Claims
- 1. A compound selected from the group consisting of:
- 17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2"'-(3-pyridyl) -2"'-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]-octacos-18-ene-2,3, 10,16-tetraone;
- 17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2"'-(3-pyridyl) -2"'-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]-octacos-18-ene-2,3, 10,16-tetraone;
- 17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-(2-thienyl) -2"'-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,23-dimethoxy-13,19,21,27-tetramethyl-11,28 -dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]octacos-18-ene-2,3, 10,16-tetraone;
- 17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2"'-(3-thienyl) -2"'-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,23-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]octacos-18-ene-2,3, 10,16-tetraone;
- 17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2"'-(2-thienyl) -2"'-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,23-dimethoxy-13,19,21,27-tetramethyl-11,28 -dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]octacos-18-ene-2,3, 10,16-tetraone;
- -17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2"'-(3-thienyl) -2"'-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,23-dimethoxy-13,19,21,27-tetramethyl-11,28 -dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]octacos-18-ene-2,3, 10,16-tetraone;
- 17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2"'-(benzothien -2-yl)-2"'-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,23-dimethoxy-13,19,21,27-tetramethyl -11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]octacos-18-ene -2,3,10,16-tetraone;
- -17Ethyl-1,14-dihydroxy-12-[2'-(4"-(2"'-(benzothien -3-yl)-2"'-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,23-dimethoxy-13,19,21,27-tetramethyl -11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]octacos-18-ene -2,3,10,16-tetraone;
- 17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-(benzothien -5-yl)-2"'-hydzoxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,23-dimethoxy-13,19,21,27-tetramethyl -11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]octacos-18-ene -2,3,10,16-tetraone;
- 17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2"'-(benzothien -6-yl)-2"'-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'methylvinyl]-23,23-dimethoxy-13,19,21,27-tetramethyl -11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]octacos-18-ene -2,3,10,16-tetraone;
- 17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2"'-(benzothien -2-yl)-2"'-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,23-dimethoxy-13,19,21,27-tetramethyl -11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]octacos-18-ene -2,3,10,16-tetraone;
- 17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2"'-(benzothien -3-yl)-2"'-oxoethyloxy)-3"-methoxycyclohexyl)-1'methylvinyl]-23,23-dimethoxy-13,19,21,27-tetramethyl -11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]octacos-18-ene -2,3,10,16-tetraone;
- 17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2"'-(benzothien -5-yl)-2"'-oxoethyloxy)-3"-methoxycyclohexyl)-1'methylvinyl]-23,23-dimethoxy-13,19,21,27-tetramethyl -11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]octacos-18-ene -2,3,10,16-tetraone;
- 17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2'"-(benzothien -6-yl)-2"'-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,23-dimethoxy-13,19,21,27-tetramethyl -11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]-octacos-18-ene -2,3,10,16-tetraone;
- 17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2"'-(benzofuran -2-yl)-2"'-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,23-dimethoxy-13,19,21,27-tetramethyl -11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]octacos-18-ene -2,3,10,16-tetraone;
- 17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2"'-(benzofuran -3-yl)-2"'-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,23-dimethoxy-13,19,21,27-tetramethyl -11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]octacos-18-ene -2,3,10,16-tetraone;
- 17-Ethyl-1,14-dihydroxy-12-[2'-( 4"-(2"'-(benzofuran -5-yl)-2"'-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,23-dimethoxy-13,19,21,27-tetramethyl -11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]octacos-18-ene -2,3,10,16-tetraone;
- 17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2"'-(benzofuran -6-yl)-2"'-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,23-dimethoxy-13,19,21,27-tetramethyl -11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]octacos-18-ene -2,3,10,16-tetraone;
- 17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2"'-(benzofuran -2-yl)-2"'-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,23-dimethoxy-13,19,21,27-tetramethyl -11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]octacos-18-ene -2,3,10,16-tetraone;
- 17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2"'-(benzofuran -3-yl)-2"'-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,23-dimethoxy-13,19,21,27-tetramethyl -11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]octacos-18-ene -2,3,10,16-tetraone;
- 17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2"'-(benzofuran -5-yl)-2"'-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,23-dimethoxy-13,19,21,27-tetramethyl -11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]octacos-18-ene -2,3,10,16-tetraone;
- 17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2"'-(benzofuran -6-yl)-2"'-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,23-dimethoxy-13,19,21,27-tetramethyl -11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]octacos-18-ene -2,3,10,16-tetraone;
- or a pharmaceutically acceptable salt thereof.
SUMMARY OF THE INVENTION
This application is a continuation-in-part of copending application Ser. No. 07/921,851, filed Aug. 5, 1992, now issued as U.S. Pat. No. 5,252,732 issued which in turn is a continuation-in-part of copending application Ser. No. 07/756,946, filed Sep. 9, 1991, now abandoned.
The present invention is related to O-heteroaryl, O-alkylheteroaryl, O-alkenylheteroaryl and O-alkynylheteroarylmacrolides which are useful in a mammalian host for the treatment of autoimmune diseases <such as juvenile-onset diabetes mellitus, multiple sclerosis and rheumatoid arthritis), immunodepression, infectious diseases, the prevention of rejection of foreign organ transplants (e.g. bone marrow and heart transplants and xeno transplants), the topical treatment of inflammatory and hyperproliferative skin diseases and cutaneous manifestations of immunologically-mediated illnesses (such as: psoriasis, atopical dermatitis, contact dermatitis and further eczematous dermatitises, seborrhoeic dermatitis, Lichen planus, Pemphigus, bullous Pemphigoid, Epidermolysis bullosa, urticaria, angioedemas, vasculitides, erythemas, cutaneous eosinophilias, Lupus erythematosus, Alopecia areata), male pattern alopecia, alopecia senilis, reversible obstructive airways disease, particularly asthma, alopecia, inflammation of mucosa and blood vessels, cytomegalovirus infection, multidrug resistance, idiopathic thrombocytopenic purpura, Behcet's syndrome, conjunctivitis, Crohn's disease, Mooren's ulcer, uveitis, severe intraocular inflammation, and/or hepatic injury associated with ischemia. The present compounds are further useful in combination with a 5.alpha.-reductase inhibitor, a cyclosporin, a potassium channel opener or a phospholipid in a mammalian host for the treatment of baldness, especially male pattern alopecia, female pattern alopecia, alopecia senills, or alopecia areata. In addition, some of the compounds of this invention may have antagonistic properties and so have utility in the reversal of immunosuppressive activity and/or diminishing the toxicity of other immunosuppressive agents.
More particularly, this invention relates to compounds of the general structural formula I: ##STR2## wherein R.sup.1, R.sup.2, R.sup.3, R.sup. 4, R.sup.5, R.sup.10, W and n are hereinafter defined.
This invention also relates to pharmaceutical compositions containing the compounds and to a method of use of the present compounds and other agents for the treatment of and prevention of certain afflictions, diseases and illnesses.
Fujisawa United States, European and Japanese patents and applications (U.S. Pat. No. 4,894,366, issued Jan. 16, 1990, EPO Publication No. 0,184,162 and PBJ Disclosure 63-17884) and publications (J. Am. Chem. Soc., 1987, 109, 5031 and J. Antibiotics 1987, 40, 1249) disclose 17-allyl-1,14-dihydroxy-12-[2'-<4"-hydroxy-3"-methoxycyclohexyl)1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo -22.3.1.0.sup.4,91 ]octacos-18-ene -2,3,10, 16-tetraone (FR-900506), (FK-506), (L-679,934), 17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl -11,28-dioxa-4azatricyclo [22 .3.1.0.sup.4,9 ]octacos-18-ene-2,3,10,16-tetraone (FR-900520) and related compounds which are the starting materials for the preparation of the compounds described. The synthetic preparation of the aforementioned starting material (FR-900506) has recently been reported (J. Am. Chem. Soc., 1989, 111, 1157). A Sandoz European patent application (EPO Publication No. 0,356,399) discloses stereoisomers of FR-900506 and derivatives at the 17-position. Fisons European and WIP0 patent applications (EPO Publication No. 0,323,042 and PCT Publication No. WO 89/05304) discloses various derivatives of FR-900506, FR-900520 and related compounds. A Sandoz European Patent application (EPO Publication No. 0,437,680) discloses chloro, bromo, iodo and azido derivatives of FR-900506, FR-900520 and related compounds. A Merck European Patent application (EPO Publication No. 0,428,365) discloses various amino derivatives of FR-900506, FR-900520 and related compounds. A Fujisawa patent application (UK Publication No. GB 2,245,891-A) discloses various derivatives of FR-900506 bearing a heterocyclic group. Merck WIPO patent applications (PCT Publication Nos. WO 93/05058 & WO 93/05059) disclose various heteroaryl derivatives of FR-900506, FR-900520 and related compounds.
