and trifluoromethyl; and the pharmaceutically acceptable salts thereof. The &#34;floating bond&#34; in formula I is intended to indicate that R 1  may be connected to any one of positions a, b and c of the aromatic ring. Position b is preferred. When R 2  is a heterocyclic group, R 2  is preferably selected from benzothiazole, isoxazole, isothiazole, oxazole, pyridine, thiazole and thiadiazole. The foregoing heterocyclic groups may be substituted as described above. 
     The present invention also relates to a pharmaceutical composition useful in the treatment of inflammation or other prostaglandin or leukotriene mediated diseases comprising an amount of a compound of the formula I effective to treat inflammation or another prostaglandin or leukotriene mediated disease and a pharmaceutically acceptable carrier. 
     The present invention also relates to a method of treating a prostaglandin or leukotriene mediated disease comprising administering to a patient in need of such treatment a compound of formula I in an amount effective to treat such disease. 
     The present invention also relates to intermediates useful in preparing the foregoing compounds and to methods of preparing the foregoing compounds. 
     A preferred embodiment of the present invention relates to compounds of the formula ##STR3## wherein R 1 , R 2  and X are as defined above and R 5  is selected from the group consisting of hydrogen, halogen, C 1  -C 6  alkyl, and trifluoromethyl, and the pharmaceutically acceptable salts thereof. More preferably R 1  is hydrogen or fluorine; R 2  is phenyl, 2,4-difluorophenyl, pyridinyl, thiazolyl, benzothiazolyl, isothiazolyl, or isoxazolyl, or isoxazolyl, and R 5  is hydrogen or fluorine. 
     Another preferred embodiment of the present invention relates to compounds of the formula ##STR4## wherein R 1 , R 2 , R 3  and X are as defined above, and the pharmaceutically acceptable salts thereof. More preferably, R 1  is hydrogen, fluoro, or trifluoromethyl; R 2  is phenyl, 2,4-difluorophenyl, pyridyl, thiazolyl, isothiazolyl, benzothiazolyl or isoxazolyl; R 3  is hydrogen, fluoro, or trifluoromethyl; and X is O, S or CH 2 . 
     Another preferred embodiment of the present invention relates to compounds of the formula ##STR5## wherein R 1 , R 2 , R 3 , R 4  and X are as defined above, with the proviso that R 3  and R 4  do not form a carbocyclic aromatic ring, and the pharmaceutically acceptable acid addition salts thereof. More preferably, R 1  is hydrogen and X is S. Most preferably, R 1  is hydrogen, R 3  is trifluoromethyl, R 4  is fluorine and X is S. 
     In each of the foregoing preferred embodiments, it is more preferred that R 1  be connected to position b of the aromatic ring. 
     Specific preferred compounds of the present invention include the following: 
     1,2-dihydro-N-phenyl-1-oxopyrrolo[3,2,1-kl]phenothiazine-2-carboxamide; 
     1,2-dihydro-N-(2,4-difluorophenyl)-1-oxopyrrolo[3,2,1-kl]phenothiazine-2-carboxamide; 
     1,2-dihydro-N-(2-pyridyl)-1-oxopyrrolo[3,2,1-kl]phenothiazine-2-carboxamide; 
     1,2-dihydro-N-[2-thiazolyl]-1-oxopyrrolo[3,2,1-kl]phenothiazine-2-carboxamide; 
     1,2-dihydro-N-phenyl-1-oxopyrrolo[3,2,1-kl]phenoxazine-2-carboxamide; 
     1,2-dihydro-N-(2-pyridyl)-1-oxopyrrolo[3,2,1-kl]phenoxazine-2-carboxamide; 
     N-(2-thiazolyl)-6H-pyrrolo[3,2,1-de]acridin-1(2H)-one-2-carboxamide; 
     N-(5-methyl-thiazolyl-2)-6H-pyrrido[3,2,1-de]acridin-1(2H)-one-2-carboxamide; 
     N-(thiazolyl-2)-4-fluoro-6H-pyrrido[3,2,1-de]acridin-1(2H)-one-2-carboxamide; 
     5-oxo-N-(2-thiazolyl)pyrrolo[1,2,3-de]-tetrahydro-1,4-benzothiazine-6-carboxamide; 
     2-oxo-N-(2-thiazolyl)-8-fluoro-4H-pyrrolo[3,2,1-ij]quinoline-1-carboxamide; and 
     5,6-dihydro-2-fluoro-5-oxo-N-(2-thiazolyl)-3-trifluoromethylpyrrolo[1,2,3-de]-1,4-benzothiazine-6-carboxamide. 
