Abstract:
Compounds having the formula wherein R 1  is hydrogen, hydroxy, alkyl, alkoxy, alkylthio, trifluoromethyl, halogen, nitro, cyano, dialkylamino or alkylsulfinyl; and R 2  is hydrogen, alkyl, aryl, arylalkyl, acyl or an aminoalkylene have useful antiinflammatory activity.

Description:
BRIEF DESCRIPTION OF THE INVENTION 
     Pyrano [4,3-c] pyrazoles having the formula ##STR1##and the pharmaceutically acceptable salts thereof, have useful antiinflammatory activity. In formula I, and throughout the specification, the symbols are as defined below. 
     R 1  can be hydrogen, hydroxy, alkyl, alkoxy, alkylthio, trifluoromethyl, halogen, nitro, cyano, dialkylamino or alkylsulfinyl; and 
     R 2  can be hydrogen, alkyl, aryl, arylalkyl, ##STR2## wherein X is alkyl or aryl, or A-NR 3  R 4  wherein A is a straight or branched chain alkylene group having 2 to 5 carbon atoms, R 3  can be hydrogen or alkyl, and R 4  can be hydrogen, alkyl, phenyl or phenylalkyl, or R 3  and R 4  together with the nitrogen atom to which they are attached can be ##STR3## wherein Z can be CH 2 , oxygen or N-R 5  wherein R 5  can be hydrogen, alkyl, aryl or arylalkyl. 
     The terms &#34;alkyl&#34; and &#34;alkoxy&#34; as used throughout the specification (individually or as part of a larger group) refer to groups having 1 to 8 carbon atoms; alkyl and alkoxy groups having 1 to 3 carbon atoms are preferred. 
     The term &#34;halogen&#34; as used throughout the specification refers to fluorine, chlorine, bromine and iodine; fluorine and chlorine are preferred. 
     The term &#34;aryl&#34; as used throughout the specification (individually or as part of a larger group) refers to phenyl or phenyl monosubstituted with an alkyl, alkoxy, halogen or trifluoromethyl group; phenyl is preferred. 
     DETAILED DESCRIPTION OF THE INVENTION 
     The compounds of formula I are prepared using as starting materials a substituted tetrahydro-4H-pyran-4-one having the formula ##STR4## and a hydrazine having the formula 
     
         H.sub.2 NNH-R.sub.2                                        III. 
    
     the compounds of formulas II and III are readily obtainable; see, for example, Journal of the American Chemical Society, 79:156 (1957) and Journal of Medicinal Chemistry, 7:493 (1964). 
     A substituted tetrahydro-4H-pyran-4-one of formula II can be prepared by reacting tetrahydro-4H-pyran-4-one with an appropriate benzaldehyde having the formula ##STR5## 
     A hydrazine of formula III can be prepared by reacting an excess of hydrazine (H 2  NNH 2 ) with a compound having the formula 
     
         R.sub.2 -Y                                                 V. 
    
     wherein Y is chlorine or bromine. 
     Reaction of a substituted tetrahydro-4H-pyran-4-one of formula II with a hydrazine of formula III yields a product of formula I. The reaction can be run in an organic solvent, preferably a lower alkanol such as methanol. While reaction conditions are not critical, the reaction will preferably be run at, or near, the reflux temperature of the solvent. 
     Alternatively, compounds of formula I wherein R 2  is hydrogen can be used as intermediates for the preparation of other compounds of formula I, by reaction with alkylating and acylating agents using procedures well known in the art. 
     Still another method for preparing the compounds of formula I wherein R 2  is A-NR 3  R 4  comprises first reacting a substituted tetrahydro-4H-pyran-4-one of formula II with a hydroxyalkyl hydrazine having the formula 
     
         H.sub.2 NNH-A-OH                                           VI. 
    
     to form an intermediate having the formula ##STR6##An alcohol of formula VII can be reacted with an alkylsulfonyl or arylsulfonyl halide, preferably p-toluenesulfonyl halide, to yield a compound of the formula ##STR7## wherein Y is alkyl or aryl. The intermediate of formula VIII can be treated with a compound having the formula 
     