Fujisawa United States patents (U.S. Pat. No. 4,929,611, issued May 29, 1990, U.S. Pat. No. 4,956.352, issued Sep. 11, 1990 and U.S. Pat. No. 5,110,811, issued May 5, 1992) discloses the use of FK-506-type compounds in treating resistance to transplantation. A Sandoz European patent application (EPO Publication No. 0,315,978) discloses the use of FR-900506 and related compounds in the topical treatment of inflammatory and hyperproliferative skin diseases and of cutaneous manifestations of immunologically-mediated illness. A Fisons WIP0 patent application (PCT Publication No. WO 91/04025) discloses the use of various derivatives of FR-900506 in the treatment of immunodepression. A Fisons WIP0 patent application (PCT Publication WO 90/14826) discloses the use of FR-900506 and related compounds in the treatment of reversible obstructive airways disease, particularly asthma. A Fujisawa European patent application (EPO Publication No. 0,423,714) discloses the use of FK-506 and derivatives as hair revitalizing agents. Various studies have suggested the efficacy of FK-506 in the treatment of a number of ailments, including rheumatoid arthitis (C. Arita, et al., Clincial exp. Immunol., 1990, 82, 456-461; N. Inamura, et al., Clin. Immunol. Immunopathol, 1988, 46, 82-90), recent-onset diabetes (N. Murase, et al., Diabetes, 1990, 39, 1584-86; N. Murase, et al., Lancet., 1990, 336, 373-74), posterior uveitis (H. Kawashima, Invest. Ophthalmol, Vis. Sci., 1988, 29, 1265-71), hepatic injury associated with ischemia (M. Sakr, et al., Life Sci., 1990, 47, 687-91) allergic encephalomyelitis (K, Deguchi, et al., Brain Nerve, 1990, 42, 391-97), glomerulonephritis (J: McCauley, et al., Lancet, 1990, 335, 674) and systemic lupus erythematosus (K. Takabayashi, et al., Clin. Immunol. Immunopathol., 1989, 51, 110-117) multidrug resistance (M. Naito, et al., Cancer Chemother, Pharmacol., 1992, 29, 195-200), inflammation of mucosa and blood vessels (PCT Publication WO 91/17754), cytomegalovirus infection (UK Publication GB 2,247,620A), and idiopathic thrombocytophenic purpura and Basedow's disease (PCT Publication WO 91/19495).
Inununoregulatory abnormalities have been shown to exist in a wide variety of "autoimmune" and chronic inflammatory diseases, including systemic lupus erythematosis, chronic rheumatoid arthritis, type I and II diabetes mellitus, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis and other disorders such as Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, ichthyosis, and Graves ophthalmopathy. Although the underlying pathogenesis of each of these conditions may be quite different, they have in common the appearance of a variety of autoantibodies and self-reactive lymphocytes. Such self-reactivity may be due, in part, to a loss of the homeostatic controls under which the normal immune system operates.
Similarly, following a bone-marrow or an organ transplantation, the host lymphocytes recognize 16/JET100 - 7 - 18513IB the foreign tissue antigens and begin to produce antibodies which lead to graft rejection.
One end result of an autoimmune or a rejection process is tissue destruction caused by inflammatory cells and the mediators they release. Antiinflammatory agents such as NSAID's and corticosteroids act principally by blocking the effect or secretion of these mediators but do nothing to modify the immunologic basis of the disease. On the other hand, cytotoxic agents such as cyclophosphamide, act in such a nonspecific fashion that both the normal and autoimmune responses are shut off. Indeed, patients treated with such nonspecific immunosuppressive agents are as likely to succumb from infection as they are from their autoimmune disease.
Cyclosporin A which was approved by the US FDA in 1983 is currently the leading drug used to prevent rejection of transplanted organs. The drug acts by inhibiting the body's immune system from mobilizing its vast arsenal of natural protecting agents to reject the transplant's foreign protein. Though cyclosporin A is effective in fighting transplant rejection, it is nephrotoxic and is known to cause several undesirable side effects including kidney failure, abnormal liver function and gastrointestinal discomfort.
Newer, safer drugs exhibiting less side effects are constantly being searched for in the field.
The 23-membered tricyclo-macrolide inununosuppressant, tacrolimus, FR-900506, FK-506, ##STR3## (17-allyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxy-cyclohexyl) -1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22-3.1.0.sup.4,9 ]-octacos-18-ene-2,3,10,16-tetraone) and related compounds which were isolated and characterized by Tanaka, Kuroda, and co-workers at Fujisawa Pharmaceutical Co. in Japan, see J. Am. Chem. Soc., 1987, 109, 5031, and U.S. Pat. No. 4,894,366, issued Jan. 16, 1990) have been shown to possess exceptional immunosuppressive activity. Fujisawa United States patents (U.S. Pat. No. 4,929,611, issued May 29, 1990 U.S. Pat. No. 4,956,352, issued Sep. 11, 1990, and U.S. Pat. No. 5,110,811, issued May 5, 1992) disclose the use of FK-506-type compounds in treating resistance to transplantation. In particular, the compound FR-900506 has been reported to be 100 times more effective than cyclosporin in the supression of in vitro immune systems (J. Antibiotics 1987, 40, 1256). In addition, these compounds are reputed to possess topical activity in the treatment of inflammatory and hyperproliferative skin diseases and cutaneous manifestations of immunologically-mediated illnesses (EPO Pub. No. 0,315,978).
The compound FK-506 and related compounds further have been suggested to be useful in the treatment of obstructive airways disease, particularly asthma (PCT Publication WO 90/14826), male pattern alopecia or alopecia senilis (EPO Publication No. 0,423,714), rheumatoid arthitis (C. Arita, et al., Clincial exp. Immunol., 1990, 82, 456-461; N. Inamura, et al., Clin. Immunol. Immunopathol. 1988, 46, 82-90), recent-onset diabetes (N. Murase, et al., Diabetes, 1990, 39, 1584-86; N. Murase, et al., Lancet, 1990, 336, 373-74), posterior uveitis (H. Kawashima, Invest. Ophthalmol. Vis. Sci., 1988, 29, 1265-71), hepatic injury associated with ischemia (M. Sakr, et al., Life Sci., 1990, 47, 687-91) allergic encephalomyelitis (K, Deguchi, et al., Brain Nerve, 1990, 42, 391-97), glomerulonephritis (J. McCauley, et al., Lancet, 1990, 335, 674) systemic lupus erythematosus (K. Takabayashi, et al., Clin. Immunol. Immunopathol., 1989, 51, 110-117) multidrug resistance (M. Naito, et al., Cancer Chemother. Pharmacol., 1992, 29, 195-200), inflammation of mucosa and blood vessels (PCT Publication WO 92/17754), cytomegalovirus infection (UK Publication GB 2,247,620A), and idiopathic thrombocytophenic purpura and Basedow's disease (PCT Publication WO 91/19495).
Baldness or alopecia, in addition to male pattern alopecia, female pattern alopecia, and alopecia senilis, includes alopecia areta, and further, diseases accompanied by the basic skin lesions such as cicatrix or infectious tumors, or accompanied by systemic disorder, for example, an internal secretion abnormality or nutritional disorder.
In regard to alopecia areata, it is considered that an autoimmune phenomenon participates therein, and therefore, the administration of a substance having an inununosuppressive action can have therapeutical effect on alopecia areata.
The causes of human pattern alopecia (also called "androgenic alopecia") and alopecia senills are considered to be: an activation of male hormones at organs such as hair roots and the sebun gland; a lowering in the amount of blood reaching the hair follicles; a scalp abnormality caused by an excessive secretion of sebun, a formation or peroxides, or a propagation of bacteria; genetic causes; and aging.
The compound minoxidil (6-amino-1,2-dihydro -1-hydroxy-2-imino-4-piperidino-pyrimidine) was approved by the FDA for the treatment of male pattern baldness in August 1988. Minoxidil was also approved by the FDA for the treatment of female adrogenetic alopecia on Aug. 13, 1991. The preparation of minoxidil is described in U.S. Pat. Nos. 3,382,247, 3,644,364 and 4,098,791. Upjohn United States Patents (U.S. Pat. Nos. 4,139,619and 4,596,812) discloses the use of minoxidil in the topical treatment of human baldness. Similarly, an Upjohn United States Patent (U.S. Pat. No. 5,026,691) discloses the use of minoxidil and an antiinflammatory agent for the treatment of patterned male and female alopecia. Japanese patent Kokai 61-260010 states that topical minoxidil formulations containing other specified agents may be prepared. An Upjohn WIP0 patent application (PCT Publication No. WO 92/09259) discloses a method and composition for promoting hair growth in mammals comprising the administration of a potassium channel opener and an androgen receptor blocker. A University of Miami WIP0 patent application (PCT Publication No. WO 92/12703) discloser a method of stimulating hair growth comprising the topical application of a phospholipid.
