JPS6013785A - Thiophenesulfonamide derivatives for high intraocular pressure local treatment - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel [phenylsulfonyl (sulfinyl or carbonyl)] thiophene sulfonamide derivatives. More specifically, the present invention relates to derivatives having the following structural formula and ophthalmically acceptable salts thereof.

R1 is a rule defined below. The present invention also relates to ophthalmic compositions for use in cases of elevated pressure within the eye, particularly with pathological insults such as in the disease known as glaucoma.

Glaucoma is an intraocular disease that involves elevated pressure within the eye that is too high for normal function and can result in irreversible loss of visual function. If untreated, glaucoma can lead to blindness.

Intraocular hypertension, a condition of elevated pressure within the eye without optic nerve head damage or glaucomatous visual defects, is now believed by many ophthalmologists to indicate the early stages of glaucoma.

Many of the medications previously used to treat glaucoma have not proven completely satisfactory. In fact, some progress has been made in the treatment of glaucoma since the introduction of pilocarpine and physostigmine. Recently, β-
It has only recently been noted by clinicians that adrenergic blocking agents are effective in lowering intraocular pressure. Although many of these therapeutic agents are effective in reducing intraocular pressure, they also have other properties, such as cell stabilizing activity, that do not lend themselves to long-term ocular use.

(S)-1-Tate21butylamino-3-[(4-morpholino-1.2.5-thiadiazol-3-yl)oxycu-2-propanol, a blocking agent for β-adrenergic action, reduces intraocular pressure. and lacks many of the undesirable side effects associated with pilocarpine, and furthermore has the effect of suppressing many other β-adrenergic blocking agents, i.e., lacks local anesthetic properties and retains long-term activity. , as well as exhibiting minimal variation.

Pilocarpine, physostigmine, and β-blocking agents reduce intraocular pressure, but these drugs are not known to be responsible for inhibiting the active enzyme, KS'-anhydrase, and thereby inhibiting aqueous fluids. The formation is carried out by the carbonic anhydrase pathway. It has not shown any activity by interfering with 4.

Drugs called carbonic anhydrase inhibitors are
Enchyme blocks or obstructs this internal inflow pathway by inhibiting carbonic anhydrase. Such carbonic anhydrase inhibitors are
Although it is now used to treat intraocular pressure by oral, intravenous, or other routes, it has the unique disadvantage of inhibiting carbonic anhydrase throughout the body.

Such total destruction of the basic enthyme system is observed only during acute episodes of alarmingly elevated intraocular pressure or when drugs are ineffective. Despite the desirability of directing carbonic anhydrase inhibitors to the desired ocular target wound, topically effective carbonic anhydrase inhibitors are not available for clinical medical use. I can't do it.

A preferred embodiment of the novel compound of the present invention has the following structural formula, or a pharmaceutically acceptable salt thereof: R1 is HO- (only when X is -C-) or 1 0 0 1 dR (0) -C-0- f), nuo or 1; R is (1) straight-chain or branched C1-u alkyl (2) cl-18 haloalkyl, especially halo is chloro, bromo, or fluoro (3) In R1, R2H-C1-5 alkyl, R1 and R2 are independently hydrogen or self-3 alkyl, or R1 and R2 together represent a petrocycle selected from piperidinyl, morpholinyl or pyrrolidinyl. (4) C1-3 alkoxycarbonyl-C1-5 alkyl (5) C3-6 cycloalkyl (6) 03-6 cycloalkyl-C,-a alkyl (7) C+-3 furkyl-03-6 cyclo Alkyl, (8) Aryl is a carbocycle or heterocycle such as phenyl, naphthylpyridinyl, furanyl, thienyl, unsubstituted or one or more C1-3 alkyl, halo or C1-3 Substituted with alkoxy, (9) Aryl-C1-3 alkyl, unsubstituted or 1
substituted with one or more halo, c, -3 alkyl or C1-3 alkoxy, C0) C2-e alkenyl (11) C2-6 furkynyl (12) aryl-C2-6 alkenyl (13) NR
3-hi/<'J'; 2/L, (here 'cR3 is C
t-s alkyl, or cz-6 alkanoyl, or (14) C1-3 alkoxy-auto-alkyl. Includes compounds in the 4 position where R is: phenyl, ethyl, propyl, 1,1-dimethylethyl, heptyl, undecanyl, 4°4-dimethylcyclohexyl; 2-chloro-1,1- Dimethylethyl; 4-methyphenyl: 4-chlorophenyl: 4-methoxyphenyl; 4-chlorobenzyl: 3-(4-ethylphenyl)ethyl; Allyl: 2-propynyl; 3-phenylallyl: cyclopentylmethyl; benzyl; Cyclohexyl: methyl; 1,1-dimethyl-2-dimethylaminoethyl JL; 2-(methoxycarbonyl)ethyl: 4
-(1-acetylpiperidinyl): and 3-pyridyl.

A compound in which R is Cl-18 alkyl, more preferably R is a straight or branched chain.

A compound that is alkyl. Other preferred compounds are:
This is a compound of formula 1 in which R1 is -OH and X is -C-.

It is likewise preferred that the hydroxyl or alkoxy group is in the 4 position of the phenyl.

