Abstract:
The present invention is directed to compounds, pharmaceutical compositions, and methods for modulating processes mediated by Progesterone Receptor. Also provided are methods of making such compounds and pharmaceutical compositions.

Description:
RELATED APPLICATIONS 
     This application claims the benefit of priority of U.S. Provisional Application Ser. No. 60/418,140 filed Oct. 11, 2002, the entire disclosure of which is incorporated herein by reference. 
    
    
     FIELD OF THE INVENTION 
     This invention relates to nonsteroidal 5-(1′,1′-cycloalkyl/alkenyl)methylidene 1,2-dihydro-5H-chromeno[3,4-f]quinolines that may be modulators (i.e., agonists, partial agonists and antagonists) of progesterone receptors and to methods for the making and use of such compounds. 
     BACKGROUND OF THE INVENTION 
     Progesterone receptor (PR) modulators have been widely used in regulation of female reproduction systems and in treatment of female hormone dependent diseases. The effectiveness of known steroidal PR modulators is often tempered by their undesired side-effect profile, particularly during long-term administration. For example, the effectiveness of synthetic progestins, such as norgestrel, as female birth control agents must be weighed against the increased risk of breast cancer and heart disease. Similarly, the progesterone antagonist, mifepristone (RU486), if administered for chronic indications, such as uterine fibroids, endometriosis and certain hormone-dependent cancers, could lead to homeostatic imbalances in a patient due to its inherent cross-reactivity as a glucocorticoid receptor (GR) antagonist. Accordingly, identification of compounds that have good receptor-selectivity for PR over other steroid hormone receptors as well as good tissue-selectivity (e.g., selectivity for uterine tissue over breast tissue) would be of significant value in the improvement of women&#39;s health. 
     A group of nonsteroidal molecules, which contain a di- or tetra-hydroquinoline ring as core pharmacophore (U.S. Pat. Nos. 5,693,646; 5,693,647 and 5,696,127; PCT Int. Pub. Nos. WO 99/41256 A1 and WO 99/41257 A1) have been described as steroid receptor modulator compounds. 
     The entire disclosures of the patents, publications and references referred to herein are incorporated by reference herein and are not admitted to be prior art. 
     SUMMARY OF THE INVENTION 
     The present invention is directed to compounds, pharmaceutical compositions, and methods for modulating processes mediated by Progesterone Receptor. More particularly, the invention relates to nonsteroidal compounds and compositions which may be high affinity, high specificity agonists, partial agonists (i.e., partial activators and/or tissue-specific activators) and/or antagonists for progesterone receptors. Also provided are methods of making such compounds and pharmaceutical compositions. 
     Compounds of the present invention may be represented by the formulae: 
                                
wherein:
 
     R 1  is selected from the group of hydrogen, C 1 –C 4  alkyl, C 1 –C 4  haloalkyl, C 1 –C 4  heteroalkyl, COR 5 , CO 2 R 5 , SO 2 R 5 , and CONR 5 R 6 ; 
     R 2  and R 3  each independently is selected from the group of hydrogen, C 1 –C 6  alkyl, and C 1 –C 6  haloalkyl; or 
     R 2  and R 3  taken together form a cycloalkyl ring of from three to twelve carbons; 
     R 4  is selected from the group of hydrogen, F, Cl, Br, CN, OR 5 , C 1 –C 4  alkyl, C 1 –C 4  haloalkyl, and C 1 –C 4  heteroalkyl; 
     R 5  and R 6  each is independently selected from the group of hydrogen, C 1 –C 4  alkyl, C 1 –C 4  heteroalkyl, and C 1 –C 4  haloalkyl; 
     R 7  through R 9  each independently is selected from the group of hydrogen, F, Cl, Br, I, NO 2 , CN, OR 5 , NR 5 R 6 , SR 5 , COR 5 , CO 2 R 5 , CONR 5 R 6 , C 1 –C 8  alkyl, C 1 –C 8  heteroalkyl, C 1 –C 8  haloalkyl, C 2 –C 8  alkenyl, C 2 –C 8  alkynyl; 
     R 10  through R 15  each independently is selected from the group of hydrogen, F, Cl, Br, OR 5 , C 1 –C 4  alkyl, C 1 –C 4  haloalkyl, and C 1 –C 4  heteroalkyl; or 
     R 12  and R 14  taken together form a bond, when Y is CR 14 R 15 ; or 
     R 10  and R 14  taken together form a bond, when Z is CR 14 R 15 ; 
     Y and Z each independently is selected from the group of O, S, NR 6  and CR 14 R 15 ; 
     n is 0, 1, 2, or 3; 
     and pharmaceutically acceptable salts and prodrugs thereof. 
     DEFINITIONS AND NOMENCLATURE 
     As used herein, the following terms are defined with the following meanings, unless explicitly stated otherwise. Furthermore, in an effort to maintain consistency in the naming of compounds of similar structure but differing substituents, the compounds described herein are named according to the following general guidelines. The numbering system for the location of substituents on such compounds is also provided. 
     A 5H-chromeno[3,4-f]quinoline is defined by the following structure: 
     
       
                 
         
             
             
         
      
     
