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FIELD OF THE INVENTION
The invention relates to novel 1-phenylsulphonyl, phenylcarbonyl and 1-phenylphosphenyl-3-phenyl-1,4,5,6-tetrahydropyridazine compounds, and to novel methods for preparing the compounds. The novel compounds are useful as contraceptives and in
the treatment of osteoporosis. The invention further relates to pharmaceutical compositions in which a compound of the present invention is the active ingredient.
BACKGROUND OF THE INVENTION
The unacylated 3-phenyl-1,4,5,6-tetrahydropyridazine, A, is described by J.-L. Aubagnac et al., Bull. Chem. Soc. France, 7, 2868, (1972). A number of 1-acylated derivatives of 1 are also disclosed. ##STR2##
W. Jones et al., J. Het. Chem., 21, 889 (1984) disclose that the thiocarbamoylation of A with methyl isothiocyanate produces the corresponding thiocarbamide derivative, B. No biological activity is disclosed. ##STR3##
S. J. Clarke et al., J. Chem. Research, (S) 310 (1985) disclose carbamate, carbamide and para-toulene sulfonamide derivatives of A. (sulfonamide derivative is C), which are prepared via cycloaddition reactions. Again, no biological activity is
disclosed.
______________________________________ ##STR4## R.sup.1 R.sup.3 R.sup.4 R.sup.5 R.sup.6 ______________________________________ H H H OEt H H H Me OEt H H Me H OEt H H H H OMe Me NO.sub.2 H H OEt H NO.sub.2 H H OMe Me Br H H OEt H Br H
Me OEt H Br Me H OEt H Br H H OMe Me ______________________________________
R. Faragher et al., in J. Chem. Soc. Perkin Trans, I, 249 (1979), disclose para-toulene sulfonamide and carbamate derivatives of A, (sulfonamide derivative is 4) which compounds are also prepared by cycloaddition reactions. As above, no
biological activity is disclosed. ##STR5##
Kalyanam et al., Synthetic Communications, 18 (16 & 17), (1988) disclose compounds of the formula: ##STR6## wherein n is 1 or 2, as being antiamoebics.
SUMMARY OF THE INVENTION
Briefly, according to the present invention, there are provided preferred progestin agonists of the general formula: ##STR7## W is absent or --CH.dbd.CH--; R.sup.1 are independently selected from the group consisting of halogen, --CF.sub.3, and
NO.sub.2, or both R.sup.1 may be joined to form a bi-radical which is --CH.dbd.CHCH.dbd.CH--;
R.sup.3 are independently selected from the group consisting of hydrogen, C.sub.1-6 branched or linear alkyl, halogen and --CF.sub.3, with the proviso that R.sup.3 at the 3-position must be H where R.sup.3 at the 4-position is H, or both R.sup.3
may be joined to form a bi-radical selected from the group consisting of --CH.dbd.CHCH.dbd.CH--, --C(NC.sub.1-4 alkyl.sub.2)=CHCH.dbd.CH-- and --(CH.sub.2).sub.4 --;
R.sup.5 is selected from the group consisting of H and Me;
with the proviso that only one of R.sup.1 and R.sup.3 forms the fused bi-radical; and the stereoisomers.
Also provided by the present invention are preferred progestin antagonists of the general formula: ##STR8## W is absent or --CH.dbd.CH--; R.sup.1 is selected from the group consisting of halogen, --CF.sub.3 and --NO.sub.2, or both R.sup.1 may be
joined to form a bi-radical which is --CH.dbd.CHCH.dbd.CH--;
R.sup.3 is hydrogen, halogen, --CF.sub.3, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, carboxy C.sub.1-4 alkyl and C.sub.1-4 alkoxy carbonyl C.sub.1-4 alkoxy with the proviso that R.sup.3 at the 2-position is not hydrogen, or R.sup.3 may be joined to form
a bi-radical which is --CH.dbd.CHCH.dbd.CH-- attached at the 2- and 3-positions;
R.sup.a are independently selected from hydrogen or halogen with the proviso that each may be halogen where R.sup.3 is selected only from halogen;
R.sup.5 is selected from the group consisting of hydrogen and methyl, or alternatively, R.sup.5 may be joined with the 6-position hydrogen to form a bi-radical which is (5)-CH.sub.2 CH.dbd.CH-(6);
with the proviso that only one of R.sup.1, R.sup.3 and R.sup.5 forms the fused bi-radical; and the steroisomers and pharmaceutically acceptable salts and esters thereof.
Also provided by the present invention are preferred compounds useful to promote bone cell gowth, said compounds having the general formula: ##STR9## Y is O or S; R.sup.3 is hydrogen or halogen with the proviso that at least two R.sup.3 are
halogen;
R.sup.5 is H or Me;
and the steroisomers thereof.
4. DETAILED DESCRIPTION OF THE INVENTION
The compounds of the present invention may be manufactured in what is basically a two step process. In the first step and as demonstrated in schemes 1 and 2, a 3-phenyl-1,4,5,6-tetrahydropyridazine intermediate is formed. In the second step and
as demonstrated in scheme 3, this 3-phenyl-1,4,5,6-tetrahydropyridazine intermediate is joined at the 1-position with the appropriately substituted phenyl or thienyl moiety. In special cases, and as exemplified in scheme 4, more advantageous processes
are available for certain substitution patterns. Of course, the substituents on the final compounds may be obtained by starting with the appropriately substituted starting materials or by modifying precursor substituents on an intermediate or final
compound. Persons skilled in the art upon understanding the particular reactions suggested herein will be readily able to determine how best to obtain a given substituent.
The substituents R.sup.1*, R.sup.3* and R.sup.5* as employed in Schemes 1-4 are intended to include not only the substituents of R.sup.1, R.sup.3 and R.sup.5 as given above for the preferred compounds, but also to include other substituents on
their respective rings of compounds disclosed herein. Subscripts w, y and z as employed in these same schemes have values ranging from 0-5, 0-3 and 0-5 respectively and are intended to show that not just the the substitution patterns of the preferred
compounds as described above may be made by this method, but that compounds with various substitution patterns may be made. Finally, Schemes 1-4 are exemplified employing phenyl as the ultimate 3-position substituent on 1,4,5,6-tetrahydropyridazine. In
each scheme, a starting material in which phenyl is replaced by the appropriate thienyl would ultimately produce, by the same method, a 3-thienyl substituent on the 1,4,5,6-tetrahydropyridazine, Thus, although Schemes 1-4 exemplify the manufacture of the
3-phenyl substituent, the 3-thienyl substituent is similarly produced.