The compound of the present invention is a compound of the following formula: I R-0-C-0-R biscarboxylate [where n = 1 or formula 0 formula% By reacting with n=o):), shitora is also suitably produced.

The reaction is carried out using at least an equimolar amount of the hydrohalide acceptor in a suitable solvent such as dimethylformamide, pyridine, acetone ethyl acetate, tetrahydrofuran or benzene and the like. triethylamine,
Bases such as pyridine and the like can be used for this purpose.

The reaction is carried out with or without a catalyst at a temperature of 0°C to the boiling point of the solvent used, preferably 15°C to 50°C.
It can be done with

When a catalyst is used, triethylamine or 4,4-sialic predominately aminopyridines such as 4-dimethylaminopyridine or 4-pyrrolidinoviridine are preferred.

Novel compounds in which R1 is HO- are prepared by preparing a compound of the following structure: 1 in a mixture with pyridine hydrochloride between its melting temperature and about 250°C, preferably at about 200°C.
It is made by heating for 5 minutes to about 2 hours.

The examples below demonstrate the general method used. Examples that do not include appendices indicating analytical data or melting points are given by way of example only and are not practiced.

However, they are consistent with the described method and are completely practicable, although only the actual yield is questionable.

Example 1 5-[(4-Hydroxyphenyl)sulfonyliothiophene-2-sulfonamide in 4-4(2-sulfamoyl-5-chenyl)sulfonyl]phenyl 2,2-dimethylpropionate acetone (90-) A solution of C4,669,0,01459 mol) was mixed with triethylamine (1,62,9,0,0160 mol) at 0°C.
and 4-dimethylaminopyridine (75■). Trimethyl acetic anhydride (298,9,0,016
0 mol) was added dropwise at 0° C. over 20 minutes. The cooling bath was removed and stirring continued for 1 hour. The acetone was removed in vacuo and the residue was dissolved in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate.

Ethyl acetate was evaporated in vacuo to give a white solid. Collection i5.
899: m, p, l Recrystallized from 1,2-dichloroethane at 92-195°C to obtain the title compound as white needles.
, m', p, 1941 9 4, - 1 9 7
℃.

Analysis Calculated value C, 4 for C15HI7NO683
4,65;H, 4,25;N, 3.47 actual value C,
44,40;H,4,11;N, 3.31 Example 2 4-CC2-Sulfamoyl-5-chenyl)sulfonyl]phenyl-2,2-dimethyl-3-dimethylaminopropionate Step A:2,2 -Dimethyl-3-dimethylaminopropionyl chloride Hydrochloride A mixture of 2,2-dimethyl-3-dimethylaminopropionyl hydrochloride (1,76f!, 0.00969 mol) and thionyl chloride (io-) is heated under reflux. Heated for 30 minutes.

Excess thionyl chloride was removed in vacuo.

The residue was treated with benzene and the benzene was removed in vacuo to give the title compound as a white solid.

Yield is 1.94. j9, m, p, 191-192°C.

Analysis Calculated value as C7Hl aCI No C+HC1) C, 42,01; H, 7,56; N, 7.00
; Actual value C, 41,95: H, 798; N, 7.
300 steps n: 4-r(2-sulfamoyl-5-
Preparation of chenyl)-sulfonyl]phenyl 2,2-dimethyl-3-dimethylaminopropionate - 5-[(4-hydroxyphenyl)sulfonylcorchioffene-2-sulfonamide in acetone (60°C) at 10°C. (319y,o,o1 mol) was treated with triethylamine (111,!i', 0.011 mol). Then, 2,2-dimethyl-3-dimethylaminopropionyl chloride hydrochloride (2,20F).

0011 mol) was added in portions over 10 minutes at -lO<0>C. The cooling bath was removed and stirring continued.

After 72 hours at room temperature, the reaction mixture was heated on a steam bath for 4 hours. The reaction mixture was cooled and triethylamine (1
,1,1&,0011 mol) and heated on a steam bath for 1 hour.

After cooling at room temperature, triethylamine hydrochloride was removed by filtration, and liquid F was evaporated in vacuo to obtain a viscous residue. A sample of the residue was seeded by placing it in a mixture of ethyl acetate and inpropyl alcohol at room temperature. m, p, 218-222℃
.

Recrystallization from acetonitrile followed by recrystallization from nitromethane yielded 184 g of the title compound as white needles.

m, p, 238℃ analysis Calculated value for C10H22N206S3 C, 45, 72; H, 4, 97; N, 6
．． 27; Actual value C, 45, 75; H, 5, 06; N
, 6.18° Example 3 4-[(2-sulfamoyl-5-chenyl)sulfonyl]phenyl 3-(methoxyacetone (60 mI
5-[(4-hydroxyphenyl)sulfonylcorchioffene-2-sulfonamide (3,19g) in V)
; 0.1 mol) was diluted with triethylamine (111
, j9, 0.011 mol). Then nodoxycarbonylpropionyl chloride (1,669,
0,011 mol) was added dropwise over 5 minutes at -10°C.