     The term “alkyl,” alone or in combination, refers to an optionally substituted straight-chain or branched-chain or cyclic-chain alkyl radical having from 1 to about 12 carbon atoms. The term also includes substituted straight-chain or branched-chain alkyl radicals having from 1 to about 6 carbon atoms as well as those having from 1 to about 4 carbon atoms. Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, tert-amyl, pentyl, hexyl, heptyl, octyl and the like. 
     The term “alkenyl,” alone or in combination, refers to an optionally substituted straight-chain or branched-chain hydrocarbon radical having one or more carbon-carbon double-bonds and having from 2 to about 18 carbon atoms. The term also includes substituted straight-chain or branched-chain alkyl radicals having one or more carbon-carbon double bonds and having from 2 to about 6 carbon atoms as well as those having from 2 to about 4 carbon atoms. Examples of alkenyl radicals include ethenyl, propenyl, 1,3-butadienyl and the like. 
     The term “alkynyl,” alone or in combination, refers to an optionally substituted straight-chain or branched-chain hydrocarbon radical having one or more carbon-carbon triple-bonds and having from 2 to about 12 carbon atoms. The term also includes substituted straight-chain or branched-chain alkyl radicals having one or more carbon-carbon triple bonds and having from 2 to about 6 carbon atoms as well as those having from 2 to about 4 carbon atoms. Examples of alkynyl radicals include ethynyl, propynyl, butynyl and the like. 
     The term “heteroalkyl,” “heteroalkenyl” and “heteroalkynyl” refer to alkyl, alkenyl and alkynyl radicals, respectively, as described above, in which one or more skeletal atoms are heteroatoms such as, for example, oxygen, nitrogen, sulfur or combinations thereof. The terms heteroalkyl, heteroalkenyl and heteroalkynyl include radicals in which 1 to about 6 skeletal atoms are oxygen, nitrogen, sulfur or combinations thereof, as well as those in which 1 to 4 skeletal atoms are oxygen, nitrogen, sulfur or combinations thereof and those in which 1 to 2 skeletal atoms are oxygen, nitrogen, sulfur or combinations thereof. 
     The terms haloalkyl, haloalkenyl, haloalkynyl and haloalkoxy include alkyl, alkenyl, and alkynyl structures, as described above, that are substituted with one or more fluorines, chlorines, bromines or iodines, or with combinations thereof. 
     The terms cycloalkyl, aryl, arylalkyl, heteroaryl, alkyl, alkynyl, alkenyl, haloalkyl and heteroalkyl include optionally substituted cycloalkyl, aryl, arylalkyl, heteroaryl, alkyl, alkynyl, alkenyl, haloalkyl and heteroalkyl radicals. 
     The term “halogen” includes F, Cl, Br and I. 
     The term “mediate” means affect or influence, frequently indirectly or via some intervening action. Thus, for example, conditions mediated by a progesterone receptor are those in which a progesterone receptor plays a role. Progesterone receptors are known to play a role in conditions including, for example, infertility, contraception, pregnancy maintenance and termination, female hormone deficiency, female sexual dysfunction, dysfunctional uterine bleeding, endometriosis, mood disorder, osteoporosis, and hormone-dependent cancers. 
     The term “receptor-selectivity” refers to the conditions where a compound displays modulating activity towards one or more particular receptors (e.g., a progesterone receptors) while displaying substantially less or no cross-reactivity towards one or more different receptors (e.g., glucocorticoid receptors). Thus, for example, selective compounds of the present invention may display modulating activity towards progesterone receptors without displaying substantial cross-reactivity towards another steroid hormone receptors. Compounds may be selective for a single receptor, group of similar receptors or multiple receptors. 
     The term “tissue-selectivity” refers to compounds that display substantial modulating activity in one tissue (e.g., uterine tissue) while displaying lesser modulating activity in at least one other tissue (e.g., breast tissue). Thus, for example, tissue-selective compounds of the present invention may display substantial modulating activity in uterine and vaginal tissues with lesser modulating activity (partial agonistic or partial antagonistic) in breast tissues relative to the activities of the marketed steroidal progestins in all of the target tissues. 
     The term “modulate” means affect or influence, for example, the amount, degree or proportion. Thus, compounds that “modulate” a receptor affect the activity, either positively or negatively, of that receptor. The term may be used to refer to the activity of compounds of a receptor as, for example, an agonist, partial agonist or antagonist. The term also may be used to refer to the effect that a compound has on a physical and/or physiological condition of an individual. For example, certain compounds of the present invention may be used to modulate fertility in an individual. That is, certain compounds of this invention may be used to increase the fertility of an individual, while other compounds of this invention may be used to decrease the fertility of an individual. 
     A compound that binds to a receptor and mimics the effect of the native or endogenous ligand is referred to as an “agonist,” while a compound that binds to a receptor and inhibits or has an effect that is opposite that of the native or endogenous ligand is called an “antagonist.” “Partial agonists” give an effect of the same type as the native or endogenous ligand, but of a lower magnitude, while “partial antagonists” are incompletely inhibitory or opposite that of the native or endogenous ligand. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     Compounds of the present invention may be represented by the formulae: 
                                
wherein:
 
     R 1  is selected from the group of hydrogen, C 1 –C 4  alkyl, C 1 –C 4  haloalkyl, C 1 –C 4  heteroalkyl, COR 5 , CO 2 R 5 , SO 2 R 5 , and CONR 5 R 6 ; 
     R 2  and R 3  each independently is selected from the group of hydrogen, C 1 –C 6  alkyl, and C 1 –C 6  haloalkyl; or 
     R 2  and R 3  taken together form a cycloalkyl ring of from three to twelve carbons; 
     R 4  is selected from the group of hydrogen, F, Cl, Br, CN, OR 5 , C 1 –C 4  alkyl, C 1 –C 4  haloalkyl, and C 1 –C 4  heteroalkyl; 
     R 5  and R 6  each is independently selected from the group of hydrogen, C 1 –C 4  alkyl, C 1 –C 4  heteroalkyl, and C 1 –C 4  haloalkyl; 
     R 7  through R 9  each independently is selected from the group of hydrogen, F, Cl, Br, I, NO 2 , CN, OR 5 , NR 5 R 6 , SR 5 , COR 5 , CO 2 R 5 , CONR 5 R 6 , C 1 –C 8  alkyl, C 1 –C 8  heteroalkyl, C 1 –C 8  haloalkyl, C 2 –C 8  alkenyl, C 2 –C 8  alkynyl; 
     R 10  through R 15  each independently is selected from the group of hydrogen, F, Cl, Br, OR 5 , C 1 –C 4  alkyl, C 1 –C 4  haloalkyl, and C 1 –C 4  heteroalkyl; or 
     R 12  and R 14  taken together form a bond, when Y is CR 14 R 15 ; or 
     R 10  and R 14  taken together form a bond, when Z is CR 14 R 15 ; 
     Y and Z each independently is selected from the group of O, S, NR 6  and CR 14 R 15 ; 
     n is 0, 1, 2, or 3; 
     and pharmaceutically acceptable salts and prodrugs thereof. 
     Compounds of the invention include those represented by the formulae: 
                                
wherein:
 
