Indole derivatives which inhibit leukotriene biosynthesis

TECHNICAL FIELD
This invention relates to compounds having pharmacological activity, to pharmaceutical compositions containing such compounds and to medical methods of treatment. More particularly, the present invention concerns certain substituted indole urea, oxime, acetamide and hydroxamic acid compounds, pharmaceutical compositions containing the compounds, and to a method of treating disease states which involve leukotrienes and other metabolic products resulting from the action of 5-lipoxygenase on arachidonic acid.
BACKGROUND OF THE INVENTION
5-Lipoxygenase is the first dedicated enzyme in the pathway leading to the biosynthesis of leukotrienes. This important enzyme has a rather restricted distribution, being found predominantly in leukocytes and mast cells of most mammals. Normally 5-lipoxygenase is present in the cell in an inactive form; however, when leukocytes respond to external stimuli, intracellular 5-lipoxygenase can be rapidly activated. This enzyme catalyzes the addition of molecular oxygen to fatty acids with cis,cis-1,4-pentadiene structures, converting them to 1-hydroperoxy-trans,cis-2,4-pentadienes. Arachidonic acid, the 5-lipoxygenase substrate which leads to leukotriene products, is found in very low concentrations in mammalian cells and must first be hydrolyzed from membrane phospholipids through the actions of phospholipases in response to extracellular stimuli. The initial product of 5-lipoxygenase action on arachidonate is 5-hydroperoxyeicosatetraenoic acid (5-HPETE) which can be reduced to 5-hydroxyeicosatetraenoic acid (5-HETE) or converted to leukotriene A.sub.4 (LTA.sub.4). This reactive leukotriene intermediate is enzymatically hydrated to leukotriene B.sub.4 (LTB.sub.4) or conjugated to the tripeptide, glutathione, to produce leukotriene C.sub.4 (LTC.sub.4). LTA.sub.4 can also be hydrolyzed nonenzymatically to form two isomers of LTB.sub.4. Successive proteolytic cleavage steps convert LTC.sub.4 to leukotrienes D.sub.4 and E.sub.4 (LTD.sub.4 and LTE.sub.4). Other products resulting from further oxygenation steps have also been described in the literature. Products of the 5-lipoxygenase cascade are extremely potent substances which produce a wide variety of biological effects, often in the nanomolar to picomolar concentration range.
The remarkable potencies and diversity of actions of products of the 5-lipoxygenase pathway have led to the suggestion that they play important roles in a variety of diseases. Alterations in leukotriene metabolism have been demonstrated in a number of disease states including asthma, allergic rhinitis, rheumatoid arthritis, gout, psoriasis, adult respiratory distress syndrome, inflammatory bowel disease, endotoxin shock syndrome, atherosclerosis, ischemia induced myocardial injury, and central nervous system pathology resulting from the formation of leukotrienes following stroke or subarachnoid hemorrhage.
The enzyme 5-lipoxygenase catalyzes the first step leading to the biosynthesis of all the leukotrienes and therefore inhibition of this enzyme provides an approach to limit the effects of all the products of this pathway. Compounds which inhibit 5-lipoxygenase are thus useful in the treatment of disease states such as those listed above in which the leukotrienes play an important role.
U.S. Pat. No. 3,859,305 to Posselt, et al. discloses certain indole aminoketones which are useful as cardiovascular agents.
U.S. Pat. No. 3,931,229 to Zinnes, et al. discloses and claims certain 3-thiomethyl-(2-[2-(dialkylamino)ethyl]indoles having utility as central nervous system depressants and anti-aggression agents.
U.S. Pat. No. 4,021,448 to Bell discloses and claims certain 2-substituted-indole-1-(lower alkane)carboxamides having utility for decreasing gastric secretions and as anti-ulcer agents.
U.S. Pat. No. 4,119,638 to Ray discloses and claims certain thioesters of 1-(4-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid useful as antiinflammatory agents.
U.S. Pat. No. 4,464,379 to Betzing, et al. discloses and claims certain 1-(4-chlorobenzoyl)-2-methyl-5-methoxyindole-3-acetic acid derivatives having antithrombic, antiarteriosclerotic, and antiphlogistic activity.
European Patent Application 87 311031.6 (Publication No. 0 275 667) to Gillard, et al. discloses and claims certain 3-(hetero-substituted)-N-benzylindoles as leukotriene biosynthesis inhibitors.
S. Raucher, et al., in "Indole Alkaloid Synthesis via Claissen Rearrangement," J. Am. Chem. Soc., 103(9): 2419-2412 (1981), disclose certain 1H-indole-2-acetic acid derivatives.
Kobayashi, et al., in "Indole Derivatives XII. Reaction of Indole-2-carboxylic Acid Derivatives with Carbon Disulfide," Yakugaku Zasshi, 91(11): 1164-1173 (1971) (in Japanese; Chemical Abstracts English-language abstract: CA76: 46033k (1972)), disclose the synthesis of certain 1-methyl-2-carboxamido-3-(dithioester)indoles.