After 15 minutes, remove triethylamine hydrochloride by filtration.
The P solution was evaporated in vacuo. The residue was dissolved in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. Ethyl acetate was removed in vacuo to give a white solid. Yield: 4.33g m, p, 121-129℃
I got it. 1. Recrystallization from 2-dichloroethane gives the title compound as white needles IT1. p.

Obtained at 135-136°C.

Analysis Calculated value C for C10Hts No8S 3
, 41,56; H, 3,49; N, 3.23; Actual value C, 41,71; H, 3,47; N, 3.43° Example 4 4-4 (2-sulfamoyl-5- 5-[(4-hydroxyphenyl) in acetone (60 ml)
Sulfonylcorchioffene-2-sulfonamide (
3,199; 0.01 mol) was treated with triethylamine (1,11,9; 0011 mol) at -10<0>C. Then acetyl chloride (0,86,9;0.Oi1
mol) was added dropwise at -1O<0>C for 5 minutes.

After 15 minutes, remove triethylamine hydrochloride by filtration.
The r liquid was evaporated in vacuo. The residue was dissolved in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. Ethyl acetate was removed in vacuo to give a white solid. The yield was 3.619: m, p, 137-141°C. Recrystallization from 1,2-dichloroethane gave the title compound a white prismatic product m, p, 143-144. , 5°C.

Analysis Calculated values for C+ 2 HI I NO6S3 C, 39,88; H, 3,07; N, 3.88;
Actual value C, 39,83I; H, 3,03; N, 3.
92° Example 5 4-4(2-Sulfamoyl-5-chenyl)sulfonyl]phenyl 1-acetyl-piperidine-4-carboxylate 5-4(4-hydroxyphenyl)sulfonylcorchioffene- in acetone (60m) 2-sulfonamide (3,19,!il; 0.01 mol) solution
Treated with triethylamine (1.11 g, 0.011 mol) at 5°C. Then 1-acetylpiperidine-4-
Carbonyl chloride hydrochloride (2,41g, 0011
mol) was added in portions at -15°C for 15 minutes.

The cooling bath was removed and stirring continued. After 20 hours, the reaction mixture was diluted with triethylamine (1, l l &, 00
11 mol). After stirring for an additional hour, the reaction mixture was treated with ]-acetylpiperazine-4-carbonyl chloride hydrochloride (2,41,!?, 0011 mol) and triethylamine (2,22 g, 0022 mol) and stirred at room temperature.

After 30 minutes, triethylamine hydrochloride was removed by filtration and F
The liquid was evaporated in vacuo. The residue was dissolved in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. Ethyl acetate was removed in vacuo to give a glassy residue. A sample of the residue was placed in 1,2-dichloromethane at room temperature to obtain seed crystals.

m, p, 178 185°C. ],] Recrystallized from 2-dichloroethane to obtain 195 g of a white solid.

A second recrystallization from acetonitrile gave the title compound. m, p, 186-189°C.

Analysis Calculated value for C1s H2o N207S3 C, 45, 75; H, 4, 27; N, 5.93; Actual value C, 45, 84; H, 4, 31; N, 6.26
Example 6 5-[(4-hydroxyphenyl)sulfonylcorchioffene-2-sulfonamide (3,199; 0.01 mol) in 4-CC2-sulfamoyl-5-chenyl)dimethylformamide (30-) A solution of 25
Treated with triethylamine (2.23 g, 0022 mol) at <0.0>C. Then nicotinyl chloride hydrochloride (1,
96 g, 0011 mol) in portions at 25°C for 15 minutes.
I added it. Stirring was continued at room temperature.

After 16 hours the reaction mixture was poured into water (150ml). The resulting oil was extracted into ethyl acetate, washed with water and saturated sodium chloride solution, and dried over sodium sulfate. Removal of ethyl acetate in vacuo gave a viscous residue.

Yield: 392g. Recrystallization from acetonitrile gave the title compound as pale yellow needles.

m, p, 200-201°C.

Analysis CI'6 HI3 Calculated value for N206S3 C, 45,27; H, 2,85; N, 6.60 Measured value C, 4544; H, 2,84; N, 679 Anhydride used in Example 1 Or, instead of the acid chloride used in Example 2-6, a 111 R-C-α (RC)02 reactant represented by the general formula O or shown in Table 1 is used as described in Example 1-6. The process is carried out essentially as follows, and the acyloxy compounds likewise listed in Table 1 are obtained by the reactions described below.

ROα or (RCO)20 (0)m Table 1 RR Phenyl 3-phenyl-2-propylethyl cyclopentylmethylpropyl Pencil n-hebutyl Cyclohexyl n-undecanyl 2,2-dimethylpropyl 4.4-
dimethylcyclohexyl cinnamyl 2-chloro-1,
1-methylethyl 4-pyridylmethyl 4-methylphenyl cyclopentyl 4-chlorophenyl 2.2.2-trifluoroethyl 4-methoxyphenyl 2-propicol-4-chlorohensyl 2-(4(tylphenyl)ethylallyl Example 7 2-methylpropyl 4 -[(2-Sulfomoyl 5
-chenyl)sulfonyl]-phenyl carbonate 5-4:(4-hydroxyphenyl)sulfonylcorchioffene-2-sulfonamide (2,5Cl, 0.00783 mol) in acetone (50+d) was treated with triethylamine at 0°C. Then, 30% of inbutyl dichloroformate (1,17F, 0.00861 mol) was added.
The mixture was added dropwise at 0-2°C for minutes.