     R 2  and R 3  each independently is selected from the group of C 1 –C 4  alkyl, and C 1 –C 4  haloalkyl; 
     R 4  is selected from the group of hydrogen, F, Cl, Br, CN, OR 5 , C 1 –C 4  alkyl, C 1 –C 4  haloalkyl, and C 1 –C 4  heteroalkyl; 
     R 5  and R 6  each is independently selected from the group of hydrogen, C 1 –C 4  alkyl, C 1 –C 4  heteroalkyl, and C 1 –C 4  haloalkyl; 
     R 7  through R 9  each independently is selected from the group of hydrogen, F, Cl, Br, CN, OR 5 , NR 5 R 6 , SR 5 , COR 5 , C 1 –C 4  alkyl, C 1 –C 4  heteroalkyl, C 1 –C 4  haloalkyl, C 2 –C 4  alkenyl; 
     n is 0, 1, 2, or 3; 
     and pharmaceutically acceptable salts and prodrugs thereof. 
     In the following table, the inventors contemplate any combination of the following Markush groups and those described above for the various variables. 
     
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE A 
               
             
             
               
                   
               
               
                 Table of Markush Groups by Variable 
               
             
          
           
               
                   
                 Markush Group A 
                 Markush Group B 
                 Markush Group C 
                 Markush Group D 
               
               
                   
               
               
                 R 1   
                 H, C 1 —C 4  alkyl, C 1 —C 4   
                 H, C 1 —C 4  alkyl, 
                 methyl and H 
                 H 
               
               
                   
                 haloalkyl, C 1 —C 4   
                 COR 5 , CO 2 R 5  and 
               
               
                   
                 heteroalkyl, COR 5 , 
                 SO 2 R 5   
               
               
                   
                 CO 2 R 5 , SO 2 R 5  and 
               
               
                   
                 CONR 5 R 6   
               
               
                 R 2   
                 H, C 1 —C 6  alkyl and 
                 C 1 —C 4  alkyl, and 
                 C 1 —C 4  alkyl 
                 CH 3   
               
               
                   
                 C 1 —C 6  haloalkyl 
                 C 1 —C 4  haloalkyl 
               
               
                   
                 R 2  and R 3  taken 
                 R 2  and R 3  taken 
                 R 2  and R 3  taken 
               
               
                   
                 together form a C 3 —C 12   
                 together form a C 4 —C 8   
                 together form a C 5 —C 6   
               
               
                   
                 cycloalkyl ring 
                 cycloalkyl ring 
                 cycloalkyl ring 
               
               
                 R 3   
                 H, C 1 —C 6  alkyl and 
                 C 1 —C 4  alkyl and 
                 C 1 —C 4  alkyl 
                 CH 3   
               
               
                   
                 C 1 —C 6  haloalkyl 
                 C 1 —C 4  haloalkyl 
               
               
                   
                 R 2  and R 3  taken 
                 R 2  and R 3  taken 
                 R 2  and R 3  taken 
               
               
                   
                 together form a C 3 —C 12   
                 together form a C 4 —C 8   
                 together form a C 5 —C 6   
               
               
                   
                 cycloalkyl ring 
                 cycloalkyl ring 
                 cycloalkyl ring 
               
               
                 R 4   
                 H, F, Cl, Br, CN, 
                 H, F, Cl, Br, C 1 —C 4   
                 F, Cl, Br, CH 3  and 
                 methyl 
               
               
                   
                 OR 5 , C 1 —C 4  alkyl, 
                 alkyl and C 1 —C 4   
                 CF 3   
               
               
                   
                 C 1 —C 4  haloalkyl 
                 haloalkyl 
               
               
                   
                 and C 1 —C 4   
               
               
                   
                 heteroalkyl 
               
               
                 R 5   
                 H, C 1 —C 4  alkyl, C 1 —C 4   
                 H and C 1 —C 4  alkyl 
                 H and methyl 
                 H 
               
               
                   
                 heteroalkyl and 
               
               
                   
                 C 1 —C 4  haloalkyl 
               
               
                 R 6   
                 H, C 1 —C 4  alkyl, C 1 —C 4   
                 H, and C 1 —C 4  alkyl 
                 H and methyl 
                 H 
               
               
                   
                 heteroalkyl and 
               
               
                   
                 C 1 —C 4  haloalkyl 
               
               
                 R 7   
                 H, F, Cl, Br, I, 
                 H, F, Cl, Br, CN, 
                 hydrogen, F, Cl, 
                 H or F 
               
               
                   
                 NO 2 , CN, OR 5 , 
                 OR 5 , NR 5 R 6 , SR 5 , 
                 Br, CN, OR 5 , C 1 —C 8   
               
               
                   
                 NR 5 R 6 , SR 5 , COR 5 , 
                 COR 5 , C 1 —C 4  alkyl, 
                 alkyl, C 1 —C 8   
               
               
                   
                 CO 2 R 5 , CONR 5 R 6 , 
                 C 1 —C 4  heteroalkyl, 
                 heteroalkyl and C 1 —C 8   
               
               
                   
                 C 1 —C 8  alkyl, C 1 —C 8   
                 C 1 —C 4  haloalkyl 
                 haloalkyl 
               
               
                   
                 heteroalkyl, C 1 —C 8   
                 and C 2 —C 4  alkenyl 
               
               
                   
                 haloalkyl, C 2 —C 8   
               
               
                   
                 alkenyl and C 2 —C 8   
               
               
                   
                 alkynyl 
               
               
                 R 8   
                 H, F, Cl, Br, I, 
                 H, F, Cl, Br, CN, 
                 H, F, Cl, Br, CN, 
                 H and F 
               
               
                   
                 NO 2 , CN, OR 5 , 
                 OR 5 , NR 5 R 6 , SR 5 , 
                 OR 5 , C 1 —C 8  alkyl, 
               
               
                   
                 NR 5 R 6 , SR 5 , COR 5 , 
                 COR 5 , C 1 —C 4  alkyl, 
                 C 1 —C 8  heteroalkyl, 
               
               
                   
                 CO 2 R 5 , CONR 5 R 6 , 
                 C 1 —C 4  heteroalkyl, 
                 and C 1 —C 8   
               
               
                   
                 C 1 —C 8  alkyl, C 1 —C 8   
                 C 1 —C 4  haloalkyl 
                 haloalkyl 
               
