Leukotriene biosynthesis inhibitors

Leukotrienes (LTs) are potent, pro-inflammatory substances that are produced in the metabolism of arachidonic acid. It is believed that LTs play a role in various inflammatory diseases, such as asthma, allergic rhinitis, rheumatoid arthritis, inflammatory bowel disease and psoriasis. Accordingly, inhibition of the biosynthesis of LTs has potential utility in the treatment of diseases in which inflammation and arachidonic acid metabolism have been implicated.
The biosynthesis of leukotrienes and their pathophysiology have been well documented. Many investigators have been seeking to block the pathophysiological effects of leukotrienes either by blocking their biosynthesis or by blocking their activity at the receptor level. Two recent reviews (J. H. Musser and A. F. Kreft, J. Med. Chem. 1992, 35,2501 and A. Shaw and R. D. Krell, J. Med. Chem. 1991, 34, 1235) describe the status of research in these areas, including results of clinical trials. Results of clinical trials such as those cited in these articles support the concept that agents that block the biosynthesis or activity of leukotrienes will be useful in asthma and possibly other inflammatory diseases mentioned above.
This invention relates to various substituted benzoxazoles, benzothiazoles, oxazolopyridines and thiazolopyridines which have the ability to inhibit leukotriene biosynthesis. Such compounds have the general formula: ##STR1## wherein X is 0 or S;
Y is C or N;
Z is C or N;
with the proviso that Y and Z are not both N; R.sub.1 and R.sub.2 are each, independent of one another, hydrogen; C.sub.1 -C.sub.6 alkyl; halo; CF.sub.3 ; nitrile; C.sub.1 -C.sub.6 alkoxy; --CO.sub.2 R.sub.7 wherein R.sub.7 is hydrogen or C.sub.1 -C.sub.6 alkyl; --C(O)NR.sub.8 R.sub.9 wherein R.sub.8 and R.sub.9 are hydrogen, C.sub.1 -C.sub.3 alkyl, methoxy or together with N form a morpholine, pyrrolidine or piperidine ring; --NO.sub.2 ; --NR.sub.10 R.sub.11 wherein R.sub.10 and R.sub.11 are hydrogen or C.sub.1 -C.sub.6 alkyl; --C(O)R.sub.12 wherein R.sub.12 is C.sub.1 -C.sub.6 alkyl; --SO.sub.2 R.sub.12 ; --NHC(O)R.sub.12 ; --NHSO.sub.2 R.sub.12 ; or--SO.sub.2 NR.sub.13 R.sub.14 wherein R.sub.13 and R.sub.14 hydrogen or C.sub.1 -C.sub.6 alkyl.
R.sub.3 is cycloehyxyl or an unsubstituted or substituted pheny ring wherein the substituents are selected from halo, CF.sub.3, C.sub.1 -C.sub.4 alkyl and C.sub.1 -C.sub.4 alkoxy; SO.sub.2 R.sub.12 ; --NHC(O)R.sub.12, --NHSO.sub.2 R.sub.12 ; --SO.sub.2 NR.sub.13 R.sub.14 or NO.sub.2 ; or R.sub.3 may be a 1-piperidinyl ring, a 2-, 3- or 4- pyridine ring, a morpholine ring, a thiomorpholine ring, a pyrrolidine ring, an imidazole ring optionally substituted on nitrogen with C.sub.1 -C.sub.4 alkyl, or a 2-thiazole ring or a 2-methyl-4-thiazole ring; R.sub.3 may also be a dialkylamine (C.sub.1 -C.sub.4) or an alkyl ether (C.sub.1 -C.sub.4).
R.sub.4 is an ester of structure --CO.sub.2 R.sub.16 wherein R.sub.16 is C.sub.1 -C.sub.4 alkyl; or an amide of structure --C(O)NR.sub.17 R.sub.18 wherein R.sub.17 and R.sub.18 are hydrogen, C.sub.1 -C.sub.3 alkyl, methoxy or together with N form a morpholine ring, or together with N form a piperidine or pyrrolidine ring; an unsubstituted or substituted phenyl ring wherein the substituents are selected from halo, C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkoxy; a 3-methyl-1,2,4-oxadiazol-5-yl group; a 2- or 3-thienyl group; or a 2-, 3-, or 4-pyridyl group; a 2-imidazole group optionally substituted on N with a methyl group; a 2-thiazole group optionally substituted on the 4-position with a methyl; a ketone of structure C(O)R.sub.19 wherein R.sub.19 is C.sub.1 -C.sub.3 alkyl, phenyl, or 1-methylimidazol-2-yl; an ether--CH.sub.2 OR.sub.20 where R.sub.20 .dbd.C.sub.1 -C.sub.3 alkyl, a thioether, --CH.sub.2 SR.sub.20 ; a sulfone,--CH.sub.2 SO.sub.2 CH.sub.3 ; an amine, --CH.sub.2 NHSO.sub.2 Me.sub.2 ; or a carbamate, --CH.sub.2 OC(O)NHMe;
R.sub.5 and R.sub.6 are independently of each other hydrogen or methyl; and
n is an integer 0, 1 or 2.
Such compounds may be in racemic form, or the pure or substantially pure enantiomers may be isolated. The preferred compounds are those wherein the R.sub.1 substituent is in the 5-position and is an C.sub.1 -C.sub.3 alkyl group or halogen, the R.sub.3 substituent is cyclohexyl, the R.sub.6 substituent is hydrogen and n is 1.
In J. Pharm. Sci (57, p. 1695) by S. Advani and J. Sam (1968) four compounds are disclosed having a basic structure like that of Formula I. The Advani publication, a publication on potential anti-neoplastic agents, discloses synthesis of these four compounds, but no biological activity is provided. In the Advani publication, Y and Z are both carbon, R.sub.4 is --CO.sub.2 C.sub.2 H.sub.5, R.sub.1 and R.sub.2 are both hydrogen and R.sub.3 is 4--C.sub.6 H.sub.4 OH, --C.sub.6 H.sub.5, 4-imidazolyl or --CH.sub.2 SCH.sub.3.
