MXPA98009114A - - Google Patents
Info
- Publication number
- MXPA98009114A MXPA98009114A MXPA/A/1998/009114A MX9809114A MXPA98009114A MX PA98009114 A MXPA98009114 A MX PA98009114A MX 9809114 A MX9809114 A MX 9809114A MX PA98009114 A MXPA98009114 A MX PA98009114A
- Authority
- MX
- Mexico
- Prior art keywords
- group
- carbon atoms
- hydrogen
- lower alkyl
- formula
- Prior art date
Links
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 101
- 125000000217 alkyl group Chemical group 0.000 claims description 56
- 150000001875 compounds Chemical class 0.000 claims description 55
- 229910052739 hydrogen Inorganic materials 0.000 claims description 44
- 239000001257 hydrogen Substances 0.000 claims description 44
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 41
- 125000003545 alkoxy group Chemical group 0.000 claims description 36
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 36
- -1 nitrate ester Chemical class 0.000 claims description 28
- 125000000304 alkynyl group Chemical group 0.000 claims description 25
- 125000003342 alkenyl group Chemical group 0.000 claims description 24
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 23
- 229910052736 halogen Inorganic materials 0.000 claims description 18
- 150000002367 halogens Chemical class 0.000 claims description 18
- 239000000460 chlorine Substances 0.000 claims description 15
- 125000001188 haloalkyl group Chemical group 0.000 claims description 15
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 14
- 229910052760 oxygen Inorganic materials 0.000 claims description 14
- 239000001301 oxygen Substances 0.000 claims description 14
- 125000000623 heterocyclic group Chemical group 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 11
- 229910052731 fluorine Inorganic materials 0.000 claims description 10
- 239000011737 fluorine Substances 0.000 claims description 10
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 10
- 150000002825 nitriles Chemical class 0.000 claims description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 10
- 229910052717 sulfur Inorganic materials 0.000 claims description 10
- 239000011593 sulfur Substances 0.000 claims description 10
- 206010061218 Inflammation Diseases 0.000 claims description 9
- 125000004429 atoms Chemical group 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 9
- 230000004054 inflammatory process Effects 0.000 claims description 9
- 125000004122 cyclic group Chemical group 0.000 claims description 8
- 150000003573 thiols Chemical class 0.000 claims description 8
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 7
- 239000003981 vehicle Substances 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- 125000002723 alicyclic group Chemical group 0.000 claims description 6
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- TUJKJAMUKRIRHC-UHFFFAOYSA-N hydroxyl radical Chemical group [OH] TUJKJAMUKRIRHC-UHFFFAOYSA-N 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 4
- KMSKQZKKOZQFFG-YHKVCKOMSA-N Pirarubicin Chemical compound O([C@H]1[C@@H](N)C[C@@H](O[C@H]1C)OC1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@@H]1CCCCO1 KMSKQZKKOZQFFG-YHKVCKOMSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 3
- 125000005243 carbonyl alkyl group Chemical group 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000004354 sulfur functional group Chemical group 0.000 claims description 2
- 230000016160 smooth muscle contraction Effects 0.000 claims 2
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims 1
- 125000004103 aminoalkyl group Chemical group 0.000 claims 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 1
- 125000004971 nitroalkyl group Chemical group 0.000 claims 1
- 239000000203 mixture Substances 0.000 description 22
- MWUXSHHQAYIFBG-UHFFFAOYSA-N nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 20
- 230000000694 effects Effects 0.000 description 15
- 239000004480 active ingredient Substances 0.000 description 9
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 102000000589 Interleukin-1 Human genes 0.000 description 7
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- 150000003431 steroids Chemical class 0.000 description 7
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- 239000003826 tablet Substances 0.000 description 6
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N Cyclic guanosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
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- 239000003862 glucocorticoid Substances 0.000 description 5
- 239000004615 ingredient Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- OIGNJSKKLXVSLS-VWUMJDOOSA-N Prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 230000001605 fetal Effects 0.000 description 4
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- 239000007924 injection Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 229960005205 prednisolone Drugs 0.000 description 4
- 150000003180 prostaglandins Chemical class 0.000 description 4
- VOVIALXJUBGFJZ-VXKMTNQYSA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3O[C@@H](CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-VXKMTNQYSA-N 0.000 description 3
- 229960004436 Budesonide Drugs 0.000 description 3
- 239000004215 Carbon black (E152) Substances 0.000 description 3
- 229940113118 Carrageenan Drugs 0.000 description 3
- 229960003957 Dexamethasone Drugs 0.000 description 3
- UREBDLICKHMUKA-CXSFZGCWSA-N Dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 3
- 210000003038 Endothelium Anatomy 0.000 description 3
- 229940065521 Glucocorticoid inhalants for obstructive airway disease Drugs 0.000 description 3
- XUJNEKJLAYXESH-REOHCLBHSA-N L-cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 3
- 229940037128 Systemic Glucocorticoids Drugs 0.000 description 3
- 238000007792 addition Methods 0.000 description 3
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- 239000000679 carrageenan Substances 0.000 description 3
- 229920001525 carrageenan Polymers 0.000 description 3
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- 125000004356 hydroxy functional group Chemical group O* 0.000 description 3
- 150000002823 nitrates Chemical class 0.000 description 3
- 101710035552 pgaE Proteins 0.000 description 3
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- XEYBRNLFEZDVAW-ARSRFYASSA-N (5Z)-7-[(1R,2R,3R)-3-hydroxy-2-[(1E,3S)-3-hydroxyoct-1-en-1-yl]-5-oxocyclopentyl]hept-5-enoic acid Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 2
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- CZMRCDWAGMRECN-UGDNZRGBSA-N D-sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
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- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 2
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 2
- KCWZGJVSDFYRIX-YFKPBYRVSA-N Ngamma-Nitro-L-arginine methyl ester Chemical compound COC(=O)[C@@H](N)CCCN=C(N)N[N+]([O-])=O KCWZGJVSDFYRIX-YFKPBYRVSA-N 0.000 description 2
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- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 2
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- 235000018417 cysteine Nutrition 0.000 description 2
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- SNIOPGDIGTZGOP-UHFFFAOYSA-N 1,2,3-propanetrioltrinitrate Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 description 1
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Description
NOVELTY PHARMACEUTICAL COMPOSITIONS THAT HAVE ESTEROID ESTEROID DERIVATIVES OF NITRATE ESTER, USEFUL AS AN INFLAMMATORY F RMACOS
BACKGROUND OF THE INVENTION
FIELD OF THE INVENTION The present invention relates to novel pharmaceutical compositions containing steroidal nitrate ester derivatives and their use in the treatment of inflammatory diseases.