               
                   
                 heteroalkyl, C 1 —C 8   
                 and C 2 —C 4  alkenyl 
               
               
                   
                 haloalkyl, C 2 —C 8   
               
               
                   
                 alkenyl, and C 2 —C 8   
               
               
                   
                 alkynyl 
               
               
                 R 9   
                 H, F, Cl, Br, I, 
                 H, F, Cl, Br, CN, 
                 H, F, Cl, Br, CN, 
                 H and F 
               
               
                   
                 NO 2 , CN, OR 5 , 
                 OR 5 , NR 5 R 6 , SR 5 , 
                 OR 5 , C 1 —C 8  alkyl, 
               
               
                   
                 NR 5 R 6 , SR 5 , COR 5 , 
                 COR 5 , C 1 —C 4  alkyl, 
                 C 1 —C 8  heteroalkyl, 
               
               
                   
                 CO 2 R 5 , CONR 5 R 6 , 
                 C 1 —C 4  heteroalkyl, 
                 and C 1 —C 8   
               
               
                   
                 C 1 —C 8  alkyl, C 1 —C 8   
                 C 1 —C 4  haloalkyl 
                 haloalkyl 
               
               
                   
                 heteroalkyl, C 1 —C 8   
                 and C 2 —C 4  alkenyl 
               
               
                   
                 haloalkyl, C 2 —C 8   
               
               
                   
                 alkenyl and C 2 —C 8   
               
               
                   
                 alkynyl 
               
               
                 R 10   
                 H, F, Cl, Br, OR 5 , 
                 H, F, Cl, OR 5 , C 1 —C 4   
                 H, F, Cl, CH 3  and 
                 H and F 
               
               
                   
                 C 1 —C 4  alkyl, C 1 —C 4   
                 alkyl and C 1 —C 4   
                 CF 3   
               
               
                   
                 haloalkyl and C 1 —C 4   
                 haloalkyl 
               
               
                   
                 heteroalkyl 
               
               
                   
                 R 10  and R 14  taken 
               
               
                   
                 together form a 
               
               
                   
                 bond 
               
               
                 R 11   
                 H, F, Cl, Br, OR 5 , 
                 H, F, Cl, OR 5 , C 1 —C 4   
                 H, F, Cl, CH 3  and 
                 H and F 
               
               
                   
                 C 1 —C 4  alkyl, C 1 —C 4   
                 alkyl and C 1 —C 4   
                 CF 3   
               
               
                   
                 haloalkyl and C 1 —C 4   
                 haloalkyl 
               
               
                   
                 heteroalkyl 
               
               
                 R 12   
                 H, F, Cl, Br, OR 5 , 
                 H, F, Cl, OR 5 , C 1 —C 4   
                 H, F, Cl, CH 3  and 
                 H and F 
               
               
                   
                 C 1 —C 4  alkyl, C 1 —C 4   
                 alkyl and C 1 —C 4   
                 CF 3   
               
               
                   
                 haloalkyl and C 1 —C 4   
                 haloalkyl 
               
               
                   
                 heteroalkyl 
               
               
                   
                 R 12  and R 14  taken 
               
               
                   
                 together form a 
               
               
                   
                 bond 
               
               
                 R 13   
                 H, F, Cl, Br, OR 5 , 
                 H, F, Cl, OR 5 , C 1 —C 4   
                 H, F, Cl, CH 3  and 
                 H and F 
               
               
                   
                 C 1 —C 4  alkyl, C 1 —C 4   
                 alkyl and C 1 —C 4   
                 CF 3   
               
               
                   
                 haloalkyl and C 1 —C 4   
                 haloalkyl 
               
               
                   
                 heteroalkyl 
               
               
                 R 14   
                 H, F, Cl, Br, OR 5 , 
                 H, F, Cl, OR 5 , C 1 —C 4   
                 H, F, Cl, CH 3  and 
                 H and F 
               
               
                   
                 C 1 —C 4  alkyl, C 1 —C 4   
                 alkyl and C 1 —C 4   
                 CF 3   
               
               
                   
                 haloalkyl and C 1 —C 4   
                 haloalkyl 
               
               
                   
                 heteroalkyl 
               
               
                   
                 R 12  and R 14  taken 
               
               
                   
                 together form a 
               
               
                   
                 bond 
               
               
                   
                 R 10  and R 14  taken 
               
               
                   
                 together form a 
               
               
                   
                 bond 
               
               
                 R 15   
                 H, F, Cl, Br, OR 5 , 
                 H, F, Cl, OR 5 , C 1 —C 4   
                 H, F, Cl, CH 3  and 
                 H and F 
               
               
                   
                 C 1 —C 4  alkyl, C 1 —C 4   
                 alkyl and C 1 —C 4   
                 CF 3   
               
               
                   
                 haloalkyl and C 1 —C 4   
                 haloalkyl 
               
               
                   
                 heteroalkyl 
               
               
                 Y 
                 O, S, NR 6  and 
                 S and CR 14 R 15   
                 S and CH 2   
                 S 
               
               
                   
                 CR 14 R 15   
               
               
                 Z 
                 O, S, NR 6  and 
                 S and CR 14 R 15   
                 S and CH 2   
                 S 
               
               
                   
                 CR 14 R 15   
               
               
                 n 
                 0, 1, 2, or 3 
                 0, 1, or 2 
                 0 or 1 
                 1 
               
               
                   
               
             
          
         
       
     