In Ger. Off. DE 3419994 there are described compounds of general formula I wherein both Y and Z are C, X is O or S, R.sub.1 and R.sub.2 are hydrogen, halo, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, CN, NO.sub.2 or CF.sub.3, R.sub.4 is --C(O)OR.sub.16, (wherein R.sub.16, is hydrogen, alkyl, alkenyl or alkynyl), --C(O)N(R.sub.18)(R.sub.19) (wherein R.sub.18 and R.sub.19 are hydrogen, C.sub.1 -C.sub.6 alkyl, phenyl or alkoxy or together with N form a pyrrolidine, piperidine or morpholine ring), --CN or --C(S)NH.sub.2. The group referred to as "Y" in such Ger. Off. DE 3419994 consists of R.sub.3 and the carbon chain, i.e., (CH.sub.2).sub.n shown in Formula I. The groups at "Y" disclosed in such German publication are straight-chain or branched alkyl (C.sub.1 -C.sub.8, with one to three carbons between N and R.sub.4, or the group designated "Z" in such published application, methylthioalkyl (one to three carbons in the alkyl) or phenylalkyl. Specifically not disclosed at R.sub.3 is a cyclohexyl group or substituted phenyl. Also, not disclosed at R.sub.4 are ketones or phenyl and heteroaromatic or publication is Y or Z being nitrogen. At R.sub.6 the German publication discloses hydrogen and C.sub.1 -C.sub.4 alkyl. Specifically not disclosed are the preferred compounds of the present invention. Compounds disclosed in the German publication are said to be useful for protecting crops against certain classes or types of herbicides.
The compounds of the present invention may be prepared by methods and processes known in the art and published in the literature. For example, compounds may be prepared by reaction of an appropriately substituted 2-chlorobenzoxazole, 2-chlorobenzothiazole, 2-chlorooxazolopyridine or 2-chlorothiazolopyridine with an amine, an amino acid or an amino acid ester. Such synthesis scheme is outlined herein below as Scheme A. ##STR2## The reaction of Scheme A may occur in an inert solvent, such as methylene chloride, toluene or DMSO, with a basic catalyst, such as triethylamine or NaOH. The optimum choice of both solvent and catalyst will depend on the nature of the reactants, as a person skilled in the art would recognize.
Alternatively, modification of a procedure known in the literature for preparation of 2-aminobenzothiazoles may be successfully employed for synthesis of compounds of general formula I. Such synthesis scheme is outlined hereinbelow as Scheme B. ##STR3## The procedure of Scheme B involves reaction of an appropriately substituted isothiocyanate with an amine or an amino acid ester in a suitable inert solvent, such as ether, followed by cyclization of the intermediate thiourea with sulfuryl chloride or bromine in another inert solvent, again such as ether or perhaps chlorobenzene. ##STR4## The synthesis of Scheme C can be employed for those compounds of general formula I wherein X is S and Z is N. A haloaminopyridine is converted to an isothiocyanate, for example by reaction with thiophosgene, in the presence of a base, such as sodium carbonate, in an inert solvent. Treatment of the isothiocyanate with an amine in an inert solvent yields a thiazolopyridine. With certain additional substituents on the 2-chloro-3-aminopyridine ring, an intermediate thiourea is isolated upon reaction with the isothiocyanate. In that case, cyclization to the thiazolopyridine product may be accomplished by heating in an inert solvent with either acid or base catalysis, for example in ethanolic HCl or DMF with K.sub.2 CO.sub.3.
Isomeric thiazolopyridines may be prepared by cyclization of a 3- halo-2-thiourea substituted pyridine. Such a synthetic scheme is outlined hereinbelow as Scheme D. ##STR5## In Scheme D, the 3-halo-2-thiourea pyridine is heated in an inert solvent with base catalysis, for example K.sub.2 CO.sub.3 in DMF. The intermediate 2-amino-3-halopyridine may be prepared, for example, by bromination of an optionally substituted 2-aminopyridine. The isothiocyanate may be prepared as described in Scheme C.
Compounds of general formula I wherein R.sub.4 is an acid or an ester may be modified to yield compounds of general formula I is an amide, a methyloxadiazole a ketone an ether, or thioether. The scheme for such modification is shown hereinbelow Scheme E. ##STR6## All the general methods exemplified in Scheme E are well known to one skilled in the art, and are also published in the chemical literature.
Concerning the stereochemistry of compounds produced via the methods and schemes outlined hereinabove, if the starting amines used in Schemes I and II above are enantiomerically pure, then a single enantiomer of the end product, having either R or S configuration at the asymmetric carbon, will be recovered. By the same token, if the starting amine is racemic, that is, a mixture of R and S, then a racemic end product will be recovered. Racemic compounds may be separated into the individual enantiomers by methods known to one skilled in the art, for example, by resolution of a diastereomeric salt, chromatography on a chiral column, etc. In the text of this specification the designation for enantiomers of amino acids D and L, or racemic DL, will be used.
The following examples are illustrative of the present invention. Such examples, however, are not to be construed as limiting the scope of the present invention, which scope is defined in the claims which follow. As would be obvious to one skilled in the art, other compounds, such as where R.sub.4 is pyrrolidine-amide, can be readily synthesized using the methods and procedures outline above.

