Patent Publication Number: US-4321254-A

Title: Antiallergic imidodisulfamides

Description:
This invention relates to novel imidodisulfamides which are useful as end-organ antagonists of slow reacting substance of anaphylaxis, pharmaceutical compositions and methods of inhibiting the symptoms of an allergic response. The substance, SRS-A, has been suggested to be an important mediator of anaphylaxis in human asthma. By antagonizing the effects of this or other pharmacologically active mediators at the end-organ, bronchial smooth muscle, the compounds of this invention are valuable in the treatment of allergic diseases such as asthma. 
     The imidodisulfamide compounds of this invention are represented by the following general structural formula (I): ##STR1## wherein X is hydrogen, bromo or chloro; and Y is a phenylsulfonamido radical of the formula: ##STR2## wherein R is hydrogen or methyl; R 1  is hydrogen, bromo, chloro, nitro, methyl, trifluoromethyl or methoxy; and R 2  is hydrogen, chloro or methyl provided that when R 2  is chloro, R 1  is chloro, methyl or trifluoromethyl, and when R 2  is methyl, R 1  is methyl; or an alkali metal salt of said compounds. 
     The compounds of the formula (I) are conveniently prepared as shown in the following scheme: ##STR3## in which X and Y are as described above. Thus, the appropriately substituted tetrahydroisoquinoline is reacted with bis(chlorosulfonyl)imide in the presence of a non-nucleophilic organic base. 
     Examples of such non-nucleophilic organic bases include tertiary alkylamines, such as triethylamine, tertiary alkylaryl amines, such as N,N-dimethylaniline and aromatic amines, such as pyridine. 
     The reaction is carried out in an inert polar organic solvent. The selection of a particular solvent is not critical provided that the solvent is substantially inert to the reagents and product. Illustrative of such a solvent is acetonitrile. 
     The reaction is usually carried out at moderate to low temperatures. For example, the reagents are usually mixed at temperatures of 0° C. or less and the reaction is allowed to warm gradually to ambient temperature. 
     The reaction time is dependent on inter alia the particular starting materials, solvent and reaction temperature. Generally, the reaction will be allowed to proceed for at least 12 hours. 
     The reaction product can be isolated by standard methods for example addition of dilute mineral acid e.g. hydrochloric acid, to the reaction mixture affords the compounds of formula (I) as the &#34;free acid&#34;. 
     Alkali metal salts of the compounds of the formula (I), for example, the sodium or potassium salts, are obtainably by treatment of the compounds with the appropriate metal alkoxide, for example methoxide, in an alkanol solvent such as methanol; by treatment of the compounds with an alkali metal hydride, such as sodium hydride or potassium hydride, in a polar non-protic solvent, such as tetrahydrofuran, or dimethoxyethane; or by treatment of the compounds with a cationic exchange resin, such as a sulfonic acid resin in the sodium form. 
     Illustrative of the instant invention wherein the tetrahydroisoquinoline moiety is substituted in the 7-position with a phenylsulfonamido group are compounds of the formula (II). ##STR4## wherein X 1  is hydrogen, methyl, bromo or chloro; R represents hydrogen or methyl; R 1  represents hydrogen, bromo, chloro, nitro, methyl, trifluoromethyl or methoxy; and R 2   represents hydrogen, chloro or methyl provided that when R 2  is chloro, R 1  is chloro, methyl or trifluoromethyl and when R 2  is methyl, R 1  is methyl or an alkali metal salt of the compounds of the formula (II). 
     Particular compounds of the instant invention are the compounds of formula (II) wherein X 1  is hydrogen. 
     Specific compounds of the instant invention when X 1  is hydrogen are the compounds of the formula (II) wherein: 
     (a) R and R 2  both represent hydrogen and R 1  represents hydrogen; 2-, 3- or 4-bromo; 2-, 3- or 4-chloro; 3-nitro; 3- or 4-trifluoromethyl; or 4-methoxy; 
     (b) R represents hydrogen; R 2  represents 3-chloro and R 1  represents 4-chloro or 4-methyl; 
     (c) R represents hydrogen; R 2  represents 4-chloro; and R 1  represents 3-trifluoromethyl; 
     (d) R represents hydrogen; R 2  represents 3-methyl; and R 1  represents 4-methyl; and 
     (e) R represents methyl; R 2  represents hydrogen; and R 1  represents 2-, 3- or 4-chloro. 