     In one aspect, the present invention provides a pharmaceutical composition comprising an effective amount of a progesterone receptor modulator compound according to any one of formulae I and II shown above wherein R 1  through R 15 , n, Y and Z all have the same definitions as given above. 
     In another aspect, the present invention comprises a method of modulating a process mediated by a progesterone receptor comprising administering to a patient having a condition mediated by a progesterone receptors an effective amount of a composition comprising a compound according to any one of the formulae I through II shown above, wherein R 1  through R 15 , n, Y and Z all have the same definitions as those given above. 
     Any of the compounds of the present invention can be synthesized as pharmaceutically acceptable salts for incorporation into various pharmaceutical compositions. As used herein, pharmaceutically acceptable salts include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, hydrofluoric, sulfuric, citric, maleic, acetic, lactic, nicotinic, succinic, oxalic, phosphoric, malonic, salicylic, phenylacetic, stearic, pyridine, ammonium, piperazine, diethylamine, nicotinamide, formic, urea, sodium, potassium, calcium, magnesium, zinc, lithium, cinnamic, methylamino, methanesulfonic, picric, tartaric, triethylamino, dimethylamino, and tris(hydroxymethyl)aminomethane. Additional pharmaceutically acceptable salts are known to those skilled in the art. 
     PR modulator compounds of the present invention may be particularly useful for female hormone replacement therapy and as modulators of fertility (e.g., as contraceptives, contragestational agents or abortifacients, in vitro fertilization, pregnancy maintenance), either alone or in conjunction with one or more estrogen receptor modulators. PR modulator compounds of this invention also may be used in the treatment of dysfunctional uterine bleeding, dysmenorrhea, endometriosis, leiomyomas (uterine fibroids), hot flushes, mood disorders, and meningiomas. PR modulator compounds of this invention also may be used in the treatment of various hormone-dependent cancers, including, without limitation, cancers of ovaries, breast, endometrium and prostate. PR modulator compounds of this invention can also be used in treatment of female osteoporosis, either alone or in combination with one or more estrogen receptor modulators. 
     It will be understood by those skilled in the art that while the compounds of the present invention will typically be employed as a selective agonists, partial agonists or antagonists, there may be instances where a compound with a mixed steroid receptor profile is preferred. For example, use of a PR agonist (i.e., progestin) in female contraception often leads to the undesired effects of increased water retention and acne flare ups. In this instance, a compound that is primarily a PR agonist, but also displays some AR and MR modulating activity, may prove useful. Specifically, the mixed MR effects would be useful to control water balance in the body, while the AR effects would help to control any acne flare ups that occur. 
     Furthermore, it will be understood by those skilled in the art that the compounds of the present invention, typically pharmaceutical compositions and formulations containing one or more of these compounds, can be used in a wide variety of combination therapies to treat the conditions and diseases described above. Thus, the compounds of the present invention can be used in combination with other hormones and other therapies, including, without limitation, chemotherapeutic agents such as cytostatic and cytotoxic agents, immunological modifiers such as interferons, interleukins, growth hormones and other cytokines, hormone therapies, surgery and radiation therapy. 
     Representative PR modulator compounds (i.e., agonists, partial agonists and antagonists) according to the present invention include: 
     9-Fluoro-5-(1,3-dithia-2-cyclohexylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (compound 10); 
     8-methoxy-5-(1,3-dithia-2-cyclohexylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (compound 13); 
     7,9-difluoro-5-(1,3-dithia-2-cyclohexylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (compound 15); 
     7-fluoro-5-(1,3-dithia-2-cyclohexylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (compound 17); 
     7-fluoro-5-cyclohexylidene-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (compound 19); 
     7,9-difluoro-5-cyclohexylidene-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (compound 20); 
     7-fluoro-5-(1,3-dithia-2-cyclohexylidene)-1,2-dihydro-2,2-dimethyl-5H-chromeno[3,4-f]quinoline (compound 21); and 
     7-fluoro-5-(2-cyclohexenylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (compound 23). 
     The sequence of steps for the general schemes to synthesize the compounds of the present invention is shown below. In each of the Schemes the R groups (e.g., R 1 , R 2 , etc.) correspond to the specific substitution patterns noted in the Examples. However, it will be understood by those skilled in the art that other functionalities disclosed herein at the indicated positions of compounds of formulae I and II also comprise potential substituents for the analogous positions on the structures within the Schemes. In a further aspect, the present invention contains a novel process for the preparation of the compounds of the present invention. 
     
       
                 
         
             
             
         
      
     