SUMMARY OF THE INVENTION
It has been found, in accordance with the present invention that certain substituted indolyl compounds are effective inhibitors of leukotriene biosynthesis and are thus useful for the treatment or amelioration of inflammatory disease states in which the leukotrienes play a role. In one embodiment of the present invention, there are provided compounds of Formula I: ##STR2## or a pharmaceutically acceptable salt, ester, or amide thereof.
In the compounds of this invention, A is selected from the group consisting of straight or branched divalent alkylene of from one to twelve carbon atoms, straight or branched divalent alkenylene of from two to twelve carbon atoms, and divalent cycloalkylene of from three to eight carbon atoms.
The substituent group R.sup.1 is selected from the group consisting of hydrogen; alkylthio of from one to six carbon atoms; phenylthio; phenylalkylthio in which the alkyl portion contains from one to six carbon atoms; 2-, 3-, and 4-pyridylthio; 2- and 3-thienylthio; 2-thiazolylthio; and a group having the structure ##STR3## with the proviso that when R.sup.1 is --C(O)(CH.sub.2).sub.n NHC(O)N(OM)R.sup.5, then R.sup.2 is selected from --COOH, --COO.sup.- B.sup.+ where B is a pharmaceutically acceptable cation, and --COO(alkyl) where the alkyl group is of from one to six carbon atoms. In the foregoing definition of R.sup.1, the phenyl ring of the phenylthio or phenylalkylthio groups are optionally substituted with one or two groups selected from alkyl of from one to six carbon atoms, haloalkyl of from one to six carbon atoms, alkoxy of from one to twelve carbon atoms, hydroxy and halogen.
The substituent group R.sup.2 is selected from the group consisting of ##STR4##
In the foregoing definitions of R.sup.2, n is an integer of from one to four, and R.sup.5 is selected from the group consisting of
(1) alkyl of from one to six carbon atoms,
(2) hydroxyalkyl of from one to six carbon atoms,
(3) phenylalkyl in which the alkyl portion contains from one to six carbon atoms,
(4) alkoxyalkyl in which the alkoxy and alkyl portions each, independently, contain from one to six carbon atoms,
(5) phenoxyalkyl in which the alkyl portion contains from one to six carbon atoms,
(6) (alkoxyalkoxyl)alkyl in which each alkoxy portion, independently, contains from one to six carbon atoms, and the alkyl portion contains from one to six carbon atoms,
(7) (alkoxycarbonyl)alkyl in which the alkoxycarbonyl portion contains from two to six carbon atoms and the alkyl portion contains from one to six carbon atoms,
(8) (aminocarbonyl)alkyl in which the alkyl portion contains from one to six carbon atoms,
(9) ((alkylamino)carbonyl)alkyl in which each alkyl portion independently contains from one to six carbon atoms,
(10) ((dialkylamino)carbonyl)alkyl in which each alkyl portion independently contains from one to six carbon atoms,
(11) 2-, 3-, and 4-pyridylalkyl in which the alkyl portion contains from one to six carbon atoms,
(12) (2-furyl)alkyl in which the alkyl portion contains from one to six carbon atoms,
(13) (3-thienyl)alkyl in which the alkyl portion contains from one to six carbon atoms,
(14) (2-benzo[b]thienyl)alkyl in which the alkyl portion contains from one to six carbon atoms,
(15) (2-benzo[b]furyl)alkyl in which the alkyl portion contains from one to six carbon atoms,
(16) (5-(1,2,4-triazolyl))alkyl in which the alkyl portion contains from one to six carbon atoms,
(17) (2-imidazolyl)alkyl in which the alkyl portion contains from one to six carbon atoms,
(18) (2-thiazolyl)alkyl in which the alkyl portion contains from one to six carbon atoms,
(19) (2-pyrimidyl)alkyl in which the alkyl portion contains from one to six carbon atoms, and
(20) (5-tetrazolyl)alkyl in which the alkyl portion contains from one to six carbon atoms.