     Preferred compositions of the present invention include the foregoing preferred and specific preferred compounds. 
     DETAILED DESCRIPTION OF THE INVENTION 
     The compounds of the present invention may be prepared as described in the following reaction scheme: ##STR6## 
     In the foregoing reaction scheme, R 1 , R 2 , R 3  and R 4  are as defined above. 
     The compound of the formula V is reacted in an inert solvent with ClCOCH 2  Cl to provide the compound of formula VI. Either or both chlorine atoms in the compound of formula VI may be replaced by a bromine atom. The solvent is preferably an aromatic hydrocarbon such as benzene or toluene or a halohydrocarbon such as methylene chloride or chloroform. The temperature is not critical and generally ranges from about 20° C. to about 120° C. Preferably, the temperature is the reflux temperature of the solvent. 
     The compound of the formula VII is generally obtained by fusion of the compound of formula VI with anhydrous AlCl 3  at a temperature within a few degrees of the melting point of the compound of formula VI, using a temperature no greater than about 200° C. 
     The compound of the formula VII is reacted in an alcoholic solvent, preferably a C 1  -C 4  alcohol, or an aprotic polar solvent (e.g., dimethylformamide (DMF)) with a base such as sodium hydride, sodium C 1  -C 4  alkoxide or potassium C 1  -C 4  alkoxide and with dialkylcarbonate or alkylchloroformate wherein the alkyl groups may contain 1 to 4 carbon atoms, preferably 1 or 2 carbon atoms, to provide the compound of formula VIII wherein R 6  is C 1  -C 4  alkyl. The temperature is not critical and generally ranges from about 0° C. to about 100° C. Preferably, the temperature is the reflux temperature of the solvent. 
     In order to prepare a compound of the formula I, the compound of the formula VII is reacted in an inert solvent in the presence of a base such as sodium hydride or potassium hydride with a compound of the formula R 2  N═C═O wherein R 2  is as defined above. The solvent is preferably DMF or diglyme. The temperature is not critical and generally ranges from about 0° C. to about 30° C. The temperature is preferably room temperature (about 22° C.). 
     The compound of the formula I may also be prepared by reacting a compound of the formula VIII, wherein R 6  is as defined above, with a compound of the formula R 2  NH 2  in an inert solvent. The colvent is preferably toluene or xylene. The temperature is not critical and generally ranges from about 100° C. to about 200° C. The temperature is preferably the reflux temperature of the solvent. 
     The pressure used in each of the foregoing reactions is not critical. Generally, a pressure of about 0.5 to about 2 atmospheres, preferably ambient pressure (about one atmosphere) will be used. 
     Salts of compounds of the formula I may be prepared in a conventional manner by reacting a compound of the formula I with an appropriate base, for example, an inorganic base such as an alkali metal hydroxide or an alkaline earth metal hydroxide. 
     The activity of the compounds of formula I in the treatment of pulmonary, asthmatic, allergic and inflammatory diseases may be determined by a standard test measuring an agent&#39;s ability to inhibit cyclooxygenase and 5-lypoxygenase enzyme activity of rat basophil leukemia (RBL-1)cells. According to this test as described by Jakschick et al., Prostaglandins, 16, 733-747 (1978), and Jakschick et al., Biochem. Biophys. Res. Commun., 95, 103-110 (1980), a monolayer of RBL-1 cells is grown for 1 or 2 days in spinner culture in Eagle&#39;s minimum essential medium, 15% heat-inactivated fetal calf serum and an antibiotic/antimycotic mixture. The cells are washed after centrifugation and incubated in a buffer. A volume of 0.5 ml of cell suspension is preincubated at 30° C. for ten minutes with a 1 microliter dimethylsulfoxide (DMSO) solution of the agent to be tested. The incubation is initiated by simultaneous addition of 5 microliters ( 14  C)-- arachidonic acid in ethanol and 2 microliters calcium ionophore (A-21387) in DMSO for final concentrations of 5 and 7.6 micromolar, respectively. Five minutes later, the incubation is terminated by the addition of 0.27 ml acetonitrile/acetic acid (100:3). High pressure liquid chromatography is performed using acetonitrile/water/acetic acid solvent. Radiolabeled prostaglandin D 2  (PGD 2 ), leukotrine B 4  (LTB 4 ), 5-hydroxyeicosatetraenoic acid (5-HETE), and unreacted arachidonic acid are determined. The inhibitory effect on the cyclooxygenase pathway is assessed from the reduction of PGD 2  levels and the inhibitory effect on the 5-lipoxygenase pathway is assessed from the decrease in the amount of LTB 4  and 5-HETE. 