     The process of Scheme I begins with addition of lithium reagents 2 to lactones 1 that were previously disclosed (Todd, Jones; et al. U.S. Pat. Nos. 5,693,646; 5,693,647 and 5,696,127) to produce hemiacetal 3. Treatment of the intermediate 3 with a Lewis acid, such as p-toluenesulfonic acid, affords the cyclic alkylidenes 4. 
     The compounds of the present invention also include racemates, stereoisomers and mixtures of said compounds, including isotopically-labeled and radio-labeled compounds. Such isomers can be isolated by standard resolution techniques, including fractional crystallization and chiral column chromatography. 
     As noted above, any of the PR modulator compounds of the present invention can be combined in a mixture with a pharmaceutically acceptable carrier to provide pharmaceutical compositions useful for treating the biological conditions or disorders noted herein in mammalian, and particularly in human patients. The particular carrier employed in these pharmaceutical compositions may take a wide variety of forms depending upon the type of administration desired. Suitable administration routes include enteral (e.g., oral), topical, suppository, inhalable and parenteral (e.g., intravenous, intramuscular and subcutaneous). 
     In preparing the compositions in oral liquid dosage forms (e.g., suspensions, elixirs and solutions), typical pharmaceutical media, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be employed. Similarly, when preparing oral solid dosage forms (e.g., powders, tablets and capsules), carriers such as starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like will be employed. Due to their ease of administration, tablets and capsules represent a desirable oral dosage form for the pharmaceutical compositions of the present invention. 
     For parenteral administration, the carrier will typically comprise sterile water, although other ingredients that aid in solubility or serve as preservatives may also be included. Furthermore, injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like will be employed. 
     For topical administration, the compounds of the present invention may be formulated using bland, moisturizing bases, such as ointments or creams. Examples of suitable ointment bases are petrolatum, petrolatum plus volatile silicones, lanolin and water in oil emulsions such as Eucerin™, available from Beiersdorf (Cincinnati, Ohio). Examples of suitable cream bases are Nivea™ Cream, available from Beiersdorf (Cincinnati, Ohio), cold cream (USP), Purpose CreaM™, available from Johnson &amp; Johnson (New Brunswick, N.J.), hydrophilic ointment (USP) and Lubriderm™, available from Warner-Lambert (Morris Plains, N.J.). 
     The pharmaceutical compositions and compounds of the present invention will generally be administered in the form of a dosage unit (e.g., tablet, capsule, etc.). The compounds of the present invention generally are administered in a daily dosage of from about 1 μg/kg of body weight to about 50 mg/kg of body weight. Typically, the compounds of the present invention are administered in a daily dosage of from about 2 μg/kg to about 25 mg/kg of body weight. Most often, the compounds of the present invention are administered in a daily dosage of from about 10 μg/kg to about 5 mg/kg body weight. As recognized by those skilled in the art, the particular quantity of pharmaceutical composition according to the present invention administered to a patient will depend upon a number of factors, including, without limitation, the biological activity desired, the condition of the patient, and tolerance for the drug. 
     Compounds of this invention also have utility when radio- or isotopically-labeled as ligands for use in assays to determine the presence of PR in a cell background or extract. They may be particularly useful due to their ability to selectively activate progesterone receptors, and can therefore be used to determine the presence of such receptors in the presence of other steroid receptors or related intracellular receptors. 
     The compounds and pharmaceutical compositions of the present invention may be extremely potent activators of PR. For example, the compounds and compositions of the present invention may display 50% maximal activation of PR at a concentration of less than 50 nM. Some compounds and compositions of the present invention may display 50% maximal activation of PR at a concentration of less than 20 nM, and some may display such activity at a concentration of less than 10 nM. 
     The invention will be further illustrated by reference to the following non-limiting Examples. 
     EXAMPLE 1 
     Preparation of 9-Fluoro-5-(1,3-dithia-2-cyclohexylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 10, Structure 4 of Scheme I, where R 4 =methyl, R 7 =R 8 =R 10 =R 11 =H, R 9 =F, Y=Z=S) 
     To a solution of 1,3-dithiane (0.24 g, 2.0 mmol) in THF (10 mL) at −70° C. was added n-BuLi (1.6 M in hexane, 1.3 mL) and the resulting mixture was stirred at −10° C. for 2 h. To the reaction mixture at −70° C. was added 9-fluoro-1,2-dihydro-2,2,4-trimethyl-5-coumarino[3,4-f]quinoline (Compound 11, Structure 1 of Scheme I, where R 4 =methyl, R 7 =R 8 =H, R 9 =F) (0.12 g, 0.40 mmol) in THF (1 mL). The dark red solution was slowly warmed to −30° C. till the red color faded away and was quenched immediately with water. Extraction with EtOAc and chromatography afforded 9-fluoro-5-(1,3-dithia-2-cyclohexyl)-5-hydroxy-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 12, Structure 3 of Scheme I, where R 4 =methyl, R 7 =R 8 =R 10 =R 11 =H, R 9 =F, Y=Z=S), which was then treated in CH 2 Cl 2  (10 mL) with catalytic amount of TsOH for 15 h. The reaction was quenched with aqueous carbonate and extracted with EtOAc. Chromatography provided compound 10 (70 mg, 42%) as a yellow solid: mp 120–122° C.,  1 H-NMR (400 MHz, CDCl 3 ) 7.34 (d, J=8.3, 1H), 7.32 (dd, J=9.7 and 2.9, 1H), 7.07 (dd, J=8.7 and 4.9, 1H), 6.84 (td, J=8.4 and 2.8, 1H), 6.62 (d, J=8.3, 1H), 5.48 (s, 1H), 4.17 (s, 1H), 3.02 (ddd, J=13.4, 8.2 and 5.1, 1H), 2.91–2.79 (m, 2H), 2.68 (dt, J=13.4 and 5.5, 1H), 2.20–2.04 (m, 2H), 1.99 (s, 3H), 1.41 (s, 3H) and 1.28 (s, 3H). 
     EXAMPLE 2 
     Preparation of 8-methoxy-5-(1,3-dithia-2-cyclohexylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 13, Structure 4 of Scheme I, where R 4 =methyl, R 7 =R 9 =R 10 =R 11 =H, R 8 =methoxy, Y=Z=S) 
     This compound was prepared in a similar fashion as that described in Example 1 from 1,3-dithiane and 8-methoxy-1,2-dihydro-2,2,4-trimethyl-5-coumarino[3,4-f]quinoline (Compound 14, Structure 1 of Scheme I, where R 4 =methyl, R 7 =R 9 =H, R 8 =methoxy) as a yellow solid:  1 H-NMR (400 MHz, CDCl 3 ) 7.39 (d, J=8.2, 1H), 7.20 (d, J=2.9, 1H), 7.07 (d, J=8.9, 1H), 6.73 (dd, J=8.9, 2.9, 1H), 6.63 (d, J=8.2, 1H), 5.47 (s, 1H), 4.1 (bs, 1H), 3.82 (s, 3H), 3.04–2.98 (m, 1H), 2.89–2.78 (m, 2H), 2.68–2.64 (m, 1H), 2.16–2.03 (m, 2H), 1.99 (s, 3H)1.41 (s, 3H), 1.25 (s, 3H). 
     EXAMPLE 3 
     Preparation of 7,9-difluoro-5-(1,3-dithia-2-cyclohexylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 15, Structure 4 of Scheme I, where R 4 =methyl, R 8 =R 10 =R 11 =H, R 7 , R 9 =fluorine, Y=Z=S) 