After an additional 15 minutes, the triethylamine hydrochloride was removed by filtration and the P solution was evaporated in vacuo to yield a soft white solid. After milling with butyl chloride, yield 3. It was 28g. m, p403-106°C. Recrystallization from butyl chloride gave the title compound as white needles. m, p, 111-
112℃ Analysis C+s H! Calculated value as t NO7S3 C, 42,95; H, 4,08; N, 3.34 Actual value C, 42,59; H, 4,05; N, 3.32 Chlorophol used in Example 7 Practicing substantially the same procedure as that for Mate, the carbonates also shown in Table H are prepared by the reactions described below.

(O)m(O)m Table ■RR Phenyl 3-phenyl-2-propeninopropyl
Cyclopentylmethylpropyl Benzyl n-hebutyl Cyclohexyl n-undecanyl Methyl 4,4-dimethylcyclohexyl 2,2-methylpropyl 2-chloro-1,1-dimethylethylcinnamyl 4
-Methylphenyl 4-pyridylmethyl4-chlorophenyl 4-nitrophenyl4-methoxyphenyl 2-
(Triethylamine)ethyl 4-chlorohensyl 2-(4-ethylphenyl)ethylallyl 2. , 2.2. -Trifluoroethyl 2-propynyl Example 8 5-(4-Hydroxybenzoyl)thiophene (2) Preparation of 2-sulfonamide Step A Preparation of 2-bromo-5-(4-methoxybenzoyl)-thiophene Methylene chloride (52 , 9, 0, 2 mol) in
-bromothiophene (32,6g, 0.2mol) and p-methoxybenzoyl chloride (32,6&,0
．． Anhydrous stannic chloride (2 mol) in a cold (0-5°C) solution of
52g, 02mol) was added dropwise over about 1 hour.

When the addition was complete, the cooling bath was removed and the solution was stirred for an additional 2 hours. A solution of water (90d) and concentrated hydrochloric acid (10m6) was added dropwise and the layers were separated. The organic layer was washed with water, saturated sodium chloride solution and dried over MgSO4. Removal of the solvent in vacuo and recovery of the solid with the aid of hexane gave 48.5 g of a gray powder. m, p, 97-99°C.

Samples were recrystallized from ligroin for analysis.

Analysis Calculated value C for C12HgBr02 S,
48,50; H, 3,05 Actual value C, 49,11; H, 3,00 Step B 2
- Pencyl mercapto-5-(4-methoxybenzoyl) Preparation of thiophene Benzyl mercaptan (1,249,0,01 mol) is stirred with sodium chloride (50% oil dispersion 0.44
g, 0.11 mol) and descaled DMF (10rn
l) was added to the mixture.

The resulting mixture was carefully warmed until gas evolution ceased. After cooling to 25°C, 2-
Bromo-5-(4-methoxybenzoyl)thiophene (
2,971,001 mol) was added dropwise. After complete addition, the mixture was heated on a steam bath for 25 hours and poured into water (200 rnl). Transfer the aqueous solution to ether (2X
200 mg) and the extract was washed with water, saturated Naα solution and dried over Na2SO4. After evaporating the solvent, the residue was collected and dried using hexane. Yield 1.98g,
m, p.

103-105°C.

Analysis Calculated value C,67 for C10HI60282
,03;H,4,74 Actual value C,67,19:H,4,64 step C5-
Preparation of (4-methoxybenzoyl)thiophene-2-sulfonamide Chlorine was mixed with 2-pencylmercapto-5-(4-methoxybenzoyl)thiophene (34 g) and a 33% aqueous acetic acid solution (
50m) into a stirred cold (0-10°C) mixture.

When the temperature no longer increases during the addition (about 20 minutes),
The pale yellow solid was filtered off and washed thoroughly with water and then hexane. The obtained solid was dissolved in acetone (50 m) and cooled (0-
5°C) was added to concentrated ammonia water ('100 m). The mixture was stirred for 16-24 hours and diluted with water. The separated solid was collected and recrystallized from 95% ethanol. m, p,
176 178℃.

Analysis Calculated value C for C12HI lNO4S2
, 48, 47; H, 3, 73; N, 4.71 actual value
C, 48,20; H, 3,70; N, 4.74 Step D: 5-(4-hydroxybenzoyl)thiophene-
2-Sulfonamide 5-(4-methoxybenzoyl)thiophene-2-sulfonamide (5,489) and pyridine hydrochloride (50g
) was heated to 200°C for 05 hours. Water ('40
0d) was added to the cooled reaction mixture and the solid was collected by filtration. This solid was stirred with IN hydrochloric acid (100ml) for 05 hours, filtered, washed with water and dried at 70°C. Yield 41
1g. m, p, 183-190°C.

