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(11) Patent Number: KE 559   
                   
( 45) Date of grant: 06/02/2013   
                       
(12) PATENT (51) Int.Cl.S:   
                       
(73) Owner:   
A 61K 31/18,31/40, A 61P 27/06, C        UNIMED PHARMA, SPOL. SR.O of Orieskova 11, 821   
07C 311/16,311/18, C 07D 295/12        05, Bratislava, Slovak Republic   
(2l)Application Number:KElP/ 2009/ 000964

(72) Inventors:    OREGAN, Fridrich, Orieskova 11, 821  05, Bratislava,   
                    Slovak Republic; REMKO, Milan, Orieskova 11, 821 05,   
(22) Filing Date:            Bratislava, Slovak Republic; SLUCIAKOVA, Elena,   
18/04/2008                    Orieskova 11, 821 05, Bratislava, Slovak Republic and   
                    KNAPIKOVA, Jarmila, Orieskova 11, 821 05,   
(30) Priority data:            Bratislava, Slovak Republic   
PP0054-2007  20/04/2007  SK           
                    (74) Agent/address for correspondence:   
(86)  PCT data            Ndungu Njoroge & Kwach Advocates, P.O. Box 41546-   
PCT/SK08/050005    18/04/2008        00100, Nairobi   
wo 2008/130332    30/10/2008           
                       

(54)    Title:

SUBSTITUTED SULPHONAMIDES, PROCESS FOR THEIR PREPARATION, PHARMACEUTICAL COMPOSITION COMPRISING THEREOF AND THEIR USE

(57)    Abstract:

Substituted sulphonamides having the general formula (I) and salts, hydrates and solvates thereof were

prepared and described, wherein R 1 is CO or S02 and RZ is NH or 0 and where R represents linear or cyclic aliphatic chain and n represents number of linking aliphatic chain carbons (n can be 0,1,2 or3), which are useful in the manufacture of the medicaments due to the carboanhydrase inhibition. These compounds are prepared by nucleophilic reactin of an amine with 4-sulfamoylbenzenesulphonyl chloride in the presence of triethylamine excess in tetrahydrofurane or in ether at temperature 0 to 20 °C. The compounds show an antiglaucomatic activity.
 

- 1 -


Substituted sulphonamides, process for their preparation, pharmaceutical composition comprising thereof and their use

Field of the invention

5

The present invention relates to the sub~tituted sulphonamides, which are useful for use as medicaments.

Background of the invention

10

Sulphonamides represent an important group of drugs, the different chemical structures of which show antibacterial, diuretic, cancerostatic p~operties, they are effective carboanhydrase inhibitors, hypoglycaemics, protease inhibitors and cyclooxygenase inhibitors (C. T. Supuran, A.

Casini, A. Scozzafava, Med. Res. Reviews 23 (2003) 535-558.

15    WO 2006014134 describes preparation of piperidine derivatives as well as salts and enantiomers thereof and pharmaceutical compositions containing the compounds. They are useful in therapy, in particular in the treatment of depression.

US  3 502 652 A describes a new basically  substituted  benzoic  acid  amides especially for

treatment of hypertension.

20    US 2 789 938 A relates to diuretic compositions containing sulfonamides which serves to increase the elimination of cations.

The subject of the present invention relates to the novel compounds with the valuable properties,

appropriate particularly in the manufacture of the pharmaceutical compositions. Proceeding from

25    the fact, that the effective sulphonamide type carboanhydrase inhibitors must have suitable spatial (30) structure to be able to fill sufficiently active enzyme position on the basis of complementarity (M. Remko, J. Phys. Chem. A 107 (2003) 720-725). In addition to the 3D

structure, for the high inhibition activity of the sulphonamides there is a certain balance needed

between their water solubility and lipophilicity. These and other physic-chemical properties of

30    sulphonamides fulfilling the conditions of Lipinsky rules are highly effective pharmaceutical agents (M. Remko, C.-W. von der Lieth, Bioorg. Med. Chern. 12 (2004) 5395-5403). On the basis of the studies of the relationship between the structure and the activity of aromatic sulphonamides, there was a group of such compounds developed, which are effective
 

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carboanhydrase inhibitors and it shows to be effective as antiglaucomatics. It was established, these compounds decrease effectively intraocular pressure.

Summary of the invention

5

The subject of the present invention relates to the novel use of the substituted sulphonamides having general formula (I)
H2N-0 2 S  --o- R'-R'-(CH),-R
2

(I)

10    wherein:

R1 is CO or S02,

R2 is NH or 0,

R includes tertiary diC1_4alkylamine group, wherein alkyl moieties are the same or different, or

amino group, alkyl moieties of which together form 5, 6 or ?-membered saturated ring, or the

15    ends of the alkyl moieties  are linked by heteroatom 0, or

R is 4-(N,N-diethylaminoethoxy)benzyl and then R1 is 802  and R2  is NH; or

R is 4-[N-(morpholinopropyl)sulfamoyl]phenyl and then R1 is CO and R2 is NH. n is a number of linking aliphatic chain carbons, wherein n is 0, 2 or 3

and/or physiologically acceptable salts,  hydrates or solvates thereof,  in the manufacture of a

20    medicament for the treatment of glaucoma.


According to the further embodiment, the subject of the invention relates to the use of compounds having general formula (1),

wherein:

25    R1 is CO, R, R2 and n are shown in the following Table:


11-1, 11-2        I    n = 2, 3    R2    = NH   
        R=-N        R2    =0   
                       
        "        n = 2, 3    R2  = NH   
11-3, 11-4        r-               
        R=-N        R2       
        "--                =0   
                           
 

                                                - 3-                       
                                                    n = 2, 3               
        11-5, 11-6        1\                               
                                    R=  -N0                    R2    = NH   
                        \ _ /                                   
                                                                R2    = 0   
                                                                       
        11-7                    R=-o-802    -N~N~    n=O        R2    = NH   
                                                        R2    =0   
                                                               
                                                ~0                       
                                                                       
                                                                       
        11-8, 11-9            ;--                n = 2, 3        R2    = NH   
                                    R=-N                    R2    = 0   
                        "----                                   
        11-10, 11-11,                    R=-N~        n = 2, 3        R2    =0   
        11-12, 11-13                                        R2    = NH   
                                                                       
                11-14, 11-15,                    R=-N~        n = 2, 3        R2    = 0   
                                                           
                11-16, 11-17                                        R2    = NH   
                                                                   
                11-18, 11-19,                    I            n = 2, 3        R2    =0   
                                    R=-N                           
                11-20, 11-21        "----                        2    = NH   
                                                                R       
                11-22, 11-23,            ; -                n = 2, 3        R2    = 0   
                                    R=-N                           
                11-24, 11-25        ~                            R2    = NH   
                                                           
                11-26, 11-27,                    R=-N~        n = 2, 3        R2    = 0   
                11-28, 11-29                                                R2    = NH   
                                                                   
                11-30, 11-31'                    R=-N~        n = 2, 3        R2 =0   
                                                       
                11-32, 11-33                                        R2    = NH   
                                                                   
                11-34, 11-35,                    R= - {)        n = 2, 3        R2    = 0   
                11-36, 11-37                                        R2    = NH   
                                                                   
                                                               
                                                           
                11-38, 11-39,                    R= - {)        n = 2, 3        R2 =0   
                11-40, 1141                                        R2    = NH   
                                                                   
                                                                       

and/or physiologically acceptable salts, hydrates or solvates thereof, in the manufacture of a

medicament for the treatment of glaucoma.


5    The subject of the present invention particularly relates to the use of the following compounds: N-(N,N-Diethylaminoethyl)benzene-1 ,4-bis(sulphonamide); (1-1 ),

N-(N, N-Diethylaminopropyl)benzene-1 ,4-bis( sui phonamide); (1-2), N-(Pyrrolidinoethyl)benzene-1 ,4-bis(sulphonamide); (1-3), N-(Pyrrolidinopropyl)benzene-1 ,4-bis( sulphonamide); (1-4),
 


-4-


N-(Morpholinoethyl)benzene-1 ,4-bis(sulphonamide); (1-5),

N-(Morpholinopropyl)benzene-1 ,4-bis(sui phonamide); (1-6),

N-(4-Diethylaminoethoxybenzyl)benzene-1 ,4-bis(sulphonamide); (1-7),

N-(Dimethylaminoethyl)benzene-1 ,4-bis(sulphonamide); (1-8),

5    N-(Dimethylaminopropyl)benzene-1 ,4-bis(sulphonamide); (1-9), N-(N,N-Dipropylaminoethyl)benzene-1 ,4-bis(sulphonamide); (1-1 0), N-(N,N-Dipropylaminopropyl)benzene-1 ,4-bis(sulphonamide); (1-11), N-(N,N-Dibuthylaminoethyl)benzene-1 ,4-bis(sulphonamide); (1-12),

N-(N,N-Dibuthylaminopropyl)benzene-1 ,4-bis(sulphonamide); (1-13),

10    N-(N-Methyi-N-ethylaminoethyl) benzene-1 ,4-bis(sulphonamide); (1-14), N-(N-Methyi-N-ethylaminopropyl)benzene-1 ,4-bis(sulphonamide); (1-15), N-(N-Ethyi-N-propylaminoethyl)benzene-1 ,4-bis( sulphonamide); (1-16), N-(N-Ethyi-N-propylaminopropyl)benzene-1 ,4-bis(sulphonamide); (1-17), N-(N-Ethyi-N-buthylaminoethyl)benzene-1 ,4-bis(sulphonamide); (1-18),