     The compounds of the formula I and their pharmaceutically acceptable salts are effective inhibitors of mammalian leukotriene or prostaglandin biosynthesis or both and are thus useful in the treatment of various leukotriene or prostaglandin mediated conditions. In particular, the compounds have utility, both as the sole active agent and also in combination with other active agents, for the treatment of various pulmonary, gastrointestinal, inflammatory, dermatological and cardiovascular conditions such as inflammation, arthritis, allergy, psoriasis, asthma, bronchitis, pulmonary hypertension and hypoxia, peptic ulcers, inflammatory bowel disease or cardiovascular spasm, such as acute myocardial infarctions, and the like in mammals, especially in humans. The compounds of the formula I and their pharmaceutically acceptable salts are particularly useful in treating arthritis. 
     For treatment of the various conditions described above, the compounds of formula I and their pharmaceutically acceptable salts may be administered to a subject in need of treatment by a variety of conventional routes of administration, including oral, by injection, topical, rectal, and in an aerosol carrier composition for administration by inhalation. 
     The exact dosage of a compound of the present invention will depend upon such factors as the age, weight and condition of the patient and the severity of disease. In general, however, a therapeutically effective dose of a compound of formula I or a pharmaceutically acceptable salt thereof will range from 0.1 to 25 mg/kg body weight of the subject to be treated per day, preferably 0.5 to 10 mg/kg per day. 
     Although the compounds of formula I and their pharmaceutically acceptable salts can be administered alone, they will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, oral administration may be in the form of tablets containing such excipients as starch or lactose, or in the form of elixirs or suspensions containing flavoring or coloring agents. In the case of animals, the compounds of the present invention are advantageously contained in an animal feed or drinking water. For parenteral injection, they may be used in the form of a sterile aqueous solution which may contain other solutes, for example, enough salt or glucose to make the solution isotonic. Other active compounds, including NSAIDS (non-steroidal antiinflammatory drugs) may be administered along with the compounds of the present invention. 
    
    
     The following non-limiting Preparations and Examples are illustrative of the preparation of compounds of the present invention. All melting points referred to in the Preparations and Examples are uncorrected. 
     PREPARATION OF STARTING MATERIALS 
     The compounds described in Table I were used in preparing compounds of the present invention. Unless a reference is given, the compounds are commercially available: 
     
                       TABLE 1______________________________________ ##STR7##                      IX ##STR8##                      X ##STR9##                      XICompoundNumber  Formula  X        R.sup.1                         R.sup.5                             Reference______________________________________P1      IX       S        H   H   Commercial materialP2      IX       O        H   H   Commercial materialP3      IX       CH.sub.2 H   H   Commercial materialP4      IX       CH.sub.2 H   F   J. Indian Chem. Soc.,                             38, 877 (1961)P5      IX       CH.sub.2 F   F   J. Am. Chem. Soc.,                             63, 1563 (1941)P6      IX       CH.sub.2 CH.sub.2                     H   H   Commercial materialP7      X        S        H   H   Acad. Sc. Paris, 265,                             758 (1967)P8      X        O        H   H   J. Het. Chem., 6, 809                             (1963)P9      X        CH.sub.2 CH.sub.2                     H   H   British Patent 897,052 P10    XI       S        H   H   Acad. Sc. Paris, 265,                             758 (1967) P11    XI       CH.sub.2 CH.sub.2                     H   H   British Patent 897,052______________________________________ 
    
     PREPARATION 1 
     2-Fluoro-3-trifluoromethyl-N-chloroacetyl-1,4-dihydrobenzothiazine 
     2-Fluoro-3-trifluoromethyl-1,4-dihydrobenzothiazine prepared as described in Chemistry Letters, 167 (1983), was reacted with chloroacetyl chloride to yield the title compound.  1  H NMR (CDCl 3 , 60 MHz), ppm (∫): 4.3 (S, 2H), 6.9-7.0 (m, 4H). 