Merck U.S. Pat. No. 4,760,071 discloses the 5.alpha.-reductase inhibitor 17.beta.-(N-tert-butylcarbamoyl) -4-aza-5.alpha.-androst-1-en-3-one. Harris, et al., (Proc. Natl. Acad. Sci. USA, 89, 10787-10791 (Nov. 1992)) and Melin, et al. (J. Steroid Biochem. Molec. Biol., 44(2), 121-131 (1993)) disclose the use of scalp-selective 5.alpha.-reductase inhibitors in the treatment of male pattern baldness, acne and hirsutism.
The present invention is directed to a compound of structural Formula I: ##STR4## or a pharmaceutically acceptable salt thereof, wherein:
R.sup.1 is selected from:
R.sup.2 is selected from:
W is 0 or (H, OH);
X, Y and Z independently are selected from:
X', Y' and Z' independently are selected from:
n is 1 or 2.
The compounds of Formula I employed in the present invention have asymmetric centers and this invention includes all of the optical isomers and mixtures thereof.
In addition compounds of Formula I with carbon-carbon double bonds may occur in Z- and E-forms with all isomeric forms of the compounds being included in the present invention.
When any variable in Formula I (e.g., alkyl, aryl, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, etc.) occurs more than one time in any variable or in Formula I, its definition on each occurrence is independent of its definition at every other occurrence.
As used herein, the term "alkyl" includes those alkyl groups of a designated number of carbon atoms of either a straight, branched, or cyclic configuration. Examples of "alkyl" include methyl, ethyl, propyl, isopropyl, butyl, sec-and tert-butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like. "Alkoxy" represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge, such as methoxy, ethoxy, propoxy, butoxy- and pentoxy. "Alkenyl" is intended to include hydrocarbon chains of a specified number of carbon atoms of either a straight- or branched-configuration and at least one unsaturation, which may occur at any point along the chain, such as ethenyl, propenyl, butenyl, pentenyl, dimethylpentyl, and the like, and includes E and Z forms, where applicable; and "heteroarylalkyl" represents heteroaryl groups as herein defined which are attached through a straight or branched chain alkyl group of from one to ten carbon atoms. "Halogen", as used herein, means fluoro, chloro, bromo and iodo,
As will be understood by those skilled in the art, pharmaceutically acceptable salts include, but are not limited to salts with inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide, and nitrate or salts with an organic acid such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate or palmoate, salicylate and stearate. Similarly pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium (especially ammonium salts with amines of the formula HNR.sup.6 R.sup.7).
The heteroaryl group as used herein includes acridine, carbazole, cinnoline, dibenzofuran, dibenzothiophene, quinoxaline, pyrrazole, indole, benzotriazole, furan, benzofuran, quinoline, isoquinoline, pyrazine, pyridazine, pyridine, pyrimidine, pyrrole which are optionally substituted.
In the compounds of Formula I the heteroaryl group may be optionally substituted with X, Y and Z at any available carbon atom or nitrogen atom (if present), but compounds bearing certain of X, Y and Z directly substituted to a nitrogen atom of the heteroaryl ring may be relatively unstable and are not preferred.
The term "heteroaryl" as utilized herein is intended to include the following heteraromatic groups which may include X, Y and Z substitution as indicated and wherein Q is --N(X)--, --O--, --S--, --DSO, or --SO.sub.2 --; ##STR9##
The aryl or aromatic group may include phenyl or naphthyl which are optionally substituted by from one- to three-members independently selected from the group consisting of: alkyl, alkenyl, halogen, carboxyl, CH.sub.0, amino, mono-alkylamino, di-alkylamino, aminoalkyl, mono-alkylaminoalkyl, di-alkylaminoalkyl, alkylthio, alkylsulfinyl, alkysulfonyl, trifluoromethyl, amido, mono-alkylamido, dialkylamido, hydroxy, hydroxyalkyl, R.sup.11 O-alkyl, alkoxy, alkoxyalkyl, formamido, alkyl-CO.sub.2 --, formamidoalkyl, alkyl-CO.sub.2 -alkyl--, carboxyl, alkyl-CO.sub.2 H, alkyl-O.sub.2 C--, alkyl-O.sub.2 C-alkyl--, and OR.sup.11.
In the compound of Formula I it is preferred that the heteroaryl is selected from the group consisting of: ##STR10##
wherein X is as defined above.
In the compound of formula I it is also preferred that
R.sup.2 is selected from:
R.sup.3 is selected from:
W is 0; and
n is 2.
In one embodiment of the compound of Formula I, heteroaryl is indole, which may be represented by: ##STR11## wherein R.sup.6 X, Y and Z are as defined above,
In the instant combination, preferred compounds of Formula I are the compounds identified as follows:
Representative compounds of the present invention include the compounds of Formula X, XI, XII and XIII: ##STR12## wherein R.sup.6a is H or CH.sub.3 and the definitions of R.sup.2, R.sup.3, R.sup.5, R.sup.6 and R.sup.7 are selected from the following groups of substituents:
The starting materials for the preparation of the compounds of Formula I are represented by Formula II: pg,107 ##STR16## wherein: E is hydrogen or methyl;
The production and characterization of compounds of Formula II is well known in the literature (see U.S, Pat. No. 4,894,366 issued Jan. 16, 1990; U.S. Pat. No. 4,929,611 issued May 29, 1990; U.S. Pat. No. 3,244,592 issued Apr. 15, 1966; EPO Publication No. 0,323,042,; EPO Publication No. 0,356, 399; PBJ Disclo sure 63-17884; J. Am. Chem. Soc., 1987, 109, 5031; J. Antibiotics, 1987, 40, 1249; J. Antibiotics, 1988, 41(11), 1952; and J. Anibiotics, 1992, 45(1), 118). Both biological fermentation and synthetic processes may be found. A synthetic route to compounds of Formula II can involve modifications of a route described in J. Am. Chem. Soc., 1989, 111, 1157.
Biological fermentation followed by synthetic modification is presently favored in the art as the method to produce compounds of Formula II. Organisms belonging to the genus Streptomyces such as Streptomyces tsukubaensis, No. 9993 and Streptomyces hygroscopicus, var. ascomycetis, No. 14891 placed in an aqueous nutrient medium will produce desired compounds in isolable amounts. The nutrient medium contains sources of assimilable carbon and nitrogen, preferably under aerobic conditions. Produced in fermentation are four compounds of Formula II, (A) where E is methyl, W is O, R.sup.3 is hydroxyl, R.sup.4 is hydrogen, R.sup.5 is allyl and n is 2; (B) where E is methyl, W is O, R.sup.3 is hydroxyl, R.sup.4 is hydrogen, R.sup.5 is ethyl and n is 2; (C) where E is methyl, W is O, R.sup.3 is hydroxyl, R.sup.4 is hydrogen, R.sup.5 is methyl and n is 2; and (D) where E is methyl W is O, R.sup.3 is hydroxyl, R.sup.4 is hydrogen, R.sup.5 is allyl and n is 1.
A lyophilized sample of the isolated Streptomyces tsukubaensis, No. 9993 was deposited with the Fermentation Research Institute, Agency of Industrial Science and Technology (No. 1-3, Higashi 1-chome, Yatabemachi Tsukuba-gun, Ibaraki Prefecture, Japan) under the deposit number of FERM P-7886 (deposit date: Oct. 5th, 1984), and then converted to Budapest Treaty route of the same depository on Oct. 19, 1985 under the new deposit number of FERM BP-927.
Using the four compounds produced in fermentation above, the remaining compounds of Formula II may be easily produced. The allyl of R.sup.5 may be conveniently reduced to propyl by well known methods, for example as described in U.S. Pat. No. 4,894,366. The hydroxy of R.sup.3 may be protected by well known methods, for example as disclosed in EPO Publication No. 0,323,042. Likewise, the hydroxyl at C-4'' may also be protected. In addition, the hydroxy of R.sup.3 may be reduced to a hydrogen or eliminated to form a double bond with R.sup.4 (by methods disclosed in U.S. Pat. No. 4,894,366, EPO Publication No. 0,323,042 or EPO Publication No. 0,413,532). The carbonyl of W may be reduced to the alcohol by methods disclosed in EPO Publication No. 0,323,042 or by methods disclosed in EPO Publication No. 0,323,042 or by methods disclosed in EPO Publication No. 0,445,975.