15    N-(N-Ethyi-N-buthylaminopropyl)benzene-1 ,4-bis(sulphonamide); (1-19), N-(N-Propyi-N-buthylaminoethyl)benzene-1 ,4-bis(sulphonamide); (1-20), N-(N-Propyi-N-buthylaminopropyl)benzene-1 ,4-bis(sulphonamide); (1-21), N-(Piperidinoethy)benzene-1 ,4-bis(sulphonamide); (1-22), N-(Piperidinopropyl)benzene-1 ,4-bis(sulphonamide); (1-23),

20    4-Sulfamoyi-N-(N, N-dimethylaminoethyl)benzamide; (11-1), 4-Sulfamoyi-N-(N,N-dimethylaminopropyl)benzamide; (11-2), 4-Sulfamoyi-N-(N,N-diethylaminoethyl)benzamide; (11-3), 4-Sulfamoyi-N-(N,N-diethylaminopropyl)benzamide; (11-4),
4-Sulfamoyi-N-(morpholinoethyl)benzamide; (11-5),

25    4-Sulfamoyi-N-(morpholinopropyl)benzamide; (11-6), 4-[N-(Morpholinopropyl)sulfamoyl]phenylsulfamoylbenzamide; (11-7), (N,N-Diethylaminoethyl)-4-sulfamoylbenzoate; (11-8),

(N, N-Diethylami nopropyl)-4-sulfamoylbenzoate; (11-9),

(N, N-Dipropylaminoethyl)-4-sulfamoylbenzoate; (11-1 0), 30 • (N,N-Dipropylaminopropyl)-4-sulfamoylbenzoate; (11-11),

4-Sulfamoyi-N-(N, N-dipropylaminoethyl)benzamide; (11-12),

4-Sulfamoyi-N-(N, N-dipropylaminopropyl)benzamide; (11-13),

(N, N-Dibuthylaminoethyl)-4-sulfamoylbenzoate; (11-14),

(N, N-Dibuthylaminopropyl)-4-sulfamoylbenzoate; (11-15),
 


- 5 -


4-Sulfamoyi-N-(N, N-dibuthylaminoethyl)benzamide; {11-16), 4-Sulfamoyi-N-(N, N-dibuthylaminopropyl) benzamide; (11-17), (N-Methyi-N-ethylami noethyl)-4-sulfamoylbenzoate; {11-18), (N-Methyi-N-ethylaminopropyl)-4-sulfamoylbenzoate; (11-19),

5    4-Sulfamoyi-N-(N-methyi-N-ethylaminoethyl)benzamide; (11-20), 4-Sulfamoyi-N-(N-methyi-N-ethylami no propyl) benzamide; (11-21), (N-Ethyi-N-propylaminoethyl)-4-sulfamoylbenzoate; (11-22), (N-Ethyi-N-propylaminopropyl)-4-sulfamoylbenzoate; (11-23), 4-Sulfamoyi-N-(N-ethyi-N-propylami noethyl) benzamide; {11-24),

10    4-Sulfamoyi-N-(N-ethyi-N-propylaminopropyl)benzamide; (11-25), (N-Propyi-N-buthylaminoethyl)-4-sulfamoylbenzoate; (11-26), (N-Propyi-N-buthylami nopropyl)-4-sulfamoylbenzoate; (11-27),

4-Sulfamoyi-N-(N-propyi-N-buthylaminoethyl)benzamide; (11-28), 4-sulfamoyi-N-(N-propyi-N-buthylaminopropyl)benzamide; (11-29),

15    (N-Ethyi-N-buthylaminoethyl)-4-sulfamoylbenzoate; (11-30), (N-Ethyi-N-buthylaminopropyl)-4-sulfamoylbenzoate; (11-31), 4-Sulfamoyi-N-(N-ethyi-N-buthylaminoethyl) benzam ide; (11-32), 4-Sulfamoyi-N-(N-ethyi-N-buthylaminopropyl)benzamide; (11-33),

(Pyrrolidi noethyl)-4-sulfamoylbenzoate; (11-34),

20    (Pyrrolidinopropyl)-4-sulfamoylbenzoate; (11-35), 4-Sulfamoyi-N-(pyrrolidinoethyl)benzamide; (11-36), 4-Sulfamoyi-N-(pyrrolidinopropyl)benzamide; {11-37),

(Piperidinoethyl)-4-sulfamoylbenzoate; (11-38), (Piperidinopropyl)4-sulfamoylbenzoate; {11-39),

25    4-Sulfamoyi-N-(piperidinoethyl)benzamide; (11-40), 4-Sulfamoyi-N-(piperidinopropyl)benzamide; (11-41 ).

The subject of the present invention also relates to the novel compounds having general formula (I),


30    wherein:

R1 is S02 and R2 is NH, and

Rand n are shown in the following Table:
 





1-1, 1-2


1-3, 1-4



1-5, 1-6



1-7


1-8, 1-9


1-10, 1-11



1-12, 1-13




1-14, 1-15


1-16, 1-17



1-18, 1-19


1-20, 1-21



1-22, 1-23
 


                                                            -6-           
            ;--            n = 2, 3       
                               
                                                    R=-N                   
                                            "-----                   
                                                                       
                                                                n = 2, 3       
                                                    R=-NCJ                   
                                                                       
                                                    r\        n = 2, 3       
                                                                   
                                                                   
                                                    R=  - N    0               
            \ _ /        n=O       
                                                    R=   rO-o~c           
                                                               
                                                               
                                                                       
                                                    I            n = 2, 3       
                                                    R=-N                   
                                        "            n =2, 3       
                                                    r                   
                                                    R=-N                   
                                        ~                   
                                                ~        n = 2, 3       
                                                               
                                                    R=-N                   
                                                                       
                                        ~               
                                                                       
                                                                       
                                                    I            n = 2, 3       
                                                    R= - N\                   
                                                               
                                            ; -            n = 2, 3       
                                                    R=-N~                   
                                                    / --            n = 2, 3       
                                                    R=-N~                   
                                                                       
                                    ~            n = 2, 3       
                                                    R=-N                   
                ~               
                                                    R= - 0            n = 2, 3       
                                                                       
                                                                       
 



The subject of the present invention particularly provides these compounds: N-(N ,N-Diethylaminoethyl)benzene-1 ,4-bis(sulphonamide); (1-1 ),

5    N-(N,N-Diethylaminopropyl)benzene-1 ,4-bis(sulphonamide); (1-2), N-(Pyrrolidinoethyl)benzene-1 ,4-bis(sulphonamide); (1-3),
 


-7-


N-(Pyrrolidinopropyl) benzene-1 ,4-bis(sulphonamide); (1-4),

N-(Morpholinoethyl) benzene-1 ,4-bis(sulphonamide); (1-5),

N-(Morpholinopropyl)benzene-1 ,4-bis(sulphonamide); (1-6),

N-( 4-Diethylaminoethoxybenzyl)benzene-1 ,4-bis(sulphonamide); (1-7),

5    N-(Dimethylaminoethyl)benzene-1 ,4-bis(sulphonamide); (1-8), N-(Dimethylaminopropyl)benzene-1 ,4-bis( sulphonamide); (1-9), N-(N,N-Dipropylaminoethyl)benzene-1 ,4-bis(sulphonamide); (1-1 0), N-(N,N-Dipropylaminopropyl)benzene-1 ,4-bis(sulphonamide); (1-11), N-(N, N-Dibuthylaminoethyl)benzene-1 ,4-bis(sulphonamide); (1-12),

10    N-(N,N-Dibuthylaminopropyl)benzene-1 ,4-bis(sulphonamide); (1-13), N-(N-Methyi-N-ethylaminoethyl)benzene-1 ,4-bis(sulphonamide); (1-14), N-(N-Methyi-N-ethylaminopropyl)benzene-1 ,4-bis(sulphonamide); (1-15), N-(N-Ethyi-N-propylaminoethyl)benzene-1 ,4-bis( sulphonamide); (1-16), N-(N-Ethyi-N-propylaminopropyl)benzene-1 ,4-bis(sulphonamide); (1-17),

15    N-(N-Ethyi-N-buthylaminoethyl)benzene-1 ,4-bis(sulphonamide); (1-18), N-(N-Ethyi-N-buthylaminopropyl)benzene-1 ,4-bis(sulphonamide); (1-19), N-(N-Propyi-N-buthylaminoethyl)benzene-1 ,4-bis(sulphonamide); (1-20),

N-(N-Propyi-N-buthylaminopropyl)benzene-1 ,4-bis(sulphonamide); (1-21 ),

N-(Piperidinoethy)benzene-1 ,4-bis(sulphonamide); (1-22),

20    N-(Piperidinopropyl)benzene-1 ,4-bis(sulphonamide); (1-23).


Substituted benzene 1 ,4-bis(sulphonamides) can be prepared by the nucleophilic reaction of amines  (IV)  with  4-sulfamoylbenzenesulphonyl  chloride  (V) in  the  presence  of triethylamine excess in tetrahydrofurane  or in  ether at the temperature 0 to  20 °C for  12 hours.  In the 25    preparation of the compounds  (1-1)  to  (1-4),  aliphatic amines  IV were used  in the  reaction, wherein one amino group is primary and the other is tertiary. Carbon linking chain between the nitrogen atoms comprises 2 or 3 carbon atoms. Tertiary amino group contains two alkyl groups,

1-1 and 1-2, or a nitrogen atom of this tertiary amino group is a part of the ring 1-3, 1-4, 1-5 and 1-6. In case of substituted 1,4-bis(sulphonamide) 1-7, there was 4-diethylaminoethoxybenzylamine

30    (XI) used as amine.

