CA1268767A - 1-phenyl-containing substituent-4-animo-pyrimidinyl substituted isoindole sulfonimide compounds exhibiting diuretic and antihypertensive properties - Google Patents
1-phenyl-containing substituent-4-animo-pyrimidinyl substituted isoindole sulfonimide compounds exhibiting diuretic and antihypertensive propertiesInfo
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- isoindole
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Abstract
Abstract of the Disclosure Novel phthalimide intermediates are reduced to 5-sulfamoyl-6-halo-3-oxoisoindole compounds bearing a sub-stituted 1-phenylalkyl-4-piperidinyl moiety as the isoin-dole N-substitutent. Preferred compounds such as 6-chloro-2,3-dihydro-3-oxo-2-[1-(phenylmethyl)-4-piperidinyl]-1H-isoindole-5-sulfonamide exhibit diuretic and antihyperten-sive properties.
Description
~268`76'7 ~J 566 This lnvention relates to isoindole derivatives, pharma-ceutically acceptable salts thereof and to processes for synthesis thereof. Other aspects of the invention concern pharmaceutical composltions containing an instant compound as active ingredient and methods of treatment where there is an indicated need for an anti-hypertensive and/or diuretic agent.
European Patent Application 26,749 discloses 2-benzyl-piperidinyl-phthalimidine derivatives useful as antipsychotic agents of the following general formula (1) O ~N-CH
(1) ' ~268767 wherein Ro~ Rl, and R2 are independently hydrogen. halogen, Cl 3 alkyl, Cl 3 alkoxy> or trifluoromethyl. The compounds of (1) are reportedly neuropharmacologically active and useful for tre~ting psychotic disorders, especially Rchizophrenia and mania.
S Corn~sh, et al, J. Phann. Pharmacol., 18, 65-80 (1966) disclose preparation of phthalimides and l-~xoisoindolines related to the diuretic clorexolone (2).
-Cl~
European Patent Application 26,749 discloses 2-benzyl-piperidinyl-phthalimidine derivatives useful as antipsychotic agents of the following general formula (1) O ~N-CH
(1) ' ~268767 wherein Ro~ Rl, and R2 are independently hydrogen. halogen, Cl 3 alkyl, Cl 3 alkoxy> or trifluoromethyl. The compounds of (1) are reportedly neuropharmacologically active and useful for tre~ting psychotic disorders, especially Rchizophrenia and mania.
S Corn~sh, et al, J. Phann. Pharmacol., 18, 65-80 (1966) disclose preparation of phthalimides and l-~xoisoindolines related to the diuretic clorexolone (2).
-Cl~
(2) HlmDri, et al, Jpn. J. Pharmacol. 1978, 28(6), 811-818;
(Chem. Abs. 90:97589t) studied the antihypertensive effect of a combination of clorexolone and the ~-adrenergic blocking agent, alprenolol in conscious renal hypertensive dogs and found a signi-ficant decrease in blood pressure after the second day of treatment.
Suzuki, et al, Nippon Yakurigaku Zasshi, 1972, 68(3), 276-289 (Chem. Abs. 81:58265d) reported that the hypotensive diuretics, hydroflumethiazide, triamterene, clorexolone, etc. have favorable effects in the spontaneously hypertensive rat.
In its broadest aspect, the present invention is concerned with 3-oxoisoindole derivatives having antihypertensive and/or diuretic properties characterized by a compound of Formula I
x~ ,~
wherein X is halogen or trifluoromethyl; Rl and R2 are independently hydrogen, lower alkyl, lower alkoxy, lower alkenyloxy, lower alkylthio, trifluoromethyl, cyano, or nitro; Y i8 a single bond or a divalent straight or branched chain alkylene radical: of 1 to 4 carbon atoms inclusive; or a pharmaceutlcally acceptable acid addltion salt thereof.
Other contemplated classes of compounds within the ambit of Formula I are those defined as:
(1) X is halogen; Rl and R2 are independently hydrogen, lower alkyl, lower alkoxy, lower alkenyloxy, lower or alkylthio, trifluoromethyl, cyano,~nitro; and Y is -CH2-.
(2) X is halogen, Rl is hydrogen, lower alkyl, lower alkoxy, lower alkenyloxy, lower alkylthio, trifluoro-methyl, cyano, nitro, R2 is hydrogen; and Y is -C~2-.
(Chem. Abs. 90:97589t) studied the antihypertensive effect of a combination of clorexolone and the ~-adrenergic blocking agent, alprenolol in conscious renal hypertensive dogs and found a signi-ficant decrease in blood pressure after the second day of treatment.
Suzuki, et al, Nippon Yakurigaku Zasshi, 1972, 68(3), 276-289 (Chem. Abs. 81:58265d) reported that the hypotensive diuretics, hydroflumethiazide, triamterene, clorexolone, etc. have favorable effects in the spontaneously hypertensive rat.
In its broadest aspect, the present invention is concerned with 3-oxoisoindole derivatives having antihypertensive and/or diuretic properties characterized by a compound of Formula I
x~ ,~
wherein X is halogen or trifluoromethyl; Rl and R2 are independently hydrogen, lower alkyl, lower alkoxy, lower alkenyloxy, lower alkylthio, trifluoromethyl, cyano, or nitro; Y i8 a single bond or a divalent straight or branched chain alkylene radical: of 1 to 4 carbon atoms inclusive; or a pharmaceutlcally acceptable acid addltion salt thereof.
Other contemplated classes of compounds within the ambit of Formula I are those defined as:
(1) X is halogen; Rl and R2 are independently hydrogen, lower alkyl, lower alkoxy, lower alkenyloxy, lower or alkylthio, trifluoromethyl, cyano,~nitro; and Y is -CH2-.
(2) X is halogen, Rl is hydrogen, lower alkyl, lower alkoxy, lower alkenyloxy, lower alkylthio, trifluoro-methyl, cyano, nitro, R2 is hydrogen; and Y is -C~2-.
(3) X is halogen; Rl is hydrogen, lower alkyl, lower alkoxy, lower alkoxy, lower alkenyloxy, trifluoromethyl;
R2 is hydrogen; and Y is -CH2-.
R2 is hydrogen; and Y is -CH2-.
(4) X is chlorine, Rl is hydrogen, lower alkyl, lower alkoxy, lower alkenyloxy, trifluoromethyl; R2 i~
hydrogen; and Y is -CH2-.
hydrogen; and Y is -CH2-.
(5) X is halogen; Rl and R2 are hydrogen; and Y is -CH2-.
6'7 It is to be understood that by employment of the term "lower alkyl" and "lower alkoxy" herein, it i8 meant that the carbon chains of each group inc~ude both straight ana brauch~ed carbon - radicals containing up to 6 carbon atoms, preferably not more than 4 carbon atoms; Exemplary of carbon chaln radicals are methyl, ethyl, isopropyl, l-butyl, l-methylpropyl, 2-methylpropyl, eert.-butyl.
hexyl and the like. Further the term "halogen" used herein connotes all members of that group but preferably chlorine, bromine and fluorine.
The pharmaceutically acceptable acid addition salts of the invention are those in which the anion does not contribu~e significantly to toxicity or pharmacological activity of the salt, and therefore are considered pharmacological equivalents of Formula I bases.
For purposes of salt formation of the substances of Formula I, there may be mentioned pharmaceutical acceptable acids such as hydro-chloric and other hydrohalic acids, sulphuric, phosphoric, nitric,aliphatic, alicyclic, aromatic or heterocyclic carboxylic acids or sulphonic acids, such as for~ic, acetic, propionic, succinic, glycollic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic or pyruvic, fumaric, benzoic, p-amino-benzoic, anthranilic, p-hydroxy-benzoic, salicyclic, or p-amino~alicyclic, methanesulphonic, ethane-sulphonic, hydroxyethanesulphonic, ethylenesulphonic; halogenobenzene-sulphonic acid, toluenesulphonic acid, naphthalenesulphonic acid or sulphanilic acid.
Conventional methods are used to prepare the salts. Thus, admixture of a For~ula I base with the selected acid in an inert solvent such as water, ethyl acetate, methanol, dimethylformamide and the like with salt isolation by conventional concentration or crystallization techniques are employed.
~268767 The Formula I salts are, in some lnstances, obtained in hydrated form, e.g., hemihydrates, monohydrates, sesquihydrates; and lt i9 to be understood that such forms are within the ambit of ehe instant invention.
According to the present invention, the compounds charac-terized by Formula I
N ~ -Y ~
(I ), R2 wherein X is halogen or trifluoromethyl; Rl and R2 are independently hydrogen, lower alkyl, lower alkoxy, lower alkenyloxy, lower alkylthio, trifluoromethyl, cyano, or nitro; and Y represents a single bond or a divalent straight or branched chain alkylene radical of 1 to 4 carbon atoms inclus_ve a~e obtained by a method compris m g (a) reducing a 1,3-dioxoisoindole compound of Formula II
or a l-hydroxy-3-oxoisoindole compound of Formula III
S~
OH
N-Y
(III) -wherein X, Rl, R2 and Y are a~ defined above; or (b) reacting a 4-~m~nopiperidin~ co~po~nd of Fonm~la IV
H2N ~ N - Y ~
(IV) R2 wherein Rl, R2 and Y are as defined above with a sulfamoyl compound of Formula V in an inert solvent X~
S02NH ~ R3 (V) wherein X is as defined above, R3 is amino, halogen, lower alkoxy; and R4 is halogen or taken as the radical R4CH2- is carbamoyl or formyl; and R3 and R4 taken together is oxygen; or (c) reacting a piperidinyl compound of Formula Vl 50~
(VI) ` i2687~i7 with a phenylalkyl co~pound of Formula VII
Z-Y ~
(VII) wherein X, Rl, R2, and Y are as defined above and Z
is a reactive leaving group.
Reduction of the l,3-dioxoisoindole compounds of Formula II
or 1-hydroxy-3-oxoisoindoles of Formula III is carried out with zinc and acetic acid or tin and concentrated hydrochloric acid at elevated temperatures generally ranging from 60-150 for periods of about 6-48 hours in a reaction inert organic solvent. In the case of zinc-acetic acid, temperatures of 100-150 are preferred and the reduction is conveniently carried out in acetic acid at reflux temperature. Further, reduction with zinc-acetic acid is parti-cularly preferred in that the compounds of Formula I are readily purified by conventional techniques such as basification, extraction and trituration of the extract or precipitation of acid addition salts from crude extracts. In the case of the tin/concentrated hydrochloric acid reduction, preferably carred out at 60-100 in methanol, the Formula I products are more difficult to purify, in some instances, in that they form relatively stable complexes with tin salts. Treatment of the tin complexed Formula I products with hydrogen sulfide under acedic conditions or tetramethylethylenKf~nine in an inert solvent such aY methanol removes the tin as the insoluble sulfide or tetramethylethylenediamine oomplex, respectively, bo ID~vide pure products with respect to elemental analysis but with traces of tin as demonstrated by flame spectrophot~metry. Reductlon of Formula II
and Formula III compounds may be carried out by other conventional means such as use of light metal hydrides.
The compounds of Formula III considerPd part ~f the present invention have antihypertensive and/or diuretic activity and are obtalned by reduction of the corresponding ~,3-dioxoisoindole with excess zinc in acetic acid below 100, preferably at or near room temperature.
The intermediates of Formula IV can be prepared by art-recognized methods involving stepwise use of an a~ino protecting group such as tert.-butoxycarbonyl, catalytic debenzylation, N-alkylation with a phenylalkyl halide and finally removal of the protecting group as illustrated by the following reaction scheme.
Preparation of Formula IV Intermediates t-butoxycarbonyl O
H2N ~ -CH2C6H5 azide or ~+ OCNH ~ -CH2C6H5 (VIII) pyrocarbonate(IX) Rl X-~'~
Pd/C + OCNH ~ K2C03 (X) OCNH ~ ~ - Y ~ ~H2N ~ - Y
(XI) (XII) The symbDl + means t-butyl in this dkx~nent.
12687~i7 The present invention is therefore concerned with a process for preparing compound of Formula IV, H2N {~ Y~
(IV) R2 wherein Rl and R2 are independently hydrogen, lower alkyl, lower alkoxy, lower alkenyloxy, lower alkylthio, tri-fluoromethyl, cyano, or nitro; and Y is a single bond or a di~alent straight or branched chain alkylene radical of 1 to 4 carbon atoms inclusive, said process comprising:
(a) contacting a compound of Formula VIII
2 ~ C 2C6H5 (VIII) with a compound having an amino protecting group, for example, t-butoxycarbonyl azide or di-t-butyl pyrocarbonate, so as to produce a compound of Formula IX:
_U
+ OCNH ~ 2 6 5 (~) (2) subjecting said compo1nd of Formula IX to catalytic debenzylation so as to produce a compound of Formula X
.. ~
t OCNH ~ NH
(X) ~ i, -8a-12687~i7 ~ 3) subjecting said compound of Formula X to N-alkyla-tion with a phenylalkyl halide, so as to produce a ~ompound of Formula XI
O ~ 1 --t --0 ~R
(XI) Z
and then removing said protecting group from the compound of Formula XI by treating said compound of Formula XI with F3CCO2H, so as to form a compound of Formula XII
2 ~ ~ R2 (XII1 wherein - - as used hereinabove means t-butyl.
The present invention is also concerned with ob-taining a compound of formula (IV) as prepared by the above described process or by an obvious chemical equivalent thereof.
-8b-It is to be understood that the sulfamoyl intermediates of Formula V particularly comprehend such compounds as:
X ~ R4 X ~ ~ R4 S0 ~ R3 S02 ~ ~ R4 O O
Va Vb X~ ~3co Vd X~2 ,.
SO ~ 2 Ve wherein X i6 halogen or trifluoromethyl, R3 i8 lower alkoxy, preferably methoxy and R4 i6 halogen.
Known methods are employed in preparation of the Formula V and VI intermediates as illustrated by European Patent Application 26,749, supra.
Regarding the reaction of a piperidinyl compound of Formula VI
with a phenylalkyl compound of Formula VII, an inert organic solvent 6uch as n-pentanol or dimethylformamide is employed at elevated temperature of from about 50-200 in the presence of a basic con-densation agent, preferably an alkali metal hydroxide, carbonate or bicarbonate, for example sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate, or an organic tertiary _ 9 _ ~26876~
nitrogen amine base, such as t~iethylamine or ~yridine. The Formula Vl lntermediate is obtained from a compound Df ~rmula I wherein the N-phenylalkyl radical i8 benzyl by catalytic debenzylation. Phenyl-alkyl compounds of Formula VII are com~ercially available or conventionally prep~red. The term "reactive leaving group" as used w~th respect to "Z" in Formula VII refers to a reactive esterified hydroxy group such as that obtained when esterified by strong inorgaQic or organic acids such as hydrochloric, hydrobromic, hytroiodic acid, sulfuric acid, or an organic sulfonic acid, for example, benzenesulfonic, p-bromobenzene-sulfonic or -toluenesulfonic acid. Particularly preferred leaving groups are chlorine or bromine.
The compounds of Formula I have antihypertensive and/or diuretic properties as can be temonstrated by standard pharmacological test models known to correlate with effects in man. With respect to antihypertensive utility, there can be mentionet such conventional models as the spontaneously hypertensive and DOCA-salt hypertensive rat. Typical tests are conducted as follows:
Spontaneously Hypertensive Rat.- Male rates weighing 300-400 g, previously conditioned to the procedure, are pre-20 warmed in a heating chamber (30C) for 10-20 min. and subsequently restrained in a wire holder at that temperature. Systolic blood pressure and heart rate are measured by the tailcuff technique using a pneumatic pulse transducer and a biotachometer before, and 2, 4, and 24 hours after oral administration of vehicle (0.25% Methocel in water) or test compounds suspended in vehicle at a dose volume equivalent to 5 ml/kg. Blood pressure and heart rate data are reported as changes from zero-hour measurements with vehicle control groups run periodically to confirm that the vehicle has no effect.
DOCA-salt Hypertensive Rat.- Male rates initially weighing 80-100 g, are ~ade hypertensive by in~ecting 10 mg. of deoxycorticosterone acetate (DOCA) subcutaneously three tlmes a week for three weeks providing 1% saline ad libitum. Ater the tenth DOCA in~ection, the 1% saline is replaced with distilled water. One week later~ animals are anesthet~zea ~ith nethoxyflurane and a catheter advanced into the aorta Yia the left common carotid artery to record mean arterial blood pressure (MABP) and he2rt rate. The heparin-filled catheter is passed beneath the skin and exteriorized behind the head. Two tays later, MABP and heart rate are determined before and four hours after oral administration of vehicle (0.25~ Methocel in 0.9% saline) or test compound suspended ~n vehicle at a dose volume equivalent to 5 ml/kg.
With respect to diuretic utility there can be mentioned the conscious rat diuretic screen of Lipschitz, et al (J. Pharmcol.
Exp. Therap. 79-97 (1943~). In this test, dose response assays of diuretic, natruiretic and kaliuretic activity are determined by oral administration of the test substance.
Preferred compounds of the invention are those which have both diuretic and antihypertensive action. This dual activity is particularly advantageous in the treatment of hypertension since the diuretic effect (reduced plasma volume) associated with antihypertensive activity is complimented by the antihypertensive action which produces an effect by a mechanism other than diuresis. A representative and particularly preferred compound, "6-chloro-2,3-dihydro-3-oxo-2{ 1-(phenylmethyl)-4-piperidiny~ -lH-isoindole-5-sulfonamide" (referred to herein as MJ 14712) has a dose-dependent diuretic/natriuretic response in a dose range of 0.3 to 3.0 mg/kg body weight. As an aDtihypertensive, MJ 14712 shows activity in the DOCA-hypertensive rat and spontaneously-hypertensive rat. In the latter, MJ 14712 exhibits a dose-dependent decrease in systolic blood pressure following doses of 3 to 100 mg/kg body weight with onset of the antihypertensive effect seen at about two hours.