     Similarly prepared were the following: 
     2-fluoro-N-chloroacetylacridan (m.p. 121°-124° C.); 
     2,7-difluoro-N-chloroacetylacridan (m.p. 128°-131° C.); 
     1,2,3,4-tetrahydro-6-fluoro-N-chloroacetylquinoline [ 1  H NMR(CDCl 3 , 60 MHz), ppm (∫) 2.0 (m, 2H), 2.7 (m, 2H), 3.7 (m, 2H), 4.2 (s, 2H), 6.7-7.2 (m, 3H)]; 
     2,3-dihydro-3,7-dimethyl-N-chloroacetyl-1,4-benzoxazine and 3,7-dimethyl-N-chloroacetyl-1,2,3,4-tetrahydrobenzoxazine (m.p. 59°-61°). 
     PREPARATION 2 
     2-Fluoro-3-trifluoromethylpyrrolo[1,2,3-de]-1,4-benzothiazin-5(6H)-one 
     A mixture of the title compound of Preparation 1 (3.11 g) and anhydrous aluminum chloride (4.0 g) was heated in an open beaker at 150° C. for 0.5 hours. After evalution of gaseous hydrogen chloride ceased, the residue was cooled to room temperature and then quenched with a mixture of 10 ml concentrated HCl and 200 ml of ice water. The resulting dark brown solid was extracted with ethyl acetate (2×100 ml) and the organic extract was evaporated to dryness. The residue was purified by chromatography over silica gel, using methylene chloride as the eluant, to obtain the title compound as a white crystalline solid, m.p. 128°-130° C. 
     Similarly prepared were the following: 
     
         ______________________________________ ##STR10##                                    Reference                                    or                                    MeltingCompound   Formula   X      R.sup.1                          R.sup.3                               R.sup.5                                    Point °C.______________________________________P12     VIII      S      H     H    --   85-87P13     VIII      CH.sub.2                    H     H    --   *P14     VII       O      CH.sub.3                          CH.sub.3                               --   96-98P15     VIII      CH.sub.2                    F     H    --   119-121P16     IX        O      H     --   H    182-183P17     IX        CH.sub.2                    H     --   H    175-176P18     IX        CH.sub.2                    H     --   F    134-138P19     IX        CH.sub.2                    F     --   F    206-208P20     VIII      CH.sub.2                    CH.sub.3                          --   --   *______________________________________ *British Patent 1,394,373 
    
     PREPARATION 3 
     5,6-Dihydro-2-fluoro-5-oxo-3-trifluoromethylpyrrolo[1,2,3-de]-1,4-benzothiazine-6-carboxylic acid, ethyl ester 
     To a solution of sodium ethoxide prepared from sodium metal (0.35 g) and ethanol (30 ml) was added the title compound of Preparation 2 (1.37 g) followed by diethyl carbonate (1.77 g). The solution was heated at 65° C. for 3 hours. The reaction mixture was cooled, poured into ice water, acidified with dilute HCl to pH about 3 and the resulting solid collected by filtration.  1  H NMR(CDCl 3 , 60 MHz), ppm (∫): 1.3 (t, J=8 Hz, 3H), 4.1 (q, J=8 Hz, 2H), 4.3 (s, 1H, 6.9-7.2 (m, 3H). 