RELATED TECHNIQUE
It is known that steroids * speci fi cally from the group of glucocorticoid molecules »possess anti-inflammatory and immunomodulatory activities and are commonly used for the treatment of numerous autoimmune and inflammatory diseases. However, their beneficial effects are often slow to appear and are accompanied by many dose-limiting side effects. Nitric oxide donors have also been used, such as "ni roglycerin", as pharmaceutical agents with prominent beneficial effects on the cardiovascular system. Many of the biological actions of nitric oxide counteract potential side effects of glucocorticoids and can improve their therapeutic actions. The present invention relates to novel stearic nitrate ester derivatives which possess the combined biological properties of glucacorticoids and nitric oxide donors in a single molecule. These molecules have an advantage over commonly used glucocorticoids because they readily induce beneficial pharmacological effects "such as bronchial relaxation" through the release of nitric oxide. It is intended that these novel molecules be used for therapy, in particular their use as an inflammatory and immunosuppressive drugs for the treatment of rheumatic diseases, immune disorders, skin disorders, inflammation, transplant rejection, cancer, osteoporosis, rhinitis and asthma. »With fewer side effects. Glucocorti oids are commonly used for the pharmacological treatment of inflammation and inappropriate reactions of the immune system. These steroids have the ability to prevent or suppress the development of inflammation resulting from several different harmful agents that include infectious »immunological» chemical »mechanical and radiation agents. Lucocorticoids are also effective in treating disorders of the immune system, including autoimmune diseases such as rheumatoid arthritis and lupus, and rejection of transplants. However »the therapeutic applications of these steroids are somewhat limited due to their toxicity and side effects. The main side effects of glucocorticoids are hypertension »peptic ulcers» increased susceptibility to infections »oeteoporosis» hyperglycemia and vascular occlusion. It is known since the beginning of the decade that the vascular relaxation produced by acetylcalin depends on the presence of the endothelium "and this activity was attributed to a labile humoral factor called endothelium-derived relaxation factor (EDRF). It has been known for more than a century the activity of nitric oxide < 0N > as a vasodilator »and the ON is the active component of the amylnitrite ester» glyceryl trinitrate and others nor trovasodilators. The recent identification of EDRF as ON has coincided with the discovery of a biochemical pathway through which NO is synthesized from the amino acid L-arginine by the enzyme nitric oxide synthetase »The NO released by the constitutive enzyme functions as a mechanism of transduction that supports several physiological responses. The ON produced by the inducible enzyme is a cytotoxic molecule for tumor cells and pathogenic microorganisms. NO is the endogenous stimulator of soluble guanylate cyclase and is involved in several biological actions in addition to endothelium-dependent relaxation, including phagocytic cell cytotoxicity and cellular communication in the system. central nervous system (see Moneada and others »Biochemical Pharmacology» 38 »1709-1715 (1989) and Moneada and others» Phar acaló ic l Revie s »43» 109-142 (1991). anti thromboembolism (see Moneada et al. »Journal af Cardiovascular Pharmacalogy 17» S25 (1991) »Byrne et al» world patent application W09403421-A2 »and Schonafinger et al» German patent application DE4223800-A1) »bronchorelaxants (Persson and others »European Journal of Pharmacology» 249 »R7-RS (1993)» anti-inflammatory and microbiocides (Alspaugh and Granger »Infection and Immunity 59» 2291-2296 (1991) and gastroprectors (see Wallace and others »European Journal of Pharmacology» 257 »249-255 (1994) in animal models Further» it has been suggested that nitric oxide is effective against bone loss in in vitro osteoporosis models (MacIntyre et al. »Proc. Nati. Acad. Sci.» USA aß »2936-2940 (1991)» and to inhibit angiogenesis tumor growth and metastasis in in vivo animal models (i-Synetos Pipil and other "British Journal of Pharmacology" 116, 1829-1834 (1995). DE-A-16 43 034 discloses a process for preparing nitric ester of tertiary or secondary sterically hindered steroid alcohols. Therefore »the following compositions are described! 17-nor tri loxi-4-pregnane-3 »0-dione» 6 «-fluoro-liß» 21-dihydroxy-16 «-methyl-1» 4- egnadiene- »2-dione» 17-nor tri-laxi- 21- acetoxy-4-pregnane-3 »20-dione» 11G »17-dini-3-methoxy-21-acetoxy-4-pregneno-3» 20-dione »9-fluoro-11 (3» 17-di i tri lo- 21-acetyl-16"-methyl" 4-pregnanediene-3 »20-dione» 6 «-fluoro-l-l-nor-di-phenylamino-21-acetoxy-16a-methyl-4-pregnadiene-3» 20-dione and 6a-fluoro-9-clear-HO-i-tetraxy-21-acetoxy-16-ethyl-4-propylene The properties mentioned above make nitric oxide an ideal agent for improving the actions of corticosteroids in the treatment of several diseases mentioned above »both by increasing their biological effects and reducing their side effects.