Aside from diuretic and antihypertensive properties, MJ 14712 has calcium channel blocking and vasodilating activity.
As stated above, Formula I compounds have diuretic and/or antihypertensive properties with those having complimentary diuretic and antihypertensive activity preferred. Thus, another embodiment of the instant invention is directed to a process for treating hypertension comprising systemically administering to a mammal in need of such treatment an antihypertensive effective amount of a compound of Formula I or a pharmaceutically acceptable acid addition salt thereof.
8y systemic administration, lt is intended to include both oral and parenteral routes with oral being preferred. Examples of parenteral administration are intramuscular, intravenous, intraperitoneal, rectal and subcutaneous administration. The dosage will vary with the form of administration and the particular compound chosen.
20 However, from about 0.05 to S00 mg per kg. of body weight of a mammal of a compound characterized by Formula I administered in effective single or multiple dosage units is generally satisfactory. In accordance with conventional clinical practice, an antihypertensive agent of Formula I is administered at a dosage substantially less than the dose of the compound which is thought to be effective. If the antihypertensive response is insufficient after a suitable trial, dosage is increased by small increments until the optimum antihyper-tensive effect is reached.
~268767 In carrying out the antihypertensive process 9 the active lngredient of Formula I and pharmaceutically acceptable acld additisn salts thereof are preferably administered with a pharmaceutlcally acceptable carrier and such composition~ const~ute ~ar~ ~ the lnstant lnvention. Sultable dosage forms for oral use are tablets, dlspersible powder~, granules~ capsu7es, syrups and elixirs. Examples of parenteral forms are solutions, suspensions, dlspersions, emulsions, and the llke. The compositions for oral use may contain one or more conventional ad~uvants, such as sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a compo-sition of suitable pharmaceutical elegance. Tablets may contain the active ingredient in admixture with conventional pharmaceutical acceptable excipients including inert diluents such ss calcium carbonate, sodium carbonate, l~ctose and talc; granulating and disintegrating agents such as starch and alginic acid; binding agents such as starch, gelatin and acacia and lubricating agents such as magnesium stearate, stearic acid and talc. The tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a gustained action over a longer period. Similarly, suspensions, syrups, and elixirs may contain the active ingredient in admixture with any of the conventional excipients utilized for the preparation of such compositions such as suspending agents (e.g., methylcellulose, tragacanth, and sodium alginate), wetting agents (e.g., lecithin, polyoxyethylene stearate) and preservatives such as ethyl-p-hydroxy-benzoate.- Capsules may contain the active ingredient alone or admixed with an inert solid diluent such as calcium carbonate, calcium phosphate and ksolin. The injectible compos~tions are ~26~3767 formulated as known in the art and may contain appropriate dispersing or wetting agents and suspending agents identical or similar eo those mentioned above.
The following examples are given by way of illustration and are not to be construed as limiting the invention in any way inasmuch as many variations of the invention are poss~ble within the spirit of the invention. All temperatures are degrees centigrade and melting points taken with a Thomas Hoover capillary apparatus are uncorrected Conventional abbreviations are employed in reporting Nuclear Magnetic Resonance (NMR) spectral data with tetramethylsilane as internal reference and chemical shift data values in parts per million.
6-Chloro-2,3-dihydro-3-oxo-2-rl-(phenyl-methyl)-4-~iperidinyl]-1~-isoindole-5-sulfonamide cl12{~
ta) 6-chloro-2~3-dihydro-l~3-dioxo-2-~l-(phenylmethyl)-4 piperidinyl]-lH-isoindole-5-sulfonamide.- A mixture of 4-chloro-5-sulfamoylphthalimide (5.6 g., 0.02 mole) and 4-amino-1-benzylpiperidine (3.8 g., 0.02 mole) in 50 ml. of n-pentanol was heated at 136-138 for 16 hr., cooled and filtered. During reflux, a gas inlet tube was placed below the solvent surface and dry nitrogen bubbled through the solution to facilitate removal of generated ammonia. The filter-cake washet with 100 ml. of 1:5 tioxane-n-hexane and dried in vacuo yielded 5.8 g. (67%) of product (a), m.p. 256-258 (dec.). The abbreviation (dRc . ) n in this document ~Eans "deccmposition". A samPle cryst21lized 126876~
from dimethylformamide-ethanol provided analytically pure 6-chloro-2,3-dihydro-1,3-dioxo~2-~1-(phenylmethyl)-4-piper~dinyl ~lH-isoindole-5-sulfon~mide, m.p. 258-259 (dec.).
Anal. Calcd. for C20H20ClN304S: C, 55.37; H, 4.65; ~, 9.68.
Found: C, 55.52; H, 4.68; N, 10.01.
NMR (DMSO-d6): 1.68 (2H,m); 2.15 (4H,m); 2.93 (2H,m~;
3.50 (2~,s); 4.00 (lH,m); 7.33 (5H,s); 8.00 (2H,bs); 8.13 (lH,s);
8.30 (lH,s).
A scaled-up 0.3 mole preparation refluxed for a 10 hr.
period provided 108.4 g. (83%) of product, m.p. 258-259 (dec.).
(b) Tin-hydrochloric Acid Reduction of 6-Chloro-2,3-dihydro-1,3-dioxo-2-11-(phenylmethyl)-4-piperidinyl~-lH-isoindole-5-sulfonamide.- A mixture of the above part (a) 1,3-dioxoisoindole (4.4 g., 0.01 mole), and 30 mesh granulated tin (2.8 g., 0.024 le) in 20 ml. of methanol and 12 ml. of concentrated hydrochloric acid was heated at 75-80 for a 8 hr. period. Additional 1 g. portions of tin were added at the end of 5 hr. and 6 hr., respectively. After cooling, the reaction mixture was diluted with 40 ml. of methanol, heated to reflux and filtered through infusorisl earth to remove unreacted tin. The filter-cake was washet with methanol and combined filtrates concentrated under reduced pressure. Residual oil slurried with warm methanol provided 1 g. of solid and cooling of the methanol decant an additional 2.1 g. of solid. The combined crude product was further purified by stirring with 65 ml. of 0.077 N hydrochloric acid while slowly introducing a gaseous stream of hydrogen sulfide (H2S) during a 2.0 hr. period. Excess H2S was removed under reduced pressure, the mixture filtered through infursorial earth and the ~26~3767 filter-cake extractet with warm methanol. Coollng the methanol filtrates provided 2.2 8. of product which cryseallized from methanol-water gave analytically pure 6-chloro-2,3-dihydro-3-o~o-2-[1-(phenyl-methyl)-4-piperidinyl]-lH-isoindole-5-sulfonamide hydrochloride as the monohydrate, m.p. 282-284.
Anal. Calcd. for C20H22ClN3S-HCl-H20: C, 50.63; H, 5-31;
N, 8.86; H20, 3.80. Found: C, 50.55; ~, 5.13; N, 8.88; ~0, 4.20.
NMR (DMS0-d6): 1.91 (2H,m); 2.29 (2H,m); 3.23 ~4H,m);
3.34 (2H, bs); 4.28 (2H,s); 4.36 (lH,m); 4.50 (2H,s); 7.47 (3H,m);
hexyl and the like. Further the term "halogen" used herein connotes all members of that group but preferably chlorine, bromine and fluorine.
The pharmaceutically acceptable acid addition salts of the invention are those in which the anion does not contribu~e significantly to toxicity or pharmacological activity of the salt, and therefore are considered pharmacological equivalents of Formula I bases.
For purposes of salt formation of the substances of Formula I, there may be mentioned pharmaceutical acceptable acids such as hydro-chloric and other hydrohalic acids, sulphuric, phosphoric, nitric,aliphatic, alicyclic, aromatic or heterocyclic carboxylic acids or sulphonic acids, such as for~ic, acetic, propionic, succinic, glycollic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic or pyruvic, fumaric, benzoic, p-amino-benzoic, anthranilic, p-hydroxy-benzoic, salicyclic, or p-amino~alicyclic, methanesulphonic, ethane-sulphonic, hydroxyethanesulphonic, ethylenesulphonic; halogenobenzene-sulphonic acid, toluenesulphonic acid, naphthalenesulphonic acid or sulphanilic acid.
Conventional methods are used to prepare the salts. Thus, admixture of a For~ula I base with the selected acid in an inert solvent such as water, ethyl acetate, methanol, dimethylformamide and the like with salt isolation by conventional concentration or crystallization techniques are employed.
~268767 The Formula I salts are, in some lnstances, obtained in hydrated form, e.g., hemihydrates, monohydrates, sesquihydrates; and lt i9 to be understood that such forms are within the ambit of ehe instant invention.
According to the present invention, the compounds charac-terized by Formula I
N ~ -Y ~
(I ), R2 wherein X is halogen or trifluoromethyl; Rl and R2 are independently hydrogen, lower alkyl, lower alkoxy, lower alkenyloxy, lower alkylthio, trifluoromethyl, cyano, or nitro; and Y represents a single bond or a divalent straight or branched chain alkylene radical of 1 to 4 carbon atoms inclus_ve a~e obtained by a method compris m g (a) reducing a 1,3-dioxoisoindole compound of Formula II
or a l-hydroxy-3-oxoisoindole compound of Formula III
S~
OH
N-Y
(III) -wherein X, Rl, R2 and Y are a~ defined above; or (b) reacting a 4-~m~nopiperidin~ co~po~nd of Fonm~la IV
H2N ~ N - Y ~
(IV) R2 wherein Rl, R2 and Y are as defined above with a sulfamoyl compound of Formula V in an inert solvent X~
S02NH ~ R3 (V) wherein X is as defined above, R3 is amino, halogen, lower alkoxy; and R4 is halogen or taken as the radical R4CH2- is carbamoyl or formyl; and R3 and R4 taken together is oxygen; or (c) reacting a piperidinyl compound of Formula Vl 50~
(VI) ` i2687~i7 with a phenylalkyl co~pound of Formula VII
Z-Y ~
(VII) wherein X, Rl, R2, and Y are as defined above and Z
is a reactive leaving group.
Reduction of the l,3-dioxoisoindole compounds of Formula II
or 1-hydroxy-3-oxoisoindoles of Formula III is carried out with zinc and acetic acid or tin and concentrated hydrochloric acid at elevated temperatures generally ranging from 60-150 for periods of about 6-48 hours in a reaction inert organic solvent. In the case of zinc-acetic acid, temperatures of 100-150 are preferred and the reduction is conveniently carried out in acetic acid at reflux temperature. Further, reduction with zinc-acetic acid is parti-cularly preferred in that the compounds of Formula I are readily purified by conventional techniques such as basification, extraction and trituration of the extract or precipitation of acid addition salts from crude extracts. In the case of the tin/concentrated hydrochloric acid reduction, preferably carred out at 60-100 in methanol, the Formula I products are more difficult to purify, in some instances, in that they form relatively stable complexes with tin salts. Treatment of the tin complexed Formula I products with hydrogen sulfide under acedic conditions or tetramethylethylenKf~nine in an inert solvent such aY methanol removes the tin as the insoluble sulfide or tetramethylethylenediamine oomplex, respectively, bo ID~vide pure products with respect to elemental analysis but with traces of tin as demonstrated by flame spectrophot~metry. Reductlon of Formula II
and Formula III compounds may be carried out by other conventional means such as use of light metal hydrides.
The compounds of Formula III considerPd part ~f the present invention have antihypertensive and/or diuretic activity and are obtalned by reduction of the corresponding ~,3-dioxoisoindole with excess zinc in acetic acid below 100, preferably at or near room temperature.
The intermediates of Formula IV can be prepared by art-recognized methods involving stepwise use of an a~ino protecting group such as tert.-butoxycarbonyl, catalytic debenzylation, N-alkylation with a phenylalkyl halide and finally removal of the protecting group as illustrated by the following reaction scheme.
Preparation of Formula IV Intermediates t-butoxycarbonyl O
H2N ~ -CH2C6H5 azide or ~+ OCNH ~ -CH2C6H5 (VIII) pyrocarbonate(IX) Rl X-~'~
Pd/C + OCNH ~ K2C03 (X) OCNH ~ ~ - Y ~ ~H2N ~ - Y
(XI) (XII) The symbDl + means t-butyl in this dkx~nent.
12687~i7 The present invention is therefore concerned with a process for preparing compound of Formula IV, H2N {~ Y~
(IV) R2 wherein Rl and R2 are independently hydrogen, lower alkyl, lower alkoxy, lower alkenyloxy, lower alkylthio, tri-fluoromethyl, cyano, or nitro; and Y is a single bond or a di~alent straight or branched chain alkylene radical of 1 to 4 carbon atoms inclusive, said process comprising:
(a) contacting a compound of Formula VIII
2 ~ C 2C6H5 (VIII) with a compound having an amino protecting group, for example, t-butoxycarbonyl azide or di-t-butyl pyrocarbonate, so as to produce a compound of Formula IX:
_U
+ OCNH ~ 2 6 5 (~) (2) subjecting said compo1nd of Formula IX to catalytic debenzylation so as to produce a compound of Formula X
.. ~
t OCNH ~ NH
(X) ~ i, -8a-12687~i7 ~ 3) subjecting said compound of Formula X to N-alkyla-tion with a phenylalkyl halide, so as to produce a ~ompound of Formula XI
O ~ 1 --t --0 ~R
(XI) Z
and then removing said protecting group from the compound of Formula XI by treating said compound of Formula XI with F3CCO2H, so as to form a compound of Formula XII
2 ~ ~ R2 (XII1 wherein - - as used hereinabove means t-butyl.
The present invention is also concerned with ob-taining a compound of formula (IV) as prepared by the above described process or by an obvious chemical equivalent thereof.
-8b-It is to be understood that the sulfamoyl intermediates of Formula V particularly comprehend such compounds as:
X ~ R4 X ~ ~ R4 S0 ~ R3 S02 ~ ~ R4 O O
Va Vb X~ ~3co Vd X~2 ,.
SO ~ 2 Ve wherein X i6 halogen or trifluoromethyl, R3 i8 lower alkoxy, preferably methoxy and R4 i6 halogen.
Known methods are employed in preparation of the Formula V and VI intermediates as illustrated by European Patent Application 26,749, supra.
Regarding the reaction of a piperidinyl compound of Formula VI
with a phenylalkyl compound of Formula VII, an inert organic solvent 6uch as n-pentanol or dimethylformamide is employed at elevated temperature of from about 50-200 in the presence of a basic con-densation agent, preferably an alkali metal hydroxide, carbonate or bicarbonate, for example sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate, or an organic tertiary _ 9 _ ~26876~
nitrogen amine base, such as t~iethylamine or ~yridine. The Formula Vl lntermediate is obtained from a compound Df ~rmula I wherein the N-phenylalkyl radical i8 benzyl by catalytic debenzylation. Phenyl-alkyl compounds of Formula VII are com~ercially available or conventionally prep~red. The term "reactive leaving group" as used w~th respect to "Z" in Formula VII refers to a reactive esterified hydroxy group such as that obtained when esterified by strong inorgaQic or organic acids such as hydrochloric, hydrobromic, hytroiodic acid, sulfuric acid, or an organic sulfonic acid, for example, benzenesulfonic, p-bromobenzene-sulfonic or -toluenesulfonic acid. Particularly preferred leaving groups are chlorine or bromine.
The compounds of Formula I have antihypertensive and/or diuretic properties as can be temonstrated by standard pharmacological test models known to correlate with effects in man. With respect to antihypertensive utility, there can be mentionet such conventional models as the spontaneously hypertensive and DOCA-salt hypertensive rat. Typical tests are conducted as follows:
Spontaneously Hypertensive Rat.- Male rates weighing 300-400 g, previously conditioned to the procedure, are pre-20 warmed in a heating chamber (30C) for 10-20 min. and subsequently restrained in a wire holder at that temperature. Systolic blood pressure and heart rate are measured by the tailcuff technique using a pneumatic pulse transducer and a biotachometer before, and 2, 4, and 24 hours after oral administration of vehicle (0.25% Methocel in water) or test compounds suspended in vehicle at a dose volume equivalent to 5 ml/kg. Blood pressure and heart rate data are reported as changes from zero-hour measurements with vehicle control groups run periodically to confirm that the vehicle has no effect.
DOCA-salt Hypertensive Rat.- Male rates initially weighing 80-100 g, are ~ade hypertensive by in~ecting 10 mg. of deoxycorticosterone acetate (DOCA) subcutaneously three tlmes a week for three weeks providing 1% saline ad libitum. Ater the tenth DOCA in~ection, the 1% saline is replaced with distilled water. One week later~ animals are anesthet~zea ~ith nethoxyflurane and a catheter advanced into the aorta Yia the left common carotid artery to record mean arterial blood pressure (MABP) and he2rt rate. The heparin-filled catheter is passed beneath the skin and exteriorized behind the head. Two tays later, MABP and heart rate are determined before and four hours after oral administration of vehicle (0.25~ Methocel in 0.9% saline) or test compound suspended ~n vehicle at a dose volume equivalent to 5 ml/kg.
With respect to diuretic utility there can be mentioned the conscious rat diuretic screen of Lipschitz, et al (J. Pharmcol.