Referring to scheme 1, 3-phenyl-1,4,5,6-tetrahydropyridazine, intermediate 1-C, is formed in two reaction steps, In a first addition reaction, diketone starting material 1-A is refluxed in an alcohol solvent with an excess of hydrazine to give
the 6-oxo compound 1-B. Suitable alcohol solvents include methanol, ethanol, etc., with the reflux carried out for from 1 to 24 hours. This addition is further described by S. Gabriel et al., Ber., 32, 395 (1879), W. Curran et al., J. Med. Chem.,
17(3), 273 (1974) and in U.S. Pat. Nos. 4,766,118 and 4,721,784, which are incorporated herein by reference. Subsequently, 6-oxo compound 1-B is reduced to intermediate 1-C in the presence of a reducing agent Suitable reducing agents include
diborane, lithium aluminum hydride and di-i-butyl aluminum hydride. Where lithium aluminum hydride is employed, the reaction should be carried out at reduced temperatures in a solvent such as THF. This reduction is further described by J. L. Aubagnac
et al., Bull. Chem. Soc. France, 2859 (1972). Of course, it is clear that intermediate 1-C cannot have R.sub.5* as a 6-position substituent. ##STR10##
Referring to Scheme 2, 3-phenyl-1,4,5,6-tetrahydropyridazine, intermediate 2-C, is formed in four reaction steps. In a first reaction, the appropriate phosphonium salt is deprotonated in ethereal solvent (ether, tetrahydrofuran, dioxane) with
strong base (such as alkyllithium, sodium or potassium hydride or lithium diisopropyl amide) and stirred at low temperature under an atmosphere of inert gas. The aldehyde 2-A is added to the cold solution and the mixture stirred for several hours at
room temperature. Excess reagent is quenched (with water or an alcohol), and the solution is filtered, dried over Na.sub.2 SO.sub.4 (or MgSO.sub.4, CaCl.sub.2, CaSO.sub.4, K.sub.2 CO.sub.3, or other similar drying agent), filtered again, and solvent is
removed to give the diene 2-A' which is used without further purification. In a second step, 4-phenylurazole is dissolved in DMSO and cooled in a dry apparatus. Tosylisocyanate is added as an oxidant and stirring continued. The diene 2-A' is added
neat and the reaction continued for about 30 min. The solution is poured into a halogenated solvent (chloroform, carbon tetrachloride, methylene chloride, dichloroethane) and washed with aqueous base (such as a solution of NaOH, KOH, NaHCO.sub.3,
Na.sub.2 CO.sub.3 or K.sub.2 CO.sub.3). The solution is dried over Na.sub.2 SO.sub.4 (or MgSO.sub.4, CaCl.sub.2, CaSO.sub.4, K.sub.2 CO.sub.3, or other similar drying agent) and the solvent is removed to give 2-B. In a third step, reduction of 2-B is
effected by shaking with H.sub.2 gas (1-3 atm) and Pd/C (5-10%) in an organic solvent such as ethanol, ethyl acetate, acetic acid or tetrahydrofuran until the theoretical amount of hydrogen is consumed. The catalyst is removed by filtration and the
solvent is evaporated to give 2-B'. Alternatively, 2-B is reduced in an ethereal solvent (ether, tetrahydrofuran, dioxane) with diborane followed by treatment with a carboxylic acid at elevated temperature. Excess acid is neutralized and the solution is
washed. The solution is dried over Na.sub.2 SO.sub.4 (or MgSO.sub.4, CaCl.sub.2, CaSO.sub.4, K.sub.2 CO.sub.3, or other similar drying agent), filtered, and solvent removed. In the final step, the urazole 2-B' is hydrolyzed with base such as NaOH, KOH
or LiOH in an alcohol solvent such as (methanol, ethanol, ethylene glycol, propylene glycol) at elevated temperatures. Air oxidation to the desired product 2-C occurs spontaneously. The solution is diluted with water, washed with an organic solvent
such as ether or methylene chloride and dried over Na.sub.2 SO.sub.4 (or other similar drying agent), filtered, and the solvent removed. Of course, it is clear that intermediate 2-C might have R.sup.5* substituents at any of positions 4,5 and 6.
##STR11##
Referring to Scheme 3, intermediate 1-C or 2-C is converted to final product in a one step acylation. In the arylation reaction, appropriately substituted 3-aryl-1,4,5,6-tetrahydropyddazine, intermediate 1-C or 2-C, is added with the appropriate
acylating agent, i.e., phenyl carbonyl halide, phenyl sulphonyl halide or phenyl phosphonyl dihalide, to an organic base such as pyridine or collidine, or to an organic solvent such as THF, methylene chloride or toluene with a base such as DMAP or
triethylamine, or to an aqueous base such as sodium or potassium hydroxide. ##STR12##
In the case of the reaction employing an phenylphosphonyl dihalide, an alcohol such as methanol, ethanol, propanol, isopropanol, cyclopentanol or phenol is added after the reaction of the tetrahydropyridazine with the phenylphosphonyl dihalide.
The halide portion of the acylating agent may be any reactive halide but preferred are chloro or bromo. The product is isolated by pouring the reaction mixture into dilute acid solution such as a hydrobromic or a hydrochloric acid solution and
extracting with an organic solvent such as methylene chloride or ethyl acetate. The organic layer is then concentrated, and the residue recrystallized or chromatographed using for example methylene chloride and/or ether and/or ethyl acetate and/or
methanol on silica gel. The fractions containing the product are evaporated and the residue recrystallized from an appropriate solvent such as acetone, ether, ethyl acetate, methanol, or hexane to afford the desired acylated compounds 3-D to 3-G.
For example, to prepare the arylsulphonyltetrahydropyridazines 3-D, the appropriate phenylsulfonyl chloride is added at about room temperature to a solution of the appropriate intermediate 1-C or 2-C in an organic solvent such as pyridine or a
solution of 4-N,N-dimethylaminopyridine in methylene chloride, and the resulting mixture is stirred for about 1 to about 72 hours. The reaction mixture is then treated with an acidic solution such as dilute to 6N HCl or HBr, followed by successive
washes with an organic solvent such as chloroform or methylene chloride. The combined organic extracts are dried with a drying agent such as sodium sulfate, magnesium sulfate or potassium carbonate, concentrated and chromatographed using for example
methylene chloride and/or ether and/or ethyl acetate and/or methanol on silica gel. The desired fractions are recrystallized from a suitable organic solvent Such as ether, ethyl acetate, methanol or hexane to yield the desired
phenylsulphonyltetrahydropyridazine 3-D.