EXAMPLE 1
DL-N-(Benzothiazol-2-yl)phenylalanine hydrochloride
11.8 g phenylalanine (71.4 mmol) was added in portions to a suspension of 5.7 g powdered NaOH (143 mmol) in 50 mL DMSO, and stirred under nitrogen. 2-Chlorobenzothiazole (11 g, 65 mmol) was added over fifteen minutes at room temperature. The reaction was heated on an oil bath at about 95.degree. C. for 4 hours. The reaction mixture was then cooled, poured into 200 mL ice and water, and the pH of the resulting mixture was adjusted to about 1-2 by addition of 10N HCl.
More ice was added, and the mixture was then stirred and filtered. The white solid was dissolved in alkaline solution, stirred with celite, filtered, acidified with 2N HCl and filtered. The resulting solid was rinsed with water, then EtOH, and dried. The product (6.47 g, 19.3 mmol, 30%) melted at 250.degree.-251.degree. C.
EXAMPLE 2
DL-N-(Benzothiazol-2-yl)phenylalanine ethyl ester Compound No. 4. Table 1
Thionyl chloride (3.82 g, 32.1 mmol) was added dropwise to the product from Example 1 (3.2 g, 10.7 mmol) suspended in 200 mL EtOH. The reaction was heated at reflux for four hours. The reaction mixture was then concentrated, the residue dissolved in EtOAc (75 mL) and extracted with saturated Na.sub.2 CO.sub.3 solution (2.times.50 mL), saturated NaCl solution (50 mL) dried (Na.sub.2 SP.sub.4) and concentrated. The product was recrystallized from EtOH giving 2.25 g (6.9 mmol, 64%) mp 137.degree.-139.degree. C.
EXAMPLE 3
DL-N-(6-Isocrocylbenzothiazol-2-yl)-4-chlorophenylalanine ethyl ester
Compound No. 7, Table 1
DL-4-Chlorophenylalanine ethyl ester hydrochloride(5 g, 18.9 mmol) was converted to the free base using triethylamine. A solution of the free base in 75 mL ether was added to a solution of 4-isopropylphenylisothiocyanate in 150 mL ether, cooled on an ice-salt bath. The temperature was maintained at about 0.degree. C. during addition. The reaction was stirred for four and one-half hours, at which time the reaction temperature was 12.degree. C.. The reaction mixture was filtered, the filtrate concentrated, and the resulting foamy residue triturated with petroleum ether while cooling on ice. This resulted in 6.1 g (15.1 mmol, 80%) N-(4-isopropylphenyl)-N'-[2-(4-chlorophenyl)-1-(ethoxycarbonyl)ethyl]thiourea, mp 73.degree.-75.degree. C.
The intermediate product (6 g, 14.8 mmol) was dissolved in 25 mL chlorobenzene and cooled on an ice bath to 0.degree. C.. Sulfuryl chloride (2.76 g, 20.4 mmol) in 5 mL chlorobenzene was added dropwise. After five and one-half hours, the reaction mixture was concentrated, the residue dissolved in EtOAc (150 mL), washed with saturated Na.sub.2 CO.sub.3 solution, then saturated NaCl solution, dried (Na.sub.2 SO.sub.4) and concentrated. The product crystallized from EtOH, giving 4.07 g(10.1 mmol, 68%), mp 105.degree.-107.degree. C.
EXAMPLE 4
2-(2-Cyclohexyl-1-phenyl)ethylaminobenzoxazole
Compound No. 51, Table 3
A mixture of 1.12 g 2-chlorobenzoxazole (7.3 mmol), 1.48 g 2-cyclohexyl-1-phenylethylamine (7.3 mmol) and 0.88 g triethylamine (8.8 mmol) in 305 mL CH.sub.2 Cl.sub.2, was refluxed for 31 hours. The reaction mixture was diluted with 50 mL CH.sub.2 Cl.sub.2, extracted with water (1.times.50 mL), lN HCl (1.times.50 mL), saturated NaCl (1.times.50 mL), dried (Na.sub.2 SO.sub.4 and concentrated. The resulting solid was recrystallized from EtOH giving 1.4 g product (4.4 mmol, 60%) mp 129.degree.-131.degree. C.
EXAMPLE 5
L-2-2-Cyclohexyl-1-(3-methyl1,2,4-oxadiazol-5-methylbenzoxazole
Compound No. 125, Table 6
0.47 g 60% NaH in mineral oil dispersion (0.28 g NaH, 11.8 mmol), 0.39 g acetamidoxime (5.3 mmol), 1.48 g N-(5-methylbenzoxazol-2-yl)cyclohexylalanine methyl ester (4.7 mmol), and several molecular sieves were combined in 20 mL THF and refluxed for two hours under nitrogen. The mixture was poured into water and extracted with EtOAc. The EtOAc was dried (Na.sub.2 SO.sub.4) and concentrated. The product was purified by flash chromatography on silca gel (99 CH.sub.2 CH.sub.2 :1 MeOH). After triturating with petroleum ether the product was obtained as a white solid, 70 mg, mp 118.degree.-119.degree. C.
EXAMPLE 6