Substituted 4-sulfamoylbenzamides can be prepared by the nucleophilic reaction of amines having general formula (IV) with 4-sulfamoylbenzoyl chloride (VI) in tetrahydrofurane or in ether in the presence of triethylamine or N,N-diisopropylethylamine excess at the temperature 0 to 20
 

- 8 -


used in the reaction, wherein one amino group is primary and the other is tertiary. Tertiary amino group comprises two alkyl groups or nitrogen atom of this tertiary amino group is a part of the ring. In case of substituted 4-sulfamoylbenzamide (11-7), 4-amino-N-(3-morpholinopropyl) benzene-sulphonamide (XIII) was used as an amine. For the preparation of the substituted

5    benzoate 11-8, 2-diethylaminoethanol was used as a compound with primary amino group. The scheme for the preparation of the substituted benzene-1 ,4-bis(sulphonamides)

901 base + H2N-(CH2)n•R

IV

so2NH:2

(Va)

10

R =diethylamine, 1-pyrrolidino, 4-morpholino, 4-(diethylaminoethoxy)benzyl, n = 0, 2, 3
 

Q
 


SOC'!
2
 
S0    2    NH    2    :snNH   
                •2    •2   
(lila)        \\1~)       

The scheme for the preparation of the substituted benzamides II



COCI





SONH
2    •2

15    (VIa)    '(il'l:a)   
           
 

- 9-


X=NH, 0

R = dimethylamino, diethylamine, 1-pyrrolidino, 4-morpholino, 4-[N-(3-morpholinopropyl)aminosulphonyl]phenyl, n =0, 2, 3



SOCI2



SONH-
.2    2

(VIlla)    '(VIa)


5    The scheme for the preparation of certain starting compounds set forth in detail in the examples of the embodiment.
 

- 10-

HJ.-o-OH  +      CI~N\I__

IX






-



    02    -NH~Nl
+    H,N~a    ~        ~0
            (XIII a)
NH-CO-CH3    NH-CO-CH 3
(XII a)           
            j
    02    -NH~Nl
    ~        ~0

(XIVa)
 







In all case.s, the ammonium salts were prepared by the acidobasic reaction of the amino group 5 of the compounds 1-7 and 11-8 with the solution of hydrogen chloride rn methanol.
 


- 11 -


Compounds of the general formula (I) were tested in the form of their salts with hydrogen chloride. The pH of aqueous solutions of these salts is close to the pH= 7 value. 1H-NMR were determined on the Mercury Plus 300 MHz spectrometer in the DMSO solution.

5    The invention also relates to the use of the compounds of the general formula (I) and physiologically and pharmaceutically acceptable salts, hydrates or solvates thereof in the manufacture of the pharmaceutical compositions. For this purpose they can be processed to the appropriate dosage form together with the auxiliaries, alternatively together with one or more other active agents, particularly with the active agents for the treatment of glaucoma.

10

These compositions according to the present invention can be used as the medicaments in the human and the veterinary medicine. Particular the auxiliaries are selected according to the pharmaceutical formulation and required way of administration.

15    In the pharmaceutical compositions according to the present invention for the oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal, rectal or intraocular administration, the active component of said general formula (I) or the acceptable salts, solvates or hydrates thereof can be administered as unit dosage forms as well as the

mixtures with the conventional pharmaceutical vehicules, to the animals and human for the

20    prophylaxis or the treatment of the disorders or diseases associated with carboanhydrase enzyme. Appropriate dosage units include the formulations for oral way administration, such as tablets, gelatine capsules, powders, granules and oral solutions or suspensions, the formulations for sublingual, buccal, intratracheal or intranasal, subcutaneous administration, the formulations for intramuscular or intravenous administration and the formulation for rectal administration. For

25    topical application the compounds of the present invention can be used in creams, ointments, solutions, emulsions, microemulsions, suspensions or in eyewash. If the topical composition is prepared in the form of the solution, specifically in the form of eye drops, main pharmaceutical component is mixed together with auxiliaries, i.e.:

0,001 to 2 % by weight, the auxiliaries maintaining the pH conditions (for example: boric acid,

30    sodium borate, sodium phosphate, potassium phosphate and others)

0,001 to 2 % by weight, the auxiliaries adjusting isotonicity of the environs (for example: sodium chloride, potassium chloride, glucose, mannitol and others)

0,001 to 2 % by weight, the preservatives (for example: benzalconium chloride, chlorohexidine and others)
 


- 12-


0,001 to 2% by weight, the auxiliaries adjusting viscosity of the environs (for example: hydroxyethyl celulose, hyidroxymethyl celulose, povidone, polyvinylalcohol and others)

0,001 to 2% by weight, the antioxidants (for example: citric acid, mannitol, EDTA and other). These auxiliaries are given as examples, otherwise many other agents can be even used.
5

Compounds of the general formula (I) and physiologically acceptable salts, hydrates or solvates thereof can be used for prophylaxis and treatment of diseases, particularly for treatment of increased intraocular pressure, glaucoma.

10    On the basis of the above described assays and below described results of the assays, the synergic effect of our compound together with other antiglaucomatics selected from these

groups can be expected: sympatomimetics (clonidine, brimonidine, epinephrine); parasympatomimetics (pilocarpine, carbachole); betablocators (timolol, betaxolol, levobunolol); prostaglandine analogues (latanoprost, bimatoprost, travoprost); and other antiglaucomatics

15    (guanetidine, dapiprazole).


The invention is illustrated by following examples of the present invention embodiment, without limiting it in any way.

20    EXAMPLES

Preparation of the starting compounds


Example 1

Preparation of 4-sulfamoylbenzenesulphonyl  chloride (V)  [Cross,  P.  E.,  Gatsby,  B.,  J.  Med.

25    Chern. 21, 845 (1978); Holland, G. F., Funderburk, W. H., J. Med. Chern. 6, 307 (1963)].


To the 700 ml Erlenmeyer flask was taken up 54 ml of the distilled water and 72 ml of the concentrated hydrochloric acid. The solution was cooled to 0 °C and 24 g (0.139 mol) of sulfanilamide Ill was added successively portionwise under stirring. The mixture was stirred at

30    this temperature another 1 hour. To this mixture, the solution of 9.6 g (0.139 mol) of sodium nitrite in 16 ml of the water was added dropwise for 30 minutes under stirring and cooling, so as the temperature of the mixture does not exceed 0 °C. The mixture was then stirred another 30 minutes at the 0 °C. In the meantime, the solution of 36 g (0.56 mol) of sulphur dioxid in 120 ml of 99% acetic acid was prepared. Sulphur dioxid was prepared by the successive addition of 100
 

- 13 -


g of sodium pyrosulphite to 250 ml 40% sulphuric acid. Prepared sulphur dioxid was taken up under cooling to the 120 ml of 99% acetic acid at +5 oc until the weight gain reaches 36 g. To this solution, 1.4 g of copper dichloride dihydrate was added and the mixture was stirred. To this mixture, the solution of prepared diazonium salt it is then added for 5 minutes under gentle

5    stirring for 10 minutes in three portions so as the temperature of the mixture did not exceed +5 °C. After about 15 min evolution of forming nitrogen occurs. The mixture was stirred another 15 min, 200 ml of the mixture of the water and the grinded ice was added and the mixture was

stirred another 20 min. Obtained solid was separated, washed 3 times with the ice water and dried. Crystallization from ethyl acetate. Colourless solid m.p. 156- 157 °C. Afforded 14,9 g (42

10    %) of 4-sulfamoylbenzenesulphonyl chloride V.


Example 2

Preparation of sodium 4-sulfamoylbenzoate (VIII) [Gubert, S., Farmaco 45, 59 (1990); Rodionov, V. H., Javorskaja, E. V., Zh. Obsc. Chim. 18, 110 (1948)].

15

In the 500 ml Erlenmeyer flask the solution of 20.1 g (0.2 mol) potassium bicarbonate in 180 ml of the distilled water was prepared. To this solution, 40.2 g (0.2 mol) of 4-sulfamoylbenzoic acid VII was added portionwise for 30 minutes under stirring at 45 °C, each time until dissolution. The mixture was fizzing by leaking C02 . Then the water was distilled off to the dryness from the

20    solution on the vacuum rotatory evaporator (the temperature of the bath did not exceed 60 °C). Remaining humidity was removed by severalfold azeotropic distillation with toluene on the vacuum evaporator. The solid residue was shaken with dichloromethane, this was decanted and the solid product was dried under the infralamp. Colourless solid. Yield 43 g (98 %) of potassium 4-sulfamoylbenzoate VIII.
25

Example 3

Preparation of 4-sulfamoylbenzoyl chloride (VI) [Gubert, S., Farmaco 45, 59 (1990); Rodionov,

V. H., Javorskaja, E. V., Zh. Obsc. Chim. 18, 110 (1948)].


30    To the 3-neck flask equipped with the stirrer and the thermometer, fresh distilled 55 ml of thionylchloride was taken up and 3 drops of dimethylformamide was added. The mixture was heated in the oil bath to 40 °C and at this temperature 35.8 g (0.149 mol) of potassium 4-

sulfamoylbenzoate VIII was added portionwise for 30 minutes under stirring. Then the mixture was heated to 55 oc for another 40 min. On the vacuum rotatory evaporator, excess
 

- 14-


thionylchloride was distilled off and the product was extracted 3 times into 100 ml of hot (60 °C) anhydrous dioxane. The solution was diluted with adding 500 ml of petroleum ether. Obtained solid was separated, washed with petroleum ether or hexane and purified by crystallization from chloroform. Almost colourless solid, m.p 151-153 °C. Afforded 20 g (61 %) of 4-sulfamoylbenzoyl

5    chloride VI.