The methyl of E as produced may be replaced with hydrogen or demethylated and subsequently protected as desired, if necessary. This demethylation of compounds wherein E is methyl may be carried out in a fermentation reaction using the compounds of Formula II as a feedstock. For instance, compound A named under Formula II above may be demethylated at E above by using the microorganism Actinomycetales ATCC No. 53771 (described in U.S. Pat. No. 4,981,792) or by using the microorganism Streptomyce tsukubaensis No. 9993 (described in EPO Publication No. 0,353,678). Similarly, compound B named under Formula II above may be demethylated at E above using the microorganism Actinoplanacete sp. ATCC No. 53771 (described in EPO Publication No. 0,349,061). In addition the compound of Formula II wherein E is H, W is O, R.sup.3 is hydroxy, R.sup.4 is hydrogen, R.sup.5 is ethyl and n is 2 may be produced directly by fermentation using the mutant microorganism Streptomyces hygroscopicus sup. ascomyceticus, No. 53855 (being a blocked mutant of Streptomyces hygroscopicus sup. ascomyceticus, No. 14891) (as described in EPO Publication No. 0,388,152). Similarly, the compound of Formula II wherein E is hydrogen, W is O, R.sup.3 is hydroxy, R.sup.4 is hydrogen, R.sup.5 is methyl and n is 2 may be produced directly by fermentation using the mutant microorganism Streptomyces hygroscopicus sup. ascomyceticus, No. 53855 (being a blocked mutant of Streptomyces hygroscopicus sup. ascomyceticus, No. 4891) (EPO Publication No. 0 388,153). The hydroxy of C-3'' may be protected by methods similar to those known for the protection of the hydroxyl groups of R.sup.3 and/or C-4'', for example as disclosed in U.S Pat. No. 4,894,366.
Suitable protecting groups for hydroxyl include those groups well known in the art such as: methylthiomethyl, ethylthiomethyl; trisubstituted silyl such as trimethylsilyl, triethylsilyl, tributylsilyl, tri-i-propylsilyl, t-butyldimethylsilyl, tri-t-butylsilyl, methyl-diphenylsilyl, ethyldiphenylsilyl, t-butyldiphenylsilyl, and the like; acyl such as acetyl, pivaloyl benzoyl, 4-methoxybenzoyl, 4-nitrobenzoyl and aliphatic acyl substituted with aromatic group, which are derived from carboxylic acids; and the like.
Compounds A, B, C and D of Formula II, organisms to produce the same, conditions of fermentation, separation techniques, and chemical modification of the products are fully described in U.S. Pat. No. 4,894,366, dated Jan. 16, 1990, U.S. Pat. No. 4,929,611, issued May 29, 1990 and U.S Pat. No. 5,110,811, issued May 5, 1992.
The 5.alpha.-reductase inhibitor may be an inhibitor of 5.alpha.-reductase isozyme 1 and/or 5.alpha.-reductase isozyme 2, A preferred 5.alpha.-reductase inhibitor is finasteride. It is also preferred that the 5.alpha.-reductase inhibitor be selective for the scalp-associated enzyme 5.alpha.-reductase isozyme 1.
4-Aza steriod compounds are known in the art as 5.alpha.-reductase inhibitors. For example, See U.S Pat. Nos. 2,227,876, 3,239,417, 3,264,301 and 3,285,918; French Patent No. 1,465,544; Doorenbos and Solomons, J. Pharm. Sci. 62, 4 pp. 638-640 (1973); Doorenbos and Brown, J. Pharm. Sci., 60, 8, pp. 1234-1235 (1971); and Doorenbos and Kim, J. Pharm. Sci. 63, 4, pp. 620-622 (1974).
In addition, U.S. Pat. Nos. 4,377 584, 4220,775, 4,859,681, 4,760,071 and the articles J. Med. Chem. 27, p. 1690-1701 (1984) and J. Med. Chem. 29, 2998-2315 (1986) of Rasmusson, et al., U.S. Pat. No. 4,845,104 to Carlin, et al., and U.S. Pat. No. 4,732,897 to Cainelli, et al. described 4-aza 17.beta.-substituted-5.alpha.-androstan-3-ones useful in the treatment of DHT-related hyper androgenic conditions.
Cyclosporin may be prepared essentially as described in U.S. Pat. No. 4 ,117,118 or by R. Wenger, Transplant. Proc., 15 (4), Suppl. 1, 2230 (1983) and is available from Sandoz Pharmaceuticals, East Hanover, N.J.
The potassium channel opener may be minoxidil, cromakalim, pinacidil, a triazine compound, a thiane-1-oxide, or other compounds.
Chemically minoxidil is 6-amino-l,2-dihydrohydroxy-2-imino-4-piperidinopyrimidine and analogs thereof. The preparation of these compounds are described in U.S Pat. Nos. 3,382,247, 3,461,461 and 3,644,364 and J. M. McCall, et al., J. Org. Chem., 40, 3304 (1975). Related compounds are sulfoxypyrimidinium, -pyridinium, and -triazinium which are described in U.S. Pat. No. 4,287,338. The term "minoxidil" includes any of the various forms of 6-amino-l,2-dihydro-hydroxy-2-imino-4-piperidinopyrimidine derivatives and analogs thereof. Minoxidil is distributed by The Upjohn Company, Kalamazoo, Mich.
Chemically cromakalim is (3S-trans) 3,4-dihydro-3-hydroxy-2, 2-dimethyl-4-(2-oxo-l-pyrrolidinyl)2H-1-benxopyran-6-carbonitrile. Cromakalim is distributed by SmithKline Consumer Products, Philadelphia, Pa.
Pinacidil is chemically, N-cyano-N'-4-pyridinyl-N''-(1,2,2-trimethylpropyl)-guanidine monohydrate. The preparation of pinacidil is described in U.S. Pat. No. 4,057,636 and is distributed by Eli Lilly and Company, Indianapolis, Ind.
S-Triazine compounds or 2,6-diamino-4-substituted-s-triazine-l-oxides are described in U.S. Pat. No. 3,270,014 assigned to The Upjohn Company, Kalamazoo, Mich. Specific examples of these compounds include: N4-hexyl-2,4,6-triamino-l,3,5-triazine1-oxide; N4-butyl-2,4,6-triamino-l,3,5-triazine-1oxide; N4-Pentyl-2,4,6-triamino-l,3,5-triazine-1oxide; 4-(N,N-dipropyl)-2,6-diamino-l,3,5-triazine1-oxide; 4-<N,N-dibutyl>-2,6-diamino-l,3,5-triazine 1-oxide; 4-(1-Pyrollidinyl)-2,6-diamino-l,3,5-triazine-1-oxide; 4-(N,N-di(2-methyl-2-proppenyl)amino)-2,6-diamino-l,3,5-triazine-l-oxide; 4-(N,N-(diallylamino) -2,6-diamino-l,3,5-triazine-l-oxide; 4-(N,N- dimethylamino)-2,6-diamino-l,3,5-triazine-l-oxide; 4(1-piperidinyl)-2,6-diamino-l,3,5-triazine-1oxide; N4-ProPYl-2,4,6-triamino-l,3,5-triazine-l-oxide; N4- ethyl-2,4,6-triamino-l,3,5-triazine-1-oxide; N4(1,1,4,4-tetramethylbutyl)-2,4 ,6-triamino-l,3,5-triazine-1-oxide; and N4-heptyl-2 ,4,6-triamino-l,3,5-triazine-1-oxide.
Thiane-1-oxide compounds are described in U.S. Pat. No. 4,568,682 assigned to Rhone-Poulenc Sante, Courbevoie, France. An example of such a compound contemplated by the subject invention is N-methyl-2-Pyridin-3-yl)tetrahydrothiopyran-2-carbothioamide1-oxide. Other derivatives include those disclosed in patent applications EP 0,321,274, A, EP 0,321,273 A, and EP 0,326,297 A.
Other potassium channel openers include pyranopyridine derivatives described in patent applications GB 2 204 868 A and benzopyran derivatives described in patent applications GB 2,204, 868 A, EP 0,314,446 A2, EP 0,339,562 A, EP 0,340,718 A, EP 0,337,179, AU A 18556/88, JA 1294, 677 A, EP 0,359,537 A, and U.S. Pat. No. 4,900,752.
The phospholipids used herein may be obtained from commercial sources. The phospholipids may also be isolated from natural sources (for example, egg yolk, soybean or other oily seed including safflower, sunflower and olive, and brain tissue) or may be produced synthetically. In either case, known techniques can be used for purification of the phospholipids (see, for example, J. of American Oil Chemists Soc. 42:53-56 (1965)).