     More specifically, compounds included in the instant invention are of the formula (II) wherein X 1 , R and R 2  represent hydrogen, and R 1  represents 4-chloro or 4-bromo and wherein X 1  and R represent hydrogen, R 2  represents 3-methyl and R 1  represents 4-methyl. 
     The compounds of the formula (II) are conveniently prepared as shown in the following scheme: ##STR5## in which X 1 , R, R 1  and R 2  are described above. 
     The starting substituted tetrahydroisoquinoline (A) may be prepared from amino tetrahydroisoquinoline (B) via the following synthetic pathway: ##STR6## The compound (B) is reacted with the appropriately substituted benzenesulfonylchloride followed by treatment with dilute mineral acid to give the appropriately substituted tetrahydroisoquinoline (A). Bis(chlorosulfonyl)imide is prepared from chlorosulfonic acid and chlorosulfonylisocyanate. The amino tetrahydroisoquinoline starting materials used as above are obtained by standard reactions well known in the art. The starting amino tetrahydroisoquinolines may be prepared from the corresponding hydroxy-2-acetyl-tetrahydroisoquinoline via a standard Bucherer reaction followed by hydrolysis of the acetyl moiety. Similarly, the starting amino tetrahydroisoquinolines may be prepared from the corresponding hydroxyisoquinoline via a standard Bucherer reaction followed by diborane hydrogenation of the amino isoquinoline intermediate. The starting amino tetrahydroisoquinoline may also be prepared by the stannous chloride reduction of the corresponding nitrotetrahydroisoquinoline. The benzenesulfonylchloride compounds are known. 
     Illustrative of the instant invention wherein the tetrahydroisoquinoline moiety is substituted in the 6-position with a phenylsulfonamido group are compounds of the formula (III): ##STR7## wherein X 2  is methyl, bromo, or chloro; R is hydrogen or methyl; R 1  is hydrogen, bromo, chloro, nitro, methyl, trifluoromethyl or methoxy; and R 2  is hydrogen, chloro or methyl provided that when R 2  is chloro, R 1  is chloro, methyl or trifluoromethyl and when R 2  is methyl, R 1  is methyl or an alkyl metal salt of said compounds. 
     The compounds of formula (III) are conveniently prepared as shown in the following scheme. ##STR8## 
     The amino tetrahydroisoquinoline (C) is converted into compounds of the formula (III) by reacting compound (C) with the appropriately substituted benzenesulfonylchloride followed by hydrolysis to give compound (D) which is then coupled with bis(chlorosulfonyl)imide. 
     The amino tetrahydroisoquinoline starting materials used as above are obtained by standard reactions well-known in the art. The benzenesulfonylchloride compounds are known. 
     Illustrative of the instant invention wherein the tetrahydroisoquinoline moiety is substituted in the 8-position with a phenylsulfonamido group are compounds of the formula (IV) ##STR9## wherein X 3  is hydrogen, methyl, bromo or chloro; R is hydrogen or methyl; R 1  is hydrogen, bromo, chloro, nitro, methyl, trifluoromethyl or methoxy; and R 2  is hydrogen, chloro or methyl provided that when R 2  is chloro, R 1  is chloro, methyl or trifluoromethyl and when R 2  is methyl, R 1  is methyl or an alkali metal salt thereof. 
     A particular compound of the instant invention of the formula (IV) is the compound wherein X 3  is 7-chloro; R and R 3  are each hydrogen; and R 1  is 3-chloro. 