Example 4

Preparation of 4-diethylaminoethoxybenzaldehyde X [Rodionov, V. H., Javorskaja, E. V., Zh. Obsc. Chim. 18, 110 (1948)].
10

To the solution of 18.4 g (0.15 mol) of 4-hydroxybenzaldehyde in 100 ml acetone, 27.5 g (0.16 mol) of N,N-diethyi-N-(2-chlorethyl)-amine IX and 22.1 g (0.16 mol) potassium carbonate was added at the room temperature under stirring. The mixture was then intensively stirred at the boiling temperature for 12 hours. The mixture was cooled, potassium chloride was separated,

15    washed with acetone. The solvent was distilled off from the solution on the vacuum rotatory evaporator. Afforded 20 g (60.6 %) of 4-diethylaminoethoxybenzaldehyde X. Colourless fluid
boiling point 120-123 oc I 0.5 torr, n20 0  = 1.536. Lit. [5] reports boiling point 123-125 °C I 0.8 torr,

n20 0  =1.530.


20    Example 5

Preparation of 4-diethylaminoethoxybenzylamine XI [Cossey, H. D., Sharpe, C. J., J. Chem. Soc. 4322 (1963).Goldberg, M. W., Moutclair, U., Schw. Pat. 365387 (1962)]

To the solution of 4-diethylaminoethoxybenzaldehyde X in 180 ml 10% solution of ammonia in

25    anhydrous ethanol, 4.5 g RaNi was added and the mixture was heated to 80 oc at the pressure 68 atm in the autoclave under hydrogen input to the reaction mixture under stirring for 12 hours. The mixture was cooled, the catalyst was filtered off, •washed with ethanol. The solvent was

distilled off from the solution and the distillation residue was purified by distillation under the

reduced pressure. Afforded 13 g (65 %) of 4-diethylaminoethoxybenzylamine XI. Colourless fluid

30    138-140 oc I 0.5 torr, n20 o = 1.520. Lit. [6, 7] reports 130 °C I 0,3 torr, n20 0  = 1.5220.


Example 6

Preparation of 4-acetamido-N-(3-morpholinopropyl)benzenesulphonamide XIII [Goldberg, M. W., Moutclair, U., US. Pat. 2.879.293 (1959)]
 

- 15-



To the solution of 2.8 g (0.020 mol) of 3-morpholinopropylamine in 15 ml of acetone, the solution of 3.3 g (0.024 mol) of potassium carbonate in 3 ml of water was added under stirring. To this mixture, 5 g (0.021 mol) of 4-acetamidobenzenesulphonyl chloride XII was added portionwise at

5    the room temperature for 15 min. The mixture was then stirred at the room temperature for another 2 hours. One half of the solvent volume was distilled off from the mixture, the mixture was cooled to 0 °C, Obtained solid was separated, washed 3 times with 5 ml of ice water and dried. Afforded 4,2 g (62 %) of 4-acetamido-N-(3-morpholinopropyl)benzenesulphonamide XIII, colourless solid, m.p. 97-98 .°C.
10

Example 7

Preparation  of 4-amino-N-(3-morpholinopropyl)benzenesulphonamide  XIV  [Goldberg,  M.  W.,

Moutclair, U., US. Pat. 2.879.293 (1959)]


15    The mixture of 3.4 g (0.001 mol) of 4-acetamido-N-(3-morpholinopropyl)benzene sulphonamide XIII and 4 ml of 17% acid was heated for 3.5 hours until slight boiling under stirring. The mixture was cooled to the room temperature and neutralized to chloroform. The solvent was distilled off from the solution and the distillation residue - oil was macerated with ether. Afforded 2.1 g of (71 %) 4-amino-N-(3-morpholinopropyl)benzenesulphonamide XIV. Colourless solid, m.p. 96-97 °C.

20    Lit. [8] reports 95 °C.


Example 8

Preparation of N-(N,N-diethylaminoethyl)benzene-1 ,4-bis(sulphonamide) (1-1)


25    To the 250 ml 3 neck flask equipped with the thermometer, the add funnel, the magnetic stirrer, 50 ml of anhydrous tetrahydrofurane (0.0485 mol), N,N-diethylaminoethylamine IV and 24 g of (33 ml) (0.238 mol) triethylamine was taken up. The solution was cooled to 0 to 5 °C and the solution of 12 g (0.0469 mol) of 4-sulfamoylbenzenesulphonyl chloride V in 50 ml anhydrous tetrahydrofurane or ether was for 30 min added under cooling and stirring at 0 to 15 °C. The

30    solid was separated. The mixture was then stirred for 12 hours at the room temperature. 100 ml of petroleum ether was added to the solution, the mixture was stirred, the semi-solid product was
 

filtered off. This was triturated with 15 ml of saturated aqueous solution of sodium chloride. The solid product was separated, washed 2 times with 10 ml ice water and dried. Purification with crystallization from the water:ethanol mixture (2:1). Afforded 7.4 g (47 %) of N-(N,N-
 


- 16-


diethylaminoethyl)benzene-1 ,4-bis(sulphonamide) 1-1. Colourless solid, m.p. 128-130 °C. Ammonium salt was prepared by acidification at pH = 4 of 5 g (0.015 mol) of this base solution in 50 ml of methanol with 10 to 20% hydrogen chloride solution in methanol. 50 ml ether was added to the mixture. Obtained solid was filtered off, washed with ether and purified with

5    crystallization from the water:ethanol mixture (3:1). Afforded 4.6 g (82 %) of ammonium salt of the agent 1-1. Colourless solid matter, m.p. 185 to 187 °C.

H-NMR of the compound I-1.HCI
1-1 (salt) o CH3  1.166, 1.177, 1.190, t (6 H), CH2 3.992, 3.112, 3.123, m (6 H) CH2 3.163, 3.169,
3.172 m (2 H) S02-NH2 7.653, s ( H) Har. 8.036, (4 H) SOTNH 8.383, 8.395, 8.405, t (1 H) NH+

10    10.173, s (1 H).


Instead of tetrahydrofurane, ether can be used (5,6 g) and instead of triethylamine, N,N'-diisopropylethylamine (DIPEA) can be used.

15    Example 9

Preparation of N-(N,N-diethylaminopropyl)benzene-1 ,4-bis(sulphonamide) (1-2)


The procedure as in Example 8 (compound 1-1). 6.3 g (0.0485 mol) N,N-Diethylamino-propylamine was used. Afforded 7.4 g (47 %) of N-(N,N-diethylaminopropyl)benzene-1 ,4-

20    bis(sulphonamide). Colourless solid, m.p. 133-135 °C. For the preparation of the ammonium salt

5.3    g (0.015 mol) of the base 1-2 was used. Afforded 5.0 g (90.3 %) of the ammonium salt of compound 1-2. Colourless solid, m.p. 198-200 °C.

H-NMR:
1-2 (salt) o CH3  1.156, 1.180, 1.205, t (6 H) CH2 1. 780 - 1.800 m (2 H) CH2 2.864- 2.884 m (2 (2
25    H) CH2 2.997, - 3.053 m (6 H) S02-NH2 1.648, s (2 H) Har 7.982, 8.011, 8.027, 8.057 dd (4 H) SOrNH 8.068, 8.090, 8.094 t (1 H) NW 10.254, s (1 H).


Example 10

Preparation of N-(pyrrolidinopropyl)benzene-1 ,4-bis(sulphonamide) (1-4)

30

The procedure as is Example 8. 6.2 g (0.0485 mol) of Pyrrolidinopropylamine was used. Afforded 6.7 g (41.0 %) of N-(pyrrolidinopropyl)benzene-1 ,4-bis(sulphonamide). Colourless solid, m.p. 120-122 °C. For the preparation of the ammonium salt 5.5 g (0.0158 mol) of the base
 

- 17-


1-4 was used. According to the procedure as in Example 8, 5.2 g (85.8 %) of the ammonium salt of compound 1-4 was afforded. Colourless solid, m.p. 180-183 °C.

H-NMR:
1-4 (salt) o CH2 1.835, 1.852, 1.875, 1.904, 1.943, 1.969 m (6 H) CH2 2.856 - 2.898 m (4 H) CH2

5    3.044- 3.113 m (2 H) Har 7.987, 8.015, 8.026, 8.054 dd (4 H) S02-NH 8.079, 8.098, 8.118 t (1 H) NW 10.868 s (1 H).

Example 11

Preparation of N-(morpholinopropyl)benzene-1 ,4-bis(sulphonamide) (1-6)

10

The procedure as is Example 8. 7 g (0.0485 mol) of Morpholinopropylamine was used. Afforded

8.2 g (48,0 %) of N-(morpholinopropyl)-1 ,4-bis(sulphonamide) 1-6. Colourless solid, m.p. 121-123

oc.