BRIEF DESCRIPTION OF THE INVENTION
The present invention relates to novel pharmaceutical compositions comprising nitrate steroid derivatives of formula 1
and pharmaceutically acceptable esters and prodrugs of the same »where? the dotted lines of formula 1 indicate a single or double bond. R 4 is selected from the group consisting of hydrogen »hydroxyl» nitrate ester (ONO.-;) »halogen» halogenoalkyl »nor troxyalkanoyl» thiol »heterocyclic» alkoxy lower »alkylsilyloxy» lower alkyl »wherein all these radicals can be optionally substituted with hydroxyl radicals» halogen »lower alkyl» lower alkenyl »lower alkynyl» lower alkoxy »amino» nitro »nitrile» carbonyl and haloalkyl or Rx is a group of the formula OCO-R. ^ wherein Ry is alkanoic acid "lower alkyl" lower alkenyl "lower alkynyl or lower alkoxy" R3 and R ^ are independently selected from the group consisting of hydrogen »hydroxy or» nitrate ester (ONO ^) » or troxialcanai the "lower alkyl" lower alkenyl "lower alkynyl and lower alkoxy" wherein all these radicals can be optionally substituted with radical hydroxy is the "lower alkyl" lower alkenyl "lower alkynyl" lower alkoxy »amino» nitro »nitrile» carboxyl and hal haloalyl »o ^ at and R« are independently selected from a group of the formula 0C0 ~ Ra where Ra is 2-furanyl »lower alkyl or lower alkoxy group or R3 and R ^ can optionally form a cyclic structure of the formula?
wherein K and L are selected from the group consisting of hydrogen and lower alkyl »or optionally K and L can form an alicyclic ring or heterocyclic ring», hydrogen or halogen »R? is hydrogen »hydroxyl or oxygen» P and £ 3 are independently selected from the group of hydrogen »chlorine» fluorine and lower alkyl and X is lower alkyl or sulfur if a is halogenalkylated, except for the compounds 17-nitri-laxy-4-pregnane- 3 »20-dione» 6 «-fl uoro-llß» 21-dihydro i-1 «-methi 1-1 4- pegnadiene-» 2-dione »17-ni tri loxi-21-acetoxy-4-pregnano-» 20-diana »113» 17-dini-triaxy-21-acetoxy-4-pregneno-3 »20-dione» 9-fluoro-llβ »17-dini tryloxy-21-ace l-16a-meti 1-1» 4- pregnane ieno-3 »20-dione» 6a-fluora-11ß- i treatment i-21-acetoxy-1 oc-methyl-1-4-pregnadiene-3 »20-dione and 6cf-fluoro-9-pale-1 L-N-N-methoxy-21-acetoxy-16-t-methyl-4-pentanediene. The compositions defined above have utility as antiinflammatory drugs and immunosuppressants for the treatment of rheumatic diseases, immunological disorders, skin disorders, inflammation, rejection of transplants, astheoporosis, rhinitis and asthma. These compounds combine the previously described actions of steroids and ON in a single molecule. The novel compositions of the present invention can exert their steroid activities directly with the ON still fixed "or after the NO is released.
DETAILED DESCRIPTION OF THE INVENTION
A preferred embodiment of the present invention is a compound of the formula (I)?
(1) where? dotted lines of formula 1 indicate a single or double bond. R 4 is selected from the group consisting of hydrogen, hydroxyl, nitrate ester (ONOg.), halogen, a heterocyclic group of 2 to 5 carbon atoms, and 2 heterogeneous atoms »a non-troxyalkanyl group of 2 to about 6 carbon atoms» thiol »halogenalkyl of approximately 6 carbon atoms» lower alkoxy group of 1 to approximately 6 carbon atoms »al group Isi li loxi of 3 a about 8 carbon atoms »lower alkyl group of about 6 carbon atoms» wherein all these radicals can be optionally substituted with hydroxyl radicals »halogen» lower alkyl »lower alkenyl» lower alkynyl »lower alkoxy» amino »nitro» nitrile » carboxyl and haloalkyl "or R is a group of the formula OCO-R-,. wherein v is an alkanoic acid group of 2 to about 6 carbon atoms »lower alkyl group of from 1 to about 6 carbon atoms» lower alkenyl group of from 2 to about 6 carbon atoms »lower alkynin group of from 2 to about 6 carbon atoms or lower alkoxy group of about 6 carbon atoms »R3 and R ^. are independently selected from the group consisting of hydrogen »hydroxyl» nitrate ester (0N0S) »group or troxyalkanoyl of 2 to approxi mately 6 carbon atoms» lower alkyl group of 1 to about 6 carbon atoms »lower alkenyl group of 2 Approximately 6 carbon atoms »lower alkyne group of from 2 to about 6 carbon atoms» lower alkoxy group of 1 to about 6 carbon atoms »wherein all radicals can be optionally substituted with hydroxyl radicals» lower alkyl »alkenyl lower »lower alkynyl» lower alkoxy »amino» nitro »nitrile» carboxyl and haloalkyl »or R3 and R ^. are independently selected from a group of the formula 0C0-Rβ where ñ &; is 2-furanyl »lower alkyl group of from 1 to about 6 carbon atoms or lower alkoxy group of from 1 to about 6 carbon atoms» Rs and R ^ can optionally form a cyclic structure of the formula wherein K and L are selected of the group consisting of hydrogen »lower alkyl group of 1 to about 8 carbon atoms» apically and L can form an alicyclic ring of 4 to about 8 carbon atoms or a heterocyclic ring of 4-6 carbon atoms and 1- 2 heterogeneous atoms selected from nitrogen »oxygen or sulfur» Rβ is hydrogen or halogen »RA is hydrogen» hydroxyl or oxygen »P and Q are independently selected from a group of hydrogen» chlorine »fluorine and lower alkyl group from 1 to 6 carbon atoms carbon "and X is a lower alkyl or sulfur group if R4 is a haloalkyl" except compounds as those mentioned above. Another preferred embodiment of the present invention is a compound of the
where »dotted lines of formula 1 indicate a single or double bond» Rx is selected from the group consisting of hydrogen »hydroxy» nitrate ester (ONO-j.) »halogen» thiol »heterocyclic group from 3 to 4 carbon atoms and 1 to 2 heterogeneous atoms »group nor troxialcanai lo of 2 to about 4 carbon atoms» lower alkoxy group of 1 to about 4 carbon atoms »lower alkyl group of about 4 carbon atoms» where all these radicals can be optionally substituted by "chloro" fluoro hydroxy radicals "lower alkyl" lower alkenyl "lower alkynyl" lower alkoxy »amino» nitro »nitrile» carboxylo and halogenoalnyl or Rt is a group of the formula 0CO-R-, , where ñ ^. is alkanoic acid group of 2 to about 4 carbon atoms »lower alkyl group of about 4 carbon atoms» lower alkene group of 2 to about 4 carbon atom »lower alkynyl group of 2 to about 4 carbon atoms or lower alkoxy group of 1 to about 4 carbon atoms »R3 and R4 are independently selected from the group consisting of hydrogen» hydroxy or »nitrate ester (ONO ^,» »group or troxyalkanoyl of 2 to approximatively 4 carbon atoms »Lower alkyl group of from about 1 to about 4 carbon atoms» lower alkenyl group of from about 4 carbon atoms »lower alkynyl group from 2 to about 4 carbon atoms» lower alkoxy group from 1 to about 4 carbon atoms »in where all radicals can be optionally substituted with hydroxyl radicals »lower alkyl» lower alkenyl »lower alkynyl» alkx and lower »amino» nitro and halogenalyl or R3 and R ^ is a group of the formula OCO-Rβ wherein Rβ is 2- uranyl »lower alkyl group of from 1 to approximately 4 carbon atoms or lower alkoxy group of about 4 carbon atoms »or R3 and R ^. can they form together optically in a cyclic structure of the formula?