     The compounds of the formula (IV) are conveniently prepared as shown in the following scheme. ##STR10## 
     The amino tetrahydroisoquinoline compound (E) is reacted with the appropriately substituted benzenesulfonylchloride to afford compound (F) which, after hydrolysis of the 2-acetyl group, is reacted with bis(chlorosulfonyl)imide to yield compounds of the formula (IV). Compound (F) may also be hydrogenated to afford the deshalo compounds (G) wherein X 3  &#39;, R 1  &#39; and R 2  &#39; are the same as X 3 , R 1  and R 2  respectively but are not bromo or chloro. Compound (G) is then coupled with bis(chlorosulfonyl)imide to afford the deshalo compounds of the formula (IV), designated above as (IV&#39;). It should be noted that the deshalo analogs of the compounds (II), (III) and (V) may also be prepared by the hydrogenolysis of the appropriate 2-acetyl-phenylsulfonamidotetrahydroisoquinoline. 
     The amino tetrahydroisoquinoline starting materials used as above are obtained by standard reactions well-known in the art. The benzenesulfonylchloride compounds are known. 
     Illustrative of the instant invention wherein the tetrahydroisoquinoline moiety is substituted in the 5-position with a phenylsulfonamide group are compounds of the formula (V) ##STR11## wherein X 4  is methyl, bromo or chloro; R is hydrogen or methyl; R 1  is hydrogen, bromo, chloro, nitro, methyl, trifluoromethyl or methoxy; and R 2  is hydrogen, chloro or methyl provided that when R 2  is chloro, R 1  is chloro, methyl or trifluoromethyl and when R 2  is methyl, R 1  is methyl or an alkali metal salt of said compounds. 
     A particular compound of the instant invention is a compound of the formula (V) wherein X 4  is 8-chloro; R and R 2  are each hydrogen; and R 1  is 3-chloro. 
     The compounds of the formula (V) are conveniently prepared as shown in the following scheme. ##STR12## 
     Following analogous procedures, for the preparation of the compounds of the formula (II) the amino tetrahydroisoquinoline compound (H) is converted into the compounds of the formula (V). 
     The amino tetrahydroisoquinoline starting materials used as above are obtained by standard reactions well-known in the art. The benzenesulfonylchloride compounds are known. 
     The SRS-A antagonist activity of the compounds of this invention is measured by the ability of the active medicament to inhibit SRS-A induced contraction of guinea pig ileum. In this test system, sections of ileum are resected from guinea pigs and placed in 5 ml. tissue baths containing a modified Tyrode&#39;s solution. One end of the tissue is fixed to a glass tissue holder, the other is connected to a force-displacement transducer and the tissue is placed under a tension of 500 mg. Isometric tissue contractions are recorded on a six channel polygraph. Baths are constantly aerated with 95% O 2  -5% CO 2 . After a 20 minute stabilization period a concentration of the appropriate agonist which provides a contraction height of 60-80% of the maximum obtainable to that agonist (as determined) from full sequential concentration--response curves in separate experiments) is added to the tissue bath and the response recorded. The procedure is repeated until reproducible responses are obtained. For most agonist, two applications in rapid succession, followed 15 minutes later by a third, is sufficient to establish reproducibility. Experimental tissues are incubated with the selected concentration of the test compounds for 15 minutes. Experimental and control tissues are subjected to 5 bath changes during the incubation interval. Changes in bath fluid during the incubation period are helpful in insuring the reproducibility of tissue responses to the agonist. The same concentration of the agonist is reapplied in the presence of the test compound and the response registered and compared with controls. Percent inhibition produced by the test compound is calculated by substracting the mean percentage change in control tissue from the mean percentage change in tissues exposed to the test compound. Additional compounds are then evaluated as long as the tissue remains reproducibly responsive to the agonist. Six tissues obtained from 6 animals are used simultaneously-3 controls and 3 experimental. 
     The compounds of this invention tested at concentrations of from 5×10 -5  M to 1×10 -6  M produce marked antagonism of partially purified slow reacting substance of anaphylaxis obtained from guinea pig lung. The agonist is employed at a concentration of 40 μg/ml. 
     At a compound concentration of 5×10 -6  M, N,N&#39;-bis-[7-(4-chlorophenylsulfonamido)-1,2,3,4-tetrahydroisoquinolyl]disulfonylimide exhibited 59 percent antagonism. 