H-NMR:

15    1-6 (base) o CH2-middle 1.533, 1.564, 1.574 t (3 H) CH2 2.377, m (4 H) CH2-N 2.806, 2.818, 2.829 t (2 H) CH2 3.557 m (6 H) S02-NH2 7.607 s (2H) S02-NH 7.865, s (1 H) Har 7.962, 7.975, 8.01 0, 8.023 dd (4 H).


For the preparation of the ammonium salt 6.0 g (0.0173 mol) of the base 1-6 was used. The

20    procedure as is Example 8. Afforded 4.9 g (86.0 %) of ammonium salt of compound 1-6. Colourless solid, m.p. 232-234 °C.

H-NMR:

1-6 (salt) o CH2 1.813 - 1.912 m (2 H) CH2 2.823- 2.881 m (2 H) CH2 2.953 - 3.102 m (4 H) CH2 3.322- 3.363 m (2 H) CH2 3.731 - 3.964 m (4 H) SOTNH2 7.642 s (2 H) Har 8.002, 8.011, 8.022,
25    8.032 dd (4 H) S02-NH 8.053, 8.076, 8.096 t (1 H) NH+ 10.893 s (1 H).


Example 12

Preparation of N-(4-diethylaminoethoxybenzyl)benzene-1 ,4-bis(sulphonamide) (1-7)


30    The procedure as in Example 8. 10.8 g (0.0485 mol) of 4-Diethylaminoethoxybenzylamine XI was used. Afforded 8.6 g (37.7%) of N-(4-diethylaminoethoxybenzyl)benzene-1 ,4-bis(sulphonamide) 1-7. Colourless solid, m.p. 72-74 °C.
 

- 18-


For the preparation of the ammonium salt, the procedure as in Example 8 was used. For the preparation of the ammonium salt, 7.8 g (0.0176 mol) of the base 1-7 was used. Afforded 6.4 g (76.2%) of the ammonium salt of compound 1-7. Colourless solid, m.p. 92-94 °C.

H-NMR:

5    1-7 (salt) o CH3 1.217, 1.242, 1.265 t (6 H) CHz 3.166- 3.217 m (4 H) CH2-N 3.960, 3.981 d (2 H) CH2-0 4.315, 4.318, 4.321 t (2 H) Har (0-phenyl) 6.87,380, 7, 6.906, 7.159, 7.188 dd (4 H) SOz-NH2 7.635 s (2H) Har (S-phenyl) 7.961 - 7.971 dd (4 H) SOz-NH 8.380, 8.384, 8.387 t (1H) NH+ 10.230 s (1 H).


10    Example 13

Preparation of 4-sulfamoyi-N-(N, N-dimethylaminoethyl) benzamide (11-1)


To the 250 ml 3 neck flask equipped with the thermometer, the add funnel and the stirrer, 40 ml of tetrahydrofurane or ether, 4.3 g (0,0485 mol) of N,N-dimethylaminoethylamine and 24 g (33

15    ml) (0.238 mol) of triethylamine or DIPEA (diisopropylethylamine) was taken up. The solution was cooled to 0 oc and the solution of 10.3 g (0.0470 mol) of sulfamoylbenzoyl chloride IX in 60 ml tetrahydrofurane or ether was added dropwise for 30 min under cooling and stirring so as the temperature did not exceed 0 to 15 °C. The mixture was then stirred for 12 hours the at room

temperature. 100 ml of petroleum ether or hexane was added to the mixture. The semi-solid

20    product was filtered off and macerated with 20 ml of ice-cooled saturated aqueous sodium chloride solution. The solid product was separated, washed once with 10 ml saturated aqueous sodium chloride solution, 2 times with ice water and purified with crystallization from the water:ethanol (2:1). Afforded 6.1 g (48.0 %) of 4-sulfamoyi-N-(2-dimethylaminoethyl)benzamide 11-1. Colourless solid, m.p. 150-151 °C.

25    H-NMR:

11-1 (base) o CH3  2.182 t (6 H) CHz-N+ 2.389, 2.412, 2.435 t (2 H) CH2-NCO 3.356 - 3.376 m (2
H) SOrNH2 7.472 s (2 H) SOz-NHz 7.472 s (2 H) Har 7.871, 7.899, 7.962, 7.991 dd (4 H), CO-

NH 8.590, 8.594, 8.958 t (1 H).


30    Ammonium salt was prepared by acidification to pH=5 of 5 g (0.015 mol) of this compound 11-1 solution in 40 ml of methanol with 10 to 20% hydrogen chloride solution in methanol. 80 ml of ether was added to the mixture, the solid was filtered off and purified with crystallization from water: ethanol (1 :2). Afforded 4,5 g (80,4 %) of ammonium salt of compound II-1.Colourless solid, m.p. 208-210 °C.
 

- 19-


H-NMR:

11-1 (salt) o CH 3 2.821 s (6 H) CH2-N+ 3.270, 3.270, 3.278, 3.297 t (2H) CHrNCO 3.630, 3.649, 3.668 t (2 H) S02-NH2 7.524 s (2 H) Har 7.896, 7.924, 8.084, 8.113 dd (4 H) CO-NH 9.087, 9.1 04, 9.123 t (1 H) NH+ 10.365 s (1 H).

5

Example 14

Preparation of 4-sulfamoyi-N-(N,N-diethylaminoethyl)benzamide (11-3)


The procedure as in Example 13. 5.6 g (0.0485 mol) of N,N-diethylaminoethylamine was used.

10    Afforded 6.2 g (44.0 %) of 4-sulfamoyi-N-(2-diethylaminoethyl)benzamide. Colourless solid, m.p. 174-176 °C.

H-NMR:

11-3 (base) o CH 3 0.945, 0.969, 0.993 t (6 H) CH2 2.501 - 2.584 m (8 H) S02-NH2 7.466 s (2 H) Har 7.873, 7.900, 7.957, 7.985 dd (4 H) CO-NH 8.568, 8.571, 8.574 t (1 H).

15

For the preparation of the ammonium salt 5.2 g (0.0184 mol) of base 11-3 was used. According to the procedure as in Example 13, 5.1 g (85,4 %) of the ammonium salt of compound 11-3 was used. Colourless solid, m.p. 201-202 °C.

H-NMR:

20    11-3 (salt) o CH3 1.203, 1.233, 1.254 t (6 H) CH2 3.161 - 3.203 m (6 H) CHrN+ 3.66 m (2 H) SOr NH2 7.51 s (2 H) Har 7.903, 7.932, 8.084, 8.101 dd (4 H) CO-NH 9.142, 9.173, 9.212 t (1 H) NW 10.383 s (1 H).


Example 15

25    Preparation of 4-sulfamoyi-N-(N,N-diethylaminopropyl)benzamide (11-4)


The procedure as in Example 13. 6.2 g (0.0485 mol) of N,N-diethylaminopropylamine was used. Afforded 6.2 g (44.0 %) of 4-sulfamoyi-N-(N,N-diethylaminopropyl)benzamide 11-4. Colourless solid, m.p. 122-123 °C. For the preparation of the ammonium salt, 5.2 g (0.0184 mol) of base

30    was used. According to the procedure as in Example 13, 5.2 g (85.4 %) of the ammonium salt of compound 11-4. was afforded. Colourless solid, m.p. 165-167 °C.

H-NMR:
 


-20-

11-4 (salt) o CH 3 1.173, 1.197, 1.221 t (6 H) CH2 middle 1.900 - 1.958 m (2 H) CH2 (3.350 - 3.358) m (2 H) S02-NH2 7.513 s (2 H) Har 7.887, 7.914, 8.018, 8.045 dd (4 H) CO-NH 8.936, 8.940, 8.944 t (1 H) NH+ 10.250 s (1 H).


5    Example 16

Preparation 4-sulfamoyi-N-(morpholinopropyl)benzamide (11-6)


The procedure as in Example 13. 7.0 g (0.0485 mol) of morpholinopropylamine was used and

7.3    g  (47.7  %)  of 4-sulfamoyi-N-(morpholinopropyl)benzamide  11-6 was  afforded.  Colourless

10    solid, m.p. 196-198 °C.

H-NMR:

11-6 (base) o CH2 (middle) 1.643, 1.666, 1.689, 1.712, 1.736 quintet (2 H) CH2 2.306-2.353 m (6H) CH2 3.272 - 3.294 m (2 H) (CH2h 0 3.548, 3.564, 3.580 t (4 H) S02-NH2 7.477 s (2 H) Har 7.874, 7.880, 7.897, 7.903, 7.971, 7.987, 7.994 m (4 H) CO-NH 8.644, 8.662, 8.680 t (1 H).

15

For the preparation of the ammonium salt, 6.0 g (0.0183 mol) of base 11-6 was used. According to the procedure as in Example 13, 5.9 g (88,0 %) of the ammonium salt of compound 11-6 was used. Colourless solid, m.p. 196-198 °C.

H-NMR:

20    11-6 (salt) o CH2 1.963- 2.040 m (2 H) CH2 2.991 - 3.152 m (4 H) S02-NH2 7.510 s (2 H) Har 7.892, 7.923, 8.021 8.053 dd (4 H) CO-NH 8.912, 8.933, 8.952 t (1 H) NW 10.992 s (1 H).


Example 17

Preparation of 4-[N-(morpholinopropyl)sulfamoyl]phenylsulfamoylbenzamide; (11-7)

25

The procedure as in Example 13. 14.6 g (0.0485 mol) of 4-Amino-N-(morpholinopropyl)-benzene-sulphonamide XIII was used and 10.1 g (44.5 %) of 4-sulfamoyi-N-[4-(morpholinopropyl) aminosulphonylphenyl]benzamide 11-7 was afforded. Pale yellow oil.