         HNR.sub.3 R.sub.4                                          IX. 
    
     to yield the products of formula I. This method is particularly useful in preparing those compounds of formula I wherein R 2  is A-NR 3  R 4 , and R 3  and R 4  are both hydrogen. 
     The compounds of formula I wherein R 2  is aminoalkylene form acid addition salts with inorganic and organic acids. These acid addition salts frequently provide useful means for isolating the products from reaction mixtures by forming the salt in a medium in which it is insoluble. The free base may then be obtained by neutralization, e.g., with a base such as sodium hydroxide. Any other salt may then be formed from the free base and the appropriate inorganic or organic acid. Illustrative are the hydrohalides, especially the hydrochloride and hydrobromide which are preferred, sulfate, nitrate, phosphate, borate, acetate, tartrate, maleate, citrate, succinate, oxalate, benzoate, ascorbate, salicylate, methanesulfonate, benzenesulfonate, toluenesulfonate and the like. 
     The compounds of formula I, and the pharmaceutically acceptable acid addition salts thereof, are useful in treating inflammation in mammalian species, e.g., rats, dogs, cats, monkeys, etc. Joint tenderness and stiffness (in conditions such as rheumatoid arthritis) are relieved by the above described compounds. 
     The compounds of this invention can be formulated for use as antiinflammatory agents according to accepted pharmaceutical practice in oral dosage forms such as tablets, capsules, elixirs, or powders, or in an injectable form in a sterile aqueous vehicle prepared according to conventional pharmaceutical practice. The compounds of this invention may be administered in amounts of 100 mg/70kg/day to 2 g/70kg/day, preferably 100 mg/70kg/day to 1 g/70kg/day. 
     The following examples are specific embodiments of this invention. 
    
    
     EXAMPLE 1 
     2,3,3a,4,6,7-Hexahydro-3-phenyl-7-(phenylmethylene)-2-propylpyrano[4,3-c]pyrazole 
     A mixture of 3.6g of tetrahydro-3,5-bis-(phenylmethylene)-4H-pyran-4-one and 1.1g of n-propylhydrazine in 250 ml of methanol is heated at reflux temperature for 3 to 4 hours. Methanol is removed in vacuo, and the residue is dissolved in chloroform. The chloroform solution is washed with dilute hydrochloric acid and water. The organic layer is then dried over anhydrous magnesium sulfate and concentrated in vacuo to give 4g of a crude oil. This is triturated with about 10 ml of acetonitrile and left at room temperature overnight. Some crystals precipitate out and are collected by filtration. The filtrate is concentrated and applied to a dry packed alumina column (neutral, activity I). The fractions eluted with hexane are combined with the crystals obtained above and recrystallized from ether/hexane to yield the title compound, melting point 113.5°-115° C. 
     EXAMPLES 2-22 
     Following the procedure of Example 1, but substituting the compound listed in column I for tetrahydro-3,5-bis-(phenylmethylene)-4H-pyran-4-one and the compound listed in column II for n-propylhydrazine, yields the compound listed in column III. 
     