(5-Methylbenzoxazol-2-cyclohexylalanine-N'-methylamide
Compound No. 44, Table 2
A solution of 1.08 g L-N-(5-methylbenzoxazol-2-yl)cyclohexylalanine (3.6 mmol) in 15 mL CH.sub.2 Cl.sub.2 was cooled on an ice bath. Carbonyldiimidazole (0.88 g, 5.4 mmol) was added in portions. After one hour methylamine gas was bubbled into the reaction mixture for about forty-five minutes. The reaction was diluted with CH.sub.2 Cl.sub.2, washed with water, saturated NaCl solution, dried (Na.sub.2 SO.sub.4) and concentrated. The product was purified by flash chromatography on silica gel, eluting with 99 CH.sub.2 Cl.sub.2 :1 MeOH, followed by recrystallization from isopropanol giving 0.2 g product, m.p. 202.degree.-204.degree. C.
EXAMPLE 7
3-[(6-Isopropylbenzothiazol-2-yl)amino]-4-phenylbutan-2-one
Compound No. 128, Table 7
A solution of 2 g N-(6-isopropylbenzothiazol-2-yl)phenylalanine (5.9 mmol) in 60 mL THF was cooled on an ice-salt bath to -5.degree. C., under nitrogen. A solution of 1.4 N MeLi in ether (26 mL, 36.4 mmol) was added via syringe over about one minute. After two hours 10 mL chlorotrimethylsilane (78 mmol) was added rapidly and the reaction warmed up to room temperature. The reaction was quenched with lN HCl and the product extracted into ether, dried (Na.sub.2 SO.sub.4) and concentrated. The product was purified by flash chromatography thru silica gel, eluting with CH.sub.2 Cl.sub.2. Recrystallization from EtOH gave 0.75 g product (2.2 mmol, 38%), mp 107.degree.-110.degree. C.
EXAMPLE 8
-[(2-Cyclohexyl-1-phenylethyl)amino]thiazolo[5,4-b]pyridine
Compound No. 172, Table 11
A mixture of 1.28 g (10 mmol) 3-amino-2-chloropyridine, 2.1 g (20 mmol) sodium carbonate and 1.38 g (12 mmol) thiophosgene in 50 mL CH.sub.2 Cl.sub.2 was stirred overnight at room temperature. The reaction mixture was poured into water, and extracted with CH.sub.2 Cl.sub.2. The combined organic extracts were washed with saturated NaCl solution, dried (Na.sub.2 SO.sub.4) and concentrated to give an oil. The product was purified by chromatography on silica gel, eluting with petroleum ether, giving 1.6 g thioisocyanate (9.4 mmol, 94%).
The thioisocyanate (0.516 g, 3.02 mmol) was added to a mixture of 0.66 g 2-cyclohexyl-1-phenylethylamine hydrochloride (2.75 mmol), and 0.278 g triethylamine (2.75 mmol) in 25 mL THF. The reaction was heated at reflux for two hours, poured into water, and extracted with ether. The organic extracts were washed with saturated NaCl solution, dried (MgSO.sub.4) and concentrated. Recrystallization of the residue from CH.sub.2 Cl.sub.2 -petroleum ether gave 0.625 g product (1.84 mmol, 67%) mp 146.degree.-148.degree. C.
EXAMPLE 9
2-{[2-Cyclohexyl-1-(2-pyridyl)ethyl]amino}-6-methylthiazolo-(4,5-b]pyridine
Compound No. 184, Table 11
Bromine (3.19 g) was added dropwise at 0.degree. C. to a solution of 2-amino-5-picoline in 75 mL CH.sub.2 Cl.sub.2. After about two hours at room temperature, the reaction was extracted with saturated sodium carbonate solution, then sodium thiosulfate solution. The combined aqueous extracts were washed with CH.sub.2 Cl.sub.2, and the combined organic extracts washed with saturated NaCl, dried (Na.sub.2 SO.sub.4) and concentrated giving 3.59 g crude material. The product was purified by flash chromatography on silica gel, eluting with petroleum ether with increasing amounts of CH.sub.2 Cl.sub.2 (0-40%), giving 3.05 g 2-amino-3-bromo-5-picoline, m.p. 68.degree.-70.degree. C.
To the above product (2.84 g, 15 mmol) in 50 mL CH.sub.2 Cl.sub.2 with 3.18 g (30 mmol) sodium carbonate, was added 2.07 g (18 mmol) thiophosgene. After stirring overnight at room temperature, the reaction was extracted with water, the aqueous phase back extracted with CH.sub.2 Cl.sub.2 and combined organic extracts washed with brine, dried (MgSO.sub.4), and concentrated giving the isothiocyanate as an oily material that crystallized on standing (3.9 g) IR 2050 cm.sup.-1.
To a solution of 1.0 g (4.3 mmol) of the isothiocyanate derivative and 1.04 g (4.3 mmol) of 2-cyclohexyl-1-phenylethylamine in 50 ml dry THF was added 438 mg (4.3 mmol) of Et.sub.3 N. The resulting mixture was refluxed for two hours. The triethylamine hydrochloride was filtered off and the filtrate concentrated to give the thiourea (1.6 g) which crystallized on standing.
