Novel Benzothiadiazines which stimulate hair growth when applied intraperitoneally, orally or topically.

Benzothiadiazine dioxides are known chemical entities with antihypertensive 
and antihypoglycemic activity. It has previously been reported that 
patients when treated for a prolonged period of time with diazoxide 
administered orally developed uncontrolled hair growth on the forehead, 
dorsal surfaces of the trunk and arms, thigh, calf and face. 
It has now been found that the novel benzothiadiazines of the present 
invention, in addition to their antihypertensive and antihypoglycemic 
properties, promote hair growth which is confined to the area of 
application. 
This invention relates to novel benzothiadiazines, namely 1, 2, 
4-benzothiadiazine 1,1-dioxides (I) and 3,4-dihydro-1,2,4-benzothiadiazine 
1,1-dioxides (II), both substituted at the benzene ring in 6 or 8 position 
and in 3 position. These new compositions are represented by the general 
formulas: 
##STR1## 
More specifically when X represents a chlorine in the 6 position, R is 
2,4,4-trimethylpentyl, octyl, or dimethylaminoethoxymethyl in compounds of 
type I, or cyclohexenyl in compounds of type II. 
When X is a chlorine in the 8 position, R is heptyl in type I and styryl in 
type II. 
Also, for compounds of general formula I when X is 6-methyl R is propyl, 
and when X is a 6-methoxy R is ethyl. 
We have found that these new benzothiadiazines facilitate hair growth, and 
such growth can be achieved by topical application, as well as by other 
routes, and that hair growth is confined to the area of application, such 
as the scalp when applied topically in suspension or in solution. Moreover 
these new compositions when applied, even at low concentration, to test 
animals, cause a growth of new hair, this growth being of cosmetic 
significance. 
Several species of hairless mice and rhinocerous mice were studied for this 
response. Only one hairless mouse species responded well. Screening 
experiments were done in these mice. These experiments consisted of daily 
i.p. injections of the chemicals in solution (DMSO) or suspension in doses 
of up to 100 mg/kg/day for two months during which time hair growth could 
be observed visually. Hairless mice responded to treatment by growing hair 
in several areas of the back. At the end of the experiment the animals 
were sacrificed, histological slides of various skin areas were prepared 
and examined microscopically. The number of hairs in various stages of 
growth were quantitatively determined (trichogram) and evaluated 
statistically. 
Selected compounds were studied in balding monkeys orally, 
intraperitoneally and topically and found to be active. Both suspensions 
and solutions were studied. Surprisingly the suspensions were found to be 
most active. Visual and histological growth was noted. We also found that 
these compounds when applied topically, retarded the loss of hair in 
monkeys. 
The following experimental drug dosage forms, and dose routes of 
administration were used in monkeys: solution in DMSO at 20 to 100 
mg/kg/day intraperitoneally, a suspension in fruit juice at up to 100 
mg/kg/day orally, a solution in DMSO at up to 10 mg/kg/day topically and a 
suspension up to 10 mg/kg/day topically. 
Observations of treated and untreated animals were made at biweekly 
intervals for 8 weeks. 
The following compounds were prepared. All were identified by l.R. 
Spectroscopy, elemental analysis or by N.M.R. 
COMPOSITIONS OF TYPE I 
1. X=6-chloro,R=2,4,4-trimethylpentyl; Mp. 243.degree.-4.degree.; 
Calculated for C.sub.15 H.sub.21 ClN.sub.2 O.sub.2 : C% 54.79, H% 6.44; N% 
8.52. Found: C% 55.08; H% 6.64; N% 8.46. 
2. X=6-chloro, R=octyl; Mp. 234.degree.-6.degree.; Calculated for C.sub.15 
H.sub.21 ClN.sub.2 O.sub.2 S: C% 54.79; H% 6.44; N% 8.52. Found: C% 55.15% 
H% 6.50; N% 8.31. 
3. X=8-chloro, R=heptyl; Mp. 168.degree.-70.degree.. NMR in acetone-d.sub.6 
shows peaks at 0.9-1; 1.2-1.6; 1.6-2.0; 2.4-2.8; 7.2-7.5; 7.6,7.7 ppm. 
Calculated for C.sub.14 H.sub.19 ClN.sub.2 O.sub.2 S: C% 53.41; H% 6.08; 
N% 8.89. Found: C% 53.71; H% 6.17; N% 9.08. 
4. X=6-chloro, R=dimethylaminoethoxymethyl; Mp 219.degree.-221.degree., NMR 
of the hydrochloride salt shows peaks at 3.5, 3.8-4.0, 4.2-4.4, 4.75, 7.3, 
7.5 and 7.6-7.9 ppm in D.sub.2 O-DDS. Calculated for C.sub.12 H.sub.16 
ClN.sub.3 O.sub.3 S: C% 45.35; H% 5.07; N% 13.22. Found: C% 45.48; H% 
5.30; N% 13.49 
5. X=6-methoxy; R=ethyl; Mp.205.degree.-7.degree.. calculated for C.sub.10 
H.sub.12 N.sub.2 O.sub.3 S: C% 49.82; H% 5.35. Found: C% 50.00; H% 5.24. 