     This compound was prepared in a similar fashion as that described in Example 1 from 1,3-dithiane and 7,9-difluoro-1,2-dihydro-2,2,4-trimethyl-5-coumarino[3,4-f]quinoline (Compound 16, Structure 1 of Scheme I, where R 4 =methyl, R 7 =R 9 =fluorine, R 8 =H) as a yellow solid:  1 H-NMR (500 MHz, CDCl 3 ) 7.31 (d, J=8.2, 1H), 7.14–7.11 (m, 1H), 6.72 (ddd, J=10.1, 8.2, 2.7, 1H), 6.62 (d, J=8.2, 1H), 5.48 (s, 1 H), 4.18 (bs, 1H), 3.07–3.01 (m, 1H), 2.92–2.82 (m, 2H), 2.72–2.67 (m, 1H), 2.18–2.07 (m, 2H), 1.99 (d, J=1.2, 3H), 1.41 (s, 3H), 1.28 (s, 3H). 
     EXAMPLE 4 
     Preparation of 7-fluoro-5-(1,3-dithia-2-cyclohexylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 17, Structure 4 of Scheme I, where R 4 =methyl, R 8 =R 9 =R 10 =R 11 =H, R 7 =fluorine, Y=Z=S) 
     This compound was prepared in a similar fashion as that described in Example 1 from 1,3-dithiane and 7-fluoro-1,2-dihydro-2,2,4-trimethyl-5-coumarino[3,4-f]quinoline (Compound 18, Structure 1 of Scheme I, where R 4 =methyl, R 7 =fluorine, R 8 =R 9 =H) as a yellow solid:  1 H-NMR (500 MHz, CDCl 3 ) 7.44–7.42 (m, 1H), 7.42 (d, J=8.2, 1H), 6.98–6.94 (m, 2H), 6.64 (d, J=8.2, 1H), 5.49 (d, J=1.5, 1H), 4.14 (bs, 1H), 3.08–3.02 (m, 1H), 2.93–2.82 (m, 2H), 2.72–2.66 (m, 1H), 2.18–2.06 (m, 2H), 2.01 (d, J=1.2, 3H), 1.42 (s, 3H), 1.29 (s, 3H). 
     EXAMPLE 5 
     Preparation of 7-fluoro-5-cyclohexylidene-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 19, Structure 4 of Scheme I, where R 4 =methyl, R 8 =R 9 =R 10 =R 11 =H, R 7 =fluorine, Y=Z=CH 2 ) 
     This compound was prepared in a similar fashion as that described in Example 1 from cyclohexylithium and 7-fluoro-1,2-dihydro-2,2,4-trimethyl-5-coumarino[3,4-f]quinoline (Compound 18, Structure 1 of Scheme I, where R 4 =methyl, R 7 =fluorine, R 8 =R 9 =H) as a yellow solid:  1 H-NMR (500 MHz, CDCl 3 ) 7.43–7.40 (m, 1H), 7.41 (d, J=8.2, 1 H), 6.96–6.86 (m, 2H), 6.61 (d, J=8.2, 1H), 5.45 (s, 1 H), 4.07 (bs, 1H), 3.03 (ddd, J=14.0, 4.9, 4.9, 1H), 2.21–2.08 (m, 2H), 1.99 (d, J=1.2, 3H), 1.92–1.86 (m, 1H), 1.76–1.70 (m, 1H), 1.62–1.57 (m, 2H), 1.45–1.24 (m, 3H), 1.40 (s, 3H), 1.18 (s, 3H). 
     EXAMPLE 6 
     Preparation of 7,9-difluoro-5-cyclohexylidene-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 20, Structure 4 of Scheme I, where R 8 =R 10 =R 11 =H, R 4 =methyl, R 7 =R 9 =fluorine, Y=Z=CH 2 ) 
     This compound was prepared in a similar fashion as that described in Example 1 from cyclohexylithium and 7,9-difluoro-1,2-dihydro-2,2,4-trimethyl-5-coumarino[3,4-f]quinoline (Compound 16, Structure 1 of Scheme I, where R 4 =methyl, R 7 =R 9 =fluorine, R 8 =H) as a yellow solid:  1 H-NMR (500 MHz, CDCl 3 ) 7.32 (d, J=8.2, 1H), 7.14–7.11 (m, 1H), 6.70 (ddd, J=10.4, 8.5, 2.8, 1H), 6.61 (d, J=8.2, 1H), 5.45 (s, 1H), 4.12 (bs, 1H), 3.05–3.01 (m, 2H), 2.20–2.08 (m, 2H), 1.97 (d, J=1.2, 3H), 1.91–1.85 (m, 1H), 1.78–1.71 (m, 1H), 1.63–1.58 (m, 2H), 1.45–1.23 (m, 3H), 1.40 (s, 3H), 1.18 (s, 3H). 
     EXAMPLE 7 
     Preparation of 7-fluoro-5-(1,3-dithia-2-cyclohexylidene)-1,2-dihydro-2,2-dimethyl-5H-chromeno[3,4-f]quinoline (Compound 21, Structure 4 of Scheme I, where R 4 =R 8 =R 9 =R 10 =R 11 =H, R 7 =fluorine, Y=Z=S) 
     This compound was prepared in a similar fashion as that described in Example 1 from 1,3-dithiane and 7-fluoro-1,2-dihydro-2,2-dimethyl-5-coumarino[3,4-f]quinoline (Compound 22, Structure 1 of Scheme I, where R 7 =fluorine, R 4 =R 8 =R 9 =H) as a yellow solid:  1 H-NMR (500 MHz, CDCl 3 ) 7.39–7.36 (m, 1H), 7.36 (d, J=8.2, 1H), 6.96–6.93 (m, 2H), 6.55 (d, J=8.8, 1H), 6.31 (d, J=10.1, 1H), 5.59 (d, J=9.8, 1H), 4.0 (bs, 1H), 3.14–3.07 (m, 1H), 2.96–2.84 (m, 2H), 2.80–2.74 (m, 1H), 2.22–2.08 (m, 2H), 1.42 (s, 3H), 1.32 (s, 3H). 
     EXAMPLE 8 
     Preparation of 7-fluoro-5-(2-cyclohexenylidene)-1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline (Compound 23, Structure 4 of Scheme I, where R 4 =methyl, R 8 =R 9 =R 11 =H, R 7 =fluorine, R 10 /R 14 =a bond, Z=CHR 14 , Y=CH 2 ) 
     This compound was prepared in a similar fashion as that described in Example 1 from cyclohexenylithium and lactone 18 (Structure 1 of Scheme I, where R 4 =methyl, R 7 =fluorine, R 8 =R 9 =H) as a yellow solid:  1 H-NMR (500 MHz, Acetone-d 6 ) 7.57–7.54 (m, 1H), 7.54 (d, J=8.2, 1H), 7.04–6.97 (m, 2H), 6.77 (d, J=8.2, 1H), 6.11 (ddd, J=10.1, 2.1, 1.8, 1H), 5.84–5.79 (m, 2H), 5.45 (s, 1H), 2.96–2.88 (m, 2H), 2.61–2.55 (m, 1H), 2.20–2.13 (m, 1H), 1.93 (d, J=1.2, 3H), 1.81–1.70 (m, 2H), 1.40 (s, 3H), 1.21 (s, 3H). 
     The activity of selected steroid receptor modulator compounds of the present invention were evaluated utilizing the cotransfection assay, and in standard receptor competitive binding assays, according to the following illustrative Examples. 
     EXAMPLE 9 
     Cotransfection Assay 
     The function and detailed preparation procedure of the cotransfection assays have been described previously (Pathirana,  Mol. Pharm.  1995, 47, 630–635). Briefly, the cotransfection assays were carried out in CV-1 cells (African green monkey kidney fibroblasts), which were transiently transfected, by the standard calcium phosphate coprecipitation procedure (Berger, et al.,  J. Steroid Biochem. Mol. Bio.  1992, 41, 733–738) with the Plasmid containing receptor, MTV-LUC reporter, pRS-β-Gal, and filler DNA (Rous sarcoma virus chloramphenicol acetyltransferase). The agonist activity was determined by examining the LUC expression (normalized response) and the efficacy readout was a relative value to the maximal LUC expression produced by progesterone. All the cotransfection experiments were carried out in 96-well plates by automation (Beckman Biomomek automated workstation). 
     Receptor Binding Assays 
     The preparation of receptor binding assays for hPR-A was described in literature (Pathirana, et al.,  Mol. Pharm.  1995, 47, 630–635.) 
     The agonist, antagonist and binding activity assay results of selected progesterone receptor modulator compounds of the present invention and the standard reference compounds on PR are shown in Table 1 below. Efficacy is reported as the percent maximal response observed for each compound relative to the reference agonist and antagonist compounds indicated above. Also reported in Table 1 for each compound is its antagonist potency or IC 50  (which is the concentration (nM), required to reduce the maximal response by 50%), and its agonist potency or EC 50  (nM), which is the effective concentration that produced 50% of the maximum response. 
                                                                                                       TABLE 1                   Agonist, antagonist and binding activity of progesterone receptor       modulator compounds of present invention and the reference agonist       compound, progesterone (Prog), and reference antagonists       compound, RU486 and ZK299.                PR Agonist       PR Antagonist               CV-1 Cells       CV-1 Cells   PR                Cmpd   Efficacy   Potency   Efficacy   Potency   Binding           No.   (%)   (nM)   (%)   (nM)   K i  (nM)                            Prog   100   2.9   na   na   3.5           RU486   na   na   96   0.18   0.58           ZK299   na   na   99   1.6    18           10   144   2.0   na   na   6.3           13   56   32   na   na   14           15   155   5.3   na   na   3.7           17   107   11   na   na   4.3           19   48   38   nt   nt   74           20   82   16   na   na   39           21   45   32   nt   nt   nt           23   70   35   na   na   22                       na = not active (i.e. efficacy of &lt;20 and potency of &gt;1,000)           nt = not tested            
Pharmacological and other Applications
 