A mixture of 540 mg (1.15 mmol) of the thiourea and 317 mg (2.3 mmol) K.sub.2 CO.sub.3 in 10 mL DMF was refluxed overnight. The reaction mixture was then poured into water and extracted with ether(3.times.) and CH.sub.2 Cl.sub.2 (1.times.). The organic extracts were washed with brine, dried (Na.sub.2 SO.sub.4) and concentrated giving 450 mg product. Recrystallization from CH.sub.2 Cl.sub.2 /ether/petroleum ether gave 210 mg product, m.p. 213.degree.-214.degree. C.
Inhibition of LTB.sub.4, biosynthesis in human polymorphonuclear leukocytes (PMNs)
The inhibition of leukotriene biosynthesis is measured by determining whether and to what extent test compounds can inhibit LTB.sub.4 production from endogenous arachidonic acid in human peripheral blood leukocytes.
To 48-well tissue culture plates was added a solution of the test compound followed by addition of human polymorphonuclear leukocytes isolated from peripheral blood at a density of 1.5.times.10.sup.6 cells/well. Culture plates were preincubated for fifteen minutes with shaking at 28.degree. C. Cells were stimulated with calcium ionosphere A23187 at a final concentration of 2.5 .mu.M for an additional ten minutes. The reaction was terminated by the addition of an EGTA solution (10 mM final concentration) followed by centrifugation at 1500 rpm at 10.degree. C. Supernatants were stored at -70.degree. C. LTB.sub.4 levels were determined by RIA using a commercially available kit. Nonlinear regression analysis was used to calculate IC50 values.
The following tables show % inhibition of LTB.sub.4 biosynthesis by compounds of the invention at test concentrations indicated, with the determined IC.sub.50 shown in .mu.M.
TABLE 1______________________________________Esters ##STR7##Comp IC.sub.50No. D/L.sup.a R.sub.1 R.sub.3.sup.b R.sub.16 X mp (.mu.M)______________________________________ 1 DL H Ph4Cl Et S Oil 0.2 2 DL H Ph4F Et S 129-131 0.33 3 DL H Ph4Br Et S 104-106 0.15 4 DL H Ph Et S 137-139 0.4 5 L H Ph4OBZ Et S Oil 0.53 6 L 6-iPr Ph Et S Oil 0.25 7 DL 6-iPr Ph4Cl Et S 105-107 0.33 8 L 6-iPr Ph Me S 114-115 0.14 9 DL 6-OMe Ph4Cl Et S 129-131 0.2310 D 6-iPr Ph Me S 115-116 0.6511 DL 6-nBu Ph4Cl Et S 113-114 0.1712 L 6-Et Ph Et S 102-104 0.2413 L H Ph t-Bu S 50-52 0.7314 L 5-Et Ph Et S Oil 0.00915 L 5-Et Cyh Et S Oil 0.02716 L H Cyh Et S resin 0.00617 L H Ph Et O Oil 0.1518 D H Ph Et O Oil 1.519 L 5-iPr Ph Et O Oil 0.0005220 L 6-iPr Ph Et O Oil 0.2221 L H Cyh Me O Oil 0.006422 D H Cyh Me O Oil 0.1023 L 5-iPr Cyh Me O Oil 0.00124 L 5-Me Cyh Me O Oil 0.001725 L 5-Me Cyh t-Bu O Oil <0.3.sup.d26 D 5-Me Cyh Me O Oil 0.01627 DL 5-OMe 2Me4Thz Et O Oil <0.3.sup.d28 DL 5-Cl 2-Thz Et O Oil <0.3.sup.d29 DL 5-Cl 2Me4Thz Et O Oil 0.08730 DL 5-iPr 3-Py Et O Oil 0.1931 DL 5-iPr 4-Py Et O Oil <0.1.sup.d32 DL 5-OMe 3-Py Et O Oil33 DL 5-iPr 2Me4Thz Et O Oil <0.03.sup.d______________________________________
TABLE 1A______________________________________Esters ##STR8##Comp IC.sub.50No. D/L R.sub.6 R.sub.5 R.sub.3' n x mp (.mu.M)______________________________________34 DL H H CH.sub.3 0 S Oil 1.435 DL H H CH.sub.3 0 S Oil 0.6836 DL CH.sub.3 H H 0 S Oil 1.037 DL H H H 1 S 69.5-72 0.5238 DL H CH.sub.3 H 0 S 97-98 0.2039 DL H CH.sub.3 H 0 O 89-91.5 0.076______________________________________ Footnotes (for TABLES 1 and 1A) .sup.a DL = racemic. L or D indicates one enantiomer with stereochemistry at chiral carbon analogous to the corresponding L or D amino acid. .sup.b Ph = phenyl, PhX = substituted phenyl, Cyh = Cyclohexyl 2Thz = 2Thiazolyl, 2Me4Thz = 2methyl-4-thiazolyl, 3Py = 3pyridyl, 4Py = 4pyridyl .sup.c One of a pair of diastereomers .sup.d Greater than 50% inhibition at this concentration, IC.sub.50 not characterized further.
TABLE 2______________________________________Ester Bioisosteres - Amides ##STR9##Comp IC.sub.50No. D/L R.sub.1 R.sub.3.sup.a R.sub.17 R.sub.18 x m.p. .degree.C. (.mu.M)______________________________________40 L H Ph H H S 94-96 341 DL H Ph Me Me S Oil 342 DL 6-iPr Ph Et H S 161-163 343 L H Ph Me OMe O Resin <1.sup.c44 L 5-Me Cyh Me H O 202-204 0.07245 L 5-Me Cyh Me OMe O Resin 0.0346 L 5-Me Cyh b b O Resin 0.19______________________________________ .sup.a See footnote b, Table 1. b R.sub.17 and R.sub.18 with nitrogen make a piperidine ring. .sup.c See footnote d, Tables 1 and 1A.