wherein K and L are selected from the group consisting of hydrogen and lower alkyl group of from 1 to about 6 carbon atoms »optionally K and L can form an alicyclic ring of 5-8 carbon atoms or a heterocyclic ring of 4-5 carbon atoms and 1-2 heterogeneous atoms selected from nitrogen »oxygen or sulfur» Rs is hydrogen or halogen »R ^ is hydrogen» hydroxyl or oxygen »P and Q are independently selected from the group consisting of hydrogen» chlorine »fluorine and group lower alkyl of 1 to 4 carbon atoms "and X is methylene or sulfur if Rx is a haloalkyl. Another preferred embodiment of the present invention is a compound of the formula (1)?
where? the dashed lines of formula 1 indicate a single or double bond »ñx is selected from the group consisting of hydrogen» hydroxyl »nitrate ester (ONO ^.)» chloro »thiol» lower alkyl group of 1 to 4 carbon atoms »Or Rx is a group of the formula OCO-R- ,. wherein R.-, is propanoic acid »methyl or ethyl» R = »RJ» are independently selected from the group consisting of hydrogen »hydroxyl» nitrate ester (ONO ^,) »methyl» lower alkynyl group of 2 to 4 atoms of carbon »or R3 and R? have the formula 0C0-Rβ wherein Ra is ethoxy »2-furanyl» methyl »ethyl» propyl or butyl or R3 and R- * can optionally together form a cyclic structure of the formula;
wherein and L are selected from the group consisting of hydrogen »methyl and butyl» or K and L can optionally form a cyclopentyl or cyclohexyl ring »Rβ is hydrogen» chlorine or bromine »RA is hydroxyl or oxygen» P and Q are independently selected from a group of hydrogen »chloro» fluorine and methyl; and X is methylene. Although it may be possible for preparations or compounds as defined above to be administered as the pure chemical, it is preferred to present them as a pharmaceutical formulation. In consecuense" The present invention provides a pharmaceutical formulation comprising a preparation or a compound as defined above or a pharmaceutically acceptable salt or eolvate thereof together with one or more pharmaceutically acceptable carriers therefor and optionally one or more other therapeutic ingredients. The vehicle (s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful (e) to the recipient thereof. The formulations include those suitable for oral administration "parenteral (including subcutaneous» intradermal »intramuscular» intravenous and intraarticular) »rectal and topical (including" buccal dermal "sublingual and intraocular)" although the most suitable route may depend "for example" on the condition and disorder of the recipient. The formulations may be conveniently presented in the form of a unit dose and may be prepared by any of the methods well known in the pharmacology art. All methods include the step of associating a preparation or a compound as defined above or a pharmaceutically acceptable salt or solvate thereof ("active ingredient") with the vehicle constituting one or more additional ingredients. In general, the formulations are prepared by uniformly and intimately associating the active ingredient with liquid carriers or finely divided solid carriers or both and then it is necessary to configure the product in the desired formulation. Formulations of the present invention suitable for oral administration can be presented with discrete units such as capsules, »stamps or tablets each containing a predetermined amount of the active ingredient» as a powder or granules »as a solution or suspension in a liquid aqueous or a non-aqueous liquid »or as a liquid emulsion of oil in water or a liquid emulsion of water in oil. The active ingredient can also be presented as an elective bolus or paste. A tablet can be made by compression or molding »optionally with one or more additional ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules »apically mixed with a binder» lubricant »inert diluent» active lubricating agent »surface-active or dispersion. The molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may also be optionally coated or scored and may be formulated to provide a slow or controlled release of the active ingredient therein. Formulations for parenteral administration include sterile aqueous and non-aqueous injection solutions which may contain pH-regulating antioxidants bacteriostats and solutes which render the formulation isotonic with the blood of the desired recipient and sterile aqueous and non-aqueous suspensions which may include suspension agents to thickening agents. The formulations can be presented in one-dose or multi-dose containers, for example, "sealed pouches and flasks" and can be stored in a cangeleda-seca condition (lyophilized) requiring only the addition of the sterile liquid vehicle, eg, saline solution. water for injection »immediately before use. Solutions and suspensions for extemporaneous injection can be prepared from powders, granules and sterile tablets of the type previously described. Formulations for rectal administration can be presented as a suppository with normal vehicles such as cocoa butter or psi lei lengl icol. Formulations for topical administration in the mouth »for example» buccal or sublingual »include tablets comprising the active ingredient in a flavored base such as sucrose and acacia or tragacanth» and tablets which comprise the active ingredient in a base such as gelatin and glycerin to sucrose and acacia. Formulations for administration by inhalation may be prepared for use as or aerosolized drugs in manners such as those described in E.U. 5 »458» 136 and E.U. 5 »447» 150. Preferred unit dose formulations are those which contain an effective dose "as mentioned hereinafter" or an "appropriate fraction thereof" of the active ingredient. It should be understood that in addition to the ingredients particularly mentioned above, "the formulations of this invention may include other agents conventional in the art which relates to the type of formulation in question" for example those suitable