H-NMR:

30    11-7 (base) o CH2 1.493, 1.522, 1.543 t (2 H) CH2 3.510 - 3.542 m (6 H) 802-NH 7.502, 7.523, 7.541 t (1 H) S02-NH_6 7.562 s (1 H) Har (CO-phenyl) 7.776, 1.805, 8.109, 8.137 dd (4 H) Har (N-phenyl) 7.961, 7.973, 7.990, 8.003 dd (4 H) CO-NH 10.763 s (1 H).
 

-21-


For the preparation of the ammonium salt, 8.0 g (0.0166 mol) of base 11-7 was used. According to the procedure as in Example 13, 7.0 g (81.4 %) of the ammonium salt of compound 11-7 was afforded. Colourless solid, m.p. 201-202 °C.

H-NMR:

5    11-7 (salt) CH2 (middle) 1.815, 1.840, 1.865 t (2 H) CH2 2.780, 2.802, 2.823, 2.844 m (2 H) CH2 3.921, 3.960 d (2 H) S02-NH2 7.500 s (2 H), S02-NH 7.706, 7.746 t (1 H) Har (CO-phenyl) 7.796, 7.825, 8.126, 8.154 dd (4 H) Har (N-phenyl) 7.962, 7.990, 8.005, 8.035 dd (4 H) NH+ 10.568 s (1 H) CO-NH 10.842 s (1 H).


10    Example 18

Preparation of N,N-diethylaminoethyl-(4-sulfamoylbenzoate) 11-8


The procedure as in Example 13. 5.7 g (0.0485 mol) of N,N-diethylaminoethanol was used. Afforded 6.1 g (43.3 %) of N,N-diethylaminoethyl-(4-sulfamoylbenzoate) 11-8. Colourless solid,

15    m.p. 159-160 °C. For the preparation of the ammonium salt, 5.1 g (0.017 mol) of base 11-8 was used. According to the procedure as in Example 13, 4.4 g (77.2 %) of the ammonium salt of compound 11-8 was afforded. Colourless solid, m.p. 185-186 °C.

H-NMR:

11-8 (salt) o CH3  1.242, 1.273, 1.291 t (3 H) CH2 3.203- 3.242 m (4 H) CH2  3.522- 3.541 m (2 H)

20    CH2 4.653- 4.702 m (2H) SOz-NHz 7.621 s (1 H) Har 7.962, 7.993, 8.210, 8.243 dd (4 H) NH+ 10.633 s (1 H).

Example 19

The results of effectiveness assays

25

Effectiveness of the compounds according to of the invention is supported with the results of the pharmacological assays.

The basic pharmacologic profile of the compounds of the general formula (1), which was focused

30    on the determination of the intraocular pressure changes, was evaluated in in vivo conditions. In addition to the main potential therapeutic effect, related side responses were also monitored. In the experiments the laboratory animals of chinchilla species were used, because the normotension eye of this animal species provides the best reactivity. Adult male Chinchilla (in the age of one to one and half year), of 2000-3500 g, examined by veterinarian, without disease
 

-22-


symptoms, grown under the standard conditions was used as the animal model. The solutions of tested compounds of the general formula (I) were always freshly prepared. The distilled water was used as a control. Measurement apparatus Tono-Pen®XL from Medtronic XOMED was used for measurement of the intraocular pressure. The intraocular pressure values were

5    expressed in Torr. At the first day of the experiment the solutions of the tested compounds of the general formula (I) were applied twice a day, specifically at 8.00 a.m. and 2.00 p.m .. At the second day of the experiment the application was still in the 30th hour (i.e. at the second day at 2.00 p.m.).

10    The solution of each compound was always applied in an amount of 2 drops into the right conjunctiva sac. The left eye served as a control. Into the conjunctiva sac of this eye (left), the same number of drop (2 drops) of distilled water was applied. The distilled water served as

placebo.

Into the conjunctiva sac of both eyes one drop of the local anesthetic (oxybuprocain) was

15    administered and massaged by careful circular movement (1-2), before the measurement of the intraocular activity both of the compound solution or the distilled water.

Standard requirements were kept in all measurements. The measurements started in the morning at 7.00 a.m. The measurement was accomplished with Tono-Pen® XL apparatus by
soft perpendicular touch of the probe to the cornea of the rabbit five times successively. The

20    measurement was accomplished on the both cornea (right and left eyes) before administration of the sample. Thus the normal values of the intraocular pressure for both the right and left eyes were obtained. Then at 8.00 a.m. 2 drops of tested compound were applied in the right eye and 2 drops of the distilled water were applied in the left eye.

Further measurements were carried out after half an hour (at 8.30 a.m.), after one hour

25    (at 9.00 a.m.), after four hours (at 12.00), after seven hours (at 3.00 p.m.), after 25 hours (on the second day at 9.00 a.m.) and after 31 hours from the application in the right eye (on the second

day at 3.00 p.m). The intraocular pressure changes in the left eye of the rabbit after placebo application, i.e. 2 drops of distilled water, were monitored in the same time intervals. Moreover, 2 drops of the tested compound in the right eye and 2 drops of distilled water in the left eye were

30    applied again in the same group of the rabbits in the first day at 2.00 p.m. (i.e. 6 hours after application of the first dose of the compound) and in the second day of the experiment at 2.00 p.m. (i.e. in the 30th hour of the experiment). Thus the changes caused by the repeated administration of the compound can be monitored. For each compound and each concentration 10 independent assays were carried out.
 

-23-
 


No negative side effects were Tables show a the absolute concentration of 2% and 2,5 time intervals.
 


observed during the experiments.

number values obtained by monitoring of compound 1-6 at the % and of compound 11-6 at the concentration of 1% in determined
 

5
 
-24-
 

                                                                                                                                                                    -    -                                       
                            Measured intraocular pressure values [Torr]                                                                                                                           
                                                                                                                                                                                                                       
n        N                        0.5 h                1h  .                f4h                        7h                ~5h                31h           
            LE        RE                LE    RE        LE        RE            LE    RE                    LE    RE        LE    RE            LE        f?E   
                                                                                                                                                   
                                                                                                                                                   
                                                                               
1                        14            14                    11        11        16            14            11        t?                    7        ~        11    12            11        11   
                                                                                                                                                                       
2                                                                                                                                                    p                    9                                    ~   
                            14            15            ~        ~        ~                11            i1    7                                    ~            ~            ~           
                                                                                                                                                                           
                                                                                                                                        !7                                           
3                        12            13            13        12            10            10        ~        8                                        ~        11    12                    ~        10   
                                                                                                                if'                                                                                                           
~                        16            14            13        15            15            13                12                        ~            7        13    12                    14        14   
5                        12            14                    12        9            ~            12            ~        !7                            ~        6        13    15                    14        ~   
6                        10            11                    ~        7            12            8            ~        ~                                    t?        10        ~    8                    12        9   
                                                                                                                                                                                                       
7                        10            12                    9        7            ~            9            ~        p        .            ~        8        11    9                    13        10   
8                                                                                                                                                                                   
                        12            13            8        8        10            9        ~        8                                    if'        8        ~    9                ~        ~   
9                        10            13                    8        9            10            9            10        9                            ~        8        10    9                12        11   
10                        10            10                    9        9            ~            8            ~        12                                10        10        ~    12                    13        13   
~verage        12            12.9                9.8        9.6            10.9        10.3            ~.5        8.4                            ~-4        7.3        10.4    10.7                    11.6        10.4   
SD            ~.11            1.52                        ~.60        ~.11        2.07            1.26        1.83        1.71                ~.01       
                                        2.35        ~.46                            1.27                                    ~.21                    1.90   
SE±            0.67            ~.48        0.74        ~.78            0.82        ~.67        ~.40    0.65            ~.40        ~.58        p.54    ~.70                p.64        0.60   
                                                   
 

p (t-test) versus N            0.003    0.001    0.069    p.ooo    p.002    p.ooo    p.001    p.ooo    p.018    p.009    p.345    0.009   
                                                           
p (t-test) L vs R        0.144        0.427        p.2s9        P.449        P.444        p.369        0.093   
--                                        ' -------    L __----    L __-    ----    --   
                                                           
Compound 1-6, concentration of 2%                                                   
N - normal value before application                LE -left eye                               
SO - standard deviation                    RE- right eye                           
SE - standard error of the average                                                   
 
-25-


                                                                                                                                                ---    -                           
                            Measured intraocular pressure values [Torr]                                                                                                       
                                                                                                                                                                                   
                            N            0.5 h                1h                            f4h                    7h                25h                31h                           
    n                                                                                                                                                               
            LE    RE    LE    RE    LE    RE                LE        RE        LE        RE    LE    RE    LE    RE                   
                                                                                                                           
                                                                                                                                                                                   
    1                15        14    10        ~        9    10                    13        11        8        ~        12    15        ~    ~                       
                                                                                                                                               
    2                14        15    10        12        12    ~                    12        10        10        10        13    13        10    16                       
                                                                                                                                               
    3.                12        12    12        9        18    13                    12        13        15        11        13    14        12    13                       
                                                                                                                                               
    4                13        14    16        16        13    16                    12        11        14        16        13    13        16    15                       
                                                                                                                                               
                                                                                                                                               
                                                                                                                                                                               