         __________________________________________________________________________Example    Column I        Column II         Column III__________________________________________________________________________2     tetrahydro-3,5-bis-[(4-methyl-                    benzylhydrazine                                 3-(4-methylphenyl)-7-[(4-methylpheny                                 l)- phenyl)methylene]-4H-pyran-4-one                                 methylene]-2-benzyl-2,3,3a,4,6,7-hex                                 a-                                 hydropyrano[4,3-c]pyrazole3     tetrahydro-3,5-bis-[(4-cyano-                    ethylhydrazine                                 3-(4-cyanophenyl)-7-[(4-cyanophenyl)                                 - phenyl)methylene]-4H-pyran-4-one                                 methylene]-2-ethyl-2,3,3a,4,6,7-hexa                                 -                                 hydropyrano[4,3-c]pyrazole4     tetrahydro-3,5-bis-[(4-nitro-                    n-octylhydrazine                                 2,3,3a,4,6,7-hexahydro-3-(4-nitrophe                                 nyl)- phenyl)methylene]-4H-pyran-4-one                                 7-[(4-nitrophenyl)methylene]-2-octyl                                 -                                 pyrano[4,3-c]pyrazole5     tetrahydro-3,5-bis-[[4-(dimethyl-                    phenylhydrazine                                 3-[4-(dimethylamino)phenyl]-7-[                                 [4-(dimethyl- amino)phenyl]methylene]-4H-pyran-                                 amino)phenyl]methylene]-2,3,3a,4,6,7                                 -hexa- 4-one                           hydro-2-phenylpyrano[4,3-c]pyrazole6     tetrahydro-3,5-bis-[(3-hydroxy-                    ethylhydrazine                                 2-ethyl-2,3,3a,4,6,7-hexahydro-3-(3-                                 hydroxy- phenyl)methylene]-4H-pyran-4-   phenyl)-7-[(3-hydroxyphenyl)methylen                                 e]- one                             pyrano[4,3-c]pyrazole7     tetrahydro-3,5-bis-[(4-methylthio-                    benzylhydrazine                                 2-benzyl-2,3,3a,4,6,7-hexahydro-3-(4                                 -methyl- phenyl)methylene]-4H-pyran-4-one                                 thiophenyl)-7-[(4-methylthiophenyl)m                                 ethylene]-                                 pyrano[4,3-c]pyrazole8     tetrahydro-3,5-bis-[(4-ethylsul-                    phenylhydrazine                                 3-(4-ethylsulfinylphenyl)-7-[(4-ethy                                 lsulfinyl- finylphenyl)methylene]-4H-pyran-                                 phenyl)methylene]-2,3,3a,4,6,7-hexah                                 ydro-2- 4-one                           phenylpyrano[4,3-c]pyrazole9     tetrahydro-3,5-bis-[(2-methyl-                    methylaminopropyl-                                 3a,4,6,7-tetrahydro-N-methyl-3-(2- phenyl)methylene]-4H-pyran-4-one                    hydrazine    methylphenyl)-7-[(2-methylphenyl)-                                 methylene]pyrano[4,3-c]pyrazole-2(3H                                 )-                                 propanamine10    tetrahydro-3,5-bis-[ (4-methoxy-                    N-benzyl-N-methyl-                                 3a,4,6,7-tetrahydro-N-benzyl-N- phenyl)methylene]-4H-pyran-4-one                    aminoethylhydrazine                                 methyl-3-(4-methoxyphenyl)-7-                                 [(4-methoxyphenyl)methylene]pyrano-                                 [4,3-c]pyrazole-2(3H)-ethanamine11    tetrahydro-3,5-bis-[(4-trifluoro-                    N-methyl-N-phenyl-                                 3a,4,6,7-tetrahydro-N-methyl-N- methylphenyl)methylene]-4H-pyran-                    aminopentylhydrazine                                 phenyl-3-(4-trifluoromethylphenyl)- 4-one                           7-[(4-trifluoromethylphenyl)methyl-                                 ene]pyrano[4,3-c]pyrazole-2(3H)-                                 pentanamine12    tetrahydro-3,5-bis-[(2-chloro-                    (2-aminoethyl)hydra-                                 3a,4,6,7-tetrahydro-3-(2-chloro- phenyl)methylene]-4H-pyran-4-one                    zine         phenyl)-7-[2-(chlorophenyl)methylene                                 ]-                                 