     Similarly, prepared were the following: 
     ethyl-5,6-dihydro-pyrrolo[1,2,3-de]-tetrahydro-1,4-benzothiazine-5(6H)-one-1-carboxylate [ 1  H NMR (CDCl 3 , 60 MHz), ppm (∫): 1.3 (t, J=8 Hz, 3H), 3.0 (m, 2H), 3.9-4.2 (m, 5H), 6.9-7.1 (m, 3H)]: 
     ethyl-2-oxo-5,6-dihydro 3,8-dimethyl-pyrrolo[1,2,3-de]tetrahydro-1,4-benzoxazin-5(6)-one-1-carboxylate [ 1  H NMR (CDCl 3 , 60 MHz), ppm(∫): 1.2 (t, J=8 Hz, 3H), 1.5 (d, J=12 Hz, 3H), 2.4 (s, 3H), 4.1 (m, 3H), 4.2 (m, 2H), 6.8 (m, 2H)]; 
     ethyl-2-oxo-1,2,5,6-tetrahydro-4-H-pyrollo[3,2,1-J]quinoline-1-carboxylate [ 1  HNMR(CDCl 3 , 60 MHz), ppm (∫): 1.5 (t, J=7 Hz, 3H), 2.1 (m, 2H), 2.9 (m, 2H), 3.9 (t, J=7 Hz, 2H), 4.2 (m, 2H), 7.2 (m, 3H)]; 
     ethyl-2-oxo-7-fluoro-1,2,5,6-tetrahydro-4-H-pyrollo[3,2,1-iJ]quinoline-1-carboxylate (m.p. 118°-120° C.); and 
     ethyl-2-oxo-7-methyl-1,2,5,6-tetrahydro-4-H-pyrollo[3,2,1-iJ]quinoline-1-carboxylate [ 1  HNMR(CDCl 3 , 60 MHz), ppm (∫): 1.5 (t, J=7 Hz, 3H), 2.0 (m, 2H), 2.4 (5,3H), 2.9 (m, 2H), 3.9 (t, J=7 Hz; 2H), 4.2 (m, 2H), 7.2 (dd, J=2, 2H)]. 
     PREPARATION 4 
     Methylpyrrolo[3,2,1-kl]phenoxazine-1-one-2-carboxylate 
     To a slurry of sodium hydride (0.39 g) in 20 ml of DMF (dimethylformamide) was added pyrrolo[3,2,1-kl]phenoxazine (1.4 g), prepared as described according to Preparation 2, and the resulting dark red solution was stirred at room temperature for 0.5 hours. To this solution, was added methyl chloroformate (0.95 g), dropwise, over a period of 10 minutes. The reaction mixture was stirred for 2 hours at room temperature, and it was then poured onto ice water (200 ml). The resulting mixture was then acidified to pH 2.0 with concentrated HCl and the mixture was then extracted with methylene chloride (200 ml). The extract was washed with water, dried and evaporated to dryness to yield the title compound as a solid (0.06 g; m.p. 124°-127° C.). 
     PREPARATION 5 
     Ethyl 6H-pyrido[3,2,1-de]acridin-1(2H)-one 10 carboxylate 
     To a freshly prepared solution of sodium ethoxide in ethanol (from 0.35 g sodium metal and 10 ml ethanol) was added 6H-pyrido[3,2,1-de]acridin-1(2H)-one (1.2 g) portionwise over a period of 10 minutes. To the resulting dark red solution was slowly added diethyl carbonate (1.77 g) and the solution was then refluxed for 3 hours. The reaction mixture was cooled, acidified to pH 2 with concentrated HCl and then extracted with methylene chloride. The organic extract was washed with water and was then collected, dried and evaporated to dryness to obtain a light amber solid (1.8 g; m.p. 113°-118° C.). 
     PREPARATION 6 
     Following the method of Preparation 4 or Preparation 5, the following compounds were prepared; 
     
         ______________________________________ ##STR11##                            MeltingCompound   X         R.sup.1                   R.sup.5                       R.sup.6                            Point °C.                                   Method______________________________________P21     S         H     H   CH.sub.3                            144-145                                   Preparation 4P22     CH.sub.2  H     H   CH.sub.3                            89-92  Preparation 4P23     CH.sub.2  F     F   C.sub.2 H.sub.5                            134-136                                   Preparation 5P24     CH.sub.2CH.sub.2             H     H   CH.sub.3                            121-123                                   Preparation 4______________________________________ 
    
     EXAMPLE 1 
     1,2-Dihydro-N-(2,4-difluorophenyl)-1-oxopyrrolo[3,2,1-kl]phenothiazine-2-carboxamide 
     To a suspension of sodium hydride (0.14 g) in DMF (10 ml) was added pyrrolo[3,2, -1kl]phenothiazine-1-one (0.48 g) and to the resulting solution was slowly added 2,4-difluorophenyl isocyanate (0.31 g). The reaction mixture was stirred for 12 hours and then poured onto ice water (50 ml). The resulting mixture was acidified to pH 2.0 with 6N HCl and the precipitated solid was collected and then air dried to yield the title compound (2.84 g). A sample recrystallized from methylene chloride had a m.p. of 208°-209° C. 