This material was treated with acetonitrile, followed by sodium bicarbonate solution, then 3N hydrochloric acid and recrystallized from water to yield 170 g.

m, p, 20'0201℃ Analysis Cr r Calculated value for H9NO4S2 C,
46,63; H, 3,20; N, 4.94 actual value C
,46,63;H,3,13;N,4.94 Example 9 5-(4-Hydroxybenzoyl)thiophene-2-sulfonamide (0,01
459 mol) was dissolved in triethylamine (0,0160 mol) at 0°C.
mol) and 4-dimethylaminopyridine (75 mg). Trimethylacetic anhydride (0,0160 mol) was added dropwise at 0° C. over a period of 20 minutes. The cooling bath was removed and stirring continued for 1 hour. The acetone was removed in vacuo and the residue was dissolved in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. Ethyl acetate was evaporated in vacuo to give the title compound.

Using the test of the general formula (R-C-) 20 shown in Table 1 using equimolar amounts of the anhydride used in Example 9, the method substantially as described in Example 9 was carried out, and the same Make the acyloxy compounds shown in Table ■: Table ■ Phenyl 3-phenyl-2-propenylethyl cyclopentylmethylpropyl benzyl 11-hebutyl cyclohexyl n-undecyl 2,2-dimethylpropyl 4,4-dimethylcyclo cinnamylhexyl 2 -chloro-1,1-4-pyridylmethyldimethylethyl 4-methylphenyl cyclopentyl 4-chlorophenyl 2.2.2-trifluoroethyl 4-methoxyphenyl 2-propynylaryl 2-methoxycarbonylethyl 1-acetyl-4-methyl A solution of 5-(4-hydroxybenzoyl)thiophene-2-sulfonamide in piperidine-3-pyridine-diacetone (genus 50)' kO ℃
treated with triethylamine (0,00861 mol),
Subsequently, isobutyl chloroformate (0,00861
mol) was added dropwise over 30 minutes at 0-2°C.

After a further 15 minutes, triethylamine hydrochloride was removed by FPE filtration and the filtrate was evaporated in vacuo to give the title compound.

Using the reagent of the general formula R-0%-α listed in Table 1 in an equimolar amount of the chloroformate used in Example 10, the method described in Example 10 was substantially carried out, and the same procedure was carried out. The carbonates listed in Table 1 were made by the following reaction.

Table ■ RR Phenyl 3-phenyl-2-propenylpropyl cyclopentylmethylpropyl benzyl n-hebutyl cyclohexyl n-undecanyl methyl 4-methylphenyl 4-pyridylmethyl 4-chlorophenyl cyclopentyl 4-toxyphenyl 4-nitrophenyl allyl
2. 2.2-Trifluoroethyl 2-propynyl In addition to the new compounds described above, a number of 5-[(phenylsulfonyl(tiid sulfinyl))-]thiophene-2-sulfonamides have been described in British Patents No. 1.459.571 and J. , Med, Chem, 24959 (198
1) and they are effective within the novel compositions of the present invention.

They have the structural formula below or are ophthalmically acceptable salts thereof.

(O)n where n is 1 or 2; R3 is 1) -OH where R6 and R71l''j: independently selected from the following; a) hydrogen b) C+s alkyl C) C25 alkanoyl d) Cse Cycloalkylcarbonyle) Benzoylf) Cl-3alkoxycarbonylg) N-C,-3alkyl Carbamoylh)-cl
-3 alkylsulfonyl where R8 and R9 are independently selected from hydrogen, C4_3 alkyl, or C3_6 cycloalkyl.

4) -cH2co□H 6) -CO2H or R8 R4 is 1) Hydrogen 2) Halo such as chloro, bromo, or fluor 3) CIs to alkino or 4) CI-s alkoxy; and R5 is l) hydrogen, 2) halo, such as chloro or fuwa, more preferred embodiments of compounds useful in the novel compositions of the present invention include the following compounds.

n or 2: R3 is 1) -0)i R6 and R7H are independently selected from the following a) hydrogen b) C2-, alkanoyl C) C,, alkoxysulfonyl d) CI-3 alkoxycarbonyl e) N -C,-3 alkylcarbamoylf)C3e
cycloalkylcarbonyl and R4 and R5 are both hydrogen.

Representative compounds are defined in the table below. Here n is 1 or 2.

R3R4R5 7-----------1 Shun--Koichi-1-1) 4-
NHCOCH3HH 2) 4-NHCOCH3HH 3) 4-8O2NH2H) 1 4) 4-NHCOCH3HH 5) 4-NHCOCH,, 2-CI, 5-CH2R3
) 4-NHCOCH3HH 7) 4-NHCOCH3HH 8) 3-NHCOCH34-OCH3H9) 4-C
H2C0OHHH lo) 4-CH2C0NHCH3HHll) 4-N
HCOCH3H3HH 12) 4-NHCOCH33-CI H13) 4-N
HCOCH3H4-Br14) 4-NHC0CH3H
3-C115) 4-NHCOCH(CH8)2HH1
6') 4-NHCOCH2CH2CH3HHlln
4-NHCOC(CH3)3HH18) 4-NHC
OCH3H4-C119)4-NHCOCH3H3-B
r 1t3R4R5 -1-暉-----Akira--■-Cicada-1--11. −
-■---20) 3-NHCOCH3HH 22) 4-CONH2HH 23 3-Co2HHH 24) 3-CONH2H, H 25 3-coNHcHs HJ( 2j3) 3 C0NHCH(CH3)2 I(,H2
7) 4-CH2C0NH2HH 28) 2-CONH2HH 29) '3-NHC0CH3HH 30) 4-OHHH 31) 4-CH2C0N)(C(CH3)s HH The most preferred type is 5-(:(4-hydroxyphenyl)sulfonylco) Thiophene-2-sulfonamide.For use in treatments released by inhibition of carbonic anhydrase, the active compound can be administered either systemically or locally for ocular treatment. One dose is sufficient, but the dosage ranges from about 0.1 to 2.
Up to 5 m9 or more can be taken once per day or 2 to 4 tablets per day.