Exp. Therap. 79-97 (1943~). In this test, dose response assays of diuretic, natruiretic and kaliuretic activity are determined by oral administration of the test substance.
Preferred compounds of the invention are those which have both diuretic and antihypertensive action. This dual activity is particularly advantageous in the treatment of hypertension since the diuretic effect (reduced plasma volume) associated with antihypertensive activity is complimented by the antihypertensive action which produces an effect by a mechanism other than diuresis. A representative and particularly preferred compound, "6-chloro-2,3-dihydro-3-oxo-2{ 1-(phenylmethyl)-4-piperidiny~ -lH-isoindole-5-sulfonamide" (referred to herein as MJ 14712) has a dose-dependent diuretic/natriuretic response in a dose range of 0.3 to 3.0 mg/kg body weight. As an aDtihypertensive, MJ 14712 shows activity in the DOCA-hypertensive rat and spontaneously-hypertensive rat. In the latter, MJ 14712 exhibits a dose-dependent decrease in systolic blood pressure following doses of 3 to 100 mg/kg body weight with onset of the antihypertensive effect seen at about two hours.
Aside from diuretic and antihypertensive properties, MJ 14712 has calcium channel blocking and vasodilating activity.
As stated above, Formula I compounds have diuretic and/or antihypertensive properties with those having complimentary diuretic and antihypertensive activity preferred. Thus, another embodiment of the instant invention is directed to a process for treating hypertension comprising systemically administering to a mammal in need of such treatment an antihypertensive effective amount of a compound of Formula I or a pharmaceutically acceptable acid addition salt thereof.
8y systemic administration, lt is intended to include both oral and parenteral routes with oral being preferred. Examples of parenteral administration are intramuscular, intravenous, intraperitoneal, rectal and subcutaneous administration. The dosage will vary with the form of administration and the particular compound chosen.
20 However, from about 0.05 to S00 mg per kg. of body weight of a mammal of a compound characterized by Formula I administered in effective single or multiple dosage units is generally satisfactory. In accordance with conventional clinical practice, an antihypertensive agent of Formula I is administered at a dosage substantially less than the dose of the compound which is thought to be effective. If the antihypertensive response is insufficient after a suitable trial, dosage is increased by small increments until the optimum antihyper-tensive effect is reached.
~268767 In carrying out the antihypertensive process 9 the active lngredient of Formula I and pharmaceutically acceptable acld additisn salts thereof are preferably administered with a pharmaceutlcally acceptable carrier and such composition~ const~ute ~ar~ ~ the lnstant lnvention. Sultable dosage forms for oral use are tablets, dlspersible powder~, granules~ capsu7es, syrups and elixirs. Examples of parenteral forms are solutions, suspensions, dlspersions, emulsions, and the llke. The compositions for oral use may contain one or more conventional ad~uvants, such as sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a compo-sition of suitable pharmaceutical elegance. Tablets may contain the active ingredient in admixture with conventional pharmaceutical acceptable excipients including inert diluents such ss calcium carbonate, sodium carbonate, l~ctose and talc; granulating and disintegrating agents such as starch and alginic acid; binding agents such as starch, gelatin and acacia and lubricating agents such as magnesium stearate, stearic acid and talc. The tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a gustained action over a longer period. Similarly, suspensions, syrups, and elixirs may contain the active ingredient in admixture with any of the conventional excipients utilized for the preparation of such compositions such as suspending agents (e.g., methylcellulose, tragacanth, and sodium alginate), wetting agents (e.g., lecithin, polyoxyethylene stearate) and preservatives such as ethyl-p-hydroxy-benzoate.- Capsules may contain the active ingredient alone or admixed with an inert solid diluent such as calcium carbonate, calcium phosphate and ksolin. The injectible compos~tions are ~26~3767 formulated as known in the art and may contain appropriate dispersing or wetting agents and suspending agents identical or similar eo those mentioned above.
The following examples are given by way of illustration and are not to be construed as limiting the invention in any way inasmuch as many variations of the invention are poss~ble within the spirit of the invention. All temperatures are degrees centigrade and melting points taken with a Thomas Hoover capillary apparatus are uncorrected Conventional abbreviations are employed in reporting Nuclear Magnetic Resonance (NMR) spectral data with tetramethylsilane as internal reference and chemical shift data values in parts per million.
6-Chloro-2,3-dihydro-3-oxo-2-rl-(phenyl-methyl)-4-~iperidinyl]-1~-isoindole-5-sulfonamide cl12{~
ta) 6-chloro-2~3-dihydro-l~3-dioxo-2-~l-(phenylmethyl)-4 piperidinyl]-lH-isoindole-5-sulfonamide.- A mixture of 4-chloro-5-sulfamoylphthalimide (5.6 g., 0.02 mole) and 4-amino-1-benzylpiperidine (3.8 g., 0.02 mole) in 50 ml. of n-pentanol was heated at 136-138 for 16 hr., cooled and filtered. During reflux, a gas inlet tube was placed below the solvent surface and dry nitrogen bubbled through the solution to facilitate removal of generated ammonia. The filter-cake washet with 100 ml. of 1:5 tioxane-n-hexane and dried in vacuo yielded 5.8 g. (67%) of product (a), m.p. 256-258 (dec.). The abbreviation (dRc . ) n in this document ~Eans "deccmposition". A samPle cryst21lized 126876~
from dimethylformamide-ethanol provided analytically pure 6-chloro-2,3-dihydro-1,3-dioxo~2-~1-(phenylmethyl)-4-piper~dinyl ~lH-isoindole-5-sulfon~mide, m.p. 258-259 (dec.).
Anal. Calcd. for C20H20ClN304S: C, 55.37; H, 4.65; ~, 9.68.
Found: C, 55.52; H, 4.68; N, 10.01.
NMR (DMSO-d6): 1.68 (2H,m); 2.15 (4H,m); 2.93 (2H,m~;
3.50 (2~,s); 4.00 (lH,m); 7.33 (5H,s); 8.00 (2H,bs); 8.13 (lH,s);
8.30 (lH,s).
A scaled-up 0.3 mole preparation refluxed for a 10 hr.
period provided 108.4 g. (83%) of product, m.p. 258-259 (dec.).
(b) Tin-hydrochloric Acid Reduction of 6-Chloro-2,3-dihydro-1,3-dioxo-2-11-(phenylmethyl)-4-piperidinyl~-lH-isoindole-5-sulfonamide.- A mixture of the above part (a) 1,3-dioxoisoindole (4.4 g., 0.01 mole), and 30 mesh granulated tin (2.8 g., 0.024 le) in 20 ml. of methanol and 12 ml. of concentrated hydrochloric acid was heated at 75-80 for a 8 hr. period. Additional 1 g. portions of tin were added at the end of 5 hr. and 6 hr., respectively. After cooling, the reaction mixture was diluted with 40 ml. of methanol, heated to reflux and filtered through infusorisl earth to remove unreacted tin. The filter-cake was washet with methanol and combined filtrates concentrated under reduced pressure. Residual oil slurried with warm methanol provided 1 g. of solid and cooling of the methanol decant an additional 2.1 g. of solid. The combined crude product was further purified by stirring with 65 ml. of 0.077 N hydrochloric acid while slowly introducing a gaseous stream of hydrogen sulfide (H2S) during a 2.0 hr. period. Excess H2S was removed under reduced pressure, the mixture filtered through infursorial earth and the ~26~3767 filter-cake extractet with warm methanol. Coollng the methanol filtrates provided 2.2 8. of product which cryseallized from methanol-water gave analytically pure 6-chloro-2,3-dihydro-3-o~o-2-[1-(phenyl-methyl)-4-piperidinyl]-lH-isoindole-5-sulfonamide hydrochloride as the monohydrate, m.p. 282-284.
Anal. Calcd. for C20H22ClN3S-HCl-H20: C, 50.63; H, 5-31;
N, 8.86; H20, 3.80. Found: C, 50.55; ~, 5.13; N, 8.88; ~0, 4.20.
NMR (DMS0-d6): 1.91 (2H,m); 2.29 (2H,m); 3.23 ~4H,m);
3.34 (2H, bs); 4.28 (2H,s); 4.36 (lH,m); 4.50 (2H,s); 7.47 (3H,m);
7.60 (2H,m); 7.76 (2H,bs); 7.96 (lH,s); 8.20 (lH,s).
Reduction of the part (a) 1,3-dioxoisoindole with metallic tin and hydrochloric acid with removal of residual ionic tin by treatment with H2S under acidic conditions was repeated to give hydrated 6-chloro-2,3-dihydro-3-oxo-2-[1-(phenylmethyl)-4-piperidinyl]-lH-isoindole-5-sulfonamide hydrochloride in yields ranging from 30-45Z. The degree of hytration appears to be generally dependent upon drying conditions and is usually within the range of 1/4 to 1.5 mole equivalent of water. Melting points of hydrated products were affected by rate of heating.
(c) Zinc-acetic Acid Reduction of 6-Chloro-2,3-dihydro-1,3-dioxo-2-[1-(phenylmethyl)-4-piperidinyl~-lH-isoindole-5-sulfonamide.-Zinc dust (12.4 g., 0.189 mole) was added in one portion to 1,3-dioxoisoindole (15.0 g., 0.034 mole) of part (a) in 300 ml. of acetic acid. The reaction mixture was stirred at room temperature for O.S hr. and then heated to reflux for a 6 hr. period during which time additional 3.0 g. port$ons of zinc were added at the end of 3, 4, and 5 hr., respectively. After stirring overnight, the reaction :126B767 mixture was filtered and the filtrate concentrated to tryness under reduced pressure with addltional water added to the resldue and removed in vacuo eo remove traces of acetic acid. Residual material was slurried in water, filtered and the filtrate concentrated to dryness. The product was stirred with hot ethyl acetate and saturated sodium bicarbonate solution and the separated ethyl acetate fraction dried over MgS04 and concentrated to a small volume. After cooling, precipitated material was collected to provide the free base 6.03 g., m.p. 232-235 (dec.). The free base taken up in dimethylformamide, acidified with ethanolic hydrogen chloride and diluted with absolute ethanol afforded 7.6 g., (49% yield) of product which was ~rystallized from 1:1 methanol-water to provide analytically pure hydrated 6-chloro-2,3-dihydro-3-oxo-2-[1-phenylmethyl)-4-piperidinyl]-lH-isoindole-5-sulfonamide hydrochloride, m.p. 271-272 (dec.).
Anal- Calcd- for C20H22ClN303S-HCl-2/3H2 N, 8.97; H20, 2.56. Found: H, 51,34; H, 5.04; N, 9.04; H20, 3.16.
N~R (DMSO-d6): 1.91 (2H,m); 2.29 (2H,m); 3.23 (4H,m); 3.31 (1.5H,bs); 4.30 (2H,s); 4.36 (lH,m); 4.50 (2H,s); 7.46 (3H,m); 7.65 (2H,m) 7.76 (2H,bs); 7.94 (lH,s); 8.19 (lH,s); 11.40 (lH,bs).
(d) 6-Chloro-2,3-dihydro-3-oxo-2-~1-(phenylmethyl)-4-piperidinyl]-lH-isoindole-5-sulfonamide.- A mixture of 4.7 g. of hydrated 6-chloro-2,3-dihydro-3-oxo-2-[1-(phenylmethyl)-4-piperidinyl~-lH-isoindole hydrochloride prepared by tin-hydrochloric acid reduction and 0.84 g of sodium bicarbonate in 140 ml. of 50~ methanol was 25 maintained at 45-55 for a 4 hr. period, filtered and the filter-cake washed with water and methanol to afford 3.8 g. of white solid.
Crystallization of this material from dimethylformamide-methanol ~;2687~i7 afforded analytically pure free base "6 chloro-2,3-dihydro-3-oxo-2-[l-(phenylmethyl~-4-piperidinyl~-lH-isoindole-5-sulfonamite", m.p.
248-250 (dec.) as the hemihydrate.
Anal- Calcd- for C20H22ClN33S- 5H2 C, 56-00; H~ 5.40;
N, 9.80, H20, 2.10. Found: C, 56.37; H, 5.23; N, 9 90; ~2' 2.34.
NMR (DMSO-t6): 1.79 t4H,m); 2.00 (2H,m); 2.89 (2~,m); 3.48 (3H,m); 4.00 (lH,m); 4.51 (2H,s); 7.29 (5H,s); 7.77 (2H,bs); 7.84 (lH,s);
Reduction of the part (a) 1,3-dioxoisoindole with metallic tin and hydrochloric acid with removal of residual ionic tin by treatment with H2S under acidic conditions was repeated to give hydrated 6-chloro-2,3-dihydro-3-oxo-2-[1-(phenylmethyl)-4-piperidinyl]-lH-isoindole-5-sulfonamide hydrochloride in yields ranging from 30-45Z. The degree of hytration appears to be generally dependent upon drying conditions and is usually within the range of 1/4 to 1.5 mole equivalent of water. Melting points of hydrated products were affected by rate of heating.
(c) Zinc-acetic Acid Reduction of 6-Chloro-2,3-dihydro-1,3-dioxo-2-[1-(phenylmethyl)-4-piperidinyl~-lH-isoindole-5-sulfonamide.-Zinc dust (12.4 g., 0.189 mole) was added in one portion to 1,3-dioxoisoindole (15.0 g., 0.034 mole) of part (a) in 300 ml. of acetic acid. The reaction mixture was stirred at room temperature for O.S hr. and then heated to reflux for a 6 hr. period during which time additional 3.0 g. port$ons of zinc were added at the end of 3, 4, and 5 hr., respectively. After stirring overnight, the reaction :126B767 mixture was filtered and the filtrate concentrated to tryness under reduced pressure with addltional water added to the resldue and removed in vacuo eo remove traces of acetic acid. Residual material was slurried in water, filtered and the filtrate concentrated to dryness. The product was stirred with hot ethyl acetate and saturated sodium bicarbonate solution and the separated ethyl acetate fraction dried over MgS04 and concentrated to a small volume. After cooling, precipitated material was collected to provide the free base 6.03 g., m.p. 232-235 (dec.). The free base taken up in dimethylformamide, acidified with ethanolic hydrogen chloride and diluted with absolute ethanol afforded 7.6 g., (49% yield) of product which was ~rystallized from 1:1 methanol-water to provide analytically pure hydrated 6-chloro-2,3-dihydro-3-oxo-2-[1-phenylmethyl)-4-piperidinyl]-lH-isoindole-5-sulfonamide hydrochloride, m.p. 271-272 (dec.).
Anal- Calcd- for C20H22ClN303S-HCl-2/3H2 N, 8.97; H20, 2.56. Found: H, 51,34; H, 5.04; N, 9.04; H20, 3.16.
N~R (DMSO-d6): 1.91 (2H,m); 2.29 (2H,m); 3.23 (4H,m); 3.31 (1.5H,bs); 4.30 (2H,s); 4.36 (lH,m); 4.50 (2H,s); 7.46 (3H,m); 7.65 (2H,m) 7.76 (2H,bs); 7.94 (lH,s); 8.19 (lH,s); 11.40 (lH,bs).
(d) 6-Chloro-2,3-dihydro-3-oxo-2-~1-(phenylmethyl)-4-piperidinyl]-lH-isoindole-5-sulfonamide.- A mixture of 4.7 g. of hydrated 6-chloro-2,3-dihydro-3-oxo-2-[1-(phenylmethyl)-4-piperidinyl~-lH-isoindole hydrochloride prepared by tin-hydrochloric acid reduction and 0.84 g of sodium bicarbonate in 140 ml. of 50~ methanol was 25 maintained at 45-55 for a 4 hr. period, filtered and the filter-cake washed with water and methanol to afford 3.8 g. of white solid.
Crystallization of this material from dimethylformamide-methanol ~;2687~i7 afforded analytically pure free base "6 chloro-2,3-dihydro-3-oxo-2-[l-(phenylmethyl~-4-piperidinyl~-lH-isoindole-5-sulfonamite", m.p.
248-250 (dec.) as the hemihydrate.
Anal- Calcd- for C20H22ClN33S- 5H2 C, 56-00; H~ 5.40;
N, 9.80, H20, 2.10. Found: C, 56.37; H, 5.23; N, 9 90; ~2' 2.34.
NMR (DMSO-t6): 1.79 t4H,m); 2.00 (2H,m); 2.89 (2~,m); 3.48 (3H,m); 4.00 (lH,m); 4.51 (2H,s); 7.29 (5H,s); 7.77 (2H,bs); 7.84 (lH,s);
8.22 (lH,s).
(e) A sample of free base prepared by zinc-acetic acid reduction dried under reduced pressure/heat provided anhydrous 6-chloro-2,3-dihydro-3-oxo-2-[1-(phenylmethyl)-4-piperidinyl]-lH-isoindole-5-sulfonamide, m.p. 227-229 (dec.).
Anal- Calcd- for C20H22ClN33S C, 57-20; H~ 5-28; N~ 10.01.
Found: C, 56.86; H, 5.26; N, 9.92.
NMR (DMS0-d6): 1.75 (2H,m); 1.98 (4H,m); 2.90 (2H,m); 3.49 (2H,s); 4.00 (lH,m); 4.52 (2H,s); 7.29 (5H,s); 7.73 (2H,bs); 7.86 ~lH,s); 8.20 (lH,s).
Melting point variations may be related to the reduction method with tin-hydrochloric acid generally providing somewhat higher melting points, possibly related to traces of tin generally ranging from 100-200 parts per million.