    5                13        16    12        11        ~    11                    12        ~        10        ~        13    15        12    12                       
    6                14        16    10        10        ~    9                    10        10        p        7        12    11        9    9                       
    7                18        17    9        11        11    10                ~        ~        ~        9        10    12        10    9                       
                                                                                                                                               
    8                18        18    10        10        10    9                    ~        ~        ~        9        13    12        13    10                I       
    9                16        15    12        12        ~    9                    ~        9        ~        8        13    12        ~    9                I       
                                                                                                                                           
    10                18        16    10        10        11    9                    13        11        11        9        13    13        12    10                I       
                                                                                                                                           
                                                                                                                                   
    Average    15.1        15.3    11.1        11        11    10.5                11        10.1        ~.7        9.6    12.5    13        11.1    11.2                I       
                                                                                                                           
    so    2.28        1.70    2.02        ~.05    ~.91    ~.32                1.83        1.45        ~.95        2.50    b.97    1.33    ~.38    2.66                i       
                                                                                                                                                                                   
    SE±    0.72        0.54    0.64        ~.65    0.92    ~.73                    0.58        0.46        ~.93        0.79    p.31    0.42    ~.75    0.84                       
                                                                                                   
                                                                                           
    p(t-test) vs N                    0.005        0.000    0.008    p.001    P.003    0.000    p.002    ~.000    0.008    p.011    p.003    0.003               
                                                                                       
    p(t-test) L vs R            0.413            0.457        ~.338                            0.119                p.468            0.175        0.465               
                                                                    L___.___ ______            -                --    L ___----    L __ -    --    ----    -    -        --               
            Compound 1-6, concentration of 2,5%                                                                                                                                   
                                            LE -left eye                                                                       
            N - normal value before application                                                                                                       
            SD - standard deviation                                                RE- right eye                                                                       
            SE - standard error of the average                                                                                                                                   
 
-26-

- •• -

Measured intraocular pressure values [Torr]

                                                                                                           
n    N        0.5 h            1h            4h                        7h            25h            31h           
                                                                                                       
        PO    to    PO        to    PO    to    PO        tO    PO    to    PO        tO    PO   
1.:0                                                                   

                                                                                                                                               
1            14    14    11        10    12        14    ~    8    r;    ~    13        12    11    10           
    2                18        14    12                9    11            9    ~    8        ~    8    13        12    12    9               
                                                                                                                       
    3                13        10    12                10    12            8    8    ~        11    6        14        12    11    11           
                                                                                                                       
    ~                18        17    18                14    13            12    12    11    13    13        14        16    11    14           
    5                17        18    15                14    15            12    12    13    11    12        12        13    14    14        I   
                                                                                                                   
    6                11        11    10                9    11            12    10    ~    9    ~        11        12    10    ~               
                                                                                                                       
    7                16        15    11                8    11            17    10    12    8    ~        11        13    10    10           
    8                15        16    13                11    13            10    11    10    9    ~        16        16    12    12           
    9                15        17    12                11    13            10    11    ~    10    ~        16        18    10    10           
    10            18.        ~6    12                10    12            10    11    11    11    11        15        13    12    12           
    [Average        15,5        15,8    12,6                10,6    12,3            10,4    10,1    ~,6    9,3    ~.1        13,5        13,7    11,3    11,1           
                                                                                                                   
    so        2,37        4,42    2,32            2,01    1,25            2,12    1,60        ~.17        1,95    ~.33        1,84        ~.16    1,25    1,85           
                                                                                                                                               
    SE±        0,75        1,40    0,73            0,64    ~.40            0,67    0,50        p,69        p,62    p,74        p,58    0,68    ~,40    0,59        I   
                                                                                                                                               
                                                                                                                                            I   
                                                                                                                                            I   
    p (t-test) versus N                        0,001        0,002    p,oo1        0,003    ~.ooo        p,ooo        ~.ooo    0,000        p,021    0,080    ~.ooo    p,002    I   
                                                                                                   
    p (t-test) L vs R                0,426                0,027                0,013                b,282            b,419        L __   __    b,413        b,390   I   
                                                                                                       
                                                                                                       
                                                                                                       
    ' ----- •                                                                                                            ' ------            ------       
                                                                                                                                       
        Compound 11-6, concentration of 1%                                                                                                               
        N - normal value before application                                        LE- left eye                                                               
        SO - standard deviation                                                    RE- right eye                                                   
        SE - standard error of the average                                                                                                               
 
-27-




Industrial utilization


Substituted sulphonamides of the general formula I are useful as active compounds in the manufacture of the pharmaceutical compositions, drugs, in human and veterinary medicine, particularly as antiglaucomatics. They are effective carboanhydrase inhibitors and therefore they can have a wide use in the treatment of all diseases, where it is necessary to inhibit this enzyme.
 
-28-


CLAIMS




1. Use of substituted sulphonamides having the general formula (I)

H2N-02S  -Q-•R1-R2-(CH2),-R
(I)


wherein:

R1 is CO or S02,

R2 is NH or 0,

R includes tertiary diC1_4alkylamino group, wherein alkyl moieties are the same or different, or amino group, alkyl moieties of which form together 5, 6 and 7-membered saturated ring, or their ends are linked by heteroatom 0, or
R is 4-(N,N-diethylaminoethoxy)benzyl when R1 is S02 and R2  is NH; or

R is 4-[N-(morpholinopropyl)sulfamoyl]phenyl when R1 is CO and R2 is NH. n is a number of carbons of linking aliphatic chain, wherein n is 0, 2 or 3,

and/or physiologically acceptable salts, hydrates or solvates thereof, in the manufacture of a medicament for the treatment of glaucoma.

2. Use of substituted sulphonamides having the general formula (1), according to claim 1, wherein when
R1 is CO,

R2 ,  Rand n are shown in the following Table:

                    I    n = 2,3    R2    = NH   
                R=-N        R2    =0   
                "'    n = 2,3    R    2    = NH   
        ; -                   
                R=-N        R2       
        "--            = 0   
                                       
            ; -    n = 2,3    R2    = NH   
                R=-N        R2       
        "--            =0   
                               
                r - \    n = 2,3    R2    = NH   
                R=  -N0        R2  =0   
        \ _ /           
                                       
 
-29-


R =-o-802-NH~N~    n=O    R2 = NH   
        R2    = 0   
~0                   
                                                   
                        ; -    n=2               
                                R=-N        R2    = NH   
"--        R2    =0   
                                               
                                               
                                R=-N~    n = 2, 3    R2    =0   
                                        R2 = NH   
                                               
                                    n = 2, 3    R2    = 0   
                                R= - N £        R2    = NH   
                                               
                                I    n = 2, 3    R2    = 0   
                                R=-N                   
"-----        R    2    = NH   
                                                   
                               
            ; -    n = 2, 3    R2 = 0   
                                R=-N                   
~        R2    = NH   
                                               
                                R=-N~    n = 2, 3    R2    = 0   
                                        R2    = NH   
                                               
                                               
                                R=-N~    n = 2, 3    R2    = 0   
                                        R2    = NH   
                                               
                                R=-NJ    n = 2, 3    R2    = 0   
                                        R2       
                                            = NH   
                                               
                                R= - 0    n = 2, 3    R2    = 0   
                                        R2    = NH   
                                               
                                                   



and/or physiologically acceptable salts, hydrates or solvates thereof, in the manufacture of a medicament for the treatment of glaucoma.

3. Use of substituted sulphonamides having the general formula (1), according to claim 1,
H2N-02S  ---o-- R'-R2-(CH2),-R
(I)

wherein

R1 is S02,

R2 is NH, and

Rand n are shown in the following Table:•


and/or physiologically acceptable salts, hydrates or solvates thereof, in the manufacture of a medicament for the treatment of glaucoma.

4. Use of substituted sulphonamides according to one of preceding claims having the general formula (I) according to claim 1, selected from the group:
 
