# Patent

## Title
Inclusion complexes of N-ethoxycarbonyl 1-3-morpholino-sydnonimine or

## Abstract

Compounds of the formula ##STR1## wherein the broken line represents an optional double bond; X is O, S, CH.sub.2 or CH.sub.2 CH.sub.2, and the pharmaceutically acceptable salts thereof. The compounds are useful in treating inflammation or other prostaglandin or leukotriene mediated diseases.

## Background
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 oxindoles as antiinflammatory agents.

United States Patent 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.

The present invention relates to compounds of the formula ##STR2## wherein the broken line represents an optional double bond; X is O, S, CH.sub.2 or CH.sub.2 CH.sub.2 ; R is selected from the group consisting of hydrogen, halogen (e.g., fluorine, chlorine, bromine and iodine), C.sub.1 -C.sub.6 alkoxy (e.g., OCH.sub.3) , C.sub.1 -C.sub.6 alkanoyl, C.sub.1 -C.sub.6 alkyl, and trifluoromethyl; R.sup.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.sub.1 -C.sub.6 alkyl, trifluoromethyl, and halogen (e.g. fluorine, chlorine, bromine and iodine);

R.sup.3 and R.sup.4 are independently selected from the group consisting of hydrogen, halogen (e.g., fluorine, chlorine, bromine and iodine), C.sub.1 -C.sub.6 alkyl, and trifluoromethyl, or R.sup.3 and R.sup.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.sub.1 -C.sub.6 alkyl, and trifluoromethyl; and the pharmaceutically acceptable salts thereof. The "floating bond" in formula I is intended to indicate that R.sup.1 may be connected to any one of positions a, b and c of the aromatic ring. Position b is preferred. When R.sup.2 is a heterocyclic group, R.sup.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.sup.1, R.sup.2 and X are as defined above and R.sup.5 is selected from the group consisting-of hydrogen, halogen, C.sub.1 -C.sub.6 alkyl, and trifluoromethyl, and the pharmaceutically acceptable salts thereof. More preferably R.sup.1 is hydrogen or fluorine; R.sup.2 is phenyl, 2,4-difluorophenyl, pyridinyl, thiazolyl, benzothiazolyl, isothiazolyl, or isoxazolyl, and R.sup.5 is hydrogen or fluorine.

Another preferred embodiment of the present invention relates to compounds of the formula ##STR4## wherein R.sup.1, R.sup.2, R.sup.3 and X are as defined above, and the pharmaceutically acceptable salts thereof. More preferably, R.sup.1 is hydrogen, fluoro, or trifluoromethyl; R.sup.2 is phenyl, 2,4-difluorophenyl, pyridyl, thiazolyl, isothiazolyl, benzothiazolyl or isoxazolyl; R.sup.3 is hydrogen, fluoro, or trifluoromethyl; and X is O, S or CH.sub.2.

Another preferred embodiment of the present invention relates to compounds of the formula ##STR5## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and X are as defined above, with the proviso that R.sup.3 and R.sup.4 do not form a carbocyclic aromatic ring, and the pharmaceutically acceptable acid addition salts thereof. More preferably, R.sup.1 is hydrogen and X is S. Most preferably, R.sup.1 is hydrogen, R.sup.3 is trifluoromethyl, R.sup.4 is fluorine and X is S.

In each of the foregoing preferred embodiments, it is more preferred that R.sup.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-ca rboxamide;

1,2-dihydro-N-(2-pyridyl)-1-oxopyrrolo[3,2,1-kl]-phenothiazine-2-carboxamid e;

1,2-dihydro-N-(2-thiazolyl]-1-oxopyrrolo[3,2,1-kl]-phenothiazine-2-carboxam ide;

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-carboxami de;

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-carbo xamide;

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-d e]-1,4-benzothiazine-6-carboxamide.

Preferred compositions of the present invention include the foregoing preferred and specific preferred compounds.

The compounds of the present invention may be prepared as described in the following reaction scheme: ##STR6##

In the foregoing reaction scheme, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as defined above.

The compound of the formula V is reacted in an inert solvent with ClCOCH.sub.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.degree. C. to about 120.degree. 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.sub.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.degree. C.

The compound of the formula VII is reacted in an alcoholic solvent, preferably a C.sub.1 -C.sub.4 alcohol, or an aprotic polar solvent (e.g., dimethylformamide (DMF)) with a base such as sodium hydride, sodium C.sub.1 -C.sub.4 alkoxide or potassium C.sub.1 -C.sub.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.sup.6 is C.sub.1 -C.sub.4 alkyl, preferably C.sub.1 -C.sub.4 alkyl. The temperature is not critical and generally ranges from about 0.degree. C. to about 100.degree. 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.sup.2 N.dbd.C.dbd.O wherein R.sup.2 is as defined above. The solvent is preferably DMF or diglyme. The temperature is not critical and generally ranges from about 0.degree. C. to about 30.degree. C. The temperature is preferably room temperature (about 22.degree. C.).