3.268767 6-Chloro-2-[1-[(4-chlorophenyl)methyl]-4-piperidinyl]-2,3-dihytro-3-oxo-lH-isoindole-5-sulfonamide Hydrochloride N-CH2 ~ Cl HCl (a) 6-Chloro-2-[1-[(4-chlorophenyl)methyl]-4-piperidinyl~-2,3-dihydro-1,3-dioxo-lH-isoindole-5-sulfonam~de.- Reaction of 4-chloro-5-sulfamoylphthalimide (5.57 g., 0.0214 mole) and 4-amino-1-(4-chlorobenzyl)piperidine (4.8 g., 0.0214 mole) in 85 ml. of n-pentanol according to the procedure of Example l(a) with heating at 130-138 for a 48 hr. period afforded 7.07 g. t71%) m.p. 248-250 (dec.) of the 1,3-dioxoisoindole product. A sample crystallized from dimethylformamide-methanol provided analytically pure 6-chloro-2-[1-[(4-chlorophenyl)methyl]-4-piperidinyl]-2~3-dihydro-l~3-dioxo-lH
isoindole-5-sulfonamide, m.p. 250-251 (dec.).
Anal. Calcd. for C20HlgC12N304S C, 51.29; H, 4.09;
- N, 8.97. Found: C, 51.53; H, 4.21; N, 8.87.
(b) TieIe Product.- Reduction of the above product (a) 1,3-dioxoisointole (5.0 g., 0.0107 mole) with zinc and acetic acid according to the method of Example l(c) and conversion of the free base (partially purified by trituration with ethyl acetate) to the hydrochloride salt in methanol afforded 6-chloro-2-[1-[(4-chloro-phenyl)-phenyl)methyl]-4-piperidinyl]-2,3-dihydro-3-oxo-lH-isoindole-5-sulfonamide hydrochloride as the sesquihydrate, m.p. 256-260 (dec.).
~2~876~' .
Anal. Calcd. for C20H2lcl2N3o3s-Hcl-l-5H2o C~ 46-39;
H, 4.87; N, 8.11; H20, 5.22. Found: C, 46.76; H, 4.68; N, 8.26;
H20. 5.74.
NMR (DMSO-d6): 1.90 (2H,m); 2.30 ~2H,m); 3.28 (4H,m); 3.33 ~2H,b3); 4.30 (2H,s); 4.38 (lH,m); 4.50 (2H,s); 7.50 (2H,m); 7.71 (2H,m); 7.76 (2~,bs); 7.94 (lH,s~; 8.19 (lH,s).
2-[1-~(4-Bromophenyl)methyl~-4-piperidinyl]-6-chloro-2 3-dihydro-3-oxo-lH-isoindole-5-sulfonamide Hydrochloride .
~2~5~XN{)~ ~19r HCl (a) 2-[1-[(4-Bromophenyl)methyl]-4-piperldinyl]-6-chloro-2,3-dihydro-1?3-dioxo-lH-isoindole-5-sulfonamide.- Reaction of a mixture of 4-chloro-5-sulfamoylphthalimide (6.48 g., 0.025 ~ole) and 4-amino-1-(4-bromobenzyl)piperidine (6.7 g., 0.025 mole) in n-pentanol according to the procedure of Example l(a) afforded the 1,3-dioxoisoindole product. Purification of the crude product by triturating with n-heptane and crystallization from DMF-methanol afforded 6.9 g.
(54~) of 2-rl-[(4-bromophenyl)methyl]-4-piperidinyl~-6-chloro-2,3-dihydro-1,3-dioxo-lH-isoindole-5-sulfonamide, m.p. 246-247 (dec.).
Anal. Calcd. for C20H19BrClN304S: C, 46-84; H, 3-74; N, 8.19.
Found: C, 46.99; H, 3.74; N, 8.31.
(b) Title Product.- Reduction of the above part (a) 1,3-dioxoisoindole (6.15 g., 0.012 mole) with zinc in acetic acid according to method of Example l(c) and conversion of the free base to the hydrochloride salt in met~anol and crystallization from DMF-isopropanol afforded 2.08 g., (32%) of analytically pure hydrated 2-[1-[(4-bromophenyl)~ethyl]-4-piperitinylJ-6-chloro-2,3-dihydro-3-oxo-lH-isoindole-S-sulfonamide hydrochloride, m.p. 215-227.
Anal. Calcd. for C2 ~ 213rClN303~-HCl-0.5 ~2 C, 44-13;
H, 4.26; N, 7.72; H20, 1.65. Found: C, 44.23; H, 4,~a; N, 7.86;
H20, 2.29.
NMR (DMS0-d6): 1.90 (2H,m); 2.30 (2U,m); 2.24 (4H,m); 3.36 (2H,bs); 4.29 (2H,s); 4.35 (lH,m); 4.50 (2H,s); 7.64 (4H,s); 7.75 (2H,bs); 7.94 (lH,s); 8.20 (lH,s); 11.45 (lH,bs).
- EX~MPLE 4 6-Chloro-2-~1-[(4-fluorophenyl)methyl]-4-piperidinyl]-2,3-dihydro-3-oxo-lH-isoindole-5-sulfonamide Hydrochloride Cl~_o 2~3 F
HCl (a) 6-Chloro-2-[1-[(4-fluorophenyl)methylJ-4-piperidinyl~-15 2,3-dihydro-1,3-dioxo-lH-isoindole-5-sulfonamide.- Reaction of 4-chloro-5-sulfamoylphthalimide (8.86 g., 0.034 mole) and 4-amino-1-[(4-fluorophenyl)methyl]piperidine (7.1 g., 0.034 mole) in 300 ml. of n-pentanol according to the proceture of Example l(a) afforded 10 g.
(65%) of the 1,3-dioxoisoindole product, m.p. 240-242 (dec.). A
sample crystallized from dimethylformamide-methanol-water provided analytically pure 6-chloro-2-[1-[(4-fluorophenyl)methyl]-4-piperidinyl]-2,3-dihydro-1,3-dioxD-lU-isoindole-5-sulfona~lde, m.p. 245-246 (dec.).
Anal. Calcd. for C20HlgClFN304S: C, 53.20; H, 4.24;
N, 9.30. Found: C, 53.23; H, 4.22; N, 9.39.
(b) Title Product.- Reduc~ion of the above product ~a) 1,3-dioxoisoindole (9.5 g.~ 0.~21 mole) ~th zinc in acetic acid according to the procedure of Example l(c), converslon of the free base of the hydrochloride salt and crystallizstion from methanol-water provided 1.5 g. (15%) of analytically pure hydrated 6-chloro-2-~ (4-fluorophenyl)methyl]-4-piperidinyl]-2,3-dihydro-3-oxo-lH-isoindole-5-sulfonamide hydrochloride, m.p. 285-287 (dec.).
Anal. Calcd. for C20H21ClFN303S.HCl-0.8H2o; C, 49.15;
H, 4.87; ~, 8.60; H20, 2.95. Found: C, 49.38; H, 4.74; N, 8.50;
H20- 3.36.
MMR (DMS0-d6): 1.92 (2H,m); 2.30 (2H,m); 3.25 (4H,m); 3.32 (2H,bs); 4.30 (2H,s); 4.36 (lH,m); 4.50 (2H,s); 7.27 (2H,t, 9.0 Hz);
7.76 (4H,m); 7.95 (lH,s); 8.19 (lH,s); 11.45 (lH,bs).
6-Chloro-2-[1-[(2-chlorophenyl)methyl]-4-piperidinyl]-2,3-dihydro-3-oxo-lH-isoindole-5-sulfonamide Hydrochloride 50~N {3CH2~
(a) 6-Chloro-2-[1-[(2-chlorophenyl)methyl]-4-piperidinyl~-2,3-dihydro-1,3-dioxo-lH-isoindole-5-sulfonamideO- Reaction of 4-chloro-5-sulfamoylphthalimide (8.3 g., 0.0316 mole) and 4-amino-1-(2-chloeophenyl)methyl piperidine (7.1 g., 0.0316 mole) in n-pentanol i2687~i7 according to the proce~ure of Example l~a) afforded 12.2 g. (82%) of the 1,3-dioxoisoindole product, m.p. 278-279 (dec.). Crystallization of a sample from DMF-methanol provided analytically p~e 6-chlDro-2-[1-[(2-chlorophenyl)methyl]-4-piperidinyl]-2,3-1,3-dioxo-lH-~soindole-5-sulfonamite.
Anal. Calcd. for C20HlgC12N304S C, 51.29; H, 4.09;
N, 8.97. Found: C, 51.30; H, 4.28; N, 9.20.
(b) Title Product.- Reduction of the above part (a) 1,3-dioxoisoindole (10 g., 0.021 mole) with zinc in acetic acid according to the method of Example l(c), conversion of the free base to the hydrochloride salt and crystallization from methanol-water afforded 1.5 g., (14%) of analytically pure hydrated 6-chloro-2-[1-[(2-chlorophenyl)methyl]-4-piperidinyl]-2,3-dihydro-3-oxo-lH-isoindole-5-sulfonamide hydrochloride, m.p. 272-274 (dec.).
Anal- Calcd- for C20H21C12N33S HCl ~H20: ~
H, 4.64; N, 8.41; H20, 1.80. Found: C, 48.00; H, 4.59; N, 8.39;
H20, 2.25.
NMR (DMS0-d6): 1.92 (2H,m); 2.35 (2H,m); 3.39 (5H,m);
4.50 (5H,m); 7.50 (3H,m); 7.75 (2H,bs); 7.94 (lH,s); 8.04 (lH,m);
8.19 (lH,s); 11.50 (lH,bs).
~ 23 -~268767 6-Chloro-2,3-dihydro-2-[1- r (4-methylphenyl)-methyl]-4-plperidinyl]-3-oxo-lH-isoindole-5-sulfonamide Hydrochloride Cl ~ N ~ NCH2 ~ CH3 SQ2~2 HCl 5 (a) 6-Chloro-2,3-dihydro-2-[1-E(4-methylphenyl)methyl]-4-piperidinyl]l,3-dioxo-lH-isoindole-5-sulfonamide.- Reaction of 4-chloro-5-sulfanoylphthalimide (7.8 g., 0.03 mole) and 4-amino-1-(4-methylbenzyl)piperidine (6.1 g., 0.03 mole) in 200 ml. of n-pentanol according to the procedure of Example l(a) afforded 8 g. (60~'.) of 10 product as a cream solid, m.p. 233-235 (dec.). Crystallization of a sample from DMF-methanol provided analytically pure 6-chloro-2,3-dihydro-2-[1-[(4-methylphenyl)methyl]-4-piperidinyl]-1,3-dioxo-lH-isoindole-5-sulfonamide, m.p. 238-240 (dec.).
Anal- Calcd- for C21H22ClN34S C, 56-31; H~ 4.95; N~ 9-38-15 Found: C, 56.15; H, 5.03; N, 9.15.
(b) Title Product.- Reduction of the above part (a) 1,3-dioxoisoindole (6.8 g., 0.0152 mole) with granulated tin and purification with H2S/dilute hydrochloric acit according to the procedure of Example l(b) with crystallization of the product from 20 50X methanol containing a trace of HCl afforded 1.3 g. (18%) of 6-chloro-2,3-dihydro-2-[1-r(4-methylphenyl)methyl]-4-piperidinyl]-3-oxo-lH-isoindole-S-sulfonamide hydrochloride as the monohydrate, m.p.
265-267.
~%68767 Anal. Calcd- for C21H24ClN303S-HCl-H20 C, 51-64; H~ 5-57;
N, 8.60; H20, 3.69. Found: C, 51.94; H, 5.36; N, 8.62; H20, 3.76.
NMR (DMSO-d6): 1.92 (2H,m); 2.32 (5H,m); 3.26 ~4~,m~; 3.33 (2H,bs); 4.23 (2H,s); 4.35 (lH,m); 4.50 (2H,s); 7,23 (2H,m); 7.55 (2H,m);
5 7.75 (2H,bs); 7.94 ~l~,s); 8.20 ~l~,s); 11.35 (lH,bs~.
6-Chloro-2,3-dihydro-2-11-[(2-methylphenyl)-methyl]-4-piperidinyl]-3-oxo-lH-isoindole-5-sulfonamide ~ydrochloride ':
~2 H U
10 (a) 6-Chloro-2,3-dihydro-2-11-[(2-methylphenyl)methyl]-4-.
Riperidinyl]-1,3-dioxo-lH-isoindole-5-sulfonamide.- A mixture of 4-chloro-5-sulfamoylphthalimide (5.74 g., 0.022 mole) and 4-amino-1-[(2-methylphenyl)methyl]piperidine (4.5 g., 0.022 mole) in 85 ml. of n-pentanol was reacted according to the procedure of Example l(a).
Addition of n-heptane to the reaction mixture afforded 7.9 g. (80%) of the 1,3-dioxoisoindole product, m.p. 238-243. Crystallization of this material from DMF-methanol provided analytically pure 6-chloro-2,3-dihydro-2-[1-[(2-methylphenyl)methyl]-4-piperidinyl]-1,3-dioxo-lH-isoindole-5-sulfonamide, m.p. 244-245 (dec.).
Anal- Calcd- for C21H22ClN304S C, 56-31; H~ 4.95; N~ 9-38-Found: C, 56.49; H, 5.08; N, 9.39.
(b) Title Product.- Reduction of the above part (a) 1,3-dioxoisoindole (5.0 g., 0.011 mole) with zinc in acetlc acid l.Z6876~
according to the method of Example l~c), conversion of the free base to the hydrochloride sale ln methanol and crystallization from DMF-lsopropanol afforded 1.8 g., (34%) of analytically pure 6-chloro-2,3-dihydro-2-~1-[(2-methylphenyl)me~hyl~-4-piperidinyll-3-o~o-~-isolndole-5-sulfonamide hytrochloride as the monohydrate, m.p. 280-284.
Anal Calcd for C H24ClN3O3s.~cl.H2o C, 51,64; ~, s.57;
N, 8.60; H2O, 3.69. Found: C, 51.45; H, 5.~9; N, 8.68; H20, 2.27.
NMR (DMSO-d6): 1.90 ~2H,m); 2.48 (5H,m); 3.39 (5H,m); 4.30 (2H,s); 4.35 (lH,m); 4.50 (2H,s); 7.29 (3H,m); 7.80 (3H,m) 7.92 (lH,s);
8.20 (lH,s); 11.15 (lH,bs).
6-Chloro-2,3-dihydro-2-[1-~(4-methoxyphenyl)methyl]-4-~iperidinvll-3-oxo-lH-isoindole-5-sulfonamide , C~3~C3~oc33 (a) 6-Chloro-2,3-dihydro-2-[1-[(4-methoxyphenyl)methyl~-4-pile_ridinyl]-1,3-dioxo-lH-isoindole-5-sulfonamide.- Reaction of 4-chloro-5-sulfamoylphthalimide (5.21 g., 0.02 le) and 4-amino-1-(4-methoxybenzyl)piperidine (4.5 g., 0.02 mole) in 80 ml. of n-pentanol according to the procedure of Example l(a) afforded the crude 1,3-dioxoisoindole product purified by chromatography (silica 20 gel, ethyl acetate-n-hexane) to yield 2.88 g. (31~) of S-chloro-2,3-dihydro-2-[1-[(4-methoxyphenyl)methyl]-4-piperidinyl]-1,3-dioxo-lH-isoindole-5-sulfonamide. The NMR spectral data was consistent for the compound used without further purification below.
~L268767 (b) Title Product.- Reduction of the above part (a) 1,3-dioxoisoindole (2.88 g., 0.0062 mole) with zinc an~ scetic acid according to the method of Example l(c) and purifica~ion of the product as the free base from ethyl acetate afforded 1.37 g. (48%) of hydrated 6-chloro-2,3-dihydro-2-[1-[(4-methoxyphenyl)methy~ -4-plperidinyl~-3-oxo-lH-isoindole-5-sulfonamide, m.p. 207-210.
Anal- Calcd- for C2lH24clN3o4s-o.8 H2O: C, 54.31; H, 5.56;
N, 9.04; H2O, 3.10. Found: C, 54.19; H, 5.26; N, 8.77; H2O, 2.34.
NMR (D~SO-d6): 1.82 (4H,m); 2.10 (2H,m); 2.95 (2H,m);
3.48 (2H,s); 3.79 (3H,s); 4.05 (lH,m); 4.60 (2H,s); 6.94 ~2H,m);
7.28 (2H,m); 7.82 (2H,bs); 7.94 tlH,s); 8.26 (lH,s).
6-Chloro-2,3-dihydro-2-[1-[2-(4-methoxyphenyl)-ethyl]-4-piperidinyl]-3-oxo-lH-isoindole-5-sulfonamide 5 ~ ~CN2CN2 ~ - OCN3 (a) 4-Chloro-5-(sulfamoyl)-1,2-benzenedicaboxami~e.-A solution of 4-chloro-S-sulfamoylphthalimide ~21.3 g., 0.076 mole) and 250 ml. of liquid ammonia was stirred at room temperature while permitting ammonia to evaporate. Water was added to residual material, the pH ad~usted to 7 with hydrochloric acid and precipitated material collectet to provide 14.5 g. (63Z) of hydrated 4-chloro-5-(sulfamoyl)-1,2-benzenedicarboxamide, m.p. 270-275C.
Anal. Calcd. for C8H8ClN3O4S-1 lt3 H2O: C, 31-85; H, 3-51;
N, 13.93. Found: C, 31.73; H, 3.26; N, 14.15.