     EXAMPLE 2 
     1,2-Dihydro-N-[2-pyridyl]-1-oxopyrrolo[3,2,1-kl]phenothiazine-1-carboxamide 
     A mixture of methyl pyrrolo[3,2,-1-kl]phenoxazine-1-one-2-carboxylate (0.7 g), 2 aminopyridine (0.28 g) and xylene (20 ml) was heated under reflux for 0.5 hours. It was then cooled to room temperature and the precipitated yellow solid was collected by filtration (0.64 g, m.p. 224°-225° C.). 
     EXAMPLES 3-5 
     Starting, in each case, from the corresponding lactam or ester, compounds E1, E2, E11-E14, E18-E21, and E43-E46, described below, were prepared by the method of Example 1 and compounds E3-E10, E15-E17, E22-E42, and E47-E83, described below, were prepared by the method of Example 2. 
     
         __________________________________________________________________________Example 3 ##STR12##Compound                     MeltingNumber X    R.sup.1        R.sup.5          R.sup.2       Point °C.__________________________________________________________________________E1    S    H H 4-Cl-phenyl   247-248E2    S    H H 2-F,4-F-phenyl                        208-209E3    S    H H phenyl        236-239E4    S    H H 2-pyridyl     228-229E5    S    H H 2-thiazolyl   203-205E6    S    H H 2-thiazolyl-5-CH.sub.3                        218E7    S    H H 5-isothiazolyl-3-methyl                        228-231E8    S    H H 2-F,6-F-phenyl                        237-241E9    S    H H 2-F,5-F-phenyl                        207-208E10   S    H H 2[1,3,4-thiazolyl]-5-CF.sub.3                        186-188E11   O    H H 4-Cl-phenyl   268-270E12   O    H H 4-F-phenyl    254-256E13   O    H H phenyl        254E14   O    H H 2-F,4-F-phenyl                        238-239E15   O    H H 2-pyridyl     224-225E16   O    H H 3-isoxozolyl-5-CH.sub.3                        197-198E17   O    H H 2-thiazolyl   206-208E18   CH.sub.2      H H 4-F-phenyl    224-226E19   CH.sub.2      H H 2-F,4-F-phenyl                        186E20   CH.sub.2      H H phenyl        209E21   CH.sub.2      H H 4-Cl-phenyl   235-237E22   CH.sub.2      H H 2-thiazolyl   231-234E23   CH.sub.2      H H 2-pyridyl     209E24   CH.sub.2      H H 2-thiazolyl-5-CH.sub.3                        231-232E25   CH.sub.2      H H 5-isothiazolyl-3-CH.sub.3                        211-213 (dec.)E26   CH.sub.2      H H 2-F,6-F-phenyl                        264-265E27   CH.sub.2      H H 2-pyridyl-6-CH.sub.3                        232-233E28   CH.sub.2      H H 3-isoxozolyl-5-CH.sub.3                        198 (dec.)E29   CH.sub.2      H H 3-1H-pyrazolyl                        248-250E30   CH.sub.2      H H 2-1H-imidazolyl                        268 (dec.)E31   CH.sub.2      H H 2-pyrimidinyl 219-221E32   CH.sub.2      H H 2-(1,2,4-thiadiazolyl)-5-CF.sub.3                        204-205 (dec.)E33   CH.sub.2      H F 5-isothiazolyl-3-CH.sub.3                        203-205E34   CH.sub.2      H F 2-[1,2,4-thiadiazolyl]-5-phenyl                        211-214E35   CH.sub.2      H F 2-F,4-F-phenyl                        222-223E36   CH.sub.2      H F 2-F,5-F-phenyl                        184-186E37   CH.sub.2      H F 2-thiazolyl   168-174 (dec.)E38   CH.sub.2      H F 2-[1,3,4-thiadiazolyl]                        208-210E39   CH.sub.2      F F 2-pyridyl     246-248E40   CH.sub.2      F F 2-thiazolyl   199-200E41   CH.sub.2      F F 2-thiazolyl-5-CH.sub.3                        223 (dec.)E42   CH.sub.2      F F 5-isothiazolyl-3-CH.sub.3                        233 (dec.)E43   CH.sub.2 CH.sub.2      H H 2-F,4-F-phenyl                        217-218E44   CH.sub.2 CH.sub.2      H H 4-Cl-phenyl   194-196E45   CH.sub.2 CH.sub.2      H H 4-F-phenyl    224-225E46   