for oral administration may include flavoring agents. The compounds of the invention can be administered orally or by injection at a dose of 0.01 to 500 mg / kg per day. The dosage regimen for adult humans is generally 0.1 mg to Ig / day. Tables or other forms of presentation provided in discrete units may conveniently contain a quantity of compound of the invention that is effective at said dosage or co or a multiple thereof "eg" units containing 0.05 mg to 250 mg. around 0.1 mg to 100 mg. The compounds of the formula (I) are preferably administered by inhalation »orally or by injection (intravenous or subcutaneous). The precise amount of compound administered to a patient will be the responsibility of the doctor. However, the dose used will depend on a number of factors including the age and sex of the patient, the precise disorder being treated and its severity. In the same way »the route of administration may vary depending on the condition and its severity. As used herein, the term "lower alkyl" "alone or in combination" means an acyclic alkyl radical containing from 1 to about 10"preferably about 1 to about S carbon atoms and most preferably 1 to about 6 carbon atoms. . Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isa-amyl, hexyl, octyl and the like. The term "lower alkenyl" refers to an unsaturated acyclic hydrocarbon radical "as long as it contains at least one double bond. Said radicals contain from about 2 to about 10 carbon atoms, preferably about 2 to about? carbon atoms and most preferably 2 to about 6 carbon atoms. Examples of suitable alkenyl radicals include p-phenylenyl buten-1-i-isabutenyl penten-1-ylo 2-2-met i Ibuten-1-i or 3-met ilbuten-ii lo »hexen-1- ilo »hepten-1-yl and octen-1-yl» and the like. The term "lower alkynyl" refers to an unsaturated acyclic hydrocarbon radical "as long as it contains one or more triple bonds" said radicals contain about 2 to about 10 carbon atoms "preferably have about 2 to about? carbon atoms and very preferably have 2 to about 6 carbon atoms. Examples of suitable alkynyl radicals include ethynyl »propynyl» butyne-1-yl »butyne-2-yl» pent in-li lo »pentin-2-yl» 3- ethyl-l-butyne-1-yl »hexin-1- ilo? hexin-2-yl »hexin-3-yl» 3 »3-dimethyl-butin-1-yl and the like. The term "alicyclic hydrocarbon" means an aliphatic radical in a ring with 3 to about 10 carbon atoms and preferably 3 to about 6 carbon atoms. Examples of suitable alicyclic radicals? O
they include cyclopropyl »cyclopropi leni lo» cyclobutyl »cyclopentyl» cyclohexyl »2-cyclohexen-l-i leni lo» cyclohexeni lo and the like. The term "alkanoyl" means acyloxy radical with 2 to about 4 carbon atoms. Suitable examples include acetyloxy »propionyloxy and the like. The term "halogen" means fluorine »chlorine» bromine or iodine. The term "heterocyclic radical" means a saturated or unsaturated cyclic hydrocarbon radical with 4 to about 10 carbon atoms "preferably about 5 to about 6" wherein 1 to about 3 carbon atoms are replaced by nitrogen »oxygen or sulfur» "heterocyclic radical" may be fused to an aromatic hydrocarbon radical. Suitable examples include pyrrolyl »pyridinyl» pirozalyl »triazolyl» pyrimidinyl »pyridazinyl» axazolyl »thiazalyl» imidazolyl »indolyl» thiophenyl »furanyl» tetrazolyl »2-pyrrole inyl» 3-pyrrolinyl »pyrral indinyl» 1 »3-dioxolani »2-imidazole in the» imidazolidinyl »2-pyrazole ini» pyrazolidinyl »isoxazolyl» isothiazolyl »1» 2 »3-oxadiazole and» 1 »2» 3-triazole i lo? 1 »3» 4- thiadiazoli »2H-Irannyl» 4H-pyranyl »piperidinyl» 1 »4-dioxanyl» morpholinyl »1» 4-di-thienyl »thiomorpholinyl» pyrazinyl »piperazinyl» 1 »3» 5-triazinyl »1 »3» 5-tri-tiani »benzo (b) thiopheni» benzimidazolyl »quinolinyl and the like. The term "lower alkoxy" "alone a in combination" means an ether radical wherein the term "alkyl" is as defined above and which most preferably contains 1 to about 4 carbon atoms. Examples of suitable ether alkyl radicals include methoxy »ethoxy» n-propoxy »isopropoxy» n-butoxy »iso-butoxy» sec-butoxy »ter-tubaxy and the like. The term "lower thioalkoxy" means the same as "alkoxy" but sulfur replaces oxygen. The term "prafármaca" refers to a compound that becomes more active in vi o. As used herein, "with reference to" treatment "of a patient is intended to include prophylaxis. All references »patents or applications of E.U. or foreigners mentioned in the application are incorporated herein by reference as if they were written here. The starting materials used to make the present invention are commercially available such as Si ma. Many compounds of the present invention have been manufactured in the art. The patents of E.U.A. Nos. 3 »930» 970 »3» 298 »941 and 3» 215 »713 describe a photochemical process for the preparation of diol onani treatments from alcohol nitrites. In the patents of E.U.A. Nos. 3 »639» 434 »3» 743 »741 and 3» 839 »369 describes the preparation of steroidal nitrate esters and their uses as intermediates.
In the German patent 1643034 a method for the preparation of esteroidal nitrate esters is described. Canadian Patent 975755 and 969927 disclose a process for the preparation and acidolysis of nitrate esters of 21-alcohols of the pregneno series, respectively. In the British patent OS2 »573 and 1» 0S2 »574 there is described a process for the preparation of esters of 11-nor treatment steroids and their uses as intermediates. As mentioned above, these references are incorporated herein by way of reference as if they were written here. In addition to the methods described in the art, the following scheme is useful for the preparation of the compounds of the present invention.
It will be obvious to one skilled in the art to make modifications in the choice of starting material and processing conditions to manufacture all of the compounds of the invention described herein. The invention is further illustrated by the following examples.
EXAMPLE 1
Combined at -10 ° C smoky nitric acid (1 ml.