~68767 (b) A ~ixture o~ 4-chloro-5-(sulfamoyl)-1,2-benzene-dicarboxamite (5.0 g., 0.018 mole) and 4-amino-1-[4-(4-methoxyphenyl)-ethyl]piperitine (4.22 g., O.Olô ~ole) in 50 ml. of n-pentanol was refluxed for a 24 hr. period, cooled and flltered. The filter cake, washed with methanol and then ether, provided 6-chloro-2,3-dihydro-2-[1-[2-(4-methoxyphenyl)ethyl]-4-piperidiny]]-1,3-dioxo~lH-Iso~ndole-5-sulfonamide, 6.7 g., (78%), m.p. 195-202 used without further purification below.
(c) Title Product.- Reduction of the above part (b) 1,3-dioxoisoindole with tin according to the method of Example l(b) sffordet the title product. Purification was carriet out by first treating the crude product with tetramethylenediamine in methanol, then dissolving the product in lN sodium hydroxide and precipitation with carbon dioxide to provide 6-chloro-2,3-dihydro-2-[1-[2-(4-meehoxy-phenyl)ethyl]-4-piperidinyl]-3-oxo-lH-isoindole-5-sulfonamide as the dihydrate, m.p. 125-135.
Anal- Calcd. for C22H26ClN304S.2H20: C, 52085; H, 6.05;
N, 8.40; H20, 7.21. Found: C, 52.90; H, 5.52; N, 8.44; H20, 2.96.
NMR ~DMSO-t6): 1.75 (2H,m); 2.08 (2H,m); 2.59 (2H,m);
3.01 (2H,m); 3.35 (lH,m); 3.70 (3H,s); 4.51 (2H,s); 6.80 (2H,m);
7.11 (2H,m); 7.55 (2H,bs); 7.88 (lH,s); 8.19 (lH,s).
~268~
6-Chloro-2,3-dihydro-3-oxo-2-[1-[[4-(2-propenyloxy)phenylh~ethyl]-4-piperidinyl]-lH
isoindole-5-sulfonamide Hydrochloride 502~OCH2~OCH2CI3=CH2 HCl (a) 6-Chloro-2~3-dihydro-1~3-dioxo-2-[1-[[4-(2-propenyloxy) phenyl]methyl]-4-piperidinyl]-lH-isoindole-5-sulfonamide.- Reaction of 4-chloro-5-sulfamoylphthalimide ~4.54 g., 0.0174 le) and 4-a~ino-1-[4-(2-propenyloxy)benzyl]piperidine (4.29 g., 0.0174 le) in 100 ml.
of n-pentanol at reflux temperature for 24 hrs. according to the procedure of Example l(a) afforded crude 1,3-dioxoisoindole product.
Purification was carried out by treating with methanol-decolorizing charcoal followed by trituration with ether to afford 4.8 g. (57%) of the 1,3-dioxoisoindole used without further purification below.
(b) Title Product.- Reduction of the abo~e part (a) 1,3-15 dioxoisoindole (1.0 g., 0.002 mole) with zinc in acetic acid according to the method of Example l(c) and conversion of the free base to the hydrochloride salt afforded 6-chloro-2,3-dihydro-3-oxo-2-[1-[[4-(2-propenyloxy)phenyl]methyl]-4-piperidinyl]-lH-isoindole-5-sulfonamide hydrochloride as the dihydrate from methanol, m.p. 177-180.
Anal Calcd- for C23H26ClN34S-HC1 2H2 N, 7.66; H2O, 6.57. Found: C, 50.32; H, 5.43; N, 7.80; H20, 6.42.
NMR (DMSO-d6): 1.95 (2H,m); 2.30 (2~,m); 3.31 (8H,m); 4.20 (3H,m); 4.55 (4H,m); 5.31 (2H,m); 6.01 (lH,m); 7.00 (2H,m); 7.55 (2H,m);
7.75 (2H,bs); 7.93 (lH,s); 8.19 (lH,s).
~26876'.' EXA~PLE 11 6-Chloro-2,3-dihydro-3-oxo-2-[1-[[3-trifluoromethyl)phenyl]methyl]-4-piperidinyl]
_lH-isoindole-5-sulfonamide Hydrochloride S"2~ {)ICH2~
~Cl (a) 6-Chloro-2,3-dihydro-1,3-dioxo-2-[1-[[3-(trifluoromethy .
phenyl]methyl]-4-piperidinyl]-lH-isoindole-5-sulfonamide.- Reaction of 4-chloro-5-sulfamoylphthalimide (10.1 g., 0.0386 mole) and 4-amino-1-~3-trifluoromethylbenzyl)piperidine (10.0 g., 0.0386 mole) in 200 ml. of n-pentanol according to the procedure of Example lta) afforded the crude 1,3-dloxoisoindole product purified by chromatography to yield 8.1 g. (42% yield) of 6-chloro-2,3-dihydro-1,3-dioxo-2-ll-1~3-(trifluoromethyl)phenyl]methyl]-4-piperidinyl]-lH-isoindole-5-sulfonamide. The NMR spectral data was consistent for the compound used without further purification below.
(b) 6-Chloro-2?3-dihydro-1-hydroxy-3-oxo-2-[1-[[3-(trifluoromethyl)phenyl]methyl]-4-piperidinyl]-lH-isoindole-5-sulfonamide.- A mixture of the 1,3-dioxoisoindole of part (a), (8.1 g., 0.0161 mole), zinc dust (5.78 g., 0.088 mole) and 150 ml. of acetic acid was stirred for 0.5 hr. at 50-70, cooled. Residual material, obtained by concentration of the filtrate in vacuo, was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution and the aqueous layer re-extracted with ethyl acetate.
Combined extracts were w&shed with saturated sodium bicarbonate, dried (MgS04) and concentrated in vacuo. Trituration of the residue 126876'7 with ethyl acetate provided 6-chloro-2,3-dihydro-1-hydroxy-3-oxo-2-[1-[[3-(trifluoromethyl)phenyl~neehyl~-4-plperidinyl~-lH-isoindole 5-sulfonamide as a white solid, m.p. 204-205.
Anal. Calcd. for C21H21ClF3N304S C, 50.05; H, 4.20;
N, 8.34. Found: C, 49.67; H, 4.10; N, 8.27.
NMR (DMSO-d6): 1.80 (2H,m); 2.11 (4H,m); 2.91 (2H,m); 3.60 (2H,s); 3.85 (lH,m); 6.02 (lH,d, 8.4 Hz); 6.78 (lH,d, 8.4 Hz); 7.60 (4H,m); 7.80 (3H,m); 8.16 (lH,s).
(c) Title Product.- Reduction of the part (b) l-hydroxy compound (3.15 g., 0.0062 mole) with zinc dust (2.24 g., 0.0344 mole) in 60 ml. of acetic acid according to the method of Example l(c) provided 2.84 g. of the free base. Conversion of the free base to the hydrochloride salt afforded 2.0 g. (59%) of analytically pure 6-chloro-2,3-dihydro-3-oxo-2-[1-[[3-ttrifluoromethyl)phenyl]methyl]-4-piperid~nyl]-lH-isoindole-5-sulfonamide as the sesquihydrate, m.p.
288-289.
Anal. Calcd. for C21H21ClF3N303S-HC1-1.5H20: C, 45-74;
H, 4.57; N, 7.62; H20, 4.90. Found: C, 45.34; H, 4.21; N, 7.44;
H20, 4.51.
NMR (DMS0-d6): 2.00 (2H,m); 2.30 (2H,m); 3.39 (4H,m);
~ 3.52 (2H,bs); 4.42 (3H,m); 4.51 (2H,s); 7.75 (4H,m); 8.01 (3H,m);
8.19 (lH,s); 11.60 (lH,bs).
6-Chloro-2,3-dihydro-1-hydroxy-3-oxo-2-[1-(phenylmethyl?-4-piperidinyl~-lH-isointole-5-sulfonamide C~
A mixture of 6-chloro-2,3-dihydro-1,3-dioxo-2-[1-(phenyl-methyl)-4-piperitinyl]-lH-isoindole-5-sulfonamide (2.0 g., 4.61 mmole) and zinc dust (1.66 g., 25.4 mmole) $n 60 ml. of glacial acetic acid was stirred at room temperature for 30-45 min. The mixture was - filtered, the filtrate concentrated in vacuo and residual ~aterial diluted with 1:1 ethyl acetate-aqueous sodium bicarbonate. The layers were separated and the aqueous phase extracted with ethyl acetate.
Combined extracts were dried (MgS04) and concentrated to about 15-20 ml.
to afford a suspension of the product which was collected and dried at 80 under vacuum providlng 0.98 g. (48%) of analytically pure 6-chloro-2,3-dihydro-1-hydroxy-3-axo-2-[1-(phenylmethyl)-4-piperidinyl~-lH-isoindole-5-sulfonamide, m.p. 208-210 (dec.).
_ Anal. Cacld- for C20H22ClN304S C, 55-10; H~ 5.09; N~ 9-64-Found: C, 55.15; H, 5.04; N, 9.72.
NMR (DMSO-d6): 1.76 (2H,m); 2.08 (4H,m); 2.90 (2H,m); 3.48 (2H,s); 3.80 (lH,m); 5.99 (lH,s); 6.78 (lH,bs); 7.28 (5H,s); 7.76 (2H,bs);
7.79 (lH,s); 8.13 (lH,s).
~L268~76''~
Preparatlon of 4-A~ino-l-(phenylalkyl)-piperidine Inter~diate~ of FonmuLa rv (a) 1,l-Dimethylethyl ~l-(phenylme~hyl~-4-piperitiny carbamate.- To a coolet mixture of N-tert.-butoxycarbonyl azide ; (0.448 mole) and sodium carbonate (0.91 mole) ln 400 ~1. of ~ater was added 4-amino-1-benzylpiperidi~e (0.426 le) over 5 minutes. The resulting suspension was stlrred at 5-10 for 1 hr., allowed to warm to room temperature and then stirred an additlonal 24 hr. period.
Dilution of the reactlon mlxture with 400 ml. of water, extraction with chloroform (6 x 300 ml.), drying and concentration of the chloroform extracts in vacuo afforded 123 g. (9g~ of the tertiary butyl carbamate (a), m.p. 112-120~.
Reaction of di-tert.-butyl pyrocarbonate (0.44 le) with 4-amino-1-benzylpiperidine (0.4 mole) and sodium carbonate (0.5 mole) in l:l-dioxane-water also provitet the tertiary butyl carbamate (a).
(b) l,l-Dimethylethyl 4-piperidinylcarbamate.- A mixture of l,l-dimethylethyl [l-(phenylmethyl)-4-piperidinyl]carbamate (0.355 mole), 10% palladium-on-carbon (10.0 g.) in 43 ml. of acetic acid and 90 ml. of ethanol was hydrogenated under low pressure at room temperature for a 96 hr. period. The reaction mixture was filtered and concen-trated in vacuo. Residual oil was taken up in chloroform, washed with 20% aqueous sodium carbonate solution and the aqueous phase extracted with additional chloroform. The combined chloroform extracts were tried (MgSO4) and evaporated in vacuo to afford 64.2 g.
(90%) of l,l-dimethylethyl 4-piperidinylcarbamate, m.p. 153-157 .
(c) l,l-Dimethylethyl l-r(4-methoxyphenyl)methyl~-4-piperidinylcarbamate.- A mixture of 4-(chloromethyl)anisole (0.04 121E;8767 mole), l,l-dimethylethyl 4-piperidinylcarbamate (0.04 mole), potassium carbonate (0.08 mole) and potassium iodide (0.05 g.~ ~n 250 ml. of acetonitrile was refluxed for a 16 hr. period. The hot solution was filtered and the filtrate concentrated in vacuo. Purification of the residual material was carried out chromatographically on silica gel using ethyl acetate as the eluant. Removal of the solvent in ~acuo afforted 6.8 g. (53%) of l,l-dimethylethyl 1-t(4-met~oxyphenyl)-methyl]-4-piperitinylcarbamate, m.p. 95-97.
(d) 4-Amino-1-~(4-methoxyphenyl)methyl]piperidine.- A
mixture of l,l-dimethylethyl 1-[(4-methoxyphenyl)methyl]-4-piperidinyl-carbamate (0.02 mole) and trifluoroacetic acid (0.01 mole) in 50 ~1.
of methylene chloride was refluxed for a 3 hr. period. Additional trifluoroacetic acid (0.08 mole) was added and reflux continued for an additional 30 minutes. The crude solution was evaporated in vacuo, residual material dissolved in water and the aqueous phase washed with ether and then made basic with 50~ sodium hydroxide.
Extraction of the basified solution with chloroform, drying of the chloroform extracts, and removal of the solvent afforded 4-amino-1-[(4-methoxyphenyl)methyl]piperidine in nearly quantitative yield.
8y substituting the appropriate phenylalkyl halide for 4-(chloromethyl)anisole in step (c) above, requisite Formula IV
4-amino-1-(phenylalkyl)piperidine intermediates are obtained as illustrated by TABLE 1 below.
126876'7 NzR ~ Rl Example No. y . Rl _ 2 13-2 CH2 4-Cl H
13-3 CH2 4-Br H
13-5 CH2 2-Cl H
13-11 CH2 4-C(CH3)3 H
13-14 CH2 4-n-C4HgS H
13-17 -(CH2)2- 3-Cl . 4-Cl 13-20 -(CH2)2- , H
13-21 CH2 2-C1 4-Cl 126876'7 TABLE 1 - contlnued Example No. Y R~ -2 13-22 bond H
13-23 ~H(CH3) H H
513-24 -tCH2)4- H H
13-25 CH2 3-C1 4-Cl Additlonal Compounds of Formula II
Reaction of the appropriate 4-amino~ phenyl81kyl)-piperidine intermediate of Formula IV and 4-(halogen)-5-sulfamoyl-phthalimide according to the procedure of Exa~ple l(a) provideq the compounds tabulated below.
52 ~ ~ ~ (Il) Example No. X Y Rl R
14-1 Cl CH2 4-C(CH3)3 H
- 6-Chloro-2-[1-[[4-(1,1-dimethylethyl)phenyl]methyl]-4-piperidinyl]-2,3-dihydro-1,3-dioxo-lH-isoindole-5-sulfonamide Hydrochloride Anal. Calcd- for C24H28ClN34S-HCl C, 54-75; H~ 5-55;
N, 7.98. Found: C, 54.90; H, 5.80; N, 7.95.
14-2 Cl CH2 4-N02 H
6-Chloro-2,3-dihydro-2-[1-[(4-nitrophenyl)methyll-4-piperidinyl]-1,3-dioxo-lH-isoindole-5-sulfonamide Anal- Calcd- for C20HlgClN406S C, 50-16; H~ 4.00; N~ 11-70-Found: C, 50.19; H, 3.98; N, 11.74 ~268767 ~ABLE 2 - continued Example No. X Y R R
14-3 Br CH2 H H
14-5 Cl CH2 4-CH3S H
14-6 Cl CH2 4-n-C4HgS H
14-7 Cl CH2 4-CN H
14-8 Cl CH2 3-C1 4-F
14-9 Cl -(~H2)2- 3-C1 4-Cl 14-10 Cl CH2 3-OCH3 4-OCH2CH=CH2 14-11 Cl CH2 3-OCH3 4-F
14-12 Cl ~CH2)2 H H
14-13 Cl CH2 2-C1 4-Cl 14-14 Cl bond H H
14-15 Cl ~CH(CH3) H (m.p. 244-247) H
14-16 Cl ( 2)4 H H
14-17 Cl CH2 3-C1 4-Cl 6-Chloro-2-[1-[(3,4-dichlorophenylmethyl]-4-piperidinyl~-2~3-dihydro-1,3-dioxo-lH-isoindole-5-sulfonamide, m.p. 245-246 (dec.).
Anal- Calcd- for C20H18C13N3O4S: C, 47-77; H, 3-61; N~ 8.36.
Found: C, 47.94; H, 3.76; N, 8.64 126876~
Additional Compounds of Formula III
Retucing the '~1,3-dioxo" compounds of ~ormula II described in the indicated example with zinc in glaclal acetic acid according to the procedure of Example 1~ provide the compounds tabulated below.
TA~LE 3 2 2 ~ 2 Starting Material Example No. Example No. X Y Rl R2 15-1 2 Cl CH2 4-Cl H
15-2 3 Cl CH2 4-Br H
15-3 4 Cl CH2 4-F H
15-4 5 Cl CH2 2-Cl H
15-5 6 Cl CH2 4-CH3 H
15-6 7 Cl CH2 2-CH3 H
15-7 8 Cl CH2 4-OCH3 H
15-8 9 Cl (CH2)2 4 OCH3 H
15-9 10 Cl CH2 4-OCH2CH=CH2 H
15-10 14-1 Cl CH2 4-C(CH3)3 H
15-11 14-2 Cl CH2 4-N02 H
15-12 14-3 Br CH2 H H
15-13 . 14-4 F CH2 H H
15-14 14-5 Cl CH2 4-CH3S H
15-15 14-6 Cl CH2 4-n-C4HgS H
~268767 TABLE 3 - coneinued Starting Material Example No. Example No. X Y ~1 R2 15-16 14-7 Cl CH2 4-CN H
15-17 14-8 Cl CH2 3-C1 4-F
15-18 14-9 Cl -(c~2)2- 3-C1 4-Cl 15-19 14-10 Cl CH2 3-OCH3 2C C 2 15-20 14-11 Cl CH2 3-OCH3 4-F
15-2 14-12 Cl ( 2)2 H H
15-22 14-13 Cl CH2 2-C1 4-Cl 15-23 14-14 Cl bond H H
15-24 14-15 Cl ~CH(CH3) H H
15-25 14-16 Cl (CH2)4 H H
15-26 14-17 Cl CH2 3-C1 4-Cl -15-27 14-18 ~ CF3 CH2 H H
Ea~'~LE 16 Additional Com~ounds of Formula I
-Reduction of appropriate co~pounds of Formula II or III set forth in TABLES 2 and 3, respectively, according to the process of the present invention provides the products tabulated below.