The processes for preparing the compounds of Formula I are illustrated as follows, wherein R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, E, W and n are as defined above unless otherwise indicated. It will be readily apparent to one of ordinary skill in the art reviewing the synthetic route depicted below that other compounds within Formula I can be synthesized by substitution of appropriate reactants and agents in the synthesis shown below. ##STR17##
As shown in Reaction Scheme A, a solution of 4''-hydroxy-3-methoxy macrolide 1 in an inert organic solvent such as methylene chloride, benzene, toluene, chloroform, or the like or mixtures thereof is treated with a triheteroarylbismuth diacetate reagent (wherein R.sup.1 is heteroaryl) (prepared immediately prior to use by the addition of acetic acid to a suspension of a triheteroarylbismuth carbonate in an inert organic solvent such as methylene chloride, chooform or the like or mixture thereof) in the presence of a catalytic amount of copper(II) acetate at a temperature of 20-50.degree. C., preferably room temperature, for a period of one hour to seven days, preferably one day, to give the 4''-O-heteroaryl-3''-methoxy macrolide 2. Alternatively, the triheteroarylbismuth(V) reagent can be prepared by treatment of a triheteroarylbismuthine with a suitable oxidant such as peracetic acid, iodobenzene diacetate, bis(trifluoroacetoxy) iodobenzene and the like in an inert solvent such as methylene chloride, chloroform, benzene, toluene and the like. The triheteroarylbismuth(V) reagent can be used without purification or can be purified by silica gel chromatography. Triheteroarylbismuthines may be prepared by the reaction of an appropriate heteroaryl Grignard reagent or lithiated heteroaryl species with bismuth trichloride in an inert organic solvent such as tetrahydrofuran, diethyl ether, or 1,4-dioxane, or mixtures thereof, at or near room temperature for a period of 1 to 48 hours. General procedures for the preparation and use of triheteroaryl bismuth reagents may be found in Barton, D.H.E., et al., J. Chem. Soc. Chem. Commun., 1986, 65 and references cited therein.
Similarly, as shown in Reaction Scheme B, a solution of the 3'', 4''-dihydroxy macrolide 3 treated with a triheteroarylbismuth diacetate reagent as described in Reaction Scheme A, to give a mixture of the 3''-hydroxy-4''-O-heteroaryl macrolide 4a, the 3''-O-heteroaryl-4''-hydroxy macrolids 4b, and the 3'', 4''-di-O-heteroaryl macrolide 4c. At this stage, a solution of 3''-hydroxy-4''-O-heteroaryl macrolide 4a, or 3''-0-heteroaryl-4''-hydroxy macrolide 4b can be treated with a triarylbismuth diacetate reagent (prepared immediately prior to use by procedures analogous to those disclosed above), to give 3''-O-aryl-4''-O-heteroaryl macrolide 5a, or 3''-O-heteroaryl-4''-O-aryl macrolide 5a, respectively.
As shown in Reaction Scheme C the 14-hydroxy group of a macrolide 5a or 5b (wherein R.sup.1, R.sup.2,R.sup.5, R.sup.10, W and n are as defined above) may be eliminated by treatment with p-toluenesulfonic acid, benzenesulfonic acid or methanesulfonic acid in an inert organic solvent such as benzene, or toluene at from 40.degree. C. to 60.degree. C., for about 0.5 to 6 hours , or a sufficient period of time to eliminate the 14-hydroxy group. Neutralization with an aqueous solution of a weak base such as aqueous saturated sodium bicarbonate gives the 14,15-dehydro macrolides 6a or 6b. The 14-hydroxy group may also be eliminated by activation followed by basic elimination, as described in U.S. Pat. No. 4,894,366.
By changing the sequence of synthetic steps, all possible variations of substitution can be achieved.
As shown in Reaction Scheme D, a solution of the 4''-hydroxy 3''-methoxy macrolide 1 in an inert organic solvent such as methylene chloride, chloroform, pentane, hexane, cyclohexane, heptane or mixtures thereof is treated with a heteroarylalkyl, heteroarylalkenyl or heteroalylalkynyl trichloroacetimidate reagent (prepared by the reaction of an appropriate sodium alkoxide with trichloroacetonitrile, such as described by Wessel, H. P., Iversen, T., Bundle, D. R., J. Chem. Soc., Perkin Trans. I, 1985, 2247) in the presence of a mild acid catalyst such as trifluoro-methanesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, or mixtures thereof at a temperature of 20-50.degree. C. for a period of from one hour to seven days to give the 4''-O-heteroarylalkyl-, 4''-O-heteroarylalkenyl- or 4''-O-heteroarylalkynyl-3''-methoxy macrolide 2a.
Similarly, as shown in Reaction Scheme E, a solution of the 3'', 4''-dihydroxy macrolide 3 in an inert organic solvent such as methylene chloride, chloroform, pentane, hexane, cyclohexane, heptane or the like or mixtures thereof is treated with a heteroarylalkyl, heteroarylalkenyl or heteroarylalkynyl trichloroacetimidate (prepared as described in Reaction Scheme D) at a temperature of 20-50.degree. C., preferably 40.degree. C., for a period of one hour to seven days, preferably 6 hours, to give a mixture of ythe 4''-O-heteroarylalkyl, 4''-O-heteroarylalkenyl, or 4''-O-heteroarylalkynyl-3-hydroxy macrolide 4a', 3''-O-heteroarylalkyl, 3''-O-heteroarylalkenyl, or 3''-O-heteroarylalkynyl-4''-hydroxymacrolide 4b'and the 3'', 4''-di-O-heteroarylalkyl,-heteroarylalkenyl or -heteroarylalkynyl macrolide 4c'. Subsequently, a solution of 4''-O-heteroaryl, 4''-O-heteroarylalkyl, 4''-O-heteroarylalkenyl or 4''-O -heteroarylalkynyl-3-hydroxy macrolide 4a (from Reaction Scheme B or 4a', or 3''-O-heteroaryl-, 3''-O-heteroarylalkyl, 3''-O-heteroarylalkenyl, 3''-O-heteroarylalkynyl-4''hydroxymacrolide 4b from Reaction Scheme B or 4b'can be treated with an arylalkyl, alkenyl or alkynyl trichloroacetimidate by procedures described above.) to give macrolides 5a'or 5b '.
The procedures described in Reaction Schemes C and D may optionally be conducted following the procedures of Reaction Scheme E or F. Alternatively, the procedures described in Reaction Scheme F may be performed.
In any of the aforementioned Reaction Schemes, the macrolide (wherein R.sup.1 and/or R.sup.2 contains an alkenyl, substituted alkenyl, alkynyl or substituted alkynyl and wherein R.sup.3 is hydroxy or C.sub.1-6 alkoxy, R.sup.4 is hydrogen, or R.sup.3 and R.sup.4 taken together form a double bond) can be reduced with tri-n-butyltin hydride in the presence of tetrakis (triphenylphosphine) palladium (0) catalyst and acetic acid in an organic solvent such as toluene or tetrahydrofuran at or near room temperature for about 2 to 10 hours to give the reduced macrolide.
The procedures described in Reaction Scheme F may be conducted on the mono-substituted products of Reaction Scheme B (and visa versa) to obtain the mixed disubstituted compounds. In fact, within Reaction Schemes B and F, treatment of the mono-substituted product with a different reagent will afford the mixed disubstituted compounds.
Protection of the C-3'', C-4''and/or the C-14 hydroxyl group(s) may be accomplished by methods known in the prior art for compounds of Formula II such as by treatment with: 2,6-lutidine and triisopropylsilyl trifluoromethanesulfonate in a solution of methylene chloride; 2,6-lutidine and t-butyldimethylsilyl trifluoromethanesulfonate in a solution of methylene chloride; pyridine and acetic anhydride in a solution of methylene chloride; pyridine and benzoyl chloride in a solution of dichloromethane; pyridine and p-nitrobenzoyl chloride in a solution of dichloromethane; imidazole and t-butyldiphenylsilyl chloride in a solution of methylene chloride; and the like. For example, as shown in Reaction Scheme F, the C-4'', 14-dihydroxy-C-3''-methoxy macrolide 7 may be protected at C-14 as the t-butyldimethylsilyl ether by treatment with t-butyldimethylsilyl trifluoromethanesulfonate in methylene chloride to give the C-4'', 14-di-O-TBDMS macrolide. Treatment with toluenesulfonic acid in methanol results in selective removal of the C-4''silyl ether to give the C-14-O-TBDMS macrolide 8.
As shown in Reaction Scheme H, the 4''-hydroxy-3''-R.sup.2 O macrolide 9 or alternatively the 3''-hydroxy-4''-R.sup.2 O macrolide (not depicted ) (wherein R.sup.3 is protected hydroxy or hydrogen) may be reacted with an alkenyl trichloroacetimidate (wherein alkenyl is C.sub.314 10 alkenyl) under conditions described in Reaction Scheme E to give the O-alkenyl macrolide 10. Treatment with a stoichiometric amount of osmium tetroxide in an inert organic solvent, such as diethyl ether or tetrahydrofuran, in the presence of an amine base, such as pyridine, at or near room temperature gives the corresponding glycol 11 (wherein A is C.sub.1-8 alkyl). Treatment of glycol 11 with sodium metaperiodate in a solution of tetrahydrofuran/water gives aldehyde 12. Alternatively, the alkenyl macrolide 10 may be treated with sodium metaperiodate in the presence of a catalytic amount of osmium tetroxide in an organic solvent to give the aldehyde directly. Aldehyde 12 can be further oxidized to carboxylic acid 13 by any number of methods commonly used.