Increased intraocular pressure! When administered for the treatment of glaucoma or glaucoma, it is most desirable to administer the active compound locally to the eye, although systemic treatment is also sufficient.

When given systemically, the drug can be given by any route, although the oral route is more preferred. For oral administration, the drug may be used in any conventional dosage form, such as tablets or capsules, either for immediate release or in sustained release form. Any number of conventional excipients or tablet auxiliaries can be included as well.

When given by the topical route, the active drug'! or its ophthalmologically acceptable salts, such as sodium or potassium salts, are included in ophthalmic preparations.

In such compositions, 0.1 to 15% by weight is used. The goal is for the administerer to give the patient a daily dose of 90.1 to 1101n per day, continuing the treatment for as long as the condition persists.

Thus, ophthalmic solutions, inserts, ointments, or suspensions for topical administration, tablets for concentrated systemic administration, and intramuscular or intravenous compositions may contain the active drug or an equivalent amount of its salt. and the remainder are carriers, excipients, preservatives, etc., as commonly used in such compositions.

In the form of ophthalmological solutions, the active agent may be combined with ophthalmically acceptable salts such as the sodium and potassium salts obtained by neutralizing equal amounts of the sulfonamide with equal amounts of base such as alkali metal hydroxides. Can be used as a salt.

The active agents of the invention are most suitably administered in the form of ophthalmic pharmaceutical compositions adapted for topical administration to the eye, such as suspensions, ointments, or solid inserts. The composition of these compounds is 0.0
It may contain from 1 to 15%, especially from 0.5 to 2% of the drug.

Higher dosages, such as about 10% or less of the dosage, can be used if the dosage is effective in reducing or regulating high intraocular pressures. 0.001 to 10
．． 0In9, preferably from 0.005 to 2.0, especially from 0.1 to 1.0 m9, is commonly applied to the human eye, so generally in single or divided dosages, as long as the condition is being treated. It is.

These dosage values listed herein are certain to be accurate for human patients and are based on known and currently understood medical science of the compound and other similar entities in the human eye. There is. As with all drug treatments, dosage requirements are variable and must be individualized based on the disease and patient response.

Pharmaceutical preparations containing the active compounds may be conveniently mixed with non-toxic pharmaceutical inorganic carriers or non-toxic pharmaceutical inorganic carriers.

Representative examples of pharmaceutically acceptable carriers are, for example, water, mixtures of water, and lower alkanols or aralcinols, vegetable oils, polyalkylene glycols, petroleum-based sherry, ethylcellulose, ethyl oleate,
Carboxymethylcellulose, polyvinylpyrrolidone,
Water-miscible solvents such as isopropyl myristate and other acceptable carriers are conveniently used. Pharmaceutical preparations likewise contain dispersants, preservatives, wetting agents, fillers, etc., such as polyethylene glycol 200.300.
400 and 600, carbowax 1.000.1,
Antibacterial ingredients such as 500, 4,000, 6,000 and 10,000 quaternary ammonium compounds, phenylmercury salts, thimerosal, methyl and propylparaben, benzyl, which are known to have low temperature stability and are non-toxic to use. Alcohol, phenylethanol; buffer components such as sodium chloride, sodium borate, sodium acetate, glycolate buffers and sorbitan monolaurate, triethanomuramine, oleate, polyoxyethylene sorbitan monopalmitylate, dioctyl
Buffers such as sodium sulfosuccinate, monothioglycerol thiosorbitol, ethylenediaminetetraacetic acid, and the like may be included.

Furthermore, suitable ophthalmic bases can be used as carriers for the purposes of the present invention. These include conventional phosphate buffer bases, isotonic boric acid bases, isotonic sodium chloride bases, isotonic sodium borate bases, and the like. Pharmaceutical dispensing is the best! It can be in the form of a solid insert.

Although many patients find liquid medications to be perfectly acceptable, others prefer solid medications that are applied topically to the eye, such as in a form suitable for pouching. . For this reason, carbonic anhydrase inhibitors contain non-bioerodible inserts, i.e., essentially intact 1
or a bioerodible insert, either soluble in lachrymal fluid or otherwise degradable.

The inserts used are non-limiting and include U.S. Patent No. 3.630.
．． 200 Higuchi, 3,811,444 Hel
4.177, 256 Michaels (r″1
icheals) et al.; 3.868.445 Ryde et al.: 3.845.201 Hadad (Ha
ddad); 3, 981.303 Higuchi; and 3
．． 867, 519 Michaels is sufficient, however, the inserts described below have generally been found to be more preferred.