Several general procedures are used for the preparation of the phenylcarbonyltetrahydropyridazines 3-E. For example, an appropriate phenylcarbonyl halide is added to a solution of the intermediate 1-C or 2-C in an organic solvent such as
dichloromethane or toluene. The resulting mixture is heated to reflux for about 1 to about 4 hours, optionally stirred at about room temperature for about 16 hours, dried and concentrated. Column chromatography employing for example methylene chloride
and/or ether and/or ethyl acetate and/or methanol on silica gel is then performed on the residue, followed by recrystallization of the desired fractions from a suitable solvent such as ether, ethyl acetate, methanol or hexane to yield the desired
phenylcarbonyltetrahydropyridazine 3-E. In another example, an appropriate phenylcarbonyl is added to a solution of the appropriate intermediate 1-C or 2-C in an organic solvent such as collidine or pyridine. The resulting mixture is stirred at about
room temperature for about 1 to about 72 hours, dried and concentrated. The isolation of the phenylcarbonyltetrahydropyridazine 3-E is undertaken as noted previously. In yet another example, an appropriate phenylcarbonyl chloride is added to a stirred
solution of the intermediate 1-C or 2-C in an organic solvent such as toluene or methylene chloride at about room temperature under an dry atmospheric conditions such as argon or N.sub.2. A tertiary amine such as dimethylaminopyridine or triethylamine
is added to the mixture and the progress of the reaction is monitored by TLC. The isolation of the phenylcarbonyltetrahydropyridazine 3-E which is prepared under these conditions is undertaken as noted previously. The following general procedure is
used for the preparation of the phenylphosphonyltetrahydropyridazines 3-F. For example an phenylphosphonyl dihalide such as 4-methoxyphenylphosphonic dichloride, 4-chlorophenyl-phosphonic dichloride or phenylphosphonic dichloride is added (preferably
dropwise) to a solution of the appropriate intermediate 1-C or 2-C in an organic solvent such as collidine or pyridine at about 0.degree. C. The reaction mixture is stirred at about 0.degree. C. for about 1 hour, and then warmed to about room
temperature. An appropriate alcohol of the formula R.sub.7 OH and including ethanol, methanol, propanol, butanol, cyclopentanol, isopropanol or phenol, is added to the resulting mixture and this mixture stirred at about room temperature for about 16
hours. The work-up of the reaction mixture and the isolation of the phenylphosphonyltetrahydropyridazine 3-F is effected in the same manner as noted previously regarding the phenylsulphonyltetrahydropyridazines.
The appropriate acylating agents are well known to persons skilled in the art and may be prepared as follows: benzenesulphonylhalide; (Beilstein 11, 34; phenylethenylsulphonyl halide, M. Culbertson, et al., J. Chem. Soc. (C) 992, (1968) and
Beilstein 11, 2; phenylmethylsulphonylhalide, Beilstein 11, 116; benzoylhalide, Beilstein 9, 182; phenylacetylhalide, Beilstein 9, 436; cinnamoylhalide, Beilstein 9, 587; and phenylphosphonyldihalide, Beilstein 16, 804.
Scheme 3 shows the following general procedure used for the preparation of the phenylthiocarbonyltetrahydropyridazines 3-H. For example, a sulfurization agent such as Lawesons reagent or phosphorous pentasulfide is added to a solution of an
appropriate phenylcarbonyltetrahydropyridazine 3-E in an inert organic solvent such as benzene or toluene. The mixture is heated to reflux under dry atmospheric conditions such as argon or N.sub.2 for about 2 hours, filtered and concentrated. The
work-up of the reaction mixture and the isolation of the phenylthiocarbonyltetrahydropyridazines 3-H is effected in the same manner as noted previously regarding the phenylcarbonyltetrahydropyridazines.
Referring to Scheme 4, compounds of the present invention in which R.sup.5* is a bivalent alkyl or alenyl radical attached at the 5- and 6-position are favorably prepared via a cycloaddition between an appropriate azoalkene and an electron-rich
alkene, e.g., dienes, including cyclopentadiene. The azoalkene is generated in situ by: (1) reacting the appropriate phenylsulphonylhydrazide with an appropriate .alpha.-bromo- or .alpha.-chloro-alkylarylketone, e.g., chloroacetophenone, to yield the
corresponding hydrazone 4-A; and (2) treating the hydrazone 4-A with a base such as sodium hydroxide, potassium carbonate, sodium carbonate or sodium bicarbonate to produce final product 4-B. This reaction if further desribed by Clarke et al., J. Chem.
Research (S), 310 (1985) and Faragher et al., J. Chem. Soc. Perkin Trans. I, 249 (1979). ##STR13##
For example, a 1-phenylsulphonyl hydrazide is added to a solution of .alpha.-chloroacetophenone in an organic solvent such as THF or ether. The mixture is heated to reflux for about 2 hours and then concentrated. Upon cooling to about 0.degree. C., a solid residue is produced. The precipitate is washed with an organic solvent such as ether or hexane and dried to yield the corresponding hydrazone 4-A'. An electron-rich diene or alkene 4-A" (preferably freshly distilled) such as indene,
1-methoxycyclohexene, dicyclopentadiene or cyclopentadiene in an organic solvent such as ether or THF is added to a solution of the hydrazone, followed by the addition of a base such as potassium carbonate or sodium bicarbonate. The mixture is stirred
at about room temperature for about 12 hours and then filtered through, for example, florisil or Celite. The filtrate is concentrated. The resulting residue is chilled to about 0.degree. C. and triturated with an alcohol such as methanol or ethanol.
A solid is precipitated out of the mixture, collected and washed with an organic solvent such as ether or hexane to yield a compound of the invention 4-B. Where the alkene employed is a diene, a product is produced that has an unsaturated moiety, e.g.,
R.sup.5* fused bi-radical such as --CH.sub.2 --CH.dbd.CH--. The compound having the unsaturated moiety may be treated with H.sub.2 and a catalytic amount of a metal such as platinum oxide or palladium on carbon in an alcohol such as isopropanol,
methanol or ethanol to yield the corresponding compound wherein the unsaturated bi-radical is hydrogenated (saturated), i.e., the fused bi-radical --CH.sub.2 --CH.dbd.CH-- is converted to --(CH.sub.2).sub.3 --. The reaction is effected by shaking a
suspension of the compound having the unsaturated moiety in a Parr Shaker apparatus under a H.sub.2 atmosphere for about 1 to 3 hours, at about 20 to 50 psi, filtering and concentrating. The resulting reduction product is purified by recrystallization
from an organic solvent such as ether, hexane, ethanol or ethyl acetate.
An alternate method by which an intermediate of the type of 1-C and 2-C may be made can be found in N. Kalyanam et al., Synthetic Communications, 18 (16 and 17) (1988). In this method, an appropriate intermediate 1-C or 2-C is prepared directly
from an appropriate 4-halobutyl aryl ketone.
The invention also pertains to the racemate, individual stereoisomers, and mixtures thereof. The isomers are isolated by standard resolution techniques including fractional crystallization and chiral column chromatography.
The compound of the present invention also include pharmaceutically acceptable salts and esters. Although the acylated tetrahydropyridzines base ring does not form salts or esters, substitutents thereon, which include carboxy or amine groups
may. In the case of salts, there are acid addition salts with amine containing substituents and base salts or alkali metal salts with carboxy containing substituents. Suitable acid addition salts may be formed upon the combination of amine containing
substituents with chlorides, such as hydrochloride; sulfates, such as hydrosulfate; acetates such as acetic acid; etc. Suitable base salts or alkali metal salts may be formed upon the combination of carboxy containing substituents with nitrogen
containing bases, such as, dimethylamine; alkali metal containing bases, such as sodium hydroxide, lithium hydroxide, or potassium carbonate. Persons skilled in the art are well familiar with these salts. In the case of esters, carboxy containing
substitutents may form desirable compounds as esters with methyl, ethyl, propyl, butyl, etc.