TABLE 3__________________________________________________________________________Ester Bioisosteres - Phenyl ##STR10##Comp. IC.sub.50No. D/L.sup.a R.sub.1 R.sub.3.sup.b R.sub.4.sup.b X m.p. .degree.C. (.mu.M)__________________________________________________________________________47 DL H Ph Ph S 54-56 0.1648 `L` H Ph Ph S Oil 0.08249 `D` H Ph Ph S Oil 0.2850 DL H Ph Ph O 154-156 <1.0.sup.d51 DL H Cyh Ph O 129-131 0.006952 `D` H Cyh Ph O 141-143 0.2653 `L` H Cyh Ph O 135.5-137 0.003654 DL 5-iPr Cyh Ph O 119-122 0.006355 DL H Cyh Ph4Cl O 142-144 0.356 DL H Cyh Ph4OMe O 63-67 0.5557 DL H Cyh Ph3Me O 136-138 0.3058 DL H Cyh Ph2Cl O 146-148 0.0859 DL 5-I Cyh Ph O 186-187 0.01360 DL 5-NHSO.sub.2 CH.sub.3 Cyh Ph O 188-190 0.1661 DL 5-NHC(O)CH.sub.3 Cyh Ph O 145-147 0.07662 DL 5-NHC(O)NHCH.sub.3 Cyh Ph O 211-212 <1.0.sup.d63 DL 5-CO.sub.2 H Cyh Ph O 232-234 0.1964 DL 5-C(O)NH.sub.2 Cyh Ph O 181-183 <1.0.sup.d65 DL 5-C(O)NMe.sub.2 Cyh Ph O 194-196 0.1766 DL 6-CO.sub.2 H Cyh Ph S 271-272 0.2267 DL 5-CN Cyh Ph O 166-168 0.1568 DL C Cyh Ph O 154-156 <1.0.sup.d69 DL CH.sub.2 OH Cyh Ph O 187-189 <1.0.sup.d70 DL 5-tetrazolyl Cyh Ph O 188-191 0.1671 DL H Cyh Ph4F O 144-145 0.1772 L 5-Cl NEt.sub.2 Ph O 242-244 0.3573 L 5-iPr NnPr.sub.2 Ph O Oil <300.sup.d74 L 5-iPr OEt Ph O Oil 0.1175 L 5-iPr OnBu Ph O Oil 0.05576 L 5-tBu morph Ph O 197-199 <0.03.sup.d77 L 5-iPr NEt.sub.2 Ph O Oil <0.3.sup.d78 L 5-Cl thiomorph Ph O 69-71 0.048__________________________________________________________________________ .sup.a DL = racemic. `L` and `D` = L = isomer designation based on potenc being greater than `D` isomer, and drawing analogy to esters where L and are known. .sup.b See footnote b, Table 1, also morph = Nmorpholinyl, thiomorph = Nthiomorpholinyl. .sup.c morpholinecarbonyl .sup.d See Footnote d, Table 1.
TABLE 4__________________________________________________________________________Ester Bioisosteres - Pyridyl ##STR11## Pyridyl IC.sub.50 79 D/L X R.sub.1 R.sub.3.sup.a Isomer mp .degree.C. (.mu.M)__________________________________________________________________________ 80 DL O H Cyh 3 Resin 0.055 81 DL O 5-Me Cyh 2 104-105 0.0031 82 DL O 5-Me Cyh 3 150-151 0.024 83 DL O 5-Me Cyh 4 188-189 0.19 84 DL O 6-NO.sub.2 Cyh 3 186-187.5 0.035 85 DL O 5-NO.sub.2 Cyh 3 189-190 0.024 86 DL O 5-Cl Cyh 3 186-187 0.023 87 (-)* O 5-Me Cyh 2 Oil 0.0013 88 (+)* O 5-Me Cyh 2 Oil 0.045 89 (-)* O 5-Me Cyh 3 150-151 0.016 90 (+)* O 5-Me Cyh 3 150-151 <1.0 91 DL O 5-Cl Cyh 2 132-134 0.002 92 DL O 5-CO.sub.2 Me Cyh 2 129-131 0.012 93 DL O 5-Cl Ph4F 2 112-114 0.019 94 DL O 5-iPr Ph4F 2 56-58 0.012 95 DL O 5-CF.sub.3 Cyh 2 91-93 0.0012 96 DL S 5-Cl Ph4F 2 133-135 0.027 97 DL S 5-Cl Cyh 2 129-132 0.004 98 DL O 5-iPr Ph4Cl 2 65-67 0.029 99 DL O 5-Cl Ph4Cl 2 132-134 0.014100 DL O 5-iPr Ph3Cl 2 51-52 0.005101 DL O 5-CO.sub.2 Me Ph4F 2 151-152 0.027102 DL S 5-Cl Cyh 2 129-132 0.004103 DL O 5-SO.sub.2 NMe.sub.2 Ph4F 2 178-179 0.050104 DL O 5-Cl Ph4NO.sub.2 2 72-74 <0.03.sup.b105 DL O 5-F Ph3Cl 2 131-133 <0.03.sup.b106 DL S 6-CF.sub.3 Ph4F 2 149-150 <1.0.sup.b107 DL O 5-CF.sub.3 Ph4F 2 105-107 0.008108 DL O 5-CF.sub.3 Cyh 2 91-93 0.001109 DL O 5-F Cyh 2 142-143.5 0.002110 DL O 5-F Ph4F 2 117-119.5 0.021111 DL O 4,5-diF Cyh 2 133-134 0.004112 DL O 5,6-diF Cyh 2 131-133 0.001113 DL O 5,6-diF Ph4F 2 143-144.5 0.024114 DL O 5-OMe Ph4F 2 111-113 0.011115 DL O 5-NO.sub.2 Ph4F 2 174-175 <0.03.sup.b116 DL O 5-iPr 2Me4Thz 2 116-117 <0.1.sup.b117 DL O 5-Cl 2Me4Thz 2 142-143 <0.1.sup.b118 (-)* O 5-Cl Ph4F 2 Oil 0.01119 (+)* O 5-Cl Ph4F 2 Oil 0.32__________________________________________________________________________ *(-) and (+) refer to the levorotatory and dextrorotatory enantiomer respectively. Enantiomers were separated by HPLC on a Chiralcel OD column eluting with hexane:iPrOH:Et.sub.2 NH 950:50:1. .sup.a See footnote b, Table 1. .sup.b See footnote d, Table 1.