~268~67 TAB~E 4 50~ ~ 1 Example No. X Y R R
16-1 Cl 2 4-C(CH3)3 ~ H
16-2 Cl CH2 4-NO2 H
16-3 Br CH2 H H
16-5 Cl CH2` 4-CH3S H
16-6 Cl CH2 4-n-C4HgS H
16-7 Cl CH2 4-CN H
16-9 C1 -(CH2)2- 3-C1 4-Cl 16-10 Cl CH2 3-OCH3 4-OCH2CH=CH2 16-11 Cl CH2 3-OCH3 4-F
16-12 Cl -tCH2)2- H H
16-13 Cl CH2 2-C1 4-Cl 16-14 Cl bond H H
16-15 Cl ~H(CH3) H H
16-16 Cl -(CH2)4- H H
126876~7 TABLE 4 - continue~
Example ~o. X Y - Rl - 2 ---16-17 Cl CH2 3-C1 4-Cl 6-Chloro-2-~ (3,4-dichlorophenyl)methyl]-4-piperidinyl]-2,3-dihydro-3-oxo-lH-iso~ndole-5-sulfonamlde Hydrochlorite Nydrate Anal. Calcd. for C20H2ocl3N3o3s~Hc~ 75*0 C- 43-14;
H, 4.44; N, 7.55 H20, 5.66. Found: C, 43.37; H, 4.21;
N, 7.80; H2O, 5.56.
NMR (DXSO-d6): 1.97 (2H,m); 2.30 (2H,m); 3.28 (4H,m); 3.33 (4H,bs); 4.32 (3H,m); 4.51 (2H,s); 7.75 (4H,m); 8.00 (2H,m);
8.20 (lH,s); 11.50 (lH,bs).
(e) A sample of free base prepared by zinc-acetic acid reduction dried under reduced pressure/heat provided anhydrous 6-chloro-2,3-dihydro-3-oxo-2-[1-(phenylmethyl)-4-piperidinyl]-lH-isoindole-5-sulfonamide, m.p. 227-229 (dec.).
Anal- Calcd- for C20H22ClN33S C, 57-20; H~ 5-28; N~ 10.01.
Found: C, 56.86; H, 5.26; N, 9.92.
NMR (DMS0-d6): 1.75 (2H,m); 1.98 (4H,m); 2.90 (2H,m); 3.49 (2H,s); 4.00 (lH,m); 4.52 (2H,s); 7.29 (5H,s); 7.73 (2H,bs); 7.86 ~lH,s); 8.20 (lH,s).
Melting point variations may be related to the reduction method with tin-hydrochloric acid generally providing somewhat higher melting points, possibly related to traces of tin generally ranging from 100-200 parts per million.
3.268767 6-Chloro-2-[1-[(4-chlorophenyl)methyl]-4-piperidinyl]-2,3-dihytro-3-oxo-lH-isoindole-5-sulfonamide Hydrochloride N-CH2 ~ Cl HCl (a) 6-Chloro-2-[1-[(4-chlorophenyl)methyl]-4-piperidinyl~-2,3-dihydro-1,3-dioxo-lH-isoindole-5-sulfonam~de.- Reaction of 4-chloro-5-sulfamoylphthalimide (5.57 g., 0.0214 mole) and 4-amino-1-(4-chlorobenzyl)piperidine (4.8 g., 0.0214 mole) in 85 ml. of n-pentanol according to the procedure of Example l(a) with heating at 130-138 for a 48 hr. period afforded 7.07 g. t71%) m.p. 248-250 (dec.) of the 1,3-dioxoisoindole product. A sample crystallized from dimethylformamide-methanol provided analytically pure 6-chloro-2-[1-[(4-chlorophenyl)methyl]-4-piperidinyl]-2~3-dihydro-l~3-dioxo-lH
isoindole-5-sulfonamide, m.p. 250-251 (dec.).
Anal. Calcd. for C20HlgC12N304S C, 51.29; H, 4.09;
- N, 8.97. Found: C, 51.53; H, 4.21; N, 8.87.
(b) TieIe Product.- Reduction of the above product (a) 1,3-dioxoisointole (5.0 g., 0.0107 mole) with zinc and acetic acid according to the method of Example l(c) and conversion of the free base (partially purified by trituration with ethyl acetate) to the hydrochloride salt in methanol afforded 6-chloro-2-[1-[(4-chloro-phenyl)-phenyl)methyl]-4-piperidinyl]-2,3-dihydro-3-oxo-lH-isoindole-5-sulfonamide hydrochloride as the sesquihydrate, m.p. 256-260 (dec.).
~2~876~' .
Anal. Calcd. for C20H2lcl2N3o3s-Hcl-l-5H2o C~ 46-39;
H, 4.87; N, 8.11; H20, 5.22. Found: C, 46.76; H, 4.68; N, 8.26;
H20. 5.74.
NMR (DMSO-d6): 1.90 (2H,m); 2.30 ~2H,m); 3.28 (4H,m); 3.33 ~2H,b3); 4.30 (2H,s); 4.38 (lH,m); 4.50 (2H,s); 7.50 (2H,m); 7.71 (2H,m); 7.76 (2~,bs); 7.94 (lH,s~; 8.19 (lH,s).
2-[1-~(4-Bromophenyl)methyl~-4-piperidinyl]-6-chloro-2 3-dihydro-3-oxo-lH-isoindole-5-sulfonamide Hydrochloride .
~2~5~XN{)~ ~19r HCl (a) 2-[1-[(4-Bromophenyl)methyl]-4-piperldinyl]-6-chloro-2,3-dihydro-1?3-dioxo-lH-isoindole-5-sulfonamide.- Reaction of a mixture of 4-chloro-5-sulfamoylphthalimide (6.48 g., 0.025 ~ole) and 4-amino-1-(4-bromobenzyl)piperidine (6.7 g., 0.025 mole) in n-pentanol according to the procedure of Example l(a) afforded the 1,3-dioxoisoindole product. Purification of the crude product by triturating with n-heptane and crystallization from DMF-methanol afforded 6.9 g.
(54~) of 2-rl-[(4-bromophenyl)methyl]-4-piperidinyl~-6-chloro-2,3-dihydro-1,3-dioxo-lH-isoindole-5-sulfonamide, m.p. 246-247 (dec.).
Anal. Calcd. for C20H19BrClN304S: C, 46-84; H, 3-74; N, 8.19.
Found: C, 46.99; H, 3.74; N, 8.31.
(b) Title Product.- Reduction of the above part (a) 1,3-dioxoisoindole (6.15 g., 0.012 mole) with zinc in acetic acid according to method of Example l(c) and conversion of the free base to the hydrochloride salt in met~anol and crystallization from DMF-isopropanol afforded 2.08 g., (32%) of analytically pure hydrated 2-[1-[(4-bromophenyl)~ethyl]-4-piperitinylJ-6-chloro-2,3-dihydro-3-oxo-lH-isoindole-S-sulfonamide hydrochloride, m.p. 215-227.
Anal. Calcd. for C2 ~ 213rClN303~-HCl-0.5 ~2 C, 44-13;
H, 4.26; N, 7.72; H20, 1.65. Found: C, 44.23; H, 4,~a; N, 7.86;
H20, 2.29.
NMR (DMS0-d6): 1.90 (2H,m); 2.30 (2U,m); 2.24 (4H,m); 3.36 (2H,bs); 4.29 (2H,s); 4.35 (lH,m); 4.50 (2H,s); 7.64 (4H,s); 7.75 (2H,bs); 7.94 (lH,s); 8.20 (lH,s); 11.45 (lH,bs).
- EX~MPLE 4 6-Chloro-2-~1-[(4-fluorophenyl)methyl]-4-piperidinyl]-2,3-dihydro-3-oxo-lH-isoindole-5-sulfonamide Hydrochloride Cl~_o 2~3 F
HCl (a) 6-Chloro-2-[1-[(4-fluorophenyl)methylJ-4-piperidinyl~-15 2,3-dihydro-1,3-dioxo-lH-isoindole-5-sulfonamide.- Reaction of 4-chloro-5-sulfamoylphthalimide (8.86 g., 0.034 mole) and 4-amino-1-[(4-fluorophenyl)methyl]piperidine (7.1 g., 0.034 mole) in 300 ml. of n-pentanol according to the proceture of Example l(a) afforded 10 g.
(65%) of the 1,3-dioxoisoindole product, m.p. 240-242 (dec.). A
sample crystallized from dimethylformamide-methanol-water provided analytically pure 6-chloro-2-[1-[(4-fluorophenyl)methyl]-4-piperidinyl]-2,3-dihydro-1,3-dioxD-lU-isoindole-5-sulfona~lde, m.p. 245-246 (dec.).
Anal. Calcd. for C20HlgClFN304S: C, 53.20; H, 4.24;
N, 9.30. Found: C, 53.23; H, 4.22; N, 9.39.
(b) Title Product.- Reduc~ion of the above product ~a) 1,3-dioxoisoindole (9.5 g.~ 0.~21 mole) ~th zinc in acetic acid according to the procedure of Example l(c), converslon of the free base of the hydrochloride salt and crystallizstion from methanol-water provided 1.5 g. (15%) of analytically pure hydrated 6-chloro-2-~ (4-fluorophenyl)methyl]-4-piperidinyl]-2,3-dihydro-3-oxo-lH-isoindole-5-sulfonamide hydrochloride, m.p. 285-287 (dec.).
Anal. Calcd. for C20H21ClFN303S.HCl-0.8H2o; C, 49.15;
H, 4.87; ~, 8.60; H20, 2.95. Found: C, 49.38; H, 4.74; N, 8.50;
H20- 3.36.
MMR (DMS0-d6): 1.92 (2H,m); 2.30 (2H,m); 3.25 (4H,m); 3.32 (2H,bs); 4.30 (2H,s); 4.36 (lH,m); 4.50 (2H,s); 7.27 (2H,t, 9.0 Hz);
7.76 (4H,m); 7.95 (lH,s); 8.19 (lH,s); 11.45 (lH,bs).
6-Chloro-2-[1-[(2-chlorophenyl)methyl]-4-piperidinyl]-2,3-dihydro-3-oxo-lH-isoindole-5-sulfonamide Hydrochloride 50~N {3CH2~
(a) 6-Chloro-2-[1-[(2-chlorophenyl)methyl]-4-piperidinyl~-2,3-dihydro-1,3-dioxo-lH-isoindole-5-sulfonamideO- Reaction of 4-chloro-5-sulfamoylphthalimide (8.3 g., 0.0316 mole) and 4-amino-1-(2-chloeophenyl)methyl piperidine (7.1 g., 0.0316 mole) in n-pentanol i2687~i7 according to the proce~ure of Example l~a) afforded 12.2 g. (82%) of the 1,3-dioxoisoindole product, m.p. 278-279 (dec.). Crystallization of a sample from DMF-methanol provided analytically p~e 6-chlDro-2-[1-[(2-chlorophenyl)methyl]-4-piperidinyl]-2,3-1,3-dioxo-lH-~soindole-5-sulfonamite.
Anal. Calcd. for C20HlgC12N304S C, 51.29; H, 4.09;
N, 8.97. Found: C, 51.30; H, 4.28; N, 9.20.
(b) Title Product.- Reduction of the above part (a) 1,3-dioxoisoindole (10 g., 0.021 mole) with zinc in acetic acid according to the method of Example l(c), conversion of the free base to the hydrochloride salt and crystallization from methanol-water afforded 1.5 g., (14%) of analytically pure hydrated 6-chloro-2-[1-[(2-chlorophenyl)methyl]-4-piperidinyl]-2,3-dihydro-3-oxo-lH-isoindole-5-sulfonamide hydrochloride, m.p. 272-274 (dec.).
Anal- Calcd- for C20H21C12N33S HCl ~H20: ~
H, 4.64; N, 8.41; H20, 1.80. Found: C, 48.00; H, 4.59; N, 8.39;
H20, 2.25.
NMR (DMS0-d6): 1.92 (2H,m); 2.35 (2H,m); 3.39 (5H,m);
4.50 (5H,m); 7.50 (3H,m); 7.75 (2H,bs); 7.94 (lH,s); 8.04 (lH,m);
8.19 (lH,s); 11.50 (lH,bs).
~ 23 -~268767 6-Chloro-2,3-dihydro-2-[1- r (4-methylphenyl)-methyl]-4-plperidinyl]-3-oxo-lH-isoindole-5-sulfonamide Hydrochloride Cl ~ N ~ NCH2 ~ CH3 SQ2~2 HCl 5 (a) 6-Chloro-2,3-dihydro-2-[1-E(4-methylphenyl)methyl]-4-piperidinyl]l,3-dioxo-lH-isoindole-5-sulfonamide.- Reaction of 4-chloro-5-sulfanoylphthalimide (7.8 g., 0.03 mole) and 4-amino-1-(4-methylbenzyl)piperidine (6.1 g., 0.03 mole) in 200 ml. of n-pentanol according to the procedure of Example l(a) afforded 8 g. (60~'.) of 10 product as a cream solid, m.p. 233-235 (dec.). Crystallization of a sample from DMF-methanol provided analytically pure 6-chloro-2,3-dihydro-2-[1-[(4-methylphenyl)methyl]-4-piperidinyl]-1,3-dioxo-lH-isoindole-5-sulfonamide, m.p. 238-240 (dec.).
Anal- Calcd- for C21H22ClN34S C, 56-31; H~ 4.95; N~ 9-38-15 Found: C, 56.15; H, 5.03; N, 9.15.
(b) Title Product.- Reduction of the above part (a) 1,3-dioxoisoindole (6.8 g., 0.0152 mole) with granulated tin and purification with H2S/dilute hydrochloric acit according to the procedure of Example l(b) with crystallization of the product from 20 50X methanol containing a trace of HCl afforded 1.3 g. (18%) of 6-chloro-2,3-dihydro-2-[1-r(4-methylphenyl)methyl]-4-piperidinyl]-3-oxo-lH-isoindole-S-sulfonamide hydrochloride as the monohydrate, m.p.
265-267.
~%68767 Anal. Calcd- for C21H24ClN303S-HCl-H20 C, 51-64; H~ 5-57;
N, 8.60; H20, 3.69. Found: C, 51.94; H, 5.36; N, 8.62; H20, 3.76.
NMR (DMSO-d6): 1.92 (2H,m); 2.32 (5H,m); 3.26 ~4~,m~; 3.33 (2H,bs); 4.23 (2H,s); 4.35 (lH,m); 4.50 (2H,s); 7,23 (2H,m); 7.55 (2H,m);
5 7.75 (2H,bs); 7.94 ~l~,s); 8.20 ~l~,s); 11.35 (lH,bs~.
6-Chloro-2,3-dihydro-2-11-[(2-methylphenyl)-methyl]-4-piperidinyl]-3-oxo-lH-isoindole-5-sulfonamide ~ydrochloride ':
~2 H U
10 (a) 6-Chloro-2,3-dihydro-2-11-[(2-methylphenyl)methyl]-4-.
Riperidinyl]-1,3-dioxo-lH-isoindole-5-sulfonamide.- A mixture of 4-chloro-5-sulfamoylphthalimide (5.74 g., 0.022 mole) and 4-amino-1-[(2-methylphenyl)methyl]piperidine (4.5 g., 0.022 mole) in 85 ml. of n-pentanol was reacted according to the procedure of Example l(a).
Addition of n-heptane to the reaction mixture afforded 7.9 g. (80%) of the 1,3-dioxoisoindole product, m.p. 238-243. Crystallization of this material from DMF-methanol provided analytically pure 6-chloro-2,3-dihydro-2-[1-[(2-methylphenyl)methyl]-4-piperidinyl]-1,3-dioxo-lH-isoindole-5-sulfonamide, m.p. 244-245 (dec.).
Anal- Calcd- for C21H22ClN304S C, 56-31; H~ 4.95; N~ 9-38-Found: C, 56.49; H, 5.08; N, 9.39.
(b) Title Product.- Reduction of the above part (a) 1,3-dioxoisoindole (5.0 g., 0.011 mole) with zinc in acetlc acid l.Z6876~
according to the method of Example l~c), conversion of the free base to the hydrochloride sale ln methanol and crystallization from DMF-lsopropanol afforded 1.8 g., (34%) of analytically pure 6-chloro-2,3-dihydro-2-~1-[(2-methylphenyl)me~hyl~-4-piperidinyll-3-o~o-~-isolndole-5-sulfonamide hytrochloride as the monohydrate, m.p. 280-284.
Anal Calcd for C H24ClN3O3s.~cl.H2o C, 51,64; ~, s.57;
N, 8.60; H2O, 3.69. Found: C, 51.45; H, 5.~9; N, 8.68; H20, 2.27.
NMR (DMSO-d6): 1.90 ~2H,m); 2.48 (5H,m); 3.39 (5H,m); 4.30 (2H,s); 4.35 (lH,m); 4.50 (2H,s); 7.29 (3H,m); 7.80 (3H,m) 7.92 (lH,s);
8.20 (lH,s); 11.15 (lH,bs).
