US3318952A - Dibenzylsulfamides - Google Patents

Description

United States Patent Ofifice 3,318,952 Patented May 9,1967

3,318,952 DIBENZYLSULFAMIDES William J. Houlihan, Mountain Lakes, N.J., assignor to Sandoz Inc., Hanover, NJ.

No Drawing. Filed Dec. 8, 1964, Ser. No. 416,907 Claims. (Cl. 260--556) This is a continuation-in-part of application Ser. No. 339,354 filed on Jan. 22, 1964, now abandoned.

The present invention is directed to dibenzylsulfamides la 1 wherein each of R R R R R R, R", and R is either a hydrogen atom (-H) or one of the following functional groups: lower alkyl, preferably having from 1 to 5 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl, butyl and amyl; lower alkoxy, preferably having from 1 to 5 carbon atoms, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy and pentoxy; di(lower)alkylamino,.each alkyl of which preferably having from 1 to 5 carbon atoms, e.g. dimethylamino and N-methyl-N-ethylamino; aziridyl; pyrrolidyl; piperidyl; homopiperidyl; a fluorine atom (-F); a chlorine atom (-Cl); a bromine atom (Br); trifiuoromethyl (CF with the proviso that a plurality of trifluoromethyl groups are not ortho to each other; and, together with the functional ,group on the adjacent ring carbon atom, methylenedioxy (OCH O). 3 r

An object of this invention is to obtain compounds which are useful as anticonvulsants. A further object is .to obtain anticonvulsants directly from starting materials a which are either readily available or prepared from readily available compounds by methods well known to the art. Additional objects are apparent from the description which follows.

The preparation of compounds I is accomplished by heating at a temperature within the range of from about to about 250 C. and in a tertiary amine (a) a dibenzylamine II and (b) sulfamide III:

A reaction temperature in excess of 50 C. is recommended, and a preferred range is from about to about 125 C. Agitation may be employed during the reaction, but none is required. j

The tertiary amine medium provides a solvent system in which the reaction takes place. Contemplated tertiary amines include, for example, tri(lower)alkylarnines, e.g. triethylamine; aryldi(lower)alkylamines, e.g. phenyldimethylarnine; (lower)alkyl pyrroles, e.g. N-propyl-pyrrole; pyridine; (lower)alkyl pyridines, e.g. 3-ethyl pyridine; (lower)alkoxy pyridines, e.g. 2,5-dimethoxypyridine; quinoline; (lower) alkyl quinolines, e.g. S-ethyl-quinolines; (lower)alkoxy quinolines, e.g. 3,6-dimethoxy-quinoline; N-(1ower)a1kyl morpholine, e.g. N-methyl-morpholine; and N,N-di(lower)alkyl piperazine, e.g. N-methyl-N- ethyl-piperazine. I

The temperature at which reaction A is conducted is usually the reflux temperature of the system.

Except for the title compound of Example 1, compounds I are anticonvulsants and antidepressants which may be administered either orally or parenterally. They are useful, for example, in the therapy of convulsive seizures. Average daily doses vary, but may be between 200 milligrams and 350 milligrams.

Each of the pharmaceutically active compounds of this invention may be, e.g., incorporated, for oral administration, in a tablet as the sole active ingredient. A typical tablet is constituted by from 1 to 3 percent binder, e.g. tragacanth; from 3 to 10 percent disintegrating agent, e.g. corn starch; from 2 to 10 percent'lubricant, e.g. talcum; from 0.25 to 1.0 percent lubricant, e.g. magnesium stearate; an average dosage of active ingredient; and q.s. 100 percent of filler, e.g. lactose; all percentages being by weight. Tablets are prepared according to standard tabletting techniques, which are well-known in the art, employing the necessary amounts of conventional granulating liquids, e.g. alcohol SD-30 and purified water. An exemplary tabletting formulation for the instant active compounds is:

Parts Title compound of Example 2 50 Tragacanth 2 Lactose 39.5

i Corn starch 5 Talcum I 3 Magnesium stearate 0.5

Alcohol SD-30 and purified water, q.s.

,The title compound of Example 1, as other compounds 2 I, possesses CNS (central nervous system) activity. However, said title compound has strong stimulant activity and is not anticonvulsant. It can be administered either orally or parenterally in daily doses of from 35 milligrams to 42 milligrams. The oral dosage form can be a tablet comparable to that heretofore exemplified.

Similar stimulant activity, but to a reduced degree, is found in such compounds as N,N-dibenzyl-N,N-'dimethylsulfamide. V

The following examples illustrate the invention, all temperatures being in degrees centigrade,.the parts and percentages being by weight unless otherwise stated, and the relationship between parts by weight and parts by volume being the same as that between the kilogram and the liter:

EXAMPLE 1 N,N-dibenzylsulfamide In a flask equipped with a stirrer and a condenser attached to a bubble detector dissolve 2157 parts 0.11 mole) of dibenzylamine and 9.6 parts (0.10 mole) of n the following table results in the preparation of the :orresponding compound I.