A variety of compounds may be prepared from aldehyde 12 as illustrated in Reaction Scheme H. Aldehyde 12 may be reacted with a primary or secondary amine, HNR.sup.6 R.sup.7 (wherein R.sup.6 and/or R.sup.7 are as defined and contain(s) a heteroaryl group) in an organic solvent such as tetrahydrofuran to give an imine which is reduced in situ with a hydride reducing agent, such as sodium cyanoborohydride, to give macrolide 1bearing an aminoalkoxy functionality at C-4''. Aidehyde 12 may also be reduced to the corresponding alcohol 15 by treatment with a hydride reducing agent, such as potassium triphenyl borohydride or sodium cyanoborohydride in an organic solvent such as tetrahydrofuran. Alcohol 15 may be further modified by utilizing the methods of Reaction Scheme B (wherein R.sup.1 is as defined) or Reaction Scheme E to produce macrolide 16. The procedures described in Reaction Scheme H are readily applicable to the preparation of compounds bearing analagous functionality at C-3''.
Amide derivatives may be prepared from the carboxylic acid 13 as illustrated in Reaction Scheme I. The carboxylic acid 13 may be coupled with a primary or secondary amine, HNR.sup.6 R.sup.7 (wherein R.sup.6 and/or R.sup.7 are as defined and contain(s) a heteroaryl group) by any of the peptide coupling methods commonly used in the art, such as with BOP reagent or DCC/HOBT.
A hydroxyl or fluoro group may be introduced at C-20 essentially by the procedures of Reaction Scheme J. As shown in Reaction Scheme R the 4'', 14-dihydroxy macrolide (or the 14-deoxymacrolide) is protected as the di(t-butyldimethylsilyl ether) by treatment with t-butyldimethylsilyl triflate in an inert organic solvent such as methylene chloride, chloroform or the like in the presence of a non-nucleophillic base such as 2,6-lutidine. The diprotected macrolide is oxidized at C-20 as further shown in Reaction Scheme J by treatment with selenium dioxide in an alcoholic solvent such as ethanol in the presence of pyridine at solvent reflux temperature to give the 20-hydroxy macrolide (18). The 20-hydroxy macrolide may be further derivatized at C-20 by alkylation, acylation or phosphorylation to give ether, ester or phosphate derivatives by procedures well known to the practitioner of the art. As further illustrated, treatment of the 20-hydroxy 4'', 14-di-OTBS macrolide with diethylaminosulfur trifluoride in an inert organic solvent such as methylene chloride, chloroform or the like at-a temperature of about 0.degree. C. to-90.degree. C., preferably about-78.degree. C., gives the 20-fluoro 4'', 14-di-OTBS macrolide (19). Removal of the silyl ether protecting groups by treatment with hydrogen fluoride-pyridine complex in tetrahydrofuran gives the 20 -fluoro 4'', 14-dihydroxy macrolide which may be further derivatized by any of the methods previously described. Reaction Scheme J may also be performed on the 3'', 4'', 14-trihydroxy macrolide to give the 20-fluoro 3'', 4'', 14-trihydroxy macrolide. The procedures of Reaction Scheme J may be conducted prior to, concurrent with, or subsequent to the procedures of Reaction Schemes A-I.
The object compounds of Formula I obtained according to the reactions as explained above can be isolated and purified in a conventional manner, for example, extraction, precipitation, fractional crystallization, recrystallization, chromatography, and the like.
In the compounds of Formula I, OR.sup.1 may be substituted at C-4''or C-3'', or both C-4''and C-3''(wherein R.sup.2 is independently selected from the definitions of R.sup.1), but it is preferred that -OR.sup.1 is substituted at C-4''.
It is to be noted that in the aforementioned reactions and the post-treatment of the reaction mixture therein, the stereoisomer(s) of starting and object compounds due to asymmetric carbon atom(s) or double bond(s) of the object compounds of Formula I may occasionally be transformed into the other stereo isomer(s), and such cases are also included within the scope of the present invention.
In the present invention, compounds of Formula I with asymmetric centers may occur as racemates, as diastereomeric mixtures and as individual diastereomers, with all isomeric forms of the compounds being included in the present invention. These may be prepared by methods such as those disclosed in publications which describe synthetic routes to fragments of the macrolide FR-900506 and the total synthesis of the macrolide FR-900506 itself (J. Am. Chem. Soc. 1989, 111, 1157; J. Am. Chem. Soc. 1990, 112, 2998; J. Org. Chem. 1990, 55, 2786; J. Am. Chem. Soc. 1990, 112, 5583. Tetrahedron Lett. 1988, 29, 277; Tetrahedron Lett. 1988, 29, 281; Tetrahedron Lett. 1988, 29, 3895; Org. Chem. 1988, 53, 4643; Tetrahedron Lett. 1988, 29, 4245; Tetrahedron Lett. 1988, 29, 4481; J. Org. Chem. 1989, 54, 9; J. Org. Chem. 1989, 54, 11; J. Org. Chem. 1989, 54, 12; J. Org. Chem. 1989, 54, 15; J. Org. Chem. 1989, 54, 17; Tetrahedron Lett. 1989, 30, 919; Tetrahedron Lett. 1989, 30, 1037; J. Org. Chem. 1989, 54, 2785; J. Org. Chem. 1989, 54, 4267; Tetrahedron Lett. 1989, 30, 5235; Tetrahedron Lett. 1989, 30, 6611; Tetrahedron Lett. 1989, 30, 6963; Synlett 1990, 38; J. Org. Chem. 1990, 55, 2284; Org. Chem. 1990, 55, 2771; J. Org. Chem. 1990, 55, 2776; Tetrahedron Lett. 1990, 31, 1439; Tetrahedron Lett. 1990, 31, 1443; Tetrahedron Lett. 1990, 3007; Tetrahedron Lett. 1990, 31, 3283, 3287).
The compounds of Formula I are capable of forming salts with various inorganic and organic acids and bases and such salts are also within the scope of this invention. Examples of such acid addition salts (which are negative counterions defined herein as M.sup.-) include acetate, adipate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, ethanesulfonate, fumarate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, methanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, oxalate, pamoate, persulfate, picrate, pivalate, propionate, succinate, tartrate, rosylate, and undecanoate. Base salts (which are positive counterions defined herein as M.sup.+) include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine and so forth. Also, the basic nitrogen-containing groups may be quaternized with such agents as: lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides: aralkyl halides like benzyl bromide and others. The non-toxic physiologically acceptable salts are preferred, although other salts are also useful, such as in isolating or purifying the product.
The salts may be formed by conventional means, such as by reacting the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is removed in vacuo or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion exchange resin.
The compounds of Formula I may be employed as immunosuppressants or antimicrobial compounds by methods and in dosages known in the prior art for compounds of Formula II. These compounds possess pharmacological activity such as immunosuppressive activity, antimicrobial activity, and the like, and therefore are useful for the treatment and prevention of the resistance to transplantation or transplantation rejection of organs or tissues (such as heart, kidney, liver, lung, bone marrow, cornea, pancreas, intestinum tenue, limb, muscle, nervus, medulla ossium, duodenum, small-bowel, medulla ossium, skin, pancreatic islet-cell, etc. including xeno transplantation), graft-versus-host diseases by medulla ossium transplantation, autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosis, nephrotic syndrome lupus, Hashimoto's thyroidiris, multiple sclerosis, myasthenia gravis, type I diabetes mellitus, type II adult onset diabetes, uveitis, nephrotic syndrome, steroid-dependent and steroid-resistant nephrosis, Palmo-planter pustulosis, allergic encephalomyelitis, glomerulonephritis, etc., and infectious diseases caused by pathogenic microorganisms.
The compounds of Formula I are also useful for treating inflammatory, proliferative and hyperproliferative skin diseases and cutaneous manifestations of immunologically-mediated illnesses such as: psoriasis, psoriatic arthritis, atopical dermatitis, contact dermatitis and further eczematous dermatitises, seborrhoeic dermatitis, Lichen planus, Pemphigus, bullous Pemphigoid, Epidermolysis bullosa, urticaria, angioedemas, vasculitides, erythemas, cutaneous eosinophilias, acne Alopecia areata, eosinophilic fasciitis, and atherosclerosis. More particularly, the compounds of Formula I are useful in hair revitalizing, such as in the treatment of male or female pattern alopecia or alopecia senilis, by providing epilation prevention, hair germination, and/or a promotion of hair generation and hair growth.