Preferred species possessing progestin agonist activity are encompassed by the compounds selected from the group consisting of: 3-(naphth-2-yl)-1-(4-iodobenzenesulphonyl)-1,4,5,6-tetrahydropyridazine;
3-(3,4-dichlorophenyl)-1-(4-trifluoromethylbenzenesulphonyl)-1,4,5,6-tetra hydropyridazine; 3-(3,4-dichlorophenyl)-1-(4-iodobenzenesulphonyl)-1,4,5,6-tetrahydropyrida zine; 3-(3,4-dichlorophenyl)-1-(4-chlorobenzenesulphonyl)-1,4,5,6-tetrahydropyri
dazine; 3-(3,4-dichlorophenyl)-1-(2-naphthylenesulfonyl)-1,4,5,6-tetrahydropyridaz ine; 3-(3,4-dichlorophenyl)-1-(4-bromobenzenesulphonyl)-1,4,5,6-tetrahydropyrid azine; 3-(3,4-dichlorophenyl)-1-(4-methylbenzenesulphonyl)-1,4,5,6-tetrahydropyri dazine;
3-(4-chloro-3-trifluoromethylphenyl)-1-(4-trifluoromethylbenzenesulphonyl) -1,4,5,6-tetrahydropyridazine; 3-(4-chloro-3-trifluoromethylphenyl)-1-(4-bromobenzenesulphonyl)-1,4,5,6-t etrahydropyridazine;
3-(4-chloro-3-trifluoromethylphenyl)-1-(4-iodobenzenesulphonyl)-1,4,5,6-te trahydropyridazine; (R,S) 3-(3,4-dichlorophenyl)-1-(4-iodobenzenesulphonyl)-6-methyl-1,4,5,6-tetrahy dropyridazine and (R,S)
3-(4-chloro-3-trifluoromethylphenyl)-1-(4-iodobenzenesulphonyl)-6-methyl-1 ,4,5,6-tetrahydropyridazine.
Preferred species possessing progestin antagonist activity encompassed by the compounds selected from the group consisting of:
3-(3,4-dichlorophenyl)-1-(2,3-dichlorobenzenesulphonyl)-1,4,5,6-tetrahydrop yridazine; 3-(3,4-dichlorophenyl)-1-(2,5-dichlorobenzenesulphonyl)-1,4,5,6-tetrahydro pyridazine;
3-(3,4-dichlorophenyl)-1-(2-(3-carbomethoxypropxy)-5-bromobenzenesulphonyl )-1,4,5,6-tetrahydropyridazine; 3-(4-chloro-3-trifluoromethylphenyl)-1-(2,5-dichlorobenzenesulphonyl)-1,4, 5,6-tetrahydropyridazine and (R,S)
3-(3,4-dichlorophenyl)-1-(2,5-dichlorobenzenesulphonyl)-5-methyl-1,4,5,6-t etrahydropyridazine.
Preferred species possessing bone growing activity encompassed by the compounds selected from the group consisting of:
1-(3,4-dichlorobenzoyl)-3-phenyl-1,4,5,6-tetrahydropyridazine; 1-(3,4-dichlorothiobenzoyl)-3-phenyl-1,4,5,6-tetrahydropyridazine; 1-(3,4-difluorothiobenzoyl)-3-phenyl-1,4,5,6-tetrahydropyridazine;
1-(3-bromo-4-fluorothiobenzoyl)-3-phenyl-1,4,5,6-1tetrahydropyridazine; (R,S)-1-(3,4-difluorobenzoyl)-5-methyl-3-phenyl-1,4,5,6-tetrahydropyridazi ne; (R,S)-1-(3,4-dichlorobenzoyl)-5-methyl-3-phenyl-1,4,5,6-tetrahydropyridazi ne;
(R,S)-1-(3,4-dichlorothiobenzoyl)-5-methyl-3-phenyl-1,4,5,6-tetrahydropyri dazine; (R,S)-1-(3,4-difluorothiobenzoyl)-5-methyl-3-phenyl-1,4,5,6-tetrahydropyri dazine
1-(3,4-dichlorobenzoyl)-3-(thien-2-yl)-1,4,5,6-tetrahydropyridazine; 1-(3,4-dichlorobenzoyl)-3-(thien-3-yl)-1,4,5,6-tetrahydropyridazine; 1-(3,4-dichlorothiobenzoyl)-3-(thien-2-yl)-1,4,5,6-tetrahydropyridazine and
1-(3,4-dichlorothiobenzoyl)-3-(thien-3-yl)-1,4,5,6-tetrahydropyridazin e.
Certain compounds of the invention exhibit in vivo activity and they are useful in treating biological disorders and conditions that are modulated agonistically or antagonistically by steroids, e.g., contraception, menopause, endometriosis,
breast cancer, cycle synchrony, uterine fibroids, cervical dilation, osteoporosis and central nervous system conditions.
Pharmaceutical compositions that are used in treating the biological disorders or conditions comprise the compounds of the invention as the active ingredients in intimate admixture with a pharmaceutical carrier can be prepared according to
conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., intravenous, oral, transdermal, intravaginal, suppository or parenteral. The
composition may also be administered by means of an aerosol. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives,
coloring agents and the like in the case of oral liquid preparations (such as, for example, suspensions, elixirs and solutions); or carriers such as starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like
in the case of oral solid preparations (such as, for example, powders, capsules and tablets). Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical
carriers are obviously employed. If desired, tablets may be sugar-coated or enteric-coated by standard techniques. For parenterals, the carrier will usually comprise sterile water, though other ingredients, for example, to aid solubility or for
preservative purposes, may be included, injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. The pharmaceutical compositions will generally be in the form of a dosage
unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, from about 1 .mu.g/kg to about 100 mg/kg, and preferably from about 20 .mu.g/kg to about 20 mg/kg of the active ingredients.
Therefore, the compounds may be useful as contraceptives, and in the treatment of menopause, endometriosis, breast cancer, cycle synchrony, uterine fibroids, cervical dilation and osteoporosis.
The following experimental examples describe
the invention in greater particularity and are intended to be a way of illustrating but not limiting the invention.
EXAMPLES
6-(4-Chlorophenyl)pyridazin-3-one
Hydrazine (8.9 mL, 0.28 mol) was added to a suspension of 3-(4-chlorobenzoyl)propionic acid (30.0 g, 0.14 mol) in EtOH. The resulting mixture was heated to reflux for 1 hour, stirred at room temperature overnight and chilled with an ice bath.
The title compound precipitated out of this mixture (23.85 g, 81%) as a yellow solid: mp 175.degree.-176.degree. C.
The following pyridazin-3-ones listed in Table 1 were prepared essentially by the above procedure, using the appropriate starting materials.