     The specificity of the antagonist activity of the compounds of this invention is demonstrated by relatively low levels of antagonism toward agonists such as potassium chloride, serotonin, histamine and the prostaglandins F 2 α and E 2 . 
     Pharmaceutical compositions of the present invention comprise a pharmaceutical carrier or diluent and an amount of a compound of the formula (I) or an alkali metal salt thereof sufficient to produce the inhibition of the symptoms of asthma and other allergic diseases. 
     When the pharmaceutical composition is employed in the form of a solution or suspension, examples of appropriate pharmaceutical carriers or diluents include: for aqueous systems, water; for non-aqueous systems, ethanol, gylcerin, propylene glycol, corn oil, cottonseed oil, peanut oil, sesame oil, liquid parafins and mixtures thereof with water; for solid systems, lactose, kaolin and mannitol; and for aerosol systems, dichlorodifluoromethane, chlorotrifluoro ethane and compressed carbon dioxide. Also, in addition to the pharmaceutical carrier or diluent, the instant compositions may include other ingredients such as, stabilizers, antioxidants, preservatives, lubricants, suspending agents, viscosity modifiers and the like, provided that the additional ingredients do not have a detrimental effect on the therapeutic action of the instant compositions. 
     The nature of the composition and the pharmaceutical carrier or diluent will of course depend upon the intended route of administration, i.e. parenterally or by inhalation. 
     In general, particularly for the prophylactic treatment of asthma, the compositions will be in a form suitable for administration by inhalation. Thus the compositions will comprise a suspension or solution of the active ingredient in water for administration by means of a conventional nebulizer. Alternatively the compositions will comprise a suspension or solution of the active ingredient in a conventional liquified propellant or compressed gas to be administered from a pressurized aerosol container. The compositions may also comprise the solid active ingredient diluted with a solid diluent for administration from a powder inhalation device. In the above compositions, the amount of carrier or diluent will vary but preferably will be the major proportion of a suspension or solution of the active ingredient. When the diluent is a solid it may be present in less, equal or greater amounts than the solid active ingredient. 
     For parenteral administration the pharmaceutical composition will be in the form of a sterile injectable liquid such as an ampul or an aqueous or nonaqueous liquid suspension. 
     Usually a compound of formula I is administered to an animal or human subject in a composition comprising an amount sufficient to produce an inhibition of the symptoms of an allergic response. When employed in this manner, the dosage of the composition is such that from 0.5 mg. to 500 mg. of active ingredient are administered at each administration. For convenience equal doses will be administered 1 to 4 times daily with the daily dosage regimen being selected from about 0.5 mg. to about 2000 mg. 
     The pharmaceutical preparations thus described are made following the conventional techniques of the pharmaceutical chemist as appropriate to the desired end product. 
     Included within the scope of this invention is the method of inhibiting the symptoms of an allergic response resulting from a mediator release which comprises administering to an animal or human subject a therapeutically effective amount for producing said inhibition of a compound of formula I, preferably in the form of a pharmaceutical composition. The administration may be carried out in dosage units at suitable intervals or in single doses as needed. Usually the method of this invention will be practiced when relief of allergic symptoms is specifically required, however, the method is also usefully carried out as continuous or prophylactic treatment. It is within the skill of the art to determine by routine experimentation the effective dosage to be administered from the dose range set forth above, taking into consideration such factors as the degree of severity of the allergic condition being treated, and so forth. 
    
    
     The following examples illustrate the preparation of compounds of formula I and their incorporation into pharmaceutical compositions and as such are not to be considered as limiting the invention set forth in the claims appended thereto. 
     EXAMPLE 1 
     Preparation of Bis(Chlorosulfonyl)Imide 
     A mixture of 166 g. (1.42 mole) of chlorosulfonic acid and 202 g. (1.42 mole) of chlorosulfonylisocyanate was heated under reflux (110° C.) in an oil bath until the evolution of carbon dioxide ceased. The crude product was distilled in vacuo to yield bis(chlorosulfonyl)imide, b.p., (1.5 mm.) 100° C., which is used as described hereinafter. 