TABLE 5______________________________________Ester Bioisosteres - Thiophene ##STR12##Comp. No. D/L mp .degree.C. IC.sub.50 (.mu.M)______________________________________120 DL 108-110 0.0062______________________________________
TABLE 6______________________________________Ester Bioisosteres - Methyloxadiazole ##STR13##Comp. No. D/L R.sub.1 R.sub.3.sup.a X mp .degree.C. IC.sub.50 (.mu.M)______________________________________121 DL H Ph S 122-124 1.3122 L H Ph S 117-119 1.8123 L 5-Et Ph S 134-136 <1.0.sup.b124 L H Cyh S 147-149 0.12125 L 5-Me Cyh O 118-119.5 0.028126 DL 5-iPr Ph4F O 86 <0.3.sup.b127 DL 5-iPr 2Me4Thz O 45-48 <1.0.sup.b______________________________________ .sup.a See footnote b, Table 1. .sup.b See footnote d, Table 1.
TABLE 7______________________________________Ester Bioisosteres - Ketones ##STR14##Comp. No. D/L R.sub.1 R.sub.3.sup.a R.sub.19 X mp .degree.C. IC.sub.50 (.mu.M)______________________________________128 L 6-iPr Ph CH.sub.3 S 107-110 0.35129 L H Ph CH.sub.3 O Oil <1.0130 L H Ph Ph O Resin <0.3131 L 5-Me Cyh Ph O Resin <1.0132 L 5-Me Cyh b O Resin 0.023______________________________________ .sup.a See footnote b, Table 1. b 1methyl-2-imidazolyl
TABLE 8__________________________________________________________________________Ester Bioisosteres - Miscellaneous Acyclic ##STR15##Comp. No. D/L R.sub.1 R.sub.3.sup.a R.sub.4 mp .degree.C. IC.sub.50 (.mu.M)__________________________________________________________________________133 L 5-iPr Ph CH.sub.2 OEt Oil 0.016134 L 5-iPr Ph CH.sub.2 OPr Oil 0.22135 L 5-Cl Ph CH.sub.2 OEt Oil 0.029136 DL 5-iPr Ph4F CH.sub.2 OMe Oil <0.03.sup.b137 DL 5-iPr Ph4F CH.sub.2 OEt Oil <0.03.sup.3138 DL 5-iPr Ph4F CH.sub.2 OnPr Oil <0.3.sup.b139 DL 5-iPr Ph4OMe CH.sub.2 OMe Oil <0.03.sup.b140 DL 5-iPr 3-Py CH.sub.2 OMe Oil <1.0.sup.b141 DL 5-iPr 2Me4Thz Ch.sub.2 OMe Oil <0.3.sup.b142 L 5-iPr Ph3Cl CH.sub.2 SMe Oil <0.03.sup.b143 DL 5-iPr 3-Py CH.sub.2 SMe Oil <1.0.sup.b144 DL 5-iPr 4-Py CH.sub.2 SMe Oil145 DL 5-iPr 2Me4Thz CH.sub.2 SMe Oil <0.1.sup.b146 DL 5-iPr Ph CH.sub.2 SO.sub.2 Me resin <0.03.sup.b147 DL 5-iPr 3-Py CH.sub.2 SO.sub.2 Me 88-92 <1.0.sup.b148 DL 5-iPr 4-Py CH.sub.2 SO.sub.2 Me 78-81149 DL 5,6-diF Ph4F CH.sub.2 SO.sub.2 Me 179-181150 L 5-iPr Ph CH.sub.2 NMe.sub.2 Oil <0.3.sup.b151 L 5-iPr Ph CH.sub.2 NHC(O)Me resin <0.1.sup.b152 L 5-iPr Ph CH.sub.2 NHSO.sub.2 NMe.sub.2 resin <0.1.sup.b153 L 5-iPr Ph CH.sub.2 NHC(O)NH.sub.2 resin <0.3.sup.b154 L 5-iPr Ph CH.sub.2 OC(O)NHMe 125-126 0.063__________________________________________________________________________ .sup.a See footnote b, Table 1 .sup.b See footnote d, Table 1
TABLE 9______________________________________Ester Bioisosteres: Miscellaneous Heterocycle ##STR16##Comp. IC.sub.50No. D/L R.sub.1 R.sub.3.sup.a R.sub.4.sup.b mp .degree.C. (.mu.M)______________________________________155 DL 5-Cl Ph4F 2-Imid 248-250 0.29156 DL 5-iPr Ph4F 2-Imid 213-219 0.09157 DL 5-iPr 2-Me4Thz 2-Imid 153-155 <1.0.sup.c158 DL 5-iPr Ph3Cl 2-Imid 210-213 <0.03.sup.c159 DL 5-iPr Ph3Cl 2-Thz resin <0.1.sup.c160 DL 5-iPr Ph3Cl 4Me2Thz resin <0.03.sup.c161 DL 5-iPr Ph 4-Pyraz 206-210 <0.1.sup.c______________________________________ .sup.a See footnote b, Table 1. .sup.b 2-Imid = 2imidazolyl, 2Thz = 2thiazolyl, 4Me2Thz = 4methyl-2-thiazolyl, 4Pyraz = 4pyrazolyl .sup.c See footnote d, Table 1.
TABLE 10______________________________________Oxazolopyridines ##STR17##Comp. mp IC.sub.50No. D/L X Y R.sub.1 R.sub.3.sup.a R.sub.4.sup.a .degree.C. (.mu.M)______________________________________162 L N C H Cyh CO.sub.2 Me 147- 0.21 149163 DL N C H Cyh Ph 189- 0.078 190.5164 DL N C 5-Me Cyh Ph 199- 0.028 200165 DL N C 5-Me Cyh 2-Py 134- 0.026 136166 (-)* N C 5-Me Cyh 2-Py 68- 0.015 75167 (+)* N C 5-Me Cyh 2-Py 68- 0.17 75168 DL N C 5-Me Cyh 3-Py 207- 0.3 208169 DL N C S-Me Ph4F 2-Py 66- <0.3.sup.b 69170 DL C N H Cyh Ph 133- 0.021 134171 DL C N 5-Me Cyh Ph 188- 0.044 191______________________________________ .sup.a See footnote b Table 1. Also 2Py 2pyridyl, 3Py = 3pyridyl. .sup.b See footnote d, Table 1. *See * Table 4.