= 1.49) and acetic anhydride (2.5 ml). To this solution was added by dripping and with stirring a pre-cooled suspension of
, 17 »21-dipropionate of 9« -chloro-1 ß-meti l pred isolone (0.5 g? 0.9 mmoles) in chloroform (20 ml). The mixture was stirred for 4 h at 0 ° C and poured onto ice and water (50 ml). The organic phase was separated and washed with water »saturated solution of sadium bicarbonate and water. After drying over sadia sulfate overnight, the solid was filtered and the filtrate was brought to dryness. The residue was purified on a Waters μBandapak column (30 cm X 5 c) using a linear gradient of 25-75% tri-acetonyl / water / trifluoroacetic acid. The desired fractions were collected and lipophilized to give 715 mg of white material. FAB-EM »(M + Li) * = 572.8? NMR * H (DMSO-d *) 0.78 (s »3H» CH., (C-18)), 1.0-1.1 (»6H, 2CHai-CHa :)» 1.2 (d »3H» CH-CH-.) »1.53 (s» 3H »CH;, (C-19)) »2.35-2.45 (m» 4H, 2CH "-CH ^)» 4.31 and 4.72 (2d »2H» CO-CH ^ -O) »5.6 (s, ÍH» CH (C-) ID), 6.05 (e »HI» CH (C-4)) »6.28 (d» ÍH »CH (C-2)), 7.1 (d, 1H» CH (CD).
EXAMPLE 2
The title compound was prepared from 9"-fluoro-16" -methyl Iprednisolone (0.5 g "1.25 mmol) in the same manner as described for Example 1" but the amount of smoking nitric acid was doubled. FAB-EM? (M + Li) * = 489? NMR * -H (CDCl3) 6 0.91-0.99 (, 6H »CH-CH-. And CH3 (C-18))» 1.45 (s »3H» CH3 (D-19)) »5.2 (q» 2H, CO -CH ^ -O), 5.56 (d, 1H »CH (C-ID), 6.2 (s, ÍH» CH (C-4 >), 6.38 (d »ÍH, CH (C-2))» 6.78 (d, 1H, CH (C-1 >
EXAMPLE 3
The title compound was prepared from 21-luaro-i6'-methyl-prednisisalana acetate (1 g? 2.3 mmoles) in the same manner as that described for example 1. FAB-MS? (M + Li > - = 486? IH NMR (CDCl3) < 5 0.93 (m, 6H »CH-CH-, and CH3 (C-18))» 1.45 (e »3H» CH3 (C-19) ) »2.15 (e» 3H CH3C0) »4.7-5.0 (q» 2H »CQ-CH ^ -O)» 5.56 (d »1H» CH (C-ll)) »6.17 (s» ÍH »CH (C-) 4)) »6.38 (d» 1H, CHIC-2)), 6.74 < d »1H» CH (C-D).
EXAMPLE 4
The title compound was prepared from 21-9a-fluars-1-methyl-1-prednisolone acetate (1 g »2.3 mmoles) in the same manner as described for Example 1. FAB-MS: (M + Li ) * = 531? NMR * H (CDCl 3) < 5 1.03 (s »3H» CH3 (C-18)) »1.07 (d» 3H »CH-CH-r), 1.45 (s» 3H, CH3 (C-19)) »2.22 (s, 3H» CH3C0) »4.9 (s» 2H »CO-CH -, - 0)» 5.58 (d »1H» CH (C-ll)) »6.17 (s» ÍH »CH (C-4))» 6.42 (d »ÍH» CH (C-2 >) »6.78 (d, 1H» CH (C-ID).
EXAMPLE 5
The title compound was prepared from prednisolone (1 g? 2.8 mmoles) in the same manner as that described for example 1. FAB-MS? (M + Li) * = 457? NMR * H (DMSO-d ^) «5 0.67 (s, 3H, CH3 (C-18>)» 1.29 (s, 3H, CH3 (C-19)) »5.61 (s, 1H» CH (C-) ll)) r 5.3-5.6 (q, 2H »CO-CH -, - 0)» 5.98 (s »1H» CH (C-4)), 6.2 (d »1H, CH (C-2))» 7.1 (d »ÍH, CH (CD).
EXAMPLE 6
The title compound is prepared from prednisolone (1 g »2" mmoles) in the same manner as that described for example 1. FAB-MS? (M + Li) * = 496.4 NMR * H (DMSO-d ^) < 5 0.82 (s »3H» CH3 (C-18)) »1.29 ís» 3H »CH3 (C-19))» 5.61 (d »1H» CH (C-ll)) »5.5-5.8 (q, 2H» C0-CHs-0) »5.98 (s» 1H »CHIC-4))» 6.18 (d, 1H »CH (C-2))» 7.03 (d »1H» CH (Cl)).
EXAMPLE 7
The title compound was prepared from 9a-fluoro-16a-hydroxyprednisolone (1g? 2.5mmol) in the same manner as that described for example 1. FAB-MS? (M + Li) * = 485? NMR * H (DMSO-d ^.) C5 0.99 (s, 3H »CH3 (C-18))» 1.48 (s »3H» CH3 (C-19)), 5.3-5.45 (q »2H» CO-CH ^ -O), 5.55 (d »1H» CH (C-ll)) »6.02 (s» 1H »CHIC-4))» 6.22 (d »ÍH» CH (C-2)) »7.27 (d» 1H »CH (Cl)).
EXAMPLE 8
The title compound was prepared from 9 < x-fluoro-16"~ hydroxy-prednisolone (1 g? 2.5 mmol) in the same manner as that described for example 1. FAB-MS? (M + Li) * =
530? NMR * H (DMSO-d ^) 6 0.81 (s »3H» CH3 (C-18)) »1.42 (s» 3H »
CH3 (C-19)) »5.3-5.4 (q» 2H »CO-CH ^ -O)» 5.49 (d »HI» CH (C-ll)) »
6. 08 (s »HI» CH (C-4)) »6.28 (d» ÍH »CH (C-2))» 7.03 (d »ÍH? CH (C-1)).
EXAMPLE 9
The title compound was prepared from 16a »17- ut i 1 idediioxy-prednisolone (1 g» 2.3 m sles) in the same manner as that described for example 1. FAB-EM? (M + Li) * = 527.7? NMR * H (CDCl3) 6 O.92 (s »3H, CH3 (C-25))» .99 (s, 3H »CH3 (C-18))» 1.36 (s, 3H »CH3 (C-19) ) »4.63 (t» ÍH »CH (C-21))» 4.87 (d »ÍH» CH (C-16)) »5.09 (t» ÍH »CH (C-2i))» 5.16 (t »ÍH» CHIC-22)) »5.63-5.69 (» ÍH »CH (C-ll))» 6.09 (s »ÍH» CHIC-4)) »6.35 (d, 1H» CH (C-2)) »6.88 (d) »1H» CH (CD).