TABLE 1 ______________________________________ ##STR14## Cpd R.sup.1 R.sup.5 mp ______________________________________ 1-1 4-Cl H 175-176 1-2 3-Cl H 148-150 1-3 4-Br H 165-166 1-4 H H 192-194 1-5 4-NMe.sub.2 H 1-6 4-OMe H 148-149 1-7 H
H 150-151 1-8 3-Cl, 4-Cl H 168-169 1-9 3-CF.sub.3, 4-Cl H 191-192 1-10 4-n-Bu H 1-11 3-Br, 4-NH.sub.2 H 1-12 3-Br, 5-Br H 1-13 3,4-(CH.sub.2).sub.4 H 1-14 3,4-O(CH.sub.2).sub.2 O H 1-15 3,4-CHCHCHCH H 209-210 1-16 2,3-CHCHCHCH H 135-136 1-17
3,4-N(Me)C(O)CH.sub.2 S(O).sub.2 H 300-301 1-18 3,4-N(Me)C(O)CH.sub.2 S H 241-242 1-19 4-SCH.sub.3 H 1-20 4-SO.sub.2 CH.sub.3 H 1-21 H 5-CH.sub.3 155-158 1-22 H 5-CH.sub.3, 5-CH.sub.3 166-167 1-23 4-Ph H 295-300
______________________________________
Example 2
(4-Chlorophenyl)pyridazine
A lithium aluminum hydride/THF solution (1 Molar, 173 mL) was added dropwise to a suspension of pyridazin-3-one 1B (R.sub.1 =4-Cl; 12.0 g, 57.5 mmol) in THF at 0.degree. C. The resulting mixture was heated to reflux for 1 hour, and cooled to
0.degree. C. Water (6.5 mL) was added to this mixture, followed by the successive addition of NaOH (1N, 6.5 mL), and of water (12 mL). The resulting precipitate was removed from the mother liquor followed by the treatment of said mother liquor with
potassium carbonate. The resulting organic solution was concentrated arylphosphonyl dihalide to give the title compound as a thick oil (9.65 g, 87%).
The following pyridazines listed in Table 2 were prepared essentially by the above procedure, using the appropriate starting materials. All of the products are oils.
TABLE 2 ______________________________________ ##STR15## Cpd R.sup.1 R.sup.5 ______________________________________ 2-1 4-Cl H 2-2 3-Cl H 2-3 H H 2-4 4-NHMe.sub.2 H 2-5 4-OMe H 2-6 H H 2-7 H 5-CH.sub.3 2-8 H 5-CH.sub.3, 5-CH.sub.3 2-9
3-Cl, 4-Cl H 2-10 3-CF.sub.3, 4-Cl H 2-11 4-n-Bu H 2-12 3-Br, 4-NH.sub.2 H 2-13 3-Br, 5-Br H 2-14 3,4-CHCHCHCH H 2-15 3,4-O(CH.sub.2).sub.2 O H 2-16 3,4-CHCHCHCH H 2-17 3,4-N(Me)C(O)CH.sub.2 S H 2-18 3,4-N(Me)C(O)CH.sub.2 S(O).sub.2 H 2-19
4-SCH.sub.3 H 2-20 4-SO.sub.2 CH.sub.3 H 2-21 4-Ph H ______________________________________
Example 3
3-(4-Chloro-3-trifluoromethylphenyl)-1-(4-iodobenzenesulfonyl)-1,4,5,6-tetr ahydropyridazine (Compound 1)
4-iodobenzenesulfonyl chloride (1.18 g, 5.03 mmol) was added at room temperature to a solution of pyridazine (1C) (R.sub.1 =3-CF.sub.3, 4-Cl: 0.62 g, 2.36 mmol) in pyridine and the resulting mixture was stirred for 16 h. 2N HCl was added to the
reaction mixture followed by successive washes with methylene chloride. The combined organic extracts were dried (K.sub.2 CO.sub.3), concentrated arylphosphonyl dihalide and passed through a column of silica gel. The desired fractions were
recrystallized from ethyl acetate/ether to give the title compound as a solid (0.30 g): mp 153.degree.-154.degree. C.
Anal. Calc'd for C.sub.17 H.sub.13 ClF.sub.3 IN.sub.2 O.sub.2 S: C, 38.61; H, 2.48; N, 5.30 Found: C, 38.81; H, 2.44; N, 5.32
The following acylated pyridazines listed in Table 3, Table 3a and Table 4 were prepared essentially by the above procedure, using the appropriate starting materials.
TABLE 3 __________________________________________________________________________ ##STR16## Analysis Cpd R.sup.1 R.sup.3 mp:(.degree.C.) C H N __________________________________________________________________________ 1 3-CF.sub.3, 4-Cl
4-I 153-154 38.81 2.44 5.32 2 H 4-Me 160-161 65.00 5.72 9.05 3 4-OMe 4-Me 141-142 62.50 5.69 8.13 4 4-Cl 4-NO.sub.2 164-165 50.73 3.58 11.15 5 4-Cl 2-Cl, 5-Cl 148-149 47.67 3.16 6.91 6 4-Cl 4-Cl 170-171 52.14 3.68 7.52 7 4-F 4-Cl
151-152 54.31 3.84 8.08 8 4-Cl 4-Me 157-158 58.57 4.86 8.01 9 4-F 4-Me 139-140 61.42 4.96 8.45 10 4-F 4-NO.sub.2 152-153 52.78 3.69 11.34 11 4-F 2-Cl, 5-Cl 122-123 49.50 3.14 7.16 12 4-Cl, 3-Cl 4-Cl 153-154 48.61 3.23 7.16 13 4-Cl
4-Br 178-180 46.50 3.18 6.56 14 4-Cl 3-NO.sub.2 162-163 50.66 3.51 10.86 15 4-Cl 2,3-CHCHCHCH 148-149 62.62 4.07 7.27 16 4-Cl 4-I 162-163 41.93 2.80 5.98 17 4-Cl 4-F 159-160 54.57 3.77 8.07 18 4-F 4-F 147-148 57.18 3.87 8.55 19
4-F 4-Br 157-158 48.34 3.23 6.87 20 4-F 4-I 150-151 43.27 2.90 6.04 21 4-F 4-F, 3-NO.sub.2 149-150 52.88 3.60 11.37 22 4-Cl, 3-Cl 2-Cl, 5-Cl 176-177 43.88 2.68 6.22 23 4-F 2-NO.sub.2, 4-NO.sub.2 149-150 46.85 3.11 13.71 24 4-F