6. X=6-methyl, R=propyl; Mp. 204.degree.-6.degree.; calculated for C.sub.11 
H.sub.14 N.sub.2 O.sub.2 S: C% 55.45; H% 5.92; N% 11.76. Found: C% 55.36; 
H% 5.96; N% 11.98. 
COMPOSITION OF TYPE II 
7. X=chloro, R=cyclohexenyl; Mp.252.degree.-4.degree.; calculated for 
C.sub.13 H.sub.15 ClN.sub.2 O.sub.2 S: C% 52.26; H% 5.06; Found: C% 52.39; 
H% 5.00. NMR shows peaks at 1.9-2.4, 3, 4.6-5, 5.7-5.8, 6-6.6,6.7-6.8, 
6.8-6.9, 6.9-7.1, 7.5, 7.65 ppm. 
8. X=8-chloro, R=styryl; Mp.225.degree.-7.degree.; calculated for C.sub.15 
H.sub.13 ClN.sub.2 O.sub.2 S: C% 56.17; H% 4.08; N% 8.73. Found: C% 56.03; 
H% 4.03; N% 8.59. 
Methods of preparation of benzothiadiazines are reported in the literature 
(J. G. Topliss, et al., U.S. Pat. No. 2,986,573 (1961), J. Med. Chem. 6, 
122-127 (1963); J. Med. Chem. 7, 269-273 (1964); B. A. Bierbaum et al., J. 
Med. Chem.6, 272-275 (1963).

The following examples are given by way of illustration of the methods of 
preparing the compounds of the present invention: 
EXAMPLE I 
6-CHLORO-3-CYCLOHEXENYL-3,4-DIHYDRO-2H-1,2,4-BENZOTHIADIAZINE 1, 1-DIOXIDE. 
4-chloro-2-aminobenzenesulfonamide (20 g.) and 12 g. of 3-cyclohexene 
carboxaldehyde are combined in 150 ml. of acetonitrile and refluxed 41/2 
hours. The precipitate which forms during refluxing and on cooling is 
collected by filtration and washed with cold acetonitrile. The crude (17.4 
g) is recrystallized from dimethylformamide-water to give a white product 
melting at 252.degree.-4.degree.. Analysis calculated for C.sub.13 
H.sub.15 ClN.sub.2 O.sub.2 S: C% 52.26, H% 5.06. Found: C% 52.39; H% 5.00. 
EXAMPLE II 
6-CHLORO-3DIMETHYLAMINOETHOXYMETHYL-2H-1,2,4-BENZOTHIADIAZINE 1, 1-DIOXIDE. 
16 g. of 6-chloro-3-chloromethyl-2H-1,2,4-benzothiadiazine, 1,1-dioxide and 
25 g. of dimethylaminoethanol are dissolved in 110 ml. of acetone and 
refluxed 45 minutes. The solvent is then removed under reduced pressure 
and the residue heated for 1-1/2 hours at 120.degree.-140.degree., oil 
bath temperature. After cooling the solid material is collected and 
recrystallized from ethanol. Mp. 219.degree.-221.degree., Yield 6.5 g. The 
hydrochloride was made (mp over 300) and the structure identified by 
N.M.R. in D.sub.2 O-DDS. This shows the methyl groups at 3.5 ppm, the 
methylene groups at 3.5, 3.8-4, 4.2-4.4 and 4.75 ppm. The protons on the 
benzene ring show at 7.3, 7.5 and 7.6-7.8 ppm. 
EXAMPLE III 
6-CHLORO-3-(2,4,4-TRIMETHYLPENTYL)-2H-1,2,4-BENZOTHIADIAZINE 1,1-DIOXIDE. 
Isononyl chloride (20 g) dissolved in 50 ml toluene is added dropwise to a 
hot and stirred solution of 20 g. of 2-aminobenzenesulfonamide in 400 ml 
benzene and 150 ml toluene. At the end of the addition stirring and 
heating is continued for 5 hrs. The solution is filtered and part of the 
solvent is evaporated. Hexane is added and the precipitate is collected 
and dried. 20 g. of this crude product are combined with 400 ml of 10% 
aqueous sodium hydroxide and heated for 2 hrs. The alkaline solution is 
then cooled and slowly acidified with hydrochloric acid. The solid formed 
is collected and washed several times with water. Yield 17.8 g. 
Recrystallized twice from methanol, m.p. 243.degree.-4.degree.. Analysis 
calculated for C.sub.15 H.sub.21 ClN.sub.2 O.sub.2 S: C% 54.79, H% 6.44, 
N% 8.52. Found: C% 55.08, H% 6.64, N% 8.46. 
It is to be understood that the form of this invention herein shown and 
described is to taken as the preferred examples of the same, and that 
various changes in the operable conditions may be resorted to without 
departing from the spirit of the invention or the scope of the subjoined 
claims.