The compounds of Formula I are further useful in the treatment of respiratory diseases, for example sarcoidosis, fibroid lung, idiopathic interstitial pneumonia, and reversible obstructive airways disease, including conditions such as asthma, including bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma and dust asthma, particularly chronic or inveterate asthma (for example late asthma and airway hyperreponsiveness), bronchitis and the like. The compounds of Formula I may also be useful for treating hepatic injury associated with ischemia.
The compounds of the invention are also indicated in certain eye diseases such as keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, conical cornea, dystorphia epithelialis corneae, corneal leukoma, ocular pemphigus, Mooren's ulcer, Scleritis, Graves' ophthalmopathy, severe intraocular inflammation, and the like.
The compounds of Formula I are also useful for treating multidrug resistance of tumor cells, (i.e. enhancing the activity and/or sensitivity of chemotherapeutic agents), preventing or treating inflammation of mucosa or blood vessels (such as leukotriene B.sub.4 -mediated diseases, gastric ulcers, vascular damage caused by ischemic diseases and thrombosis, ischemic bowel disease, inflammatory bowel disease (e.g., Crohn's disease and ulcerative coliris) necrotizing enterocolitis), or intestinal lesions associated with thermal burns, cytomegalovirus infection, particularly HCMV infection.
Further, the compounds of Formula I are also useful for treating or preventing renal diseases including interstitial nephritis, Goodpasture's syndrome, hemolytic-uremic syndrome and diabetic nephropathy; nervous diseases selected from multiple myositis, Guillain-Barre syndrome, Meniere's disease and radiculopathy; endocrine diseases including hyperthyroidism and Basedow's disease; hematic diseases including pure red cell aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis and anerythroplasia; bone diseases including osteoporosis; respiratory diseases including sarcoidosis, fibroid lung and idiopathic interstitial pneumonia; skin diseases including dermato,myositis, leukoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity and cutaneous T cell lymphoma; circulatory diseases including arteriosclerosis, aortitis syndrome, polyarteritis nodosa and myocardosis; collagen including scleroderma, Wegener's granuloma and Sjogren's syndrome; adiposis; eosinophilic fasciitis; periodontal disease; nephrotic syndrome; hemolytic-uremic syndrome; and muscular dystrophy.
Further, the compounds of the invention are indicated in the treatment of diseases including intestinal inflammations/allergies such as Coeliac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease and ulcerative colitis; and food related allergic diseases which have symptomatic manifestation remote from the gastrointestinal tract, for example migraine, rhinitis and eczema.
The compounds of the invention also have liver regenerating activity and/or activity in stimulating hypertrophy and hyperplasia of hepatocytes. Therefore, they are useful for the treatment and prevention of hepatic diseases such as immunogenic diseases (e.g. chronic autoimmune liver diseases including autoimmune hepatitis, primary biliary cirrhosis and sclerosing cholangitis), partial liver resection, acute liver necrosis (e.g. necrosis caused by toxins, viral hepatitis, shock or anoxia), B-virus hepatitis, non-A/non-B hepatitis and cirrhosis.
The compounds of the invention are also indicated for use as antimicrobial agents, and thus may be used in the treatment of diseases caused by pathogenic microorganisms and the like.
The compounds of Formula I may also be useful in the prevention or treatment of immunodepression (such as AIDS, HIV infection, cancer, senile dementia, trauma (including wound healing, surgery and shock), chronic bacterial infection and certain central nervous system disorders), overdosages or toxicity of such immunosuppressive compounds, and as an adjunct to the administration of an antigen in vaccination.
The pharmaceutical compositions of this invention can be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains one or more of the compounds of the present invention, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications. The active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The carriers which can be used are water, glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form, and in addition auxiliary, stabilizing, thickening and coloring agents and perfumes may be used. For example, the compounds of Formula I may be utilized with hydroxypropyl methylcellulose essentially as described in U.S Pat. No. 4,916,138, issued Apr. 10, 1990, or with a surfactant essentially as described in EPO Publication 0,428,169. Oral dosage forms may be prepared essentially as described by T. Hondo, et al., Transplantation Proceedings, 1987, XIX, Supp. 6, 17-22. Dosage forms for external application may be prepared essentially as described in EPO Publication 0,423,714. The active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of diseases.
For the treatment of these conditions and diseases caused by immunoirregularity a compound of Formula I may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
For the treatment of reversible obstructive airways disease, it is preferable that the compound of Formula I be administered by inhalation to the lung, especially in the form of a powder.
For modifying the activity and/or toxicity of FK-506-type immunosuppressants, a compound of Formula I may be administered prior to, in conjuction with or subsequent to the administration of an FK-506-type of a compound.
The compounds of Formula I may optionally be employed in co-therapy with anti-proliferative agents. Particularly preferred is co-therapy with an antiproliferative agent selected from the group consisting of azathioprine (AZA), brequinar sodium, deoxyspergualin (DSG), mizaribine, mycophenolic acid morpholino ester (RS-61443), cyclosporin and rapamycin.
The compounds of Formula I may also be employed in conjunction with (or in a pharmaceutical composition additionally comprising):
Such co-therapy is particularly useful in hair revitalizing, such as in the treatment of male pattern alopecia, female pattern alopecia, alopecia senilis or alopecia areata, by providing epilation prevention, hair germination, and/or a promotion of hair generation and hair growth.
Such co-therapy is further useful in treating the hyperandrogenic conditions of androgenic alopecia, acne vulgaris, seborrhea, and female hirsutism.
For co-therapy of these conditions and diseases a compound of Formula I may be administered in combination with prior to, concurrent to, or subsequent to the administration of other agent(s).
For hair revitalizing the compound of Formula I may be administered topically or orally. Cyclosporin may be administered topically or orally. Although the 5a-reductase inhibitor or the potassium channel opener may be administered topically or orally, it is preferable that it be administered topically to the scalp. For unitary formulation, however, the preferred mode of administration is topically. It is especially preferred that the hair revitalizing composition of the present invention is administered by a percutaneous administration or by spraying onto the skin.
Dosage levels of the compounds of the present invention are of the order from about 0.005 mg to about 50 mg per kilogram of body weight per day, preferably from about 0.1 mg to about 10 mg per kilogram of body weight per day, are useful in the treatment of the above-indicated conditions (from about 0.7 mg to about 3.5 mg per patient per day, assuming a 70 kg patient). In addition, the compounds of the present invention may be administered on an intermittent basis; i.e. at daily, semiweekly, weekly, semi-monthly or monthly intervals.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration of humans may contain from 0.5 mg to 5 gm of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Dosage unit forms will generally comprise from about 0.01 mg to about 500 mg, and preferably about 0.5 mg to about 100 mg of active ingredient. For external administration the compound of Formula I may be formulated within the range of, for example, 0.0001% to 60% by weight, preferably from 0.001 to 10% by weight, and most preferably from about 0.005 to 0.8% by weight.
It will be understood, however, that the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
The following examples are given for the purpose of illustrating the present invention and shall not be construed as being limitations on the scope or spirit of the instant invention.
A solution of 500 mg of 17-ethyl-1,14-di -hydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl -11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]octacos-18-ene-2,3,10,16-tetraone in 7 ml of benzene was treated with 10 mg of p-toluenesulfonic acid and the solution was heated at 60.degree. C. for two hours. The reaction mixture was quenched into saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were washed with water and saturated sodium chloride solution, dried with anhydrous magnesium sulfate and concentrated. The residue was chromatographed on silica gel (66% ethyl acetate: 33% hexane: 1% methanol) to give 350 mg of product. This material was dissolved in 10 ml of ethyl acetate and treated with 15 mg of 5% Rh/C. A balloon containing hydrogen was placed over the reaction mixture and the mixture stirred until the reaction was complete. The mixture was filtered through diatomaceous earth, concentrated and the residue subjected to chromatography (75% CH.sub.2 Cl.sub.2 : 5% MeOH: 20% Hexane) to give 294 mg of product.
A solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa -4-azatricyclo-[22.3.1.0.sup.4,9 ]octacos-18-ene-2,3,10,16-tetraone (210 mg) and a catalytic amount of p-toluenesulfonic acid in 40 ml of benzene was refluxed for 4 hours under a nitrogen atmosphere. The solvent was removed under reduced pressure and the dark residue was purified by chromatography (silica gel, 7% i-propanol/CH.sub.2 Cl.sub.2) to give 17-ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-isopropyloxy-cyclohexyl) -1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo -[22.3.1.0.sup.4,9 ]octacos-14,18-diene-2,3,10,16-tetraone (180 mg) as a white solid. This material was dissolved in ethanol (20 ml) and treated with 5% Rh/C (40 mg). Hydrogen was introduced via balloon for 30 min. and the mixture was filtered through celite. Removal of solvent followed by chromatography (silica gel) gave 172 mg of the title compound. Mass, .sup.1 H and .sup.13 C NMR data were consistant with the title structure.