TABLE 11__________________________________________________________________________Thiazolopyridines ##STR18##Comp. No. DL X Y R.sub.1 R.sub.4.sup.b R.sub.3.sup.b mp .degree.C. IC.sub.50 (.mu.M)__________________________________________________________________________172 DL C N H Ph Cyh 146-148 0.027173 DL C N H 3-Py Cyh 222-224.sup.a 0.17174 DL C N H 2-Py Cyh 176-178.sup.a 0.027175 DL C N 5-Me-6-Br 2-Py Cyh 215-217 0.009176 DL C N 5-Me 2-Py Cyh 109-113 0.01177 DL C N 5-Me 3-Py Cyh 174-175.5 0.11178 DL C N 6-Cl 3-Py Cyh 207-209 0.044179 DL C N 6-Cl 2-Py Cyh 180-182 0.006180 DL C N 4-Me 2-Py Cyh 144-146 <1.0.sup.c181 DL C N 6-Cl 3-Py Cyh 207-209 0.044182 DL C N 6-Cl 2-Py Ph4F 151-153 0.110183 DL C N 5-Cl 2-Py Ph4F 146-149 0.280184 DL N C 6-Me 2-Py Cyh 214-216 0.031185 DL N C 5-Me-6-Br 2-Py Cyh 209-210 0.0065186 DL N C 5-Me-6-Br 3-Py Cyh 241-243.5 0.021187 DL N C 5-Me 2-Py Cyh 167-171 0.013188 DL N C 6-Cl 2-Py Cyh 198.5-200.5 0.0039189 DL N C 6-Cl 2-Py Ph4F 204-205 0.028190 DL C N 5-Me-6-Br 3-Py Cyh 211-212 <1.0.sup.c191 DL N C 6-Me Ph Cyh 213-214 <1.0.sup.c192 DL N C 6-Me 2-Py Ph4F 184-185 <0.3.sup.c__________________________________________________________________________ .sup.a Hydrochloride salt. .sup.b See footnote b Table 1. Also 2Py = 2pyridyl, 3Py = 3pyridyl. .sup.c See footnote d, Table 1.
TABLE 12______________________________________Miscellaneous Compounds ##STR19##Comp. No. DL R.sub.1 R.sub.4 X mp .degree.C. IC.sub.50 (.mu.M)______________________________________193 L 5-iPr Ph.sup.b C 165.sup.a 0.1194 L 5-Me Ph C >150.sup.a 0.23195 L 5-iPr 2-Py `C 128 0.19196 L 5-iPr 2-Py O 135-137.5 <0.1.sup.c______________________________________ .sup.a Dihydrochloride salt, broad melting range. (No. 143) .sup.b See footnote b, Table 1. .sup.c See footnote d, Table 1. .sup.d 2-py = 2pyridyl
TABLE 13______________________________________Miscellaneous Compounds ##STR20##Comp. No. DL R.sub.1 R.sub.3.sup.a mp .degree.C. IC.sub.50 (.mu.M)______________________________________197 DL 5-Cl 2-Py 180-183 0.22198 DL 5-iPr 2-Py 150-151.sup.b 0.12199 DL 5-iPr 4-Py 145.sup.b <0.3.sup.c200 DL 5-iPr 3-Py resin <0.3.sup.c______________________________________ .sup.a 2-Py 2pyridyl, 4Py = 4Pyridyl, 3Py = 3Pyridyl .sup.b Tosylate salt .sup.c See footnote d, Table 1.
TABLE 14______________________________________Miscellaneous Compounds ##STR21##Comp.No. DL R.sub.1 R.sub.4 R.sub.3 mp IC.sub.50 (.mu.M)______________________________________201 L 5-iPr CO.sub.2 Me c 143-146.sup.a <1.sup.b202 DL 5-iPr d Ph3Cl 168.5-170 <0.1.sup.b______________________________________ .sup.a Hydrochloride Salt .sup.b See footnote d, Table 1. .sup.c 1-methyl-imidazol-4-yl .sup.d 1-methyl-imidazol-2yl
Antigen-induced bronchoconstriction in guinea pigs.
This model measures the ability of a compound to block the leukotriene component of antigen-induced bronchoconstriction. Male Hartley guinea pigs are actively sensitized to ovalbumin, pretreated with meptyramine and indomethacin (to block the histamine and cyclooxygenase metabolite componens respectively), and test compound (by aerosol administration). the guinea pigs are challenged with antigen (inhaled ovalbumin). Pulmonary function is measured by oscillatory mechanics as described by W. W. Wolyniec et. al. (Agents and Actions 1991, 34, 1/2, 73). Results are expressed as percent inhibition or bronchoconstriction (impedance) in the test compound treated guinea pigs compared to placebo treated controls.
______________________________________Compound No. Dose (Micrograms)* N % Inhibition______________________________________51 274 6 8656 95 6 4381 308 6 64 28 4 64 2.8 10 61165 274 7 85 28 6 64 5.6 4 0______________________________________ *Refers to amount of test compound inhaled by guinea pig. Compounds administered by aerosolized freon/ethanol soltuion from metered dose inhaler.

Leukotriene biosynthesis inhibitors

Information

Patent Number

Date Filed

Date Issued

Inventors

Original Assignees

Examiners

Agents

CPC

US Classifications

Field of Search

US

International Classifications

Abstract

Description

Claims

Parent Case Info

US Referenced Citations (1)

Non-Patent Literature Citations (2)

Continuation in Parts (1)

Entry
Advani et al. J. Pharm. Sci. 57 (10) pp. 1693-1696 (1968).
Kaupp et al. Chem. Ber. 119 (5) pp. 1525-1539 (1986).