The compound of the formula I may also be prepared by reacting a compound of the formula VIII, wherein R.sup.6 is as defined above, with a compound of the formula R.sup.2 NH.sub.2 in an inert solvent The solvent is preferably toluene or xylene. The temperature is not critical and generally ranges from about 100.degree. C. to about 200.degree. 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'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'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.degree. 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 (.sup.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.sub.2 (PGD.sub.2), leukotrine B.sub.4 (LTB.sub.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.sub.2 levels and the inhibitory effect on the 5-lipoxygenase pathway is assessed from the decrease in the amount of LTB.sub.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.

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: ______________________________________ ##STR7## ##STR8## Compound Number  Formula  X        R.sup.1 R.sup.5 Reference ______________________________________ P1      IX       S        H   H   Commercial material P2      IX       O        H   H   Commercial material P3      IX       CH.sub.2 H   H   Commercial material P4      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 material P7      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 ______________________________________

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. .sup.1 H NMR (CDCl.sub.3, 60 MHz), ppm (.delta.): 4.3 (S, 2H), 6.9-7.0 (m, 4H).

Similarly prepared were the following:

2-fluoro-N-chloroacetylacridan (m.p. 121.degree.-124.degree. C.);

2,7-difluoro-N-chloroacetylacridan (m.p. 128.degree.-131.degree. C.);

1,2,3,4-tetrahydro-6-fluoro-N-chloroacetylquinoline [.sup.1 H NMR(CDCl.sub.3, 60 MHz), ppm (.delta.) 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.degree.-61.degree.).

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.degree. 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.times.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.degree.-130.degree. C.

Similarly prepared were the following: ##STR9## Reference or Melting Compound Formula  X       R.sup.1 R.sup.3 R.sup.5 Point .degree.C. ______________________________________ P12     VIII     S       H    H    --  85-87 P13     VIII     CH.sub.2 H    H    --  * P14     VII      O       CH.sub.3 CH.sub.3 --  96-98 P15     VIII     CH.sub.2 F    H    --  119-121 P16     IX       O       H    --   H   182-183 P17     IX       CH.sub.2 H    --   H   175-176 P18     IX       CH.sub.2 H    --   F   134-138 P19     IX       CH.sub.2 F    --   F   206- 208 P20     VIII     CH.sub.2 CH.sub.3 --   --  * ______________________________________ *British Patent 1,394,373 zine-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.degree. 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. .sup.1 H NMR(CDCl.sub.3, 60 MHz) , ppm (.delta.): 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 [.sup.1 H NMR (CDCl.sub.3, 60 MHz), ppm (.delta.): 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-carboxy late [.sup.1 H NMR (CDCl.sub.3, 60 MHz), ppm (.delta.): 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 [.sup.1 HNMR(CDCl.sub.3, 60 MHz) , ppm (.delta.): 1.5 (t, J=7Hz, 3H), 2.1 (m, 2H), 2.9 (m, 2H), 3.9 (t, J=7 Hz, 2 H), 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.degree.-120.degree. C.); and

ethyl-2-oxo-7-methyl-1,2,5,6-tetrahydro-4-H-pyrollo[3,2,1-iJ]quinoline-1-ca rboxylate [.sup.1 HNMR(CDCl.sub.3, 60 MHz), ppm. (.delta.): 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)].

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.degree.-127.degree. C.).

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.degree.-118.degree. C.).

Following the method of Preparation 4 or Preparation 5, the following compounds were prepared: ##STR10## Melting Compound X         R.sup.1 R.sup.5 R.sup.6 Point .degree.C. Method ______________________________________ P21     S         H     H   CH.sub.3 144-145 Preparation 4 P22     CH.sub.2  H     H   CH.sub.3 89-92  Preparation 4 P23     CH.sub.2  F     F   C.sub.2 H.sub.5 134-136 Preparation 5 P24     CH.sub.2CH.sub.2 H     H   CH.sub.3 121-123 Preparation 4 ______________________________________ rboxamide

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.degree.-209.degree. C.

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.degree.-225.degree. C.).