To a cooled solution (0.degree. C.) of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl) -1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetra -methyl-11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]-octacos-18-ene-2,3,10,16-tetraone (120 mg) in dry methylene chloride (15 ml) was added 2,6-lutidine (64.3 mg) followed by triisopropylsilyl trifluoro-methanesulfonate (184 mg). Reaction temperature was raised to r.t. and stirred overnight under nitrogen atmosphere. The reaction was quenched with 10 ml of water and extracted with ethyl acetate. Organic layer was washed (water, sat'd NaHCO.sub.3, sat'd NaCl) and dried (anhydrous MgSO.sub.4). Removal of solvent followed by chromatography on silica gel (70% hexane/ethyl acetate) gave 150 mg of product.
MASS: (FAB) 1110 (M.sup.+ +Li).
The title compound from the previous preparation (680 mg) was dissolved in methylene chloride (45 ml) and 10% solution of p-toluenesulfonic acid in methanol (45 ml) was added with stirring. The mixture was stirred at room temperature and the progress was followed by tlc analysis. After 4 hr, reaction was quenched with sat'd sodium bicarbonate and extracted with ethyl acetate three times. Normal work-up and removal of solvent followed by purification on silica gel column (80% ethyl acetate/hexane) gave 560 mg of the product (2a) as a white solid. MASS: (FAB) 954 (M.sup.+ +Li).
To a cooled solution (0.degree. C.) of 17-ethyl -1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclo -hexyl)-1'-methylvinyl ]-23,25-dimethoxy-13,19,21,27-tetra-methyl-11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]-octacos-18-ene-2,3,10,16-tetraone (1a) (395 mg) in dry methylene chloride (15 ml) was added 2,6-lutidine (160 mg) followed by t-butyldimethylsilyl triflouromethanesulfonate (250 mg). Reaction temperature was raised to r.t. and stirred under nitrogen atmosphere. After 6 hr, the reaction was quenched with 10 ml of water and extracted with ethyl acetate. Organic layer was washed (water, saturated NaHCO.sub.3, saturated NaCl) and dried (anhydrous MgSO.sub.4). Removal of solvent under reduced pressure gave 500 mg of crude product. MASS: (FAB) 1023 (M.sup.+ +Li).
The product from the previous example (500 mg) was dissolved in acetonitrile (20 ml) and 100 ml of hydrogen fluoride (48%) was added. Reaction was stirred for 20 minutes at room temperature, quenched with saturated sodium bicarbonate, then extracted with ethyl acetate. Removal of solvent in vacuo followed by chromatography on silica gel (80% ethyl acetate/hexane) gave 300 mg of product (Mass, .sup.1 H and .sup.13 C NMR data consistent with the title compound.
To a solution of 17-ethyl-1-hydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0.sup.4,9 ]octacos-18-ene-2,3,10,16-tetraone (3.01 g) in dry methyl ene chloride (70 ml) was added an excess of imidazole (809 mg) followed by tert-butyldimethylsilyl chloride (716 mg). After 3 days of stirring at room temperature, the mixture was diluted with ethyl acetate which in turn was washed with 1N HCl, saturated sodium bicarbonate and brine, dried over magnesium sulfate and purified by flash chromatography (ethyl acetae:hexane (1:3)) to give the title compound (941 mg). .sup.1 H NMR consistent with the desired structure.
To a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25 -dimethoxy-13,19,21,-27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]octacos-18-ene-2,3,10,16-tetraone (200 mg) in dry methylene chloride (3 ml) was added an excess of 2,6-lutidine (45 .mu.l) and the mixture was stirred at room temperature. After 10 minutes, tert-butyldimethylsilyl trifluoromethane-sulfonate (64 .mu.l) was added by syringe. After 15 minutes the reaction mixture was diluted with ethyl acetate, extracted from saturated bicarbonate, washed with brine and the organic phase dried over magnesium sulfate. Removal of solvent in vacuo and flash chromatography on silica gel (ethyl acetate: hexane (1:2)+1% methanol) gave the title compound (235 mg).
(.sup.1 H NMR consistent with the desired structure).
To a stirred solution of 17-ethyl-1-hydroxy -12-[2'-(4"-(tert-butyldimethylsilyloxy)-3"-methoxy -cyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21, 27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]octacos-18-ene-2,3,10,16-tetraone (235 mg) in 95% ethanol (2.2 ml) was added 53 .mu.l of pyridine followed by selenium dioxide (58 mg). The flask was fitted with a water condenser and heated to 70.degree. C. on a mantle. After 20 hours the mixture was cooled to room temperature filtered through diatomaceous earth and the filtrate poured into a saturated sodium bicarbonate solution. This was extracted with ethyl acetate, washed with brine and dried over magnesium sulfate. The solution was concentrated and purified by flash chromatography on silica gel (ethyl acetate: hexane (1:2)+1% methanol) to give the title compound (89 mg). (.sup.1 H NMR consistent with the desired structure).
A solution of 17-ethyl-20-dihydroxy-12-[2'-(4"-(tert-butyldimethylsiloxy)-3"-methoxycyclohexyl) -1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetra -methyl-11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]octacos -18-ene-2,3,10.16-tetraone (30.5 mg) in methylene chloride (0.5 ml) was cooled to -78.degree. C. in a dry ice/isopropanol bath. To this stiff ed solution, diethylaminosulfur trifluoride (4.5 .mu.l) was added. After 3 minutes, saturated sodium bicarbonate (500 .mu.l) was added followed by ethyl acetate (2 ml) and the mixture was warmed to room temperature. Extraction from ethyl acetate, drying over magnesium sulfate and purification by flash chromatography on silica gel (ethyl acetate: hexane (1:2)+1% MeoH) gave the title compound (22 mg). (.sup.1 H NMR consistent with the desired structure).
To a solution of 17-ethyl-1,20-dihydroxy -12-[2'-(4"-(tert-butyldimethylsiloxy)-3"-methoxy -cyclohexyl)-1'-methylvinyl]23,25-dimethoxy-13,19,21,27 -tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]-octacos-18-ene-2,3,10.16-tetraone (7 mg) in acetonitrile (0.3 ml) was added a solution of 2% hydrogen fluoride in aqueous acetonitrile (100 .mu.l), and the mixture stirred at room temperature. After 28 hours the solution was diluted with ethyl acetate, extracted with saturated sodium bicarbonate and the organic phase dried by passage through a magnesium sulfate column. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate: hexane (2:1)+1% methanol) gave the title compound.
To a solution of 17-ethyl-20-fluoro-1-hydroxy-12-[2'-(4"-(tert-butyldimethylsiloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]23,25-dimethoxy -13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo -[22.3.1.0.sup.4,9 ]octacos-18-ene-2,3,10.16-tetraone (7 mg) in acetonitrile (0.3 ml) was added a solution of 2% hydrogen fluoride in aqueous acetonitrile (100 .mu.l), and the mixture stirred at room temperature. After 2 hours the solution was diluted with ethyl acetate, extracted with saturated sodium bicarbonate and the organic phase dried by passage through a magnesium sulfate column. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate: hexane (1:1)+1% methanol) gave the title compound.
MASS: (FAB) 816 (M+Na).
partial .sup.13 C NMR .delta.: 211.5 (C-16); 196.1 (2) 169.3
(10); 165.0 (3); 138.1 (C-19); 135.8 (C-1');
121.0 (C-18'major); 84.1 (C-3"); 43.1
(C-15); 26.0 (C-21).
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa -4-azatricyclo[22.3.1.0.sup.4,9 ]octacos-18-ene-2,3,10,16-tetraone (5.15 gm, 0.065 mol) in glacial acetic acid (500 ml) at room temperature, was added a solution of selenium dioxide (9.27 gm, 0.083 mol) in H.sub.2 O (90 ml). The reaction mixture was stirred at room temperature for 41 hours whereupon, it was poured into a stirred mixture of H.sub.2 O (3L) and celite. After stir ring for 15 minutes, the mixture was filtered through a pad of celite and extracted with diethyl ether (1.times.2 L, 2.times.1 L). The organic fractions were washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, filtrated and evaporated in vacuo. The product was purified by chromatography (silica, acetone:hexanes 2:5) to give the title compound MASS and .sup.1 H NMR were consistent with the structure.
US Referenced Citations (10)
Continuation in Parts (2)
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Number |
Date |
Country |
| Parent |
921851 |
Aug 1992 |
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| Parent |
756946 |
Sep 1991 |
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Patent Grant
5349061