For example, solid water-soluble polymers can be used as drug carriers. The polymer used to form the insert can be any water-soluble, non-toxic polymer.

Cellulose derivatives such as methyl cellulose sodium carboxymethyl cellulose or hydroxy lower alkyl cellulose such as hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose etc., acrylates such as polyacrylates ethyl acrylates, polyacrylamides; gelatin; Natural products such as alginates, pectins, tragacanth, chalaza, contras, agar, and acacia; starch derivatives such as acetic acid starch hydroxyethyl starch ethers and hydroxypropyl starch; as well as polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl methyl ether, Polyethylene oxide, neutralized Carbopol
and other whole acid derivatives such as xanthan gum and mixtures of the polymer.

Preferably, the solid insert is of cellulose derivatives such as methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose or hydroxypropylmethylcellulose, or polyvinyl alcohol,
Made of polyvinylpyrrolidone, polyethylene oxide or other synthetic materials such as polyvinyl methyl ether. Hydroxypropyl cellulose, one of the preferred polymers for making inserts, is used in several polymeric forms, all of which are suitable for making these inserts. In this way, KLUCEL HFXHWF, Machi, GF, and JF are sold by Hercules Company of Wilmington, Delaware under the name KLUCEL.
Products such as , LF and EF are particularly effective. These products are intended for food or pharmaceutical use. The molecular weight of these polymers for the purposes described herein can be from at least 30,000 to about 1,000,000 or more.

Example 11 Solution composition 2-Methylpropyl 4. -4(2-1~15m9Sulfamoyl5-"F-enyl)sulfonyl]phenyl carbonate monobasic sodium phosphate 9', 38mg6.1
0m9=2H20 Dibasic Sodium Phosphate・28.4.8m916
．． 80m 2H20 Benzalkonium Chloride 0, 1 Team 0, 1
0m9 Water for injection (sufficient amount) LOml 1.0ml of the sterile composition was added and suspended in sterile water. pH of suspension:
The solution was adjusted aseptically to 6.8 and diluted in the neck of the container.

4-((2-sulfamoyl-5-5rngthenyl)
Sulfonyl]phenylnicotinate (I) Petrolatum (sufficient quantity) 17 Compound I and petrolatum were mixed preservatively.

Example 13 4-[:(2-sulfamoyl-5-chenyl) 1 mg
Sulfonyl phenyl acetate hydroxypropyl cellulose (sufficient quantity) 12 mg insert is made from a compression molded film.

The film was manufactured by Carverpress
s) to the powdered mixture of the above ingredients on 5.448 kg
(12,000 pounds) (148 to the compressive force of gauge pressure)
．． Prepared by heating at 9°C (300'F) for 1 to 10 minutes. The film was cooled by circulating cold water through the platen under pressure. The eye inserts were then individually cut from the film with a presentation punch. Place the insert into the vial. The vial was then placed in a humidifying chamber (88°C at 30°C).
% relative humidity) for 2 to 4 days. After removal from the humidification chamber, the vial was stoppered and then capped. The vial containing the hydration insert was then 121. ．． 1℃ (25
Autoclave at 0'F for 1/2 hour.

4-4 (2-sulfamoyl-5-che 1η-nyl)
Sulfonyl] phenyl 2,2-dimethylpropionate hydroxypropyl cellulose 12 m9 (add enough) Eye inserts are prepared by making a viscous solution of the powdered ingredients listed above using methanol as the solvent p1 Made from solvent cast film. The solution was placed on a Teflon plate and allowed to dry under ambient conditions. After drying, the film was placed in an 88% relative humidity chamber until it became pliable. Inserts of appropriate size were cut from the film.

Example 15 4-[(2-sulfamoyl-5-chemyl)sulfonylsiphenyl 2,2-dimethyl-3-dimethylaminopropionate Hydroxypropyl methylcellulose 12 mg (add sufficient amount) Add the eye insert to the above A viscous solution of a powdered blend of the ingredients was prepared using a methanol/water solvent system to form a solvent cast film. lO pumethanol'z
2.5 mg was added to the powdered blend. 11d of water (in 3 parts) was added to the blend. The solution was placed on a Teflon plate and allowed to dry at ambient conditions.

After drying, the film was placed in an 88% relative humidity chamber until pliable. Inserts of approximate dimensions were cut from the film.

Example 16 4-L: (2-sulfamoyl-5-chenyl) 1rn
9sulfonyl]-phenyl 3-(methoxycarbonyl)propionate hydroxypropyl methylcellulose (add sufficient amount)
The 12 mg insert was made from compression molded film.

The film was made by applying a compressive force of 12,000 pounds (gauge) to a compacted mixture of the above components on a Culver press at 350 DEG F. (176.7 DEG C.) for 1 minute. The film was cooled by circulating cold water through the platen under pressure. The eye inserts were then individually cut out from the film with a presentation punch. Each insert was placed in a vial. The medicine bottle is then placed in the humidifying room (3
The samples were placed at 0° C. (88% relative humidity) for 2 to 4 days. After removal from the humidification chamber, the vial was stoppered and then capped. The vial containing the hydrated insert was then 121
．． Autoclaved at 1°C (250°F) for 1/2 hour.