2-NO.sub.2 159-160 52.48 3.76 11.44 25 4-F 3,4-CHCHCHCH 179-180 65.14 4.63 7.64 26 4-F 2-CO.sub.2 Me 150-151 57.22 4.51 7.40 27 4-Cl 2-NO.sub.2 182-183 50.68 3.74 11.34 28 4-Cl 2-NO.sub.2, 4-NO.sub.2 186-187 45.22 2.97 13.20 29 4-Cl
2-CO.sub.2 Me 153-154 55.15 4.22 7.12 30 4-Cl 3-Cl, 4-Cl 163-164 47.63 3.18 7.08 31 4-Cl 3-Cl, 5-Cl 149-150 47.70 3.14 6.93 32 4-Cl 2-F, 4-F 115-116 52.11 3.46 7.51 33 4-Cl 3-CF.sub.3, 5-CF.sub.3 154-155 45.99 2.66 5.75 34 4-Cl
3-NO.sub.2 187-188 46.24 3.12 10.10 35 4-Cl 3-CF.sub.3 178-179 50.76 3.47 6.93 36 4-Cl 4-CF.sub.3 126-127 50.97 3.38 6.90 37 4-Cl H 203-204 57.38 4.37 8.35 38 4-Cl, 3-Cl 4-NO.sub.2 174-175 46.54 3.14 10.18 39 4-Cl, 3-Cl 4-Br 175-176
42.42 2.99 6.43 40 4-Cl, 3-Cl 4-I 184-185 39.24 2.67 5.76 41 4-Cl, 3-Cl 4-Me 150-151 53.65 4.17 7.29 42 4-Cl, 3-Cl 3,4-CHCHCHCH 136-137 57.49 3.79 6.74 43 4-Cl, 3-Cl H 160-161 52.00 3.88 7.75 44 4-Cl 2,3-CHCHCHCH 195-196 62.35 4.39
7.30 45 4-Cl, 3-Cl 4-n-Bu 140-141 61.39 5.90 7.21 46 4-Cl, 3-Cl 3,4-C(NMe.sub.2)CHCHCH 164-165 61.80 5.36 9.89 47 4-Cl, 3-Cl 2-CO.sub.2 Me 121-122 50.63 3.75 6.49 48 H 4-Cl 153-154 57.24 4.34 8.66 49 H 4-Br 145-146 50.65 3.64 7.68
50 H 4-I 143-144 44.99 3.15 6.70 51 H 3,4-CHCHCHCH 137-138 68.37 5.19 8.28 52 H 2-Cl, 5-Cl 140-141 51.93 3.59 7.16 53 H 4-NO.sub.2 170-171 55.88 3.97 11.77 54 H 4-F 125-126 60.54 4.45 8.39 55 H 4-n-Bu 84-85 67.34 6.46 7.52 56 H
2,3-CHCHCHCH 177-178 68.23 5.10 7.91 57 H 3,4-C(NMe.sub.2)CHCHCH 139-140 67.04 5.66 10.39 58 H 4-Cl, 3-NO.sub.2 127-128 50.50 3.45 10.98 59 H 2-F, 4-F 120-121 56.97 3.84
8.30 60 H 3-Cl, 4-Cl 140-141 51.99 3.54 7.55 61 H 4-CF.sub.3 155-156 55.77 3.94 7.67 62 H 3-NO.sub.2 173-174 55.61 3.99 11.90 63 4-OMe 4-Cl 164-165 56.11 4.47 7.61 64 4-OMe H 185-186 61.85 5.22 8.45 65 4-OMe 3,4-CHCHCHCH
145-147 66.28 5.22 7.40 66 H H 167-168 64.04 5.29 9.32 67 4-Cl 4-Cl, 4-NO.sub.2 186-187 46.51 3.31 10.22 69 4-n-Bu 2-Cl, 5-Cl 95-97 56.41 5.22 6.59 70 4-n-Bu 3-NO.sub.2 119-120 59.91 5.61 10.31 71 4-n-Bu 4-I 121-122 49.65 4.69
5.63 72 4-n-Bu 3,4-CHCHCHCH 140-141 70.87 6.33 6.74 73 4-n-Bu 4-Cl 108-109 61.32 5.74 7.04 74 4-n-Bu 4-Me 106-107 68.10 7.01 7.58 75 4-n-Bu 4-n-Bu 102-103 69.66 7.79 6.83 76 4-n-Bu H 109-110 67.24 6.71 7.93 77 3-CF.sub.3, 4-Cl 4-Cl
134-135 46.78 2.91 6.47 78 3-CF.sub.3, 4-Cl 3,4-(CH.sub.2).sub.4 - 130-131 38.81 2.44 5.32 79 3-CF.sub.3, 4-Cl 2-Cl, 5-Cl 160-161 55.56 3.44 6.26 80 3-CF.sub.3, 4-Cl 3-Cl, 5-Cl 124-125 43.42 2.54 6.02 81 3-CF.sub.3, 4-Cl 3-Cl, 4-Cl
138-139 43.27 2.52 5.87 82 3-CF.sub.3, 4-Cl 4-Me 136-137 43.77 2.55 6.10 83 3-CF.sub.3, 4-Cl H 155-156 52.21 3.73 6.80 84 4-Ph 4-Cl 194-195 64.08 4.62 6.78 85 4-Ph 3,4-CHCHCHCH 193-194 73.28 5.07 6.52 86 4-Ph H 204-205 69.92 5.34
7.42 87 3,4-(CH.sub.2).sub.4 - 4-Me 143-144 68.43 6.81 7.46 88 3,4-(CH.sub.2).sub.4 - 4-Cl 165-166 61.72 5.57 7.11 89 3,4-(CH.sub.2).sub.4 - 2-Cl, 5-Cl 153-153 56.75 4.60 6.56 90 3,4-(CH.sub.2).sub.4 - H 151-153 67.52 6.37 7.91 91
3-Cl 2-Cl, 5-Cl 115-116 47.64 3.01 6.82 92 3-Cl 4-Me 129-130 58.53 4.91 8.07 93 3-Cl 4-Cl 123-124 51.95 3.66 7.53 94 3-Cl 3,4-CHCHCHCH 154-155 51.95 3.66 7.53 95 3-Cl H 129-130 57.22 4.37 8.36 96 3-Cl 4-I 131-132 41.75 2.98 6.04
97 4-Cl, 3-Cl 4-CF.sub.3 139-141 46.48 2.92 6.46 98 4-Cl, 3-Cl 3-CF.sub.3 185-186 46.64 2.76 6.18 99 4-Br 4-Cl 182-183 46.13 3.18 6.38 100 4-Br 4-Br 192-193 41.80 2.96 5.73 101 4-Br 4-Me 175-176 51.94 4.29 6.90 102 4-Br 2-Cl, 5-Cl
168-169 42.56 2.86 5.99 103 4-Br H 205-206 50.59 3.92 7.09 104 4-Cl, 3-Cl 3-Cl, 5-Cl 142-143 43.76 2.59 6.10 105 4-Cl, 3-Cl 2-Cl, 3-Cl 142-144 43.81 2.66 6.25 106 4-Cl, 3-Cl 4-F 141-142 49.52 3.30 7.03 108 4-Cl, 3-Cl 4-n-Bu
128-129 56.43 5.18 6.28 109 4-Cl, 3-Cl 3-Cl 189-190 47.49 3.23 6.62 110 4-Cl, 3-Cl 2,3-CHCHCHCH 150-151 57.16 3.81 6.46 111 4-Cl, 3-Cl 3-NO.sub.2, 4-Cl 157-158 42.93 2.60 8.98 112 3,4-C(OMe)HCHCHCH 4-I 143-145 50.19 3.68 5.37
113 3,4-(CH.sub.2).sub.4 - 4-I 170-172 50.03 4.47 5.86 114 4-Cl, 3-Cl 3,4-(CH.sub.2).sub.4 - 135-136 56.59 4.53 6.55 115 3-CF.sub.3, 4-Cl 4-Br 139-140 42.45 2.70 5.82 116
3-CF.sub.3, 4-Cl 4-n-Bu 95-96 54.97 4.79 6.04 117 3,4-CHCHCHCH 4-Cl 160-161 62.38 4.30 7.24 118 3,4-CHCHCHCH 2-Cl, 5-Cl 158-159 57.26 3.72 6.69 119 3,4-CHCHCHCH 4-I 169-170 50.27 3.48 5.67 120 3,4-CHCHCHCH 4-Me 153-154