CH.sub.2 CH.sub.2      H H phenyl        224-225E47   CH.sub.2 CH.sub.2      H H 2-pyridyl     202-204E48   CH.sub.2 CH.sub.2      H H 2-thiazolyl   248-249E49   CH.sub.2 CH.sub.2      H H 3-methylthioethyl                        158-159E50   CH.sub.2 CH.sub.2      H H 3-isoxazolyl-5-CH.sub.3                        168-169E51   CH.sub.2 CH.sub.2      H H 2-thiazolyl-4CH.sub.35CH.sub.3                        261-262E52   CH.sub.2 CH.sub.2      H H 2-benzothiazolyl                        167-168E53   CH.sub.2 CH.sub.2      H H 2-thiazolyl-5-CH.sub.3                        234-236__________________________________________________________________________Example 4 ##STR13##CompoundNumber/                         MeltingFormula X  R.sup.1       R.sup.2      R.sup.4                        R.sup.3                           Point °C.__________________________________________________________________________E54/II O  CH.sub.3        CH.sub.3                        H  205-206E55/II O  CH.sub.3       2-pyridyl    CH.sub.3                        H  168-169E56/II O  CH.sub.3       phenyl       CH.sub.3                        H  190-191E57/II O  CH.sub.3       2F,4F-phenyl CH.sub.3                        H  181-183E58/II O  CH.sub.3       2-thiazolyl  CH.sub.3                        H  172-174E59/II O  CH.sub.3       2-benzothiazolyl                    CH.sub.3                        H  184-185E60/II O  CH.sub.3       2[1,3,4-thiadiazolyl]-5-CF.sub.3                    CF.sub.3                        H  186-188E61/II O  CH.sub.3       2-oxazolyl-5-CH.sub.3                    CH.sub.3                        H  194-195E62/II O  CH.sub.3       5-isothiazolyl-3-CH.sub.3                    CH.sub.3                        H  219-220E63/III S  H  2-thiazolyl  F   CF.sub.3                           211E64/III S  H  2-F,4-F-phenyl                    F   CF.sub.3                           214-216E65/III S  H  5-isothiazolyl-3-CH.sub.3                    F   CF.sub.3                           240-242__________________________________________________________________________ 
    
     EXAMPLE 
     
         ______________________________________ ##STR14##Compound                          MeltingNumber    R.sup.1 R.sup.2         Point °C.______________________________________E66       H       2-Cl, 4-Cl-phenyl                             199-200E67       H       phenyl          175-176E68       H       2-pyridyl       246-247E69       H       3-methyl-2-pyridyl                             213-214E70       H       4-F-phenyl      191-194E71       H       2-thiazolyl     208-210E72       H                       164-168E73       H       2-Cl, 5-Cl-phenyl                             187-189E74       H       3-Cl, 4-Cl-phenyl                             200-201E75       H       4-Br-phenyl     206-207E76       H       2-F, 5-F-phenyl 176-180E77       H       2-F, 4-F-phenyl 174-175E78       H       4-methyl-2-thiazolyl                             202-205E79       H       4,5-dimethyl-2-thiazolyl                             249-252E80       F       2-thiazolyl     213-214                             (dec.)E81       CH.sub.3             2-pyridyl       189-190E82       CH.sub.3             5-isothiazolyl-3-methyl                             174-177E83       CH.sub.3             2-benzothiazolyl                             178-180______________________________________ 
    
     EXAMPLE 6 
     The compounds numbered E1-E83 and the compounds of Examples 1 and 2 were assayed according to the method of Jakschick et al. described above. The compounds were found to have inhibitory activity against cyclooxygenase or 5-lipoxygenase or both.