     EXAMPLE 2 
     Preparation of 2-Acetyl-7-Amino-1,2,3,4-Tetrahydroisoquinoline 
     A mixture of 2.5 g. (16.8 mmol) 7-amino-1,2,3,4-tetrahydroisoquinoline, 30 ml. ethyl acetate and 2 ml. isopropenyl acetate was refluxed for approximately 16 hours and was then concentrated to dryness at reduced pressure. The residue was then recrystallized from a mixture of ethyl acetate and petroleum ether to afford 2-acetyl-7-amino-1,2,3,4-tetrahydroisoquinoline with a melting point of 98°-100° C. 
     Preparation of 2-Acetyl-7-(4-Chlorophenylsulfonamide)-1,2,3,4-Tetrahydroisoquinoline 
     A mixture of 1.75 g. (9.0 mmol) 2-acetyl-7-amino-1,2,3,4-tetrahydroisoquinoline, 1.90 g. (9.0 mmol) 4-chlorophenylsulfonylchloride, 20 ml. dry acetone and 2 ml. of dry pyridine was refluxed for 2 hours. The reaction mixture was stirred at ambient temperature for approximately 16 hours and was then concentrated to dryness at reduced pressure. The residue was dissolved in methylene chloride and washed with dilute hydrochloric acid and then with water. The methylene chloride solution was then extracted with 10% aqueous sodium hydroxide and water. The combined sodium hydroxide and water was washed with diethyl ether and then acidified with dilute hydrochloric acid to afford the crude product as a white solid. The crude product was recrystallized from methanol-chloroform to yield 2-acetyl-7-(4-chlorophenylsulfonamido) 1,2,3,4-tetrahydrosoquinoline as a white solid with a melting point of 205°-207° C. 
     Preparation of 7-(4-Chlorophenylsulfonamido)-1,2,3,4-Tetrahydroisoquinoline, Hydrochloride 
     A mixture of 2.2 g. (6.0 mmol) 2-acetyl-7-(4-chlorophenylsulfonamide)-1,2,3,4-tetrahydroisoquinoline, 25 ml. dilute hydrochloric acid and 15 ml. n-butanol was refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure to afford a white solid. The white solid was dissolved in water and extracted with diethyl ether. The aqueous phase was then made basic with 5% sodium bicarbonate and extracted with a mixture of ethyl acetate and methylene chloride. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to afford the hydrochloride as a white solid with a melting point of 211°-13° C. 
     Preparation of N,N&#39;-bis[7-(4-Chlorophenylsulfonamide)-1,2,3,4-Tetrahydroisoquinolyl]Disulfonylimide 
     To 0.33 g. (1.54 mmol.) bis(chlorosulfonyl)imide in 15 ml., dry acetonitrile at -40° C. was added dropwise 0.22 g. (2.1 mmol. ) dry triethylamine. The reaction mixture was warmed to 0° C. and 1.5 g. (3.09 mmol.) 7-(4-chlorophenylsulfonamide)-1,2,3,4-tetrahydroisoquinoline hydrochloride in 2.5 g. (2.5 mmol.) triethylamine and 20 ml. acetonitrile was added slowly. The resultant mixture was stirred at ambient temperature for about 16 hours. The reaction mixture was concentrated under reduced pressure at less than 35° C. The residue was dissolved in methylene chloride and washed with dilute hydrochloric acid and then with water. The methylene chloride solution was then dried over anhydrous sodium sulfate and concentrated to dryness at reduced pressure to afford the crude product. The crude product was partitioned between ethyl acetate and dilute hydrochloric acid. The ethyl acetate fraction was dried over anhydrous sodium sulfate and the product recrystallized from ethyl acetate-petroleum ether. N,N&#39;-bis[7-(4-chlorophenylsulfonamido)-1,2,3,4-tetrahydroisoquinoline]disulfonylimide was a solid with a melting point of 130°-192° C. (dec.). 