EXAMPLE 10
The title compound was prepared from prednisisalana 21-acetate (1 g »2.5 mmol) in the same manner as that described for Example 1. FAB-MS; (M + Li) * = 448 »1H NMR (CDCl 3) < 5 1.07 (s, 3H »CH3 (C-18) >» 1.45 (s »3H» CH3 (C19)) »2.20 (s» 3H »CH3-C0), 4.50-4.55 (m» 1H »CH (C -ÍÍ)) »6.05 (s, 1H» CH »(C ~ 4))» 6.25 (d, ÍH »CH (C-2))» 7.25 (d »ÍH» CH (Cl)).
EXAMPLE 11
The title compound was prepared from prednisalone 21-acetate (1 g »2.5 mMales) in the same manner as that described for example 1. FAB-MS; (M + Li) * = 448? NMR * H (CDCl3) 6 0.87 (s »3H» CH3 (C-18)) »1.36 (s» 3H, CH3 (C-19)) »2.16 (s» 3H »CH3-C0)» 5.63-5.67 ( m »1H» CH (C-ll)) »6.05 (s, ÍH» CHIC-4)) »6.30 (d» ÍH »CH (C-2 >)» 6.90 (d »ÍH» CH (CD).
EXAMPLE 12
The title compound was prepared from 21-prednisolone acetase (i g »2.5 mmol) in the same manner as that described for example 1. FAB EM? (M + H> * = 493? NMR-XH (CDCl3) c5 0.96 (s, 3H »CH3 (C-18))» 1.35 (s »3H» CH3 (C-19)) »2.17 (s» 3H , CH3-C0) »4.60 (d» 1H »CH (C-21))» 5.62-5.66 (m »ÍH» CH (C-L)) »6.08 (s» ÍH »CH (C-4))» 6.35 <1 H »CH (C-2))» 6.90 (d »1H» CH (CD).
The titre compound was prepared from 16 »17-acetonide of 6a» 9? -di-uoro-16a-hydroxy-prednisolone (1 g »2.2 mmol) in the same manner as that described for example 1» FAB- EM? (M + Li) * = 549.4? NMR- * H (CDCl 3) < 5 0.84 (s »3H» CH3 (C-18)), 1.46 (s, 3H, C ^ (C-18)) »1.46 (s» 3H »CH3 (C-19))» 5.00 (d »1H» CH (C-21)) »5.02 (d» 1H »CH (C-16))» 5.34 (d, ÍH »CH (C-21))» 5.56- 5.62 (»ΔH» CH (C-11)) , 6.46 (d »ÍH» CH (C-2)), 6.5 (s »ÍH» CH (C-4)), 6.7 (d »ÍH, CH (CD).
EXAMPLE 14
The title compound was prepared from 21-chloro-9a-fluoro-HE-idroxy-16 «» 17 «-isoprori lidendioxy-4- pregneno-3» 20-dione (1 g? 2.2 mmoles) thereof way that described for example 1. FAB-EM? (M + Li) * = 506.1? NMR- * H (CDCl3) 6 0.79 (d, 3H »CH3 (C-18))» 1.46 (s, 3H »CH3 (C-19))» 4.12 (d »1H» CH (C-21)), 4.58 (d »ÍH» CH (C-21)) »5.07 (d» 1H »CH (C-16))» 5.50-5.56 (m »1H» CH (C-11)) »5.84- íd» ÍH » CH (C-2)) »7.26 (s, ÍH» CH (Cl)).
EXAMPLE 15
The title compound was prepared from 16,17-acetonide of 6 < x-fluoro-1 a-hi droxi-prednisolone (1 g »2.3 mmolee) in the same manner as that described for example 1.
FAB-E? ÍM + Li) * 531.1? NMR- * H (CDCl3) 6 0.84 ís »3H» CH-, (C-18)) »1.47 (d» 3H »CH3 (C-19))» 4.98 (d »ÍH» CH (C-21)) »5.02 (d» ÍH »CH (C-16))» 5.34 (d, 1H »CH (C-21))» 5.64-5.68 (, HH »CH (C-11))» 6.42- (s, ÍH »CH (C-4))» 6.87 (d »ÍH, CH (C-2))» 7.25 (s »ÍH» CH (Cl)).
EXAMPLE 16
The title compound was prepared from 16"17-acetonide of 16" -hydroxyprednisolone (1 g "2.4 mmol) in the same manner as that described for example 1. FAB-MS? (M + Li) * = 513.1? NMR ~ lH (CDCl3> <0.84 (s »3H» CH3 (C-18)) »1.37 (s, 3H» CH3 IC-19)) »4.99 (d» ÍH »CH (C-21)) »5.00 (d» ÍH »CH (C-16)), 5.34 (d» ÍH, CH (C-21)), 5.64-5.68 (m, ÍH, CH (C-11)), 6.13 (s, ÍH , CH (C-4)) »6.38 (d» ÍH, CH (C-2)), 6.93 (d »HI» CH (Cl)).
EXAMPLE 17
The title compound was prepared from 21-acetate-9-fluo-16β-methyl-1-prednisolone in the same manner as described in example i.
EXAMPLE 18
The title compound was prepared from 9"-fluoro-160-methyl-prednisolone in the same manner as described for example 1.
EXAMPLE 19
The title compound was prepared from 9oc »21-diclara-16« -eti-prednisalone furoata in the same manner as that described for example 1.
EXAMPLE 20
The title compound was prepared from 16"17-acetonide of 9" -fluoro-16? -hydroxy-prednisolone in the same manner as described for example 1.
EXAMPLE 21
The title compound was prepared from 16 »17-9a-fluoro-16" -hydroxy-prednisolone acetonide in the same manner as described for example i.
The title compound was prepared from 21-acetate of 16"17-acetonide of 9" -fluoro-16"-hydroxy-prednisolone in the same manner as that described for example 1.