69.27 5.26 7.73 121 4-Cl, 3-Cl 4-n-Hex 96-97 58.17 5.63 6.10 122 2,3-CHCHCHCH 4-Me 159-163 61.99 4.25 7.09 123 3,4-O(CH.sub.2).sub.2 O- 2-Cl, 5-Cl 147-148 50.61 3.53 6.56 124 3,4-O(CH.sub.2).sub.2 O- 4-Cl 143-145 55.21 4.04 7.17
125 3-CF.sub.3, 4-Cl 4-CF.sub.3 104-106 46.30 2.54 2.65 126 3-CF.sub.3, 4-Cl 3-CF.sub.3 144-145 45.88 2.72 5.84 127 3-CF.sub.3, 4-Cl 3-NO.sub.2 149-150 45.58 2.82 9.19 128 3-CF.sub.3, 4-Cl 4-NO.sub.2 172-173 45.66 2.81 8.98 129
3,4-CHCHCHCH 4-CF.sub.3 166-167 60.08 3.74 6.67 130 3,4-CHCHCHCH 3-CF.sub.3 154-155 60.14 3.79 6.66 131 3,4-CHCHCHCH H 198-200 68.39 5.01 8.00 132 3,4-CHCHCHCH 3,4-CHCHCHCH 173-174 71.63 4.67 6.91 133 H 4-OCH.sub.3 115-117 61.89
5.41 8.15 134 4-SCH.sub.3 4-CH.sub.3 159-161 60.02 5.56 7.74 135 4-SCH.sub.3 4-I 177-179 43.39 3.57 5.84 136 4-Cl, 3-Cl 2-O(CH.sub.2).sub.3 CO.sub.2 Me, 5-Br 76-79 45.66 4.06 4.61 137 4-OMe 2-O(CH.sub.2).sub.3 CO.sub.2 Me, 5-Br 96-97
51.20 5.01 5.12 138 3,4-N(Me)C(O)CH.sub.2 S 4-I 199-203 43.62 3.09 7.65 139 3,4-N(Me)C(O)CH.sub.2 S 4-I 127-131 39.97 3.01 7.02 140 H 4-SCH.sub.3 120-121 58.89 5.26 7.99
__________________________________________________________________________
TABLE 3a ______________________________________ ##STR17## Analysis Cpd R.sup.1 R.sup.3 R.sup.a mp:(.degree.C.) C H N ______________________________________ 68 4-Cl 2-Cl, 4-Cl 5-Cl 151-152 43.87 2.83 6.42 107 4-Cl, 3-Cl 2-Cl, 4-Cl
5-Cl 184-185 40.60 2.34 5.85 ______________________________________
TABLE 4 ______________________________________ ##STR18## Analysis Cpd. R.sup.1 R.sup.3 R.sup.5 mp:(.degree.C.) C H N ______________________________________ 141 H 3-CF.sub.3 5-Me 30-131 56.37 4.14 7.32 142 H 4-Br 5-Me 34-135 52.00 4.26
7.11 143 H 4-Me 5-Me 38-139 65.55 6.24 8.48 144 H 2-Cl, 5-Cl 5-Me 54-155 53.25 4.00 7.24 ______________________________________
Example 4
3-(Dibenzofuran-3-yl)-1-(4-iodobenzenesulfonyl)-1,4,5,6-tetrahydropyradazin e (Compound 145)
4-Iodobenzenesulfonyl chloride (0.54 g, 2.16 mmol) was added at room temperature to a solution of 4-oxo-4-(dibenzofuran-4-yl)butyric acid (0.65 g, 2.16 mmol) in pyridine and the resulting mixture was stirred for 16 hours. 2N HCl was added to the
reaction mixture followed by successive washes with methylene chloride. The combined organic extracts were dried (K.sub.2 CO.sub.3), concentrated arylphosphonyl dihalide and passed through a column of silica gel. The desired fractions were
recrystallized from ethyl acetate/ether/hexane to give the title compound as a solid (0.14 g): mp 166.degree.-169.degree. C.
Anal. Calc'd for C.sub.22 H.sub.17 IN.sub.2 O.sub.3 S: C, 51.17; H, 3.32; N, 5.43 Found: C, 51.27; H, 3.30; N, 5.23
Example 5
1-(4-Methylbenzoyl)-3-(4-chlorophenyl)-1,4,5,6-tetrahydropyridazine (Compound 146)
The title compound was prepared as described in Example 4 starting with 4-oxo-4-(dibenzofuran-4-yl)butyric acid (0.54 g, 2.16 mmol) and 4-chlorobenzenesulfonyl chloride (0.46 mL, 2.16 mmol) to give a solid: mp 163.degree.-166.degree. C.
Anal. Calc'd for C.sub.22 H.sub.17 ClN.sub.2 O.sub.3 S: C, 69.10; H, 5.49; N, 8.95 Found: C, 69.31; H, 5.35; N, 9.02
Example 6
1-(4-Methylsulfinylbenzenesulfonyl)-3-phenyl-1,4,5,6-tetrahydropyridazine (Compound 1471)
MCPBA (0.63 g) was added at room temperature to a solution of 3-phenyl-1-(4-thiomethylbenzenesulfonyl)-1,4,5,6-tetrahydropyridazine (1.0 g) in methylene chloride. The resulting mixture was stirred and monitored by TLC until the starting
pyridazine was exhausted. The mixture was concentrated arylphosphonyl dihalide and purified by column chromatography on silica gel using methylene chloride as an eluent to give a solid: mp 137.degree.-139.degree. C.
Anal. Calc'd for C.sub.17 H.sub.18 N.sub.2 O.sub.3 S2: C, 56.33; H, 5.00; N, 7.73 Found: C, 56.37; H, 4.87; N, 7.54
Example 7
1-(4-Iodobenzenesulfonyl)-3-(4-methylsulfinylphenyl)-1,4,5,6-tetrahydropyri dazine (Compound 148)
A solution of 1-(4Iodobenzenesulfonyl)-3-(4-methylthiophenyl)-1,4,5,6-tetrahydropyridazi ne (1.27 g, 2.69 mmol) in methanol (450 mL) was added to a solution of sodium periodate (0.61 g, 2.82 mmol) in water (6 mL) and stirred at a low heat for 16
hours. The resulting mixture was filtered, concentrated arylphosphonyl dihalide and purified by column chromatography on silica gel using ether/methylene chloride as an eluent to give the title compound as a solid: mp 191.degree.-193.degree. C.