     
         ______________________________________                                    
Analysis     C        H        N      S                                   
______________________________________                                    
Calculated   45.80    3.71     8.90   16.30                               
Found        45.59    3.63     8.94   16.51                               
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     Following the procedures of Example 2, the appropriately substituted tetrahydroisoquinoline may be reacted with bis(chlorosulfonyl)imide to afford the compounds in the following table: 
     
         ______________________________________                                    
Compound   COMPOUNDS OF THE FORMULA (II)                                  
Number     R        R.sub.1   R.sub.2 X.sub.1                             
______________________________________                                    
2          H        3-Cl      H       H                                   
3          H        H         H       H                                   
4          H        2-Cl      H       H                                   
5          H        4-Cl      H       H                                   
6          H        2-Br      H       H                                   
7          H        3-Br      H       H                                   
8          H        4-Br      H       H                                   
9          H        3-NO.sub.2                                            
                              H       H                                   
10         H        3-CF.sub.3                                            
                              H       H                                   
11         H        4-CF.sub.3                                            
                              H       H                                   
12         H        4-Cl      3-Cl    H                                   
13         H        3-CF.sub.3                                            
                              4-Cl    H                                   
14         H        4-CH.sub.3                                            
                              3-CH.sub.3                                  
                                      H                                   
15         H        4-CH.sub.3                                            
                              3-Cl    H                                   
16         CH.sub.3 4-Cl      H       H                                   
17         H        3-Cl      H       8-Cl                                
18         H        3-Cl      H       5-Br                                
19         H        3-Cl      H       6-Cl                                
20         H        3-Br      H       8-Br                                
21         H        3-Br      H       5-Br                                
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Compound   COMPOUNDS OF THE FORMULA (III)                                 
Number     R        R.sub.1   R.sub.2 X.sub.2                             
______________________________________                                    
22         H        H         H       7-Br                                
23         H        3-Br      H       7-Br                                
24         H        4-CH.sub.3                                            
                              3-CH.sub.3                                  
                                      8-Cl                                
25         H        4-Cl      H       8-Cl                                
26         CH.sub.3 4-Cl      H       7-Cl                                
27         H        4-CH.sub.3                                            
                              3-Cl    5-Br                                
28         H        3-Br      H       5-Cl                                
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Compound   COMPOUNDS OF THE FORMULA (IV)                                  
Number     R        R.sub.1   R.sub.2 X.sub.3                             
______________________________________                                    
29         H        3-Cl      H       7-Cl                                
30         H        H         H       H                                   
31         H        3-Br      H       6-Br                                
32         CH.sub.3 4-Cl      H       7-Cl                                
33         H        4-CH.sub.3                                            
                              3-CH.sub.3                                  
                                      H                                   
34         H        4-CH.sub.3                                            
                              3-Cl    6-Cl                                
35         H        3-Br      H       7-Cl                                
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Compound   COMPOUNDS OF THE FORMULA (V)                                   
Number     R        R.sub.1   R.sub.2 X.sub.4                             
______________________________________                                    
36         H        3-Cl      H       8-Cl                                
37         H        H         H       6-Br                                
38         H        3-Br      H       8-Br                                
39         H        4-CH.sub.3                                            
                              3-CH.sub.3                                  
                                      7-Cl                                
40         CH.sub.3 4-Cl      H       8-Cl                                
41         H        4-CH.sub.3                                            
                              3-Cl    8-Cl                                
42         H        3-Br      H       7-Cl                                
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     EXAMPLE 3 
     Preparation of the Sodium Salt of Compound 1 
     A solution of N,N&#39;-bis[7-(4-chlorophenylsulfonamide)-1,2,3,4-tetrahydroisoquinolyl]disulfonylimide in methanol is passed through an ion exchange column (IR 120-sulfonic acid type in the sodium form) and the column eluted with methanol. The eluant is concentrated to near dryness and the resultant material is triturated with diethyl ether which after filtration under nitrogen affords the desired salt. 
     Similarly, alkali metal salts of the compounds of the present invention may be prepared. 
     EXAMPLE 4 
     As a specific embodiment of a composition of this invention an active ingredient, such as N,N&#39;-bis[7-(4-chlorophenylsulfonamido)-1,2,3,4-tetrahydroisoquinolyl]disulfonylimide, is dissolved in sterile water at a concentration of 0.5% and aerosolized from a nebulizer operating at an air flow adjusted to deliver the desired aerosolized weight of drug.