4. EXAMPLE 3 N benzy l-N -2,4-dichlorobenzy lsul fwmid e In a flask equipped with a stirrer and a condenser attached to a bubble detector dissolve 13.2 parts (0.05

R R l R 4 R4 i R i R R R Me -H -H -11 Me H -11 H -H Et F H -H Et F -11 CF; -H -Pr -01 CF; H Pr -01 H Br Br H H Br Br H -01 -H Et F -01 H Et -F H OF3 H CFa H CFa H CFa -Me H H H Et F -H CF; H Pr Ol Br CFa OEt iPr Bu F H OiPr OPr Am H H -11 OBu -0F Br F H OAm H H -01 O-CHzO- -11 -01 -0'-0H20- -11 -Br Br H -01 -H Et; CF3 OMe CFa H H CFa H CFQ EXAMPLE 2 mole) of N-benzy1-N-2,4-dichl-orobenzylamine and 7.0 N ben l N 34 dichlorobenz [Sal amide parts (0.07 mole) of sulfamide in 40 parts by vo1um e U y f of pyridine. Stir and reflux the resulting solution until gassing is no longer detected in the bubble detector. Remove the solvent in vacuo on a rotary evaporator. Crys- 3 tallize the viscous residue from methanol/water. There NSOaNHz 35 are thus obtained 5.2 parts of title compound, M.P. 95.5"

In a flask equipped with a stirrer and a condenser attached to a bubble detector dissolve 13.2 parts (0.05

Replacing the Nbenzyl-N-2,4-dichlorobenzylamine with an equivalent amount of each of the compounds II represented by substituents in the following table results in mole) of N-benzyl-N-3,4-dichlorobenzylamine and 7.0 the preparation of the corresponding compound I.

l R1 R, 3 R4 R5 IN E R8 CF3 OMe -0F3 H H -0F3 OMe ora H Br r H Br Br H -11 -01 O-OHz-O- -o-oH2-o- 01 H -01 -.o-0H,-0 F Et H -01 N (Me) Et H l HO H Py H -Ho H parts (0.07 mole) of sulfamide in 100 parts by volume EXAMPLE 4 of pyridine. Stir and reflux the resulting solution until 2 h gassing is no longer detected in the bubble detector. Rel w lorobenzyl) sulfamlde move the solvent in vacuo on a rotary evaporator. Crystallize the viscous residue from methanol/water. There CH are thus obtained 4.9 parts of title compound, M.P. to 9 6O III-SOr-NH:

Replacing the N-benzyl-N-3,4-dichlorobenzy1amine with 01 CH, an equivalent amount of each of the compounds II represented by substituents in the following table results in 01 the preparation of the corresponding compound I. In a flask equipped with a stirrer and a condenser at- R1 R R R4 R5 R R7 I R8 Br -01? OEt iPr -N(Me)a -H -H Az Bu F H OiPr -H H Py H OPr Am -11 H -11 Pi -0-0H -0- -11 OBu -01 Br Ho N(Pr)Bu Az -11 -F H OAm H Az Iy H -Pr H 01 -0-0 E -o- -Pi OMe N(Et)Am Ho -H -Az -11 -01 -H H -11 H Py H -OGH -O H H H -11 CF' H P1 H H H H H tached to a bubble detector dissolve 36.6 parts (0.11 mole) of bis-2,4-dichlorobenzylamine and 9.6 parts (0.10 mole) 6 What is claimed is: 1. A compound of the formula of sulfamide in 40 parts by volume of pyridine. Stir and R R reflux the resulting solution until gassing is no longer de- I I tected in the bubble detector. Remove the solvent in 5 R CH: vacuo on a rotary evaporator. Crystallize the viscous I residue from methanol/water. The title compound is R H thus obtained. H V

Replacing the bis-2,4-dichlorobenzylamine with an I l I equivalent amount of each of the compounds 11 repre- BL- sented by substituents in the following table results in I the preparation of the corresponding compound I. R7 R R1 R2 R1 R4 R5 I R6 R1 Rs I In the preceding tables abbreviations, in addition to standard elementalsymbols, were employed as follows:

Arn-amyl Az-aziridyl Bubutyl Etethyl iPrisopropyl Ho-homopiperidyl Me-methyl Pi-piperidyl Prpropy1 Py-pyrrolidyl Compounds II are either known or are prepared by known procedures from available compounds. Various changes can be made in compounds I without departing from the spirit or scope of the present invention or sacrificing its material advantages, the compounds hereinbefore described being merely illustrative embodiments of the invention.

No references cited.

WALTER A. MODANCE, Primary Examiner. JOHN D. RANDOLPH, Examiner.

HARRY MOATZ, Assistant Examiner.

Claims (1)

1. A COMPOUND OF THE FORMULA