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. ##STR11## Com- pound                                Melting Number X        R.sup.1 R.sup.5 R.sup.2    Point .degree.C. ______________________________________ E1     S        H     H   4-Cl-phenyl 247-248 E2     S        H     H   2-F,4-F-phenyl 208-209 E3     S        H     H   phenyl     236-239 E4     S        H     H   2-pyridyl  228-229 E5     S        H     H   2-thiazolyl 203-205 E6     S        H     H   2-thiazolyl-5-CH.sub.3 218 E7     S        H     H   5-isothiazolyl-3- methyl     228-231 E8     S        H     H   2-F,6-F-phenyl 237-241 E9     S        H     H   2-F,5-F-phenyl 207-208 E10    S        H     H   2[1,3,4-thiazolyl]- 186-188 5-CF.sub.3 E11    O        H     H   4-Cl-phenyl 268-270 E12    O        H     H   4-F-phenyl 254-256 E13    O        H     H   phenyl     254 E14    O        H     H   2-F,4-F-phenyl 238-239 E15    O        H     H   2-pyridyl  224-225 E16    O        H     H   3-isoxozolyl-5- 197-198 CH.sub.3 E17    CH.sub.2 H     H   2-thiazolyl 206-208 E18    CH.sub.2 H     H   4-F-phenyl 224-226 E19    CH.sub.2 H     H   2-F,4-F-phenyl 186 E20    CH.sub.2 H     H   phenyl     209 E21    CH.sub.2 H     H   4-Cl-phenyl 235-237 E22    CH.sub.2 H     H   2-thiazolyl 231-234 E23    CH.sub.2 H     H   2-pyridyl  209 E24    CH.sub.2 H     H   2-thiazolyl-5-CH.sub.3 231-232 E25    CH.sub.2 H     H   5-isothiazolyl-3- 211-213 (dec.) CH.sub.3 E26    CH.sub.2 H     H   2-F,6-F-phenyl 264-265 E27    CH.sub.2 H     H   2-pyridyl-6-CH.sub.3 232-233 E28    CH.sub.2 H     H   3-isoxozolyl-5- 198 (dec.) CH.sub.3 E29    CH.sub.2 H     H   3-1H-pyrazolyl 248-250 E30    CH.sub.2 H     H   2-1H-imidazolyl 268 (dec.) E31    CH.sub.2 H     H   2-pyrimidinyl 219-221 E32    CH.sub.2 H     H   2-(1,2,4-thiadia- 204-205 (dec.) zolyl)-5-CF.sub.3 E33    CH.sub.2 H     F   5-isothiazolyl-3- 203-205 CH.sub.3 E34    CH.sub.2 H     F   2-[1,2,4-thiadia- 211-214 zolyl]-5-phenyl E35    CH.sub.2 H     F   2-F,4-F-phenyl 222- 223 E36    CH.sub.2 H     F   2-F,5-F-phenyl 184-186 E37    CH.sub.2 H     F   2-thiazolyl 168-174 (dec.) E38    CH.sub.2 H     F   2-[1,3,4-thiadia- 208-210 zolyl] E39    CH.sub.2 F     F   2-pyridyl  246-248 E40    CH.sub.2 F     F   2-thiazolyl 199-200 E41    CH.sub.2 F     F   2-thiazolyl-5-CH.sub.3 223 (dec.) E42    CH.sub.2 F     F   5-isothiazolyl-3- 233 (dec.) CH.sub.3 E43    CH.sub.2 CH.sub.2 H     H   2-F,4-F-phenyl 217-218 E44    CH.sub.2 CH.sub.2 H     H   4-Cl-phenyl 194-196 E45    CH.sub.2 CH.sub.2 H     H   4-F-phenyl 224-225 E46    CH.sub.2 CH.sub.2 H     H   phenyl     224-225 E47    CH.sub.2 CH.sub.2 H     H   2-pyridyl  202-204 E48    CH.sub.2 CH.sub.2 H     H   2-thiazolyl 248-249 E49    CH.sub.2 CH.sub.2 H     H   3-methylthioethyl 158-159 E50    CH.sub.2 CH.sub.2 H     H   3-isoxazolyl-5-CH.sub.3 168-169 E51    CH.sub.2 CH.sub.2 H     H   2-thiazolyl-4CH.sub.3 - 261-262 5CH.sub.3 E52    CH.sub.2 CH.sub.2 H     H   2-benzothiazolyl 167-168 E53    CH.sub.2 CH.sub.2 H     H   2-thiazolyl-5-CH.sub.3 234-236 ______________________________________ ##STR12## Compound Number/                                   Melting Formula X     R.sup.1 R.sup.2    R.sup.4 R.sup.3 Point .degree.C. ______________________________________ E54/II  O     CH.sub.3          CH.sub.3 H    205-206 E55/II  O     CH.sub.3 2-pyridyl  CH.sub.3 H    168-169 E56/II  O     CH.sub.3 phenyl     CH.sub.3 H    190-191 E57/II  O     CH.sub.3 2F,4F-phenyl CH.sub.3 H    181-183 E58/II  O     CH.sub.3 2-thiazolyl CH.sub.3 H    172-174 E59/II  O     CH.sub.3 2-benzothia- CH.sub. 3 H    184-185 zolyl E60/II  O     CH.sub.3 2[1,3,4-thia- CF.sub.3 H    186-188 diazolyl]-5- CF.sub.3 E61/II  O     CH.sub.3 2-oxazolyl-5- CH.sub.3 H    194-196 CH.sub.3 E62/II  O     CH.sub.3 5-isothia- CH.sub.3 H    219-220 zolyl-3-CH.sub.3 E63/III S     H      2-thiazolyl F    CF.sub.3 211 E64/III S     H      2-F,4-F-phenyl F    CF.sub.3 214-216 E65/III S     H      5-isothia- F    CF.sub.3 240-242 zolyl-3-CH.sub.3 ______________________________________ ##STR13## Compound                           Melting Number   R.sup.1 R.sup.2           Point .degree.C. ______________________________________ E66      H       2-Cl,4-Cl-phenyl  199-200 E67      H       phenyl            175-176 E68      H       2-pyridyl         246-247 E69      H       3-methyl-2-pyridyl 213-214 E70      H       4-F-phenyl        191-194 E71      H       2-thiazolyl       208-210 E72      H                         164-168 E73      H       2-Cl,5-Cl-phenyl  187-189 E74      H       3-Cl,4-Cl-phenyl  200-201 E75      H       4-Br-phenyl       206-207 E76      H       2-F,5-F-phenyl    176-180 E77      H       2-F,4-F-phenyl    174-175 E78      H       4-methyl-2-thiazolyl 202-205 E79      H       4,5-dimethyl-2-thiazolyl 249-252 E80      F       2-thiazolyl       213-214 (dec.) E81      CH.sub.3 2-pyridyl         189-190 E82      CH.sub.3 5-isothiazolyl-3-methyl 174-177 E83      CH.sub.3 2-benzothiazolyl  178-180 ______________________________________