BIOLOGICAL DATA
It has been found that the present compounds of the formula (i) are donors of nitric oxide while maintaining their steroid activities and that they possess useful pharmacological properties as demonstrated in one or more of the following tests? Selected compounds were tested in three in v tro and one in vivo tests. The in vitro tests consisted of the following? to measure the effect of the compounds to inhibit the increase of prostaglandin after the treatment of human fetal fibroblast cells with interleukin-1 (IL-1) and interleukin-i followed by arachidonic acid »by measuring the effect of the compounds in cyclic GMP in the human fetal fibroblasts »and measuring smooth muscle relaxant activity in rat aortic rings. The in vivo test consists of measuring the anti-inflammatory properties of the compounds in the rat air sac model treated with carrageenan.
A. Synthesis test of in vitro inhibition of prostaglandin E-. (PGEa) Human fetal fibroblast cells were treated with IL-1 for 16 hours and prostaglandin E.- »was measured by ELISA. The compounds were administered at the time of the addition of IL-i. This test provides a determination of the ability of the compound to block the induction of the pro-inflammatory agent prostaglandin Es. (PGEs.)?
PGE treatment-, (ng)
Basic 0.6 IL-1 9.4 IL-1 and dexamethasone (iOμM) 0.6 SL-1 and Example 2 (10uM) 0.8 IL-1 and Example 6 (10uM) 1.0
These data indicate that the esteraides with the modifications for the generation of nitric oxide are effective to inhibit the increase in PGE ^ and maintain the glucocorticoid action of the prevention of prostalandine formation.
B. In vitro stimulation test of cGMP production Human fetal fibroblasts in the presence of isabuti Imeti Ixanthin »a phosphodiesterase inhibitor» were treated with compueetoe for 120 minutes and intracellular cyclic GMP levels were measured by a radioimmunological test. The cell line is used as a reporter cell test to monitor the production of nitric oxide.
Treatment f cyclic GMP / cell
Basis or 145 Example 1 170 Example 2 260 Example 3 350 Example 4 225 Example 5 485 Example 6 330
These data show that the compounds possess the ability to increase levels of cyclic GMP in the nitric oxide reporter cell test »indicating that these compounds release nitric oxide during the treatment of the cells. C. Test of smooth muscle relaxant activity in vitro The selected co-beds were examined to verify their ability to relax smooth muscle. The rat aortic ring test was used as a biatest to measure the relaxing activity. The rings were precontracted with ileum (0.3uM) and subsequently were added to the tissue bath in the absence or in the presence of cysteine (Cys) and methyl ester of Nß-L-nor troarginine (L-NAME).
I. Test of smooth muscle relaxant activity in vitro in the absence of Cvs and L-NAME Compound Relaxation »EC. ^ Cμm3
Beclomethasone dipropianate MOO Example 1 > 1 0 Dexamethasone MOO Example 2 1.5 Example 4 10.0 MOO Prednisolone Example 5 5.0 Example 6 10.0 MOO Budesonide Example 9 3.0 II Smooth muscle relaxant activity test in vitro in the presence of Cvs v L-NAME Compound Relaxation »EC ^^ CμmL]
Beclomethasone dipropionate L > 100 Example 1 2.O Budesonide 100 Example 9 10.0 Example 11 40.O Example 14 70.0
Examples 1 »2» 4 »5» 6 and 9 were all tested in the absence of cietein / NAME and »except for Example 1» they were found to possess varying degrees of smooth muscle relaxant activity. In addition »examples 1» 9 »11 and 14 also caused relaxation in the presence of cysteine and L-NAME. These data indicate that these compounds have smooth muscle relaxant activity »while the control compounds budesonide» dexamethasone »prednisolone and beetle etaeone dipropionate showed no effect.
D. Anti-inflammatory test in vivo The compound of Example 2 was tested for its anti-inflammatory activity in vivo in the rat air bag test with carrageenan. The rats were injected subcutaneously with a volume of air for several days to form a bag. Inflammation was subsequently induced in the pouch by the addition of the pro-inlamatory agent carrageenan. Inflammation was measured by testing the fluid in the bag for prostaglandin Ez by ELISA. The compound of Example 2 at a dose of Img / kg blocked the increase in prostaglandin E2 by 98%. These data indicate that these compounds possess the ability to reduce inflammation in vivo.
Claims (2)
1-2 heterogeneous atoms selected from nitrogen »oxygen or sulfur» Rg- is hydrogen or halogen? Ré is hydrogen »hydroxyl or oxygen? P and Q are independently selected from the group consisting of hydrogen »chloro» fluorine and lower alkyl group of 1 to 4 carbon atoms? and X is methylene or sulfur if Rx is a haloalkyl? and together with a pharmaceutically acceptable vehicle. 4. The pharmaceutical composition according to claim 1 »further characterized in that the dotted lines of the formula I indicate a single or double bond» R ± is selected from the group consisting of hydrogen »hydroxyl» nitrate ester (ONO.- .) »Chloro» thiol »lower alkyl group of 1 to 4 carbon atoms or Ra is a group of the formula OCO-R ,. where R ^. is propanoic acid »methyl or ethyl? R3 and R- * are independently selected from the group consisting of hydrogen »hydroxyl» nitrate ester (ONO ^,) »methyl» lower alkynyl group of 2 to 4 carbon atoms? or R 3 R. * have the formula 0C0 ~ Rβ wherein Rβ is ethoxy »
2-furanyl» methyl »ethyl» propyl or butyl? or R3 and R ^ can optionally together form a cyclic structure of the formula? i wherein K and L are selected from the group consisting of hydrogenated »methyl and butyl? or and L can optionally form a cyclopentyl or cyclohexyl ring. R 'is hydrogen, chlorine or bromine, hydroxy, or oxygen? P and Q are selected 10 independently of a group of hydrogen »chlorine» fluorine and methyl? and X ee meti leño "and together with a pharmaceutically acceptable vehicle. 5. The use of the pharmaceutical composition according to claims 1, 2, 3 or 4 to prepare 15 a medicine to treat a patient with inflammation. 6. The use of the pharmaceutical composition according to claims 1, 2, 3 or 4 to prepare a medicament for treating a patient with unwanted smooth muscle contractions. 7. The use of the pharmaceutical composition according to claims 1, 2, 3 or 4 for preparing a medicament for treating a patient with unwanted smooth muscle contractions and inflammation.
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA98009114A true MXPA98009114A (en) | 1999-04-06 |
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