6-Chloro-2,3-dihydro-2-[1-~(4-methoxyphenyl)methyl]-4-~iperidinvll-3-oxo-lH-isoindole-5-sulfonamide , C~3~C3~oc33 (a) 6-Chloro-2,3-dihydro-2-[1-[(4-methoxyphenyl)methyl~-4-pile_ridinyl]-1,3-dioxo-lH-isoindole-5-sulfonamide.- Reaction of 4-chloro-5-sulfamoylphthalimide (5.21 g., 0.02 le) and 4-amino-1-(4-methoxybenzyl)piperidine (4.5 g., 0.02 mole) in 80 ml. of n-pentanol according to the procedure of Example l(a) afforded the crude 1,3-dioxoisoindole product purified by chromatography (silica 20 gel, ethyl acetate-n-hexane) to yield 2.88 g. (31~) of S-chloro-2,3-dihydro-2-[1-[(4-methoxyphenyl)methyl]-4-piperidinyl]-1,3-dioxo-lH-isoindole-5-sulfonamide. The NMR spectral data was consistent for the compound used without further purification below.
~L268767 (b) Title Product.- Reduction of the above part (a) 1,3-dioxoisoindole (2.88 g., 0.0062 mole) with zinc an~ scetic acid according to the method of Example l(c) and purifica~ion of the product as the free base from ethyl acetate afforded 1.37 g. (48%) of hydrated 6-chloro-2,3-dihydro-2-[1-[(4-methoxyphenyl)methy~ -4-plperidinyl~-3-oxo-lH-isoindole-5-sulfonamide, m.p. 207-210.
Anal- Calcd- for C2lH24clN3o4s-o.8 H2O: C, 54.31; H, 5.56;
N, 9.04; H2O, 3.10. Found: C, 54.19; H, 5.26; N, 8.77; H2O, 2.34.
NMR (D~SO-d6): 1.82 (4H,m); 2.10 (2H,m); 2.95 (2H,m);
3.48 (2H,s); 3.79 (3H,s); 4.05 (lH,m); 4.60 (2H,s); 6.94 ~2H,m);
7.28 (2H,m); 7.82 (2H,bs); 7.94 tlH,s); 8.26 (lH,s).
6-Chloro-2,3-dihydro-2-[1-[2-(4-methoxyphenyl)-ethyl]-4-piperidinyl]-3-oxo-lH-isoindole-5-sulfonamide 5 ~ ~CN2CN2 ~ - OCN3 (a) 4-Chloro-5-(sulfamoyl)-1,2-benzenedicaboxami~e.-A solution of 4-chloro-S-sulfamoylphthalimide ~21.3 g., 0.076 mole) and 250 ml. of liquid ammonia was stirred at room temperature while permitting ammonia to evaporate. Water was added to residual material, the pH ad~usted to 7 with hydrochloric acid and precipitated material collectet to provide 14.5 g. (63Z) of hydrated 4-chloro-5-(sulfamoyl)-1,2-benzenedicarboxamide, m.p. 270-275C.
Anal. Calcd. for C8H8ClN3O4S-1 lt3 H2O: C, 31-85; H, 3-51;
N, 13.93. Found: C, 31.73; H, 3.26; N, 14.15.
~68767 (b) A ~ixture o~ 4-chloro-5-(sulfamoyl)-1,2-benzene-dicarboxamite (5.0 g., 0.018 mole) and 4-amino-1-[4-(4-methoxyphenyl)-ethyl]piperitine (4.22 g., O.Olô ~ole) in 50 ml. of n-pentanol was refluxed for a 24 hr. period, cooled and flltered. The filter cake, washed with methanol and then ether, provided 6-chloro-2,3-dihydro-2-[1-[2-(4-methoxyphenyl)ethyl]-4-piperidiny]]-1,3-dioxo~lH-Iso~ndole-5-sulfonamide, 6.7 g., (78%), m.p. 195-202 used without further purification below.
(c) Title Product.- Reduction of the above part (b) 1,3-dioxoisoindole with tin according to the method of Example l(b) sffordet the title product. Purification was carriet out by first treating the crude product with tetramethylenediamine in methanol, then dissolving the product in lN sodium hydroxide and precipitation with carbon dioxide to provide 6-chloro-2,3-dihydro-2-[1-[2-(4-meehoxy-phenyl)ethyl]-4-piperidinyl]-3-oxo-lH-isoindole-5-sulfonamide as the dihydrate, m.p. 125-135.
Anal- Calcd. for C22H26ClN304S.2H20: C, 52085; H, 6.05;
N, 8.40; H20, 7.21. Found: C, 52.90; H, 5.52; N, 8.44; H20, 2.96.
NMR ~DMSO-t6): 1.75 (2H,m); 2.08 (2H,m); 2.59 (2H,m);
3.01 (2H,m); 3.35 (lH,m); 3.70 (3H,s); 4.51 (2H,s); 6.80 (2H,m);
7.11 (2H,m); 7.55 (2H,bs); 7.88 (lH,s); 8.19 (lH,s).
~268~
6-Chloro-2,3-dihydro-3-oxo-2-[1-[[4-(2-propenyloxy)phenylh~ethyl]-4-piperidinyl]-lH
isoindole-5-sulfonamide Hydrochloride 502~OCH2~OCH2CI3=CH2 HCl (a) 6-Chloro-2~3-dihydro-1~3-dioxo-2-[1-[[4-(2-propenyloxy) phenyl]methyl]-4-piperidinyl]-lH-isoindole-5-sulfonamide.- Reaction of 4-chloro-5-sulfamoylphthalimide ~4.54 g., 0.0174 le) and 4-a~ino-1-[4-(2-propenyloxy)benzyl]piperidine (4.29 g., 0.0174 le) in 100 ml.
of n-pentanol at reflux temperature for 24 hrs. according to the procedure of Example l(a) afforded crude 1,3-dioxoisoindole product.
Purification was carried out by treating with methanol-decolorizing charcoal followed by trituration with ether to afford 4.8 g. (57%) of the 1,3-dioxoisoindole used without further purification below.
(b) Title Product.- Reduction of the abo~e part (a) 1,3-15 dioxoisoindole (1.0 g., 0.002 mole) with zinc in acetic acid according to the method of Example l(c) and conversion of the free base to the hydrochloride salt afforded 6-chloro-2,3-dihydro-3-oxo-2-[1-[[4-(2-propenyloxy)phenyl]methyl]-4-piperidinyl]-lH-isoindole-5-sulfonamide hydrochloride as the dihydrate from methanol, m.p. 177-180.
Anal Calcd- for C23H26ClN34S-HC1 2H2 N, 7.66; H2O, 6.57. Found: C, 50.32; H, 5.43; N, 7.80; H20, 6.42.
NMR (DMSO-d6): 1.95 (2H,m); 2.30 (2~,m); 3.31 (8H,m); 4.20 (3H,m); 4.55 (4H,m); 5.31 (2H,m); 6.01 (lH,m); 7.00 (2H,m); 7.55 (2H,m);
7.75 (2H,bs); 7.93 (lH,s); 8.19 (lH,s).
~26876'.' EXA~PLE 11 6-Chloro-2,3-dihydro-3-oxo-2-[1-[[3-trifluoromethyl)phenyl]methyl]-4-piperidinyl]
_lH-isoindole-5-sulfonamide Hydrochloride S"2~ {)ICH2~
~Cl (a) 6-Chloro-2,3-dihydro-1,3-dioxo-2-[1-[[3-(trifluoromethy .
phenyl]methyl]-4-piperidinyl]-lH-isoindole-5-sulfonamide.- Reaction of 4-chloro-5-sulfamoylphthalimide (10.1 g., 0.0386 mole) and 4-amino-1-~3-trifluoromethylbenzyl)piperidine (10.0 g., 0.0386 mole) in 200 ml. of n-pentanol according to the procedure of Example lta) afforded the crude 1,3-dloxoisoindole product purified by chromatography to yield 8.1 g. (42% yield) of 6-chloro-2,3-dihydro-1,3-dioxo-2-ll-1~3-(trifluoromethyl)phenyl]methyl]-4-piperidinyl]-lH-isoindole-5-sulfonamide. The NMR spectral data was consistent for the compound used without further purification below.
(b) 6-Chloro-2?3-dihydro-1-hydroxy-3-oxo-2-[1-[[3-(trifluoromethyl)phenyl]methyl]-4-piperidinyl]-lH-isoindole-5-sulfonamide.- A mixture of the 1,3-dioxoisoindole of part (a), (8.1 g., 0.0161 mole), zinc dust (5.78 g., 0.088 mole) and 150 ml. of acetic acid was stirred for 0.5 hr. at 50-70, cooled. Residual material, obtained by concentration of the filtrate in vacuo, was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution and the aqueous layer re-extracted with ethyl acetate.
Combined extracts were w&shed with saturated sodium bicarbonate, dried (MgS04) and concentrated in vacuo. Trituration of the residue 126876'7 with ethyl acetate provided 6-chloro-2,3-dihydro-1-hydroxy-3-oxo-2-[1-[[3-(trifluoromethyl)phenyl~neehyl~-4-plperidinyl~-lH-isoindole 5-sulfonamide as a white solid, m.p. 204-205.
Anal. Calcd. for C21H21ClF3N304S C, 50.05; H, 4.20;
N, 8.34. Found: C, 49.67; H, 4.10; N, 8.27.
NMR (DMSO-d6): 1.80 (2H,m); 2.11 (4H,m); 2.91 (2H,m); 3.60 (2H,s); 3.85 (lH,m); 6.02 (lH,d, 8.4 Hz); 6.78 (lH,d, 8.4 Hz); 7.60 (4H,m); 7.80 (3H,m); 8.16 (lH,s).
(c) Title Product.- Reduction of the part (b) l-hydroxy compound (3.15 g., 0.0062 mole) with zinc dust (2.24 g., 0.0344 mole) in 60 ml. of acetic acid according to the method of Example l(c) provided 2.84 g. of the free base. Conversion of the free base to the hydrochloride salt afforded 2.0 g. (59%) of analytically pure 6-chloro-2,3-dihydro-3-oxo-2-[1-[[3-ttrifluoromethyl)phenyl]methyl]-4-piperid~nyl]-lH-isoindole-5-sulfonamide as the sesquihydrate, m.p.
288-289.
Anal. Calcd. for C21H21ClF3N303S-HC1-1.5H20: C, 45-74;
H, 4.57; N, 7.62; H20, 4.90. Found: C, 45.34; H, 4.21; N, 7.44;
H20, 4.51.
NMR (DMS0-d6): 2.00 (2H,m); 2.30 (2H,m); 3.39 (4H,m);
~ 3.52 (2H,bs); 4.42 (3H,m); 4.51 (2H,s); 7.75 (4H,m); 8.01 (3H,m);
8.19 (lH,s); 11.60 (lH,bs).
6-Chloro-2,3-dihydro-1-hydroxy-3-oxo-2-[1-(phenylmethyl?-4-piperidinyl~-lH-isointole-5-sulfonamide C~
A mixture of 6-chloro-2,3-dihydro-1,3-dioxo-2-[1-(phenyl-methyl)-4-piperitinyl]-lH-isoindole-5-sulfonamide (2.0 g., 4.61 mmole) and zinc dust (1.66 g., 25.4 mmole) $n 60 ml. of glacial acetic acid was stirred at room temperature for 30-45 min. The mixture was - filtered, the filtrate concentrated in vacuo and residual ~aterial diluted with 1:1 ethyl acetate-aqueous sodium bicarbonate. The layers were separated and the aqueous phase extracted with ethyl acetate.
Combined extracts were dried (MgS04) and concentrated to about 15-20 ml.
to afford a suspension of the product which was collected and dried at 80 under vacuum providlng 0.98 g. (48%) of analytically pure 6-chloro-2,3-dihydro-1-hydroxy-3-axo-2-[1-(phenylmethyl)-4-piperidinyl~-lH-isoindole-5-sulfonamide, m.p. 208-210 (dec.).
_ Anal. Cacld- for C20H22ClN304S C, 55-10; H~ 5.09; N~ 9-64-Found: C, 55.15; H, 5.04; N, 9.72.
NMR (DMSO-d6): 1.76 (2H,m); 2.08 (4H,m); 2.90 (2H,m); 3.48 (2H,s); 3.80 (lH,m); 5.99 (lH,s); 6.78 (lH,bs); 7.28 (5H,s); 7.76 (2H,bs);
7.79 (lH,s); 8.13 (lH,s).
~L268~76''~
Preparatlon of 4-A~ino-l-(phenylalkyl)-piperidine Inter~diate~ of FonmuLa rv (a) 1,l-Dimethylethyl ~l-(phenylme~hyl~-4-piperitiny carbamate.- To a coolet mixture of N-tert.-butoxycarbonyl azide ; (0.448 mole) and sodium carbonate (0.91 mole) ln 400 ~1. of ~ater was added 4-amino-1-benzylpiperidi~e (0.426 le) over 5 minutes. The resulting suspension was stlrred at 5-10 for 1 hr., allowed to warm to room temperature and then stirred an additlonal 24 hr. period.
Dilution of the reactlon mlxture with 400 ml. of water, extraction with chloroform (6 x 300 ml.), drying and concentration of the chloroform extracts in vacuo afforded 123 g. (9g~ of the tertiary butyl carbamate (a), m.p. 112-120~.
Reaction of di-tert.-butyl pyrocarbonate (0.44 le) with 4-amino-1-benzylpiperidine (0.4 mole) and sodium carbonate (0.5 mole) in l:l-dioxane-water also provitet the tertiary butyl carbamate (a).
(b) l,l-Dimethylethyl 4-piperidinylcarbamate.- A mixture of l,l-dimethylethyl [l-(phenylmethyl)-4-piperidinyl]carbamate (0.355 mole), 10% palladium-on-carbon (10.0 g.) in 43 ml. of acetic acid and 90 ml. of ethanol was hydrogenated under low pressure at room temperature for a 96 hr. period. The reaction mixture was filtered and concen-trated in vacuo. Residual oil was taken up in chloroform, washed with 20% aqueous sodium carbonate solution and the aqueous phase extracted with additional chloroform. The combined chloroform extracts were tried (MgSO4) and evaporated in vacuo to afford 64.2 g.
(90%) of l,l-dimethylethyl 4-piperidinylcarbamate, m.p. 153-157 .
(c) l,l-Dimethylethyl l-r(4-methoxyphenyl)methyl~-4-piperidinylcarbamate.- A mixture of 4-(chloromethyl)anisole (0.04 121E;8767 mole), l,l-dimethylethyl 4-piperidinylcarbamate (0.04 mole), potassium carbonate (0.08 mole) and potassium iodide (0.05 g.~ ~n 250 ml. of acetonitrile was refluxed for a 16 hr. period. The hot solution was filtered and the filtrate concentrated in vacuo. Purification of the residual material was carried out chromatographically on silica gel using ethyl acetate as the eluant. Removal of the solvent in ~acuo afforted 6.8 g. (53%) of l,l-dimethylethyl 1-t(4-met~oxyphenyl)-methyl]-4-piperitinylcarbamate, m.p. 95-97.
(d) 4-Amino-1-~(4-methoxyphenyl)methyl]piperidine.- A
mixture of l,l-dimethylethyl 1-[(4-methoxyphenyl)methyl]-4-piperidinyl-carbamate (0.02 mole) and trifluoroacetic acid (0.01 mole) in 50 ~1.
of methylene chloride was refluxed for a 3 hr. period. Additional trifluoroacetic acid (0.08 mole) was added and reflux continued for an additional 30 minutes. The crude solution was evaporated in vacuo, residual material dissolved in water and the aqueous phase washed with ether and then made basic with 50~ sodium hydroxide.
Extraction of the basified solution with chloroform, drying of the chloroform extracts, and removal of the solvent afforded 4-amino-1-[(4-methoxyphenyl)methyl]piperidine in nearly quantitative yield.
8y substituting the appropriate phenylalkyl halide for 4-(chloromethyl)anisole in step (c) above, requisite Formula IV
4-amino-1-(phenylalkyl)piperidine intermediates are obtained as illustrated by TABLE 1 below.
126876'7 NzR ~ Rl Example No. y . Rl _ 2 13-2 CH2 4-Cl H
13-3 CH2 4-Br H
13-5 CH2 2-Cl H
13-11 CH2 4-C(CH3)3 H
13-14 CH2 4-n-C4HgS H
13-17 -(CH2)2- 3-Cl . 4-Cl 13-20 -(CH2)2- , H
13-21 CH2 2-C1 4-Cl 126876'7 TABLE 1 - contlnued Example No. Y R~ -2 13-22 bond H
13-23 ~H(CH3) H H
513-24 -tCH2)4- H H
13-25 CH2 3-C1 4-Cl Additlonal Compounds of Formula II
Reaction of the appropriate 4-amino~ phenyl81kyl)-piperidine intermediate of Formula IV and 4-(halogen)-5-sulfamoyl-phthalimide according to the procedure of Exa~ple l(a) provideq the compounds tabulated below.
52 ~ ~ ~ (Il) Example No. X Y Rl R
14-1 Cl CH2 4-C(CH3)3 H
- 6-Chloro-2-[1-[[4-(1,1-dimethylethyl)phenyl]methyl]-4-piperidinyl]-2,3-dihydro-1,3-dioxo-lH-isoindole-5-sulfonamide Hydrochloride Anal. Calcd- for C24H28ClN34S-HCl C, 54-75; H~ 5-55;
N, 7.98. Found: C, 54.90; H, 5.80; N, 7.95.