pyrano[4,3-c]pyrazole-2(3H)-ethanami                                 ne13    tetrahydro-3,5-bis-(phenylmethyl-                    phenylaminopropyl-                                 3a,4,6,7-tetrahydro-N-phenyl-3-pheny                                 l- ene)-4H-pyran-4-one                    hydrazine    7-(phenylmethylene)pyrano[4,3-c]pyra                                 zole-                                 2(3H)-propanamine14    tetrahydro-3,5-bis-(phenylmethyl-                    benzylaminopropyl-                                 3a,4,6,7-tetrahydro-N-benzyl-3-pheny                                 l- ene)-4H-pyran-4-one                    hydrazine    7-(phenylmethylene)pyrano[4,3-c]pyra                                 zole-                                 2(3H)-propanamine15    tetrahydro-3,5-bis-[(4-propoxy-                    3-(dimethylamino)-                                 3a,4,6,7-tetrahydro-N,N,β-trime                                 thyl-3- phenyl)methylene]-4H-pyran-                    2-methyl-propyl-                                 (4-propoxyphenyl)-7-[(4-propoxypheny                                 l)- 4-one              hydrazine    methylene]pyrano[4,3-c]pyrazole-2(3H                                 )-                                 propanamine16    tetrahydro-3,5-bis-(phenyl-                    3-(4-methyl-1-piper-                                 2,3,3a,4,6,7-hexahydro-2-[3-(4- methylene)-4H-pyran-4-one                    azinyl)propylhydrazine                                 methyl-1-piperazinyl)propyl]-3-                                 phenyl-7-(phenylmethylene)pyrano-                                 [4,3-c]pyrazole; melting point                                 101-104° C; melting point of                                 di-                                 maleate salt 173-175° C17    tetrahydro-3,5-bis-[(4-methyl-                    3-(4-methyl-1-piper-                                 2,3,3a,4,6,7-hexahydro-2-[3-(4- sulfinyl)phenylmethylene]-4H-                    azinyl)propylhydrazine                                 methyl-1-piperazinyl)propyl]-3- pyran-4-one                     [4-(methylsulfinyl)phenyl]-7-[4- pyran-4-one                     [4-(methylsulfinyl)phenyl]-7-[4-                                 (methylsulfinyl)phenylmethylene]-                                 pyrano[4,3-c]pyrazole; melting                                 point of dimaleate salt                                 172-174° C18    tetrahydro-3,5-bis-(phenyl-                    2-(1-piperazinyl)ethyl-                                 2,3,3a,4,6,7-hexahydro-2-[2-(1- methylene)-4H-pyran-4-one                    hydrazine    piperazinyl)ethyl]-3-phenyl-7-                                 (phenylmethylene)pyrano[4,3-c]-                                 pyrazole19    tetrahydro-3,5-bis-(phenyl-                    3-(4-phenyl-1-pipera-                                 2,3,3a,4,6,7-hexahydro-2-[3-(4- methylene)-4H-pyran-4-one                    zinyl)propylhydrazine                                 phenyl-1-piperazinyl)propyl]-3-                                 phenyl-7-(phenylmethylene)pyrano-                                 [4,3-c]pyrazole20    tetrahydro-3,5-bis-(phenyl-                    4-(4-phenylmethyl-1-                                 2,3,3a,4,6,7-hexahydro-2-[4-(4- methylene-4H-pyran-4-one                    piperazinyl)butylhydra-                                 phenylmethyl-1-piperazinyl)butyl]-                    zine         3-phenyl-7-(phenylmethylene)pyrano-                                 [4,3-c]pyrazole21    tetrahydro-3,5-bis-(2-methyl-                    3-(4-morpholinyl)propyl-                                 2,3,3a,4,6,7-hexahydro-2-[3-(4- phenyl)methylene]-4H-pyran-4-one                    hydrazine    morpholinyl)propyl]-3-(2-methyl-                                 phenyl)-7-[(2-methylphenyl)methylene                                 ]-                                 pyrano[4,3-c]pyrazole22    tetrahydro-3,5-bis-(phenyl-                    2-(1-piperidinyl)ethyl-                                 2,3,3a,4,6,7-hexahydro-2-[2-(1-piper                                 - methylene)-4H-pyran-4-one                    hydrazine    idinyl)ethyl]-3-phenyl-7-(phenyl-                                 methylene)pyrano[4,3-c]pyrazole__________________________________________________________________________