     The following Example provides illustrative pharmaceutical composition formulations: 
     EXAMPLE 10 
     Hard gelatin capsules are prepared using the following ingredients: 
                                                           Quantity           (mg/capsule)                                        COMPOUND 10   16               Starch, dried   100           Magnesium stearate   10           Total   120   mg                        
The above ingredients are mixed and filled into hard gelatin capsules in 120 mg quantities.
 
     A tablet is prepared using the ingredients below: 
                                                           Quantity           (mg/tablet)                                        COMPOUND 10   10               Cellulose, microcrystalline   200           Silicon dioxide, fumed   10           Stearic acid   10           Total   230   mg                        
The components are blended and compressed to form tablets each weighing 230 mg.
 
Tablets, each containing 10 mg of active ingredient, are made as follows:
 
     
       
         
               
               
             
               
               
               
               
             
           
               
                   
                   
               
               
                   
                 Quantity 
               
               
                   
                 (mg/tablet) 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 COMPOUND 10 
                 10 
                   
               
               
                   
                 Starch 
                 45 
               
               
                   
                 Cellulose, microcrystalline 
                 35 
               
               
                   
                 Polyvinylpyrrolidone (PVP) 
                 4 
               
               
                   
                 (as 10% solution in water) 
               
               
                   
                 Sodium carboxymethyl starch (SCMS) 
                 4.5 
               
               
                   
                 Magnesium stearate 
                 0.5 
               
               
                   
                 Talc 
                 1.0 
               
               
                   
                 Total 
                 100 
                 mg 
               
               
                   
                   
               
             
          
         
       
     
     The active ingredient, starch and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The solution of PVP is mixed with the resultant powders, which are then passed through a No. 14 mesh U.S. sieve. The granules so produced are dried at 50° C. and passed through a No. 18 mesh U.S. sieve. The SCMS, magnesium stearate and talc, previously passed through a No. 60 mesh U.S. sieve are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg. 
     Suppositories, each containing 225 mg of active ingredient, may be made as follows: 
     
       
         
               
               
             
               
               
               
               
             
           
               
                   
                   
               
               
                   
                 Quantity 
               
               
                   
                 (mg/suppository) 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 COMPOUND 10 
                 20 
                   
               
               
                   
                 Saturated fatty acid glycerides 
                 2,000 
               
               
                   
                 Total 
                 2,020 
                 mg 
               
               
                   
                   
               
             
          
         
       
     
     The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of normal 2 g capacity and allowed to cool. 
     An intravenous formulation may be prepared as follows: 
     
       
         
               
               
             
               
               
               
             
           
               
                   
                   
               
               
                   
                 Quantity 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 COMPOUND 10 
                     10 mg 
               
               
                   
                 isotonic saline 
                 1000 mL 
               
               
                   
                 glycerol 
                  100 mL 
               
               
                   
                   
               
             
          
         
       
     
     The compound is dissolved in the glycerol and then the solution is slowly diluted with isotonic saline. The solution of the above ingredients is then administered intravenously at a rate of 1 mL per minute to a patient. 
     The present invention includes any combination of the various species and subgeneric groupings falling within the generic disclosure. This invention therefore includes the generic description of the invention with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein. 
     The scope of the invention is not to be limited by the description of the examples. Modifications and alterations of the present invention will be apparent to those skilled in the art without departing from the scope and spirit of the present invention. 
     Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims, rather than by the specific examples which have been presented by way of example.