14-2 Cl CH2 4-N02 H
6-Chloro-2,3-dihydro-2-[1-[(4-nitrophenyl)methyll-4-piperidinyl]-1,3-dioxo-lH-isoindole-5-sulfonamide Anal- Calcd- for C20HlgClN406S C, 50-16; H~ 4.00; N~ 11-70-Found: C, 50.19; H, 3.98; N, 11.74 ~268767 ~ABLE 2 - continued Example No. X Y R R
14-3 Br CH2 H H
14-5 Cl CH2 4-CH3S H
14-6 Cl CH2 4-n-C4HgS H
14-7 Cl CH2 4-CN H
14-8 Cl CH2 3-C1 4-F
14-9 Cl -(~H2)2- 3-C1 4-Cl 14-10 Cl CH2 3-OCH3 4-OCH2CH=CH2 14-11 Cl CH2 3-OCH3 4-F
14-12 Cl ~CH2)2 H H
14-13 Cl CH2 2-C1 4-Cl 14-14 Cl bond H H
14-15 Cl ~CH(CH3) H (m.p. 244-247) H
14-16 Cl ( 2)4 H H
14-17 Cl CH2 3-C1 4-Cl 6-Chloro-2-[1-[(3,4-dichlorophenylmethyl]-4-piperidinyl~-2~3-dihydro-1,3-dioxo-lH-isoindole-5-sulfonamide, m.p. 245-246 (dec.).
Anal- Calcd- for C20H18C13N3O4S: C, 47-77; H, 3-61; N~ 8.36.
Found: C, 47.94; H, 3.76; N, 8.64 126876~
Additional Compounds of Formula III
Retucing the '~1,3-dioxo" compounds of ~ormula II described in the indicated example with zinc in glaclal acetic acid according to the procedure of Example 1~ provide the compounds tabulated below.
TA~LE 3 2 2 ~ 2 Starting Material Example No. Example No. X Y Rl R2 15-1 2 Cl CH2 4-Cl H
15-2 3 Cl CH2 4-Br H
15-3 4 Cl CH2 4-F H
15-4 5 Cl CH2 2-Cl H
15-5 6 Cl CH2 4-CH3 H
15-6 7 Cl CH2 2-CH3 H
15-7 8 Cl CH2 4-OCH3 H
15-8 9 Cl (CH2)2 4 OCH3 H
15-9 10 Cl CH2 4-OCH2CH=CH2 H
15-10 14-1 Cl CH2 4-C(CH3)3 H
15-11 14-2 Cl CH2 4-N02 H
15-12 14-3 Br CH2 H H
15-13 . 14-4 F CH2 H H
15-14 14-5 Cl CH2 4-CH3S H
15-15 14-6 Cl CH2 4-n-C4HgS H
~268767 TABLE 3 - coneinued Starting Material Example No. Example No. X Y ~1 R2 15-16 14-7 Cl CH2 4-CN H
15-17 14-8 Cl CH2 3-C1 4-F
15-18 14-9 Cl -(c~2)2- 3-C1 4-Cl 15-19 14-10 Cl CH2 3-OCH3 2C C 2 15-20 14-11 Cl CH2 3-OCH3 4-F
15-2 14-12 Cl ( 2)2 H H
15-22 14-13 Cl CH2 2-C1 4-Cl 15-23 14-14 Cl bond H H
15-24 14-15 Cl ~CH(CH3) H H
15-25 14-16 Cl (CH2)4 H H
15-26 14-17 Cl CH2 3-C1 4-Cl -15-27 14-18 ~ CF3 CH2 H H
Ea~'~LE 16 Additional Com~ounds of Formula I
-Reduction of appropriate co~pounds of Formula II or III set forth in TABLES 2 and 3, respectively, according to the process of the present invention provides the products tabulated below.
~268~67 TAB~E 4 50~ ~ 1 Example No. X Y R R
16-1 Cl 2 4-C(CH3)3 ~ H
16-2 Cl CH2 4-NO2 H
16-3 Br CH2 H H
16-5 Cl CH2` 4-CH3S H
16-6 Cl CH2 4-n-C4HgS H
16-7 Cl CH2 4-CN H
16-9 C1 -(CH2)2- 3-C1 4-Cl 16-10 Cl CH2 3-OCH3 4-OCH2CH=CH2 16-11 Cl CH2 3-OCH3 4-F
16-12 Cl -tCH2)2- H H
16-13 Cl CH2 2-C1 4-Cl 16-14 Cl bond H H
16-15 Cl ~H(CH3) H H
16-16 Cl -(CH2)4- H H
126876~7 TABLE 4 - continue~
Example ~o. X Y - Rl - 2 ---16-17 Cl CH2 3-C1 4-Cl 6-Chloro-2-~ (3,4-dichlorophenyl)methyl]-4-piperidinyl]-2,3-dihydro-3-oxo-lH-iso~ndole-5-sulfonamlde Hydrochlorite Nydrate Anal. Calcd. for C20H2ocl3N3o3s~Hc~ 75*0 C- 43-14;
H, 4.44; N, 7.55 H20, 5.66. Found: C, 43.37; H, 4.21;
N, 7.80; H2O, 5.56.
NMR (DXSO-d6): 1.97 (2H,m); 2.30 (2H,m); 3.28 (4H,m); 3.33 (4H,bs); 4.32 (3H,m); 4.51 (2H,s); 7.75 (4H,m); 8.00 (2H,m);
8.20 (lH,s); 11.50 (lH,bs).
Claims (29)
1. A compound of Formula I
Formula I
wherein X is halogen or trifluoromethyl;
R1 and R2 are independently hydrogen, lower alkyl, lower alkoxy, lower alkenyloxy, lower alkylthio, trifluoromethyl, cyano, or nitro;
Y is a single bond or a divalent straight or branched chain alkylene radical of 1 to 4 carbon atoms inclusive;
or a pharmaceutically acceptable acid addition salt thereof.
Formula I
wherein X is halogen or trifluoromethyl;
R1 and R2 are independently hydrogen, lower alkyl, lower alkoxy, lower alkenyloxy, lower alkylthio, trifluoromethyl, cyano, or nitro;
Y is a single bond or a divalent straight or branched chain alkylene radical of 1 to 4 carbon atoms inclusive;
or a pharmaceutically acceptable acid addition salt thereof.
2. The compound of Claim 1 Formula I wherein X is halogen;
R1 is hydrogen, lower alkyl, lower alkoxy, lower alkenyloxy, lower alkylthio, trifluoromethyl, cyano, or nitro; R2 is hydrogen; and Y is -CH2-.
R1 is hydrogen, lower alkyl, lower alkoxy, lower alkenyloxy, lower alkylthio, trifluoromethyl, cyano, or nitro; R2 is hydrogen; and Y is -CH2-.
3. The compound of Claim 1 Formula I wherein X is chlorine;
R1 is hydrogen, lower alkyl, lower alkoxy, lower alkenyloxy, or trifluoro-methyl; R2 is hydrogen; and Y is -CH2-.
R1 is hydrogen, lower alkyl, lower alkoxy, lower alkenyloxy, or trifluoro-methyl; R2 is hydrogen; and Y is -CH2-.
4. The compound of Claim 1 Formula I wherein X is halogen;
R1 and R2 are hydrogen; and Y is -CH2-.
R1 and R2 are hydrogen; and Y is -CH2-.
5. The compound of claim 1 which is 6-chloro-2,3-dihydro-3-oxo-2-[1-(phenylmethyl)-4-piperidinyl]-1H-isoindole-5-sulfonamide.
6. The compound of claim 1 which is 6-chloro-2,3-dihydro-3-oxo-2-[1-(phenylmethyl)-4-piperidinyl]-1H-isoindole-5-sulfonamide hydrochloride.
7. The compound of claim 1 which is 6-chloro-2-[1-[(4-chloro-phenyl)methyl]-4-piperidinyl]-2,3-dihydro-3-oxo-1H-isoindole-5-sulfonamide.
8. The compound of claim 1 which is 2-[1-[(4-bromophenyl)-methyl]-4-piperidinyl]-6-chloro-2,3-dihydro-3-oxo-1H-isoindole-5-sulfonamide.
9. The compound of claim 1 which is 6-chloro-2-[1-[(4-fluoro-phenyl)methyl]-4-piperidinyl]-2,3-dihydro-3-oxo-1H-isoindole-5-sulfonamide.
10. The compound of claim 1 which is 6-chloro-2-[1-[(2-chlorophenyl)methyl]-4-piperidinyl]-2,3-dihydro-3-oxo-1H-isoindole-5-sulfonamide.
11. The compound of claim 1 which is 6-chloro-2,3-dihydro-2-[1-[(4-methylphenyl)methyl]-4-piperidinyl]-3-oxo-1H-isoindole-5-sulfonamide.
12. The compound of claim 1 which is 6-chloro-2,3-dihydro-2-[1-[(2-methylphenyl)methyl]-4-piperidinyl]-3-oxo-1H-isoindole-5-sulfonamide.
13. The compound of claim 1 which is 6-chloro-2,3-dihydro-2-[1-[(4-methoxyphenyl)methyl]-4-piperidinyl]-3-oxo-1H-isoindole-5-sulfonamide.
14. The compound of claim 1 which is 6-chloro-2,3-dihydro-2-[1-[2- (4-methoxyphenyl)ethyl]-4-piperidinyl]-3-oxo-1H-isoindole-5-sulfonamide.
15. The compound of claim 1 which is 6-chloro-2,3-dihydro-3-oxo-2-[1-[[4-(2-propenyloxy)phenyl]methyl]-4-piperidinyl]-1H-isoindole-5-sulfonamide.
16. The compound of claim 1 which is 6-chloro-2,3-dihydro-3-oxo-2-[1-[[3-trifluoromethyl)phenyl]methyl]-4-piperidinyl]-1H-isoindole-5-sulfonamide.
17. The compound of claim 1 which is 6-chloro-2-[1-[(3,4-dichlorophenyl)methyl]-4-piperidinyl]-2,3-dihydro-3-oxo-1H-isoindole-5-sulfonamide.
18. The pharmaceutical composition comprising an anti-hypertensive amount of a compound of claim 1 or a pharmaceutically acceptable acid addition salt thereof snd a pharmaceutically acceptable carrier.
19. The composition of claim 18 wherein the compound is 6-chloro-2,3-dihydro-3-oxo-2-[1-(phenylmethyl)-4-piperidinyl]-1H-isoindole-5-sulfonamide.
20. The composition of claim 18 wherein the compound is 6-chloro-2,3-dihydro-3-oxo-2-[1-(phenylmethyl)-4-piperidinyl]-1H-isoindole-5-sulfonamide hydrochloride.
21. A process for preparing a compound of Formula I
Formula I
wherein X is halogen or trifluoromethyl;
R1 and R2 are independently hydrogen, lower alkyl, lower alkoxy, lower alkenyloxy, lower alkylthio, trifluoromethyl, cyano, or nitro;
Y is a single bond or a divalent straight or branched chain alkylene radical of 1 to 4 carbon atoms inclusive;
or a pharmaceutically acceptable acid addition salt thereof, said process comprising:
(a) reducing a 1,3-dioxoisoindole compound of Formula II
or a 1-hydroxy-3-oxoisoindole compound of Formula III
(II) (III) wherein X, R1, R2 and Y are as defined above; or (b) reacting a 4-aminopiperidine compound of Formula IV
(IV) wherein R1, R2 and Y are as defined above with a sulfamoyl compound of Formula V in an inert solvent (V) wherein X is as defined above, R3 is amino, halogen, lower alkoxy; and R4 is halogen or taken as the radical R4CH2- is carbamoyl or formyl; and R3 and R4 taken together is oxygen; or (c) reacting a piperidinyl compound of Formula VI
(VI) with a phenylalkyl compound of Formula VII
(VII) wherein X, R1, R2, and Y are as defined above and Z
is reactive leaving group: and, then, optionally following either step (a), (b), or (c), if the salt is desired, then admixing a Formula I base with a pharmaceutically acceptable acid in an inert solvent, and then isolating the produced salt by conventional concentration or crystallization techniques.
Formula I
wherein X is halogen or trifluoromethyl;
R1 and R2 are independently hydrogen, lower alkyl, lower alkoxy, lower alkenyloxy, lower alkylthio, trifluoromethyl, cyano, or nitro;
Y is a single bond or a divalent straight or branched chain alkylene radical of 1 to 4 carbon atoms inclusive;
or a pharmaceutically acceptable acid addition salt thereof, said process comprising:
(a) reducing a 1,3-dioxoisoindole compound of Formula II
or a 1-hydroxy-3-oxoisoindole compound of Formula III
(II) (III) wherein X, R1, R2 and Y are as defined above; or (b) reacting a 4-aminopiperidine compound of Formula IV
(IV) wherein R1, R2 and Y are as defined above with a sulfamoyl compound of Formula V in an inert solvent (V) wherein X is as defined above, R3 is amino, halogen, lower alkoxy; and R4 is halogen or taken as the radical R4CH2- is carbamoyl or formyl; and R3 and R4 taken together is oxygen; or (c) reacting a piperidinyl compound of Formula VI
(VI) with a phenylalkyl compound of Formula VII
(VII) wherein X, R1, R2, and Y are as defined above and Z
is reactive leaving group: and, then, optionally following either step (a), (b), or (c), if the salt is desired, then admixing a Formula I base with a pharmaceutically acceptable acid in an inert solvent, and then isolating the produced salt by conventional concentration or crystallization techniques.
22. A process according to claim 21, wherein said step (a) is utilized, and wherein reduction of said Formula II compound or said Formula III compound is carried out with zinc and acetic acid or tin and concentrated hydrochloric acid at an elevated temperature generally within the range from 60-150°C for a period of time within the range from about 6-48 hours in a reaction inert organic solvent.
23. A process according to claim 21, wherein step (b) is used.
24 A process according to claim 21, wherein step (c) is used and wherein said compound of Formula VI and said compound of Formula VII are reacted in an inert organic solvent at elevated temperature within the range from about 50-200°C in the presence of a basic conden-sation agent or an organic tertiary nitrogen amine base.
25. A pharmaceutical composition for administration to a normal comprising a compound of claim 1 or a pharmaceutically accept-able acid addition salt thereof present in a dosage amount within the range from about 0.05 to 500 mg per kg. of body weight of said mammal and a pharmaceutically acceptable carrier.
26. The use of a compound of Formula I
wherein X is halogen or trifluoromethyl;
R1 and R2 are independently hydrogen, lower alkyl, lower alkoxy, lower alkenyloxy, lower alkylthio, trifluoromethyl, cyano or nitro;
Y is a single bond or a divalent straight or branched chain alkylene radical of 1 to 4 carbon atoms inclusive;
or a pharmaceutically acceptable acid addition salt thereof to treat hypertension in a mammal.
wherein X is halogen or trifluoromethyl;
R1 and R2 are independently hydrogen, lower alkyl, lower alkoxy, lower alkenyloxy, lower alkylthio, trifluoromethyl, cyano or nitro;
Y is a single bond or a divalent straight or branched chain alkylene radical of 1 to 4 carbon atoms inclusive;
or a pharmaceutically acceptable acid addition salt thereof to treat hypertension in a mammal.
27. The use of claim 26 wherein the compound is 2,3-dihydro-3-oxo-2-[1-(phenyl)(methyl)-4-piperidinyl]-1H-isoindole-5-sulfonamide.
28. The use of claim 26 wherein the compound is 2,3-dihydro-3-oxo-2-[1-(phenyl)(methyl)-4-piperidinyl]-1H-isoindole-5-sulfonamide hydrochloride.
29. The use of a compound of Formula I
Formula I
wherein X is halogen or trifluoromethyl;
R1 and R2 are independently hydrogen, lower alkyl, lower alkoxy, lower alkenyloxy, lower alkylthio, trifluoromethyl, cyano or nitro;
Y is a single bond or a divalent straight or branched chain alkylene radical of 1 to 4 carbon atoms inclusive;
or a pharmaceutically acceptable acid addition salt thereof to reduce excess water retention in a mammal.
Formula I
wherein X is halogen or trifluoromethyl;
R1 and R2 are independently hydrogen, lower alkyl, lower alkoxy, lower alkenyloxy, lower alkylthio, trifluoromethyl, cyano or nitro;
Y is a single bond or a divalent straight or branched chain alkylene radical of 1 to 4 carbon atoms inclusive;
or a pharmaceutically acceptable acid addition salt thereof to reduce excess water retention in a mammal.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000583066A CA1268767A (en) | 1982-11-12 | 1988-11-14 | 1-phenyl-containing substituent-4-animo-pyrimidinyl substituted isoindole sulfonimide compounds exhibiting diuretic and antihypertensive properties |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US441,204 | 1982-11-12 | ||
| US06/441,204 US4495194A (en) | 1982-11-12 | 1982-11-12 | Antihypertensive isoindole derivatives |
| CA000440844A CA1246081A (en) | 1982-11-12 | 1983-11-09 | 1-phenyl-containing substituent-4-amino-pyrimidine compounds |
| CA000583066A CA1268767A (en) | 1982-11-12 | 1988-11-14 | 1-phenyl-containing substituent-4-animo-pyrimidinyl substituted isoindole sulfonimide compounds exhibiting diuretic and antihypertensive properties |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000440844A Division CA1246081A (en) | 1982-11-12 | 1983-11-09 | 1-phenyl-containing substituent-4-amino-pyrimidine compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1268767A true CA1268767A (en) | 1990-05-08 |
Family
ID=25670205
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000583066A Expired - Fee Related CA1268767A (en) | 1982-11-12 | 1988-11-14 | 1-phenyl-containing substituent-4-animo-pyrimidinyl substituted isoindole sulfonimide compounds exhibiting diuretic and antihypertensive properties |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1268767A (en) |
-
1988
- 1988-11-14 CA CA000583066A patent/CA1268767A/en not_active Expired - Fee Related
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