Most preferably, the solid insert of the present invention is available to the patient for use in a pathogen-free manner. in this way,
Preferably, the insert is sterilized, and sterilization is preferably performed after packaging to ensure against recontamination. The best method of sterilization is to subject it to ionizing radiation, including radiation emitted from cobalt-60 or high-energy electron beams.

After packaging the insert in a convenient amount of the usual-dosing amount,
Expose the packaged item to a sterilizing dose of radiation. A preferred method of packaging is to provide sealing of the insert between layers of film or foil, and to laminate or laminate the layers around the entire periphery. Sterilization techniques are well known and accepted, for example as outlined by the International Atomic Energy Commission. Code of methods for radiation sterilization and disinfection of pharmaceutical products, 1967pI) 423-431
and Block, Disinfection, Sterilization, and Storage, 2nd edition, Lear Mant-Fuebiger, Philadelphia, 1977, I) I) 542-561° The required amount of radiation is 1, which irradiates viable bacteria. This can be determined experimentally by testing the inserted material. In general, the amount of irradiation required to achieve disinfection is: Defined by value. The DIO value is the radiation dose at which a given biological population is reduced by 1/0. Bacillus pumilla: Z
Based on experimentally obtained *D, o values and pre-sterilization contamination levels for Bacillus pumilus, a dose of 1.36 megarads was effective in obtaining a sterilized product.

Continued from page 1 211:12 7138-4C 333:00 ) (C07D 409/12 213:00 7138-4C 333:00 ) Priority claim @ June 20, 1983 ■ United States (US) 0
505618 Priority claim 06/20/1983■United States (US)■
505604

Claims (1)

[Claims] 1. A compound of the following structural formula or a pharmaceutically acceptable salt thereof: R1 is HO- (only when X is -C-) 1 0 1 or R(0)-C-0- : n is 0 or 1: R is (1) straight chain or branched cl-18 fluorine), 2) C1-1s haloalkyl is \, and halo is chloro, bromo, or fluoro), (3) R'' lR2N -R1 with \ to C1-5 alkyl
(4) C1-3 alkoxycarbonyl-01- 5 alkyl (5) C3-6 cycloalkyl (6) C3-6 cycloalkyl-01-3 alkyl, (7) C1-a alkyl-C3-6 cycloalkyl, (8-aryl to \ to aryl is phenyl, Carbocycle or heterocycle selected from naphthyl, pyridinyl, furanyl, chenyl, etc., substituted or unsubstituted with one or more cl-3 alkyl, halo or cl-3 alkoxy) (9) One or more Halo, Cl-3 alkyl spanning 01-
Aryl-C1-3 substituted or unsubstituted with 3 alkoxy
Alkyl, (10) C2-s alkenyl (11) C2-s alkynyl (12) aryl-02-6 alkenyl (13) NR
In 3-piperidinyl, R3 is C1-3 alkyl, or C2-5 alkanoyl) or (14) C1-3 alkoxy-C1-5 alkyl. ] The compound according to claim 1, which is part of the 4-@ substituent. 3. Claim 4, wherein R is HO- and X is -C-, comprising an effective amount of the compound of claim 1 to reduce intraocular pressure and an ophthalmologically acceptable carrier. Ophthalmic composition for topical treatment of glaucoma and orbital blood pressure. 5. The composition of claim 4, wherein R of the anti-seizure inhibitor is a part of auto-18 alkyl and a 4-monosubstituted substance. 6. The composition according to claim 4, wherein R is HO- and X is 101. 7. Compound of the following structural formula: Formula: R(0) C-α or formula: R-0-
A process for producing a compound of structural formula: by reacting a compound of C-OR with n-1) at \ or an anhydride of formula (RC)20 with n-0) at β. B. x is -S-, R is cl-18 alkyl and 4
8. The method of claim 7 which is a substituted part. 9. An effective amount of a compound of the following formula or an ophthalmically acceptable salt thereof to reduce intraocular pressure: n [where n is 1 or 2: R3 is 1) -OH and R6 and R7 are independently a) hydrogen b) C+3 alkyl c) C2-5 alkanoyl d) C3-6 cycloalkyl carbonyl e) benzoyl f) C1-3 alkoxycarbonyl g) N-cl, alkylcarbamoyl, or h ) C1-a alkylsulfonyl where R8 and R9 are independently a) hydrogen b) Cta alkyl still c) C3-6 cycloalkyl 4) -CH2CO2H 6) C0zH or 2) halo, 3) C1- 3 alkyl or 4) C1-a alkoxy; R5 is 1) hydrogen 2) halo. An ophthalmic composition for topical treatment of glaucoma and ocular hypertension. 10, R is 1) -OH where R6 and R7 are independently a hydrogen b) c,5 alkanoyl c) Cl-3 alkyl sulfonyl d) C1-3 alkoxycarbonyl e) N C1-3 alkyl 10. The composition of claim 9, wherein carbamoyl f) C3-a cycloalkylcarbonyl: and R4 and R5 are both hydrogen.