- 31-


N-(N, N-Diethylam inoethyl)benzene-1 ,4-bis( sulphonamide); (1-1),

N-(N, N-Diethylaminopropyl)benzene-1 ,4-bis(sulphonamide); (1-2),

N-(Pyrrolidinoethyl)benzene-1 ,4-bis(sulphonamide); (1-3),

N-(Pyrrolidinopropyl)benzene-1 ,4-bis(sulphonamide); (1-4),

N-(Morpholinoethyl)benzene-1 ,4-bis(sulphonamide); (1-5),

N-(Morpholinopropyl)benzene-1 ,4-bis(sulphonamide); (1-6),

N-(4-Diethylaminoethoxybenzyl)benzene-1 ,4-bis(sulphonamide); (1-7),

N-(Dimethylaminoethyl)benzene-1 ,4-bis(sulphonamide); (1-8),

N-(Dimethylaminopropyl)benzene-1 ,4-bis(sulphonamide); (1-9),

N-(N,N-Dipropylaminoethyl)benzene-1 ,4-bis(sulphonamide); (1-1 0),

N-(N,N-Dipropylaminopropyl)benzene-1 ,4-bis(sulphonamide); (1-11),

N-(N ,N-Dibuthylaminoethyl)benzene-1 ,4-bis(sulphonamide); (1-12),

N-(N,N-Dibuthylaminopropyl)benzene-1 ,4-bis(sulphonamide); (1-13),

N-(N-Methyi-N-ethylaminoethyl)benzene-1 ,4-bis(sulphonamide); (1-14), N-(N-Methyi-N-ethylaminopropyl)benzene-1 ,4-bis(sulphonamide); (1-15), N-(N-Ethyi-N-propylaminoethyl)benzene-1 ,4-bis(sulphonamide); (1-16), N-(N-Ethyi-N-propylaminopropyl)benzene-1 ,4-bis(sulphonamide); (1-17), N-(N-Ethyi-N-buthylaminoethyl)benzene-1 ,4-bis(sulphonamide); (1-18), N-(N-Ethyi-N-buthylaminopropyl)benzene-1 ,4-bis(sulphonamide); (1-19), N-(N-Propyi-N-buthylaminoethyl)benzene-1 ,4-bis(sulphonamide); (1-20), N-(N-Propyi-N-buthylaminopropyl)benzene-1 ,4-bis( sulphonamide); (1-21 ), N-(Piperidinoethy)benzene-1 ,4-bis(sulphonamide); (1-22), N-(Piperidinopropyl)benzene-1 ,4-bis(sulphonamide); (1-23), 4-Sulfamoyi-N-(N,N-dimethylaminoethyl)benzamide; (11-1), 4-Sulfamoyi-N-(N,N-dimethylaminopropyl)benzamide; (11-2), 4-Sulfamoyi-N-(N, N-diethylaminoethyl)benzamide; (11-3), 4-Sulfamoyi-N-(N,N-diethylaminopropyl)benzamide; (11-4), 4-Sulfamoyi-N-(morpholinoethyl)benzamide; (11-5), 4-Sulfamoyi-N-(morpholinopropyl)benzamide; (11-6),

4-[N-(M orphol i nopropyl)sulfamoyl]phenylsulfamoyl benzam ide; (11-7), (N,N-Diethylaminoethyl)-4-sulfamoylbenzoate; (11-8),

(N, N-Diethylaminopropyl)-4-sulfamoylbenzoate; (11-9), (N,N-Dipropylaminoethyl)-4-sulfamoylbenzoate; (11-1 0), (N, N-Dipropylaminopropyl)-4-sulfamoylbenzoate; (11-11 ),

4-Sulfamoyi-N-(N,N-dipropylaminoethyl)benzamide; (11-12), 4-Sulfamoyi-N-(N, N-dipropylaminopropyl)benzamide; (11-13), (N,N-Dibuthylaminoethyl)-4-sulfamoylbenzoate; (11-14),
 
-32-


(N,N-Dibuthylaminopropyl)-4-sulfamoylbenzoate; (11-15), 4-Sulfamoyi-N-(N,N-dibuthylaminoethyl)benzamide; (11-16), 4-Sulfamoyi-N-(N, N-dibuthylaminopropyl)benzamide; (11-17), (N-Methyi-N-ethylaminoethyl)-4-sulfamoylbenzoate; (11-18), (N-Methyi-N-ethylaminopropyl)-4-sulfamoylbenzoate; (11-19), 4-Sulfamoyi-N-(N-methyi-N-ethylaminoethyl)benzamide; (11-20), 4-Sulfamoyi-N-(N-methyi-N-ethylaminopropyl) benzam ide; (11-21 ), (N-Ethyi-N-propylaminoethyl)-4-sulfamoylbenzoate; (11-22), (N-Ethyi-N-propylaminopropyl)-4-sulfamoylbenzoate; (11-23), 4-Sulfamoyi-N-(N-ethyi-N-propylaminoethyl)benzamide; (11-24), 4-Sulfamoyi-N-(N-ethyi-N-propylaminopropyl)benzamide; (11-25), (N-Propyi-N-buthylaminoethyl)-4-sulfamoylbenzoate; (11-26), (N-Propyi-N-buthyl ami nopropyl)-4-sulfam oylbenzoate; (11-27), 4-Sulfamoyi-N-(N-propyl-N-buthylaminoethyl)benzamide; (ll-28), 4-sulfamoyi-N-(N-propyi-N-buthylaminopropyl)benzamide; (11-29), (N-Ethyi-N-buthylaminoethyl)-4-sulfamoylbenzoate; (11-30), (N-Ethyi-N-buthylaminopropyl)-4-sulfamoylbenzoate; (11-31 ), 4-Sulfamoyi-N-(N-ethyi-N-buthylaminoethyl)benzamide; (11-32), 4-S ulfamoyi-N-(N-ethyi-N-buthylam i nopropyl) benzam ide; (11-33), (Pyrrolidinoethyl)-4-sulfamoylbenzoate; (11-34), (Pyrrolidinopropyl)-4-sulfamoylbenzoate; (11-35), 4-Sulfamoyi-N-(pyrrolidinoethyl)benzamide; (11-36), 4-Sulfamoyi-N-(pyrrolidinopropyl)benzamide; (11-37), (Piperidinoethyl)-4-sulfamoylbenzoate; (11-38), (Piperidinopropy1)4-sulfamoylbenzoate; ( 11-39), 4-Sulfamoyi-N-(piperidinoethyl)benzamide; (11-40), 4-Sulfamoyi-N-(piperidinopropyl)benzamide; (11-41 ).



5. Substituted sulphonamides having the general formula (I)








wherein R1 is S02,
R2 is NH, and

Rand n are shown in the following Table:
 

and physiologically acceptable salts, hydrates or solvates thereof.


6. Substituted sulphonamides having the general formula (1), according to claim 5, which is: N-(N,N-Diethylaminoethyl)benzene-1 ,4-bis(sulphonamide); (1-1 ), N-(N,N-Diethylaminopropyl)benzene-1 ,4-bis(sulphonamide); (1-2),
 
-34-


N-(Pyrrolidinoethyl)benzene-1 ,4-bis(sulphonamide); (1-3),

N-(Pyrrolidinopropyl)benzene-1 ,4-bis(sulphonamide); (1-4),

N-(Morpholinoethyl)benzene-1 ,4-bis(sulphonamide ); (1-5),

N-(Morpholinopropyl)benzene-1 ,4-bis(sulphonamide); (1-6),

N-(4-Diethylaminoethoxybenzyl)benzene-1 ,4-bis(sulphonamide); (1-7),

N-(Dimethylaminoethyl)benzene-1 ,4-bis(sulphonamide); (1-8),

N-(Dimethylaminopropyl)benzene-1 ,4-bis(sulphonamide); (1-9),

N-(N,N-Dipropylaminoethyl)benzene-1 ,4-bis(sulphonamide); (1-1 0),

N-(N, N-Dipropylam inopropyl)benzene-1 ,4-bis( sulphonamide); (1-11),

N-(N,N-Dibuthylaminoethyl)benzene-1 ,4-bis(sulphonamide); (1-12),

N-(N ,N-Dibuthylaminopropyl)benzene-1 ,4-bis(sulphonamide); (1-13),

N-(N-Methyi-N-ethylaminoethyl)benzene-1 ,4-bis(sulphonamide); (1-14),

N-(N-Methyi-N-ethylaminopropyl)benzene-1 ,4-bis(sulphonamide); (1-15),

N-(N-Ethyi-N-propylaminoethyl)benzene-1 ,4-bis(sulphonamide); (1-16),

N-(N-Ethyi-N-propylaminopropyl)benzene-1 ,4-bis(sulphonamide); (1-17),

N-(N-Ethyi-N-buthylaminoethyl)benzene-1 ,4-bis(sulphonamide ); (1-18),

N-(N-Ethyi-N-buthylaminopropyl)benzene-1 ,4-bis(sulphonamide); (1-19),

N-(N-Propyi-N-buthylaminoethyl)benzene-1 ,4-bis(sulphonamide); (1-20),

N-(N-Propyi-N-buthylaminopropyl)benzene-1 ,4-bis(sulphonamide); (1-21 ),

N-(Piperidinoethy)benzene-1 ,4-bis(sulphonamide); (1-22),

N-(Piperidinopropyl)benzene-1 ,4-bis(sulphonamide); (1-23).


7.    Substituted sulphonamide of the general formula (I) according to claim 5 or 6, and/or physiologically acceptable salts, hydrates or solvates thereof, for use as carboanhydrase inhibitors, such as antiglaucomatics.

8.    A  pharmaceutical  composition  for  the  prophylaxis  and  the  treatment  of  diseases,

characterized    in  that  comprises  substituted  sulphonamide  of  the  general  formula

(I) according to claim 5 or 6 and/or physiologic acceptable salts, hydrates or solvates thereof as the active compound and the pharmaceutical carrier.

9. A pharmaceutical composition according to claim 8, characterized in that it additionally comprises further active agent for the prophylaxis or the treatment of diseases, particularly for the treatment of eye diseases selected from the group consisting of sympatomimetics such as brimonidil}e, clonidine, apraclonidine; parasympatomimetics such as pilocarpine, carbachole; betablocators such as timolol, betaxolol, levobunolol; and prostagladine
 
- 35-


analougues such as latanoprost, bimaprost, travaprost; and other antiglaucomatics such as guanethidine or dapiprazole.

10. A process for preparing the compounds having the general formula (I) according to claim 5, characterized in that the amine of the general formula (IV)


(IV)


wherein R is as defined in claim 5,

is treated with 4-sulfamoylbenzenesulphonyl chloride of the formula (V)

in organic solvent in the presence of base excess at the temperature 0 to 20 °C, wherein a nucleophilic reaction gives substituted 1 ,4-bis sulphonamide.

11. A process according to claim 10, characterized in that tetrahydrofurane or ether are used as organic solvents and triethylamine is used as base.

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