Anal. Calc'd for C.sub.17 H.sub.17 IN.sub.2 O.sub.3 S.sub.2 : C, 41.81; H, 3.52; N, 5.73 Found: C, 42.21; H, 3.77; N, 5.46
Example 8
1-(4-Methylnenzenesulfonyl)-3-(4-methylsulfinylphenyl)-1,4,5,6-tetrahydropy ridazine (Compound 149)
The title compound was prepared as described in Example 7 starting with 1,4,5,6-tetrahydro-1-(4-methylbenzenesulfonyl)-3-(4-methylthiophenyl)pyrid azine (1.0 g, 2.77 mmol) and sodium periodate (0.62 g, 2.91 mmol) in water (5.82 mL) to give a
solid: mp 212.degree.-213.degree. C.
Anal. Calc'd for C.sub.18 H.sub.20 N.sub.2 O.sub.3 S.sub.2 : C, 57.42; H, 5.37; N, 7.44 Found: C, 57.32; H, 5.45; N, 7.52
Example 9
1-(Methylbenzenesulfonyl)-3-(4-methylsulfonylphenyl)-1,4,5,6-tetrahydropyri dazine (Compound 150)
The title compound was prepared as described in Example 6 staring with 1-(4-methylbenzenesulfonyl)-3-(4-methylsulfinylphenyl)-1,4,5,6-tetrahydrop yridazine (0.5 g, 1.33 mmol) and MCPBA (0.28 g, 1.33 mmol) to give a solid: mp
229.degree.-230.degree. C.
Anal. Calc'd for C.sub.18 H.sub.20 N.sub.2 O.sub.4 S.sub.2 : C, 55.08; H, 5.15; N, 7.13 Found: C, 54.73; H, 5.28; N, 6.82
Example 10
1-(4-Iodobenzenesulfonyl)-3-(4-methylsulfonylphenyl)-1,4,5,6-tetrahydropyri dazine (Compound 151)
The title compound was prepared as described in Example 6 staring with 1-(4-iodobenzenesulfonyl)-3-(4-methylsulfinylphenyl)-1,4,5,6-tetrahyclropy ridazine (0.5 g, 1.02 mmol) and MCPBA (0.22 g, 1.02 mmol) to give a solid: mp
198.degree.-204.degree. C.
Anal. Calc'd for C.sub.18 H.sub.20 IN.sub.2 O.sub.4 S.sub.2 : C, 40.48; H, 3.40; N, 5.55 Found: C, 40.45; H, 3.07; N, 5.44
Example 11
3-(4-Fluorophenyl)-1-(pentafluorobenzenesulfonyl)-1,4,5,6-tetrahydropyridaz ine (Compound 152)
The title compound was prepared as described in Example 3 starting with pyridazine (1C) (R.sub.1 =4-F) and pentafluorobenzenesulfonyl chloride to give a solid: mp 140.degree.-141.degree. C.
Anal. Calc'd for C.sub.16 H.sub.10 F.sub.6 N.sub.2 O.sub.2 S: C, 47.06; H, 2.47; N, 686 Found: C, 47.14; H, 2.32; N, 6.85
Example 12
1-(4-Aminobenzenesulfonyl)-3-(4-chlorophenyl)-1,4,5,6-tetrahydropyridazine (Compound 153)
(4-Chlorophenyl)-1-(4-nitrobenzenesulfonyl)-1,4,5,6-tetrahydropyridazine (2.12 g, 5.60 mmol) was suspended in acetic acid at 80.degree. C. Iron filings (3.0 g) were added to this suspension and the resulting reaction mixture was heated at
80.degree. C. for 30 minutes and filtered. Upon cooling the title compound precipitated out of this mixture as a solid: mp 205.degree.-206.degree. C.
Anal. Calc'd for C.sub.16 H.sub.16 ClN.sub.3 O.sub.2 S: C, 54.92; H, 4.61; N, 12.01 Found: C, 54.92; H, 4.64; N, 12.17
Example 13
1-(4-Aminoacetylbenzenesulfonyl)-3-(4-chlorophenyl)-1,4,5,6-tetrahydropyrid azine (Compound 154)
(4-Aminobenzenesulfonyl)-3-(4-chlorophenyl)-1,4,5,6-tetrahydropyridazine (0.52 g) was dissolved in acetic anhydride and stirred at room temperature for 1.5 hours. Upon cooling the title compound precipitated out of this mixture as a solid: mp
247.degree.-248.degree. C.
Anal. Calc'd for C.sub.18 H.sub.18 ClN.sub.3 O.sub.3 S: C, 55.16; H, 4.64; N, 10.72 Found: C, 55.34; H, 4.60; N, 10.74
Example 14
3-Phenyl-1-(4-methylbenzenesulfonyl)-4,4a,5,7a-tetrahydro-1 H-cyclopenta[c]pyridazine (Compound 155)
4-Toluenesulfonylhydrazide (5 g) was added to a solution of alphachloroacetophenone (4.55 g) in ether. The mixture was heated at reflux for 2 hours and concentrated arylphosphonyl dihalide. Cooling the resulting residue to 0.degree. C.
produced a solid precipitate which was washed with hexane and dried to give the hydrazone (4A') (X=Cl, H.sub.1 =H, R.sub.3 =4-CH.sub.3 ; 5.3 g) as a solid:
Freshly distilled cyclopentadiene (3 mL) was added to a solution of hydrazone (4A') (X=Cl, H.sub.1 =H, R.sub.3 =4-CH.sub.3 ; 1.5 g) in THF, followed by the addition of sodium bicarbonate (2.5 g). The mixture was stirred at 22.degree. C. for 12
hours and filtered through celite. The filtrate was concentrated arylphosphonyl dihalide, and the resulting residue was chilled with ice and triturated with ethanol. A solid precipitated out of this mixture which was collected and washed with hexane to
give the title compound as a solid: mp 163.degree.-165.degree. C.
Anal. Calc'd for C.sub.20 H.sub.20 N.sub.2 O.sub.2 S: C, 68.15; H, 5.73; N, 7.94 Found: C, 67.97; H, 5.94; N, 8.26
Example 15
4,4a,5,6,7,7a-Hexahydro-3-phenyl-1-(4-methylbenzenesulfonyl)-1H-cyclopenta[ c]pyridazine (Compound 156)
A catalytic amount of palladium on carbon was added to a solution of 3-phenyl-1-(4-tolylsulfonyl)-4,4a,5,7a-tetrahydro-1H-cyclopenta[c]pyridazi ne (0.5 g) in ethanol. The suspension was placed in a Parr Shaker apparatus under a H.sub.2
atmosphere (40 PSI) and shaken for 3 hours. The mixture was filtered through celite and concentrat | | |