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.

## Claims

1. A compound of the formula ##STR14## wherein the broken line represents an optional double bond; X is S; R.sup.1 is selected from the group consisting of hydrogen, halogen, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkanoyl, C.sub.1 -C.sub.6 alkyl, and trifluoromethyl; R.sup.2 is selected from the group consisting of phenyl, substituted phenyl, heterocyclic selected from the group consisting of pyridyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyrimidinyl, thiadiazolyl, and benzothiazolyl, 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.sub.1 -C.sub.6 alkyl, trifluoromethyl, and halogen; R.sup.3 and R.sup.4 are independently selected from the group consisting of hydrogen, halogen, C.sub.1 -C.sub.6 alkyl, and trifluoromethyl, or R.sup.3 and R.sup.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.sub.1 -C.sub.6 alkyl, and trifluoromethyl; or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, wherein said heterocyclic groups are substituted with one or two substituents selected from the group consisting of halogen, C.sub.1 -C.sub.6 alkyl, and trifluoromethyl.

3. A compound according to claim 1, said compound being a compound of the formula ##STR15## wherein R.sup.1, R.sup.2 and X are as defined above and R.sup.5 is selected from the group consisting of hydrogen, halogen, C.sub.1 -C.sub.6 alkyl, and trifluoromethyl, or a pharmaceutically acceptable salt thereof.

4. A compound according to claim 3, wherein R.sup.1 is hydrogen or fluorine; R.sup.2 is phenyl, 2,4-difluorophenyl, pyridinyl, thiazolyl, benzothiazolyl, isothiazolyl, or isoxazolyl, and R.sup.5 is hydrogen or fluorine.

5. A compound according to claim 1, said compound being a compound of the formula ##STR16## wherein R.sup.1, R.sup.2, R.sup.3 and X are as defined above, or a pharmaceutically acceptable salt thereof.

6. A compound according to claim 5, wherein R.sup.1 is hydrogen, fluoro, or trifluoromethyl; R.sup.2 is phenyl, 2,4-difluorophenyl, pyridyl, thiazolyl, isothiazolyl, benzothiazolyl or isoxazolyl; R.sup.3 is hydrogen, fluoro, or trifluoromethyl; and X is O, S or CH.sub.2.

7. A compound according to claim 1, said compound being a compound of the formula ##STR17## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and X are as defined above, with the proviso that R.sup.3 and R.sup.4 do not form a carbocyclic aromatic ring, or a pharmaceutically acceptable acid addition salt thereof.

8. A compound according to claim 7, wherein R.sup.1 is hydrogen.

9. A compound according to claim 8, wherein R.sup.3 is trifluoromethyl and R.sup.4 is fluorine.

10. A compound according to claim 1, said compound being selected from the group consisting of rboxamide; e; and ide; and the pharmaceutically acceptable salts thereof.

11. A method of treating inflammation comprising administering to a patient in need of such treatment an effective amount of a compound of claim 1.

12. A pharmaceutical composition for the treatment of inflammation comprising an effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.