In the foregoing definition of R.sup.2, the substituent group R.sup.6 is, at each occurrence, selected from hydrogen, and alkyl of from one to six carbon atoms and the substituent group R.sup.7 is selected from the group consisting of
(1) alkyl of from one to six carbon atoms,
(2) hydroxyalkyl of from one to six carbon atoms,
(3) phenylalkyl in which the alkyl portion contains from one to six carbon atoms,
(4) ((carboxy)phenyl)alkyl in which the alkyl portion contains from one to six carbon atoms,
(5) alkoxylalkyl in which the alkoxy and alkyl portions each, independently, contain from one to six carbon atoms,
(6) phenoxyalkyl in which the alkyl portion contains from one to six carbon atoms,
(7) (carboxyl)alkyl in which the alkyl portion contains from one to six carbon atoms,
(8) (C-malanato)alkyl in which the alkyl portion contains from one to six carbon atoms,
(9) (C-(dialkylmalanato))alkyl in which each alkyl portion, independently, contains from one to six carbon atoms,
(10) (alkoxyalkoxyl)alkyl in which each alkoxy portion, independently, contains from one to six carbon atoms, and the alkyl portion contains from one to six carbon atoms,
(11) (alkoxycarbonyl)alkyl in which the alkoxycarbonyl portion contains from two to six carbon atoms and the alkyl portion contains from one to six carbon atoms,
(12) ((N-alkyl-N-hydroxyamino)carbonyl)alkyl in which each alkyl portion, independently, contains from one to six carbon atoms,
(13) (aminocarbonyl)alkyl in which the alkyl portion contains from one to six carbon atoms,
(14) ((alkylamino)carbonyl)alkyl in which each alkyl portion independently contains from one to six carbon atoms,
(15) ((dialkylamino)carbonyl)alkyl in which each alkyl portion independently contains from one to six carbon atoms,
(16) (N-morpholinyl)alkyl in which the alkyl portion contains from one to six carbon atoms,
(17) (N-thiomorpholinyl)alkyl in which the alkyl portion contains from one to six carbon atoms,
(18) (N-piperidinyl)alkyl in which the alkyl portion contains from one to six carbon atoms,
(19) (N-piperazinyl)alkyl in which the alkyl portion contains from one to six carbon atoms,
(20) 2-, 3-, and 4-pyridylalkyl in which the alkyl portion contains from one to six carbon atoms,
(21) (2-furyl)alkyl in which the alkyl portion contains from one to six carbon atoms,
(22) (3-thienyl)alkyl in which the alkyl portion contains from one to six carbon atoms,
(23) (2-benzo[b]thienyl)alkyl in which the alkyl portion contains from one to six carbon atoms,
(24) (2-benzo[b]furyl)alkyl in which the alkyl portion contains from one to six carbon atoms,
(25) (5-(1,2,4-triazolyl))alkyl in which the alkyl portion contains from one to six carbon atoms,
(26) (2-imidazolyl)alkyl in which the alkyl portion contains from one to six carbon atoms,
(27) (2-thiazolyl)alkyl in which the alkyl portion contains from one to six carbon atoms,
(28) (2-pyrimidyl)alkyl in which the alkyl portion contains from one to six carbon atoms, and
(29) (5-tetrazolyl)alkyl in which the alkyl portion contains from one to six carbon atoms.
The group M is selected from the group consisting of hydrogen, a pharmaceutically acceptable cation, and a pharmaceutically acceptable metabolically cleavable group.
R.sup.3 is selected from the group consisting of phenylalkyl in which the alkyl portion contains from one to six carbon atoms; and heteroarylalkyl in which the alkyl portion contains from one to six carbon atoms and the heteroaryl group is selected from the group consisting of 2-, 3- and 4-pyridyl, 2- and 3-thienyl, 2- and 3-furyl, indolyl, pyrazinyl, isoquinolyl, quinolyl; imidazolyl, pyrrolyl, pyrimidyl, benzofuryl, benzothienyl, thiazolyl; and carbazolyl.
In the foregoing definition of R.sup.3, the rings of the phenylalkyl or heteroarylalkyl groups are optionally substituted with one or two groups selected from alkyl of from one to six carbon atoms; alkoxy of from one to twelve carbon atoms; phenyl, optionally substituted with alkyl of from one to six carbon atoms, haloalkyl of from one to six carbon atoms, alkoxy of from one to six carbon atoms, hydroxy, or halogen; phenoxy, optionally substituted with alkyl of from one to six carbon atoms, haloalkyl of from one to six carbon atoms, alkoxy of from one to six carbon atoms, hydroxy, or halogen; 2-, 3-, or 4-pyridyl, optionally substituted with alkyl of from one to six carbon atoms, haloalkyl of from one to six carbon atoms, alkoxy of from one to six carbon atoms, hydroxy, or halogen; and 2-, 3-, or 4-pyridyloxy, optionally substituted with alkyl of from one to six carbon atoms, haloalkyl of from one to six carbon atoms, alkoxy of from one to six carbon atoms, hydroxy, or halogen; and --(CH.sub.2).sub.n N(OH)C(O)NR.sup.5 R.sup.6 ; and --(CH.sub. 2).sub.n N(R.sup.5)C(O)N(OM)R.sup.6 ; with the proviso that when R.sup.3 is --(CH.sub.2).sub.n N(OH)C(O)NR.sup.5 R.sup.6 or --(CH.sub.2).sub.n N(R.sup.6)C(O)N(OM)R.sup.6, then R.sup.2 is selected from --COOH, --COO.sup.- B.sup.+ where B is a pharmaceutically acceptable cation, and --COO(alkyl) where the alkyl group is of from one to six carbon atoms.
In the compounds of this invention, R.sup.4 is selected from the group consisting of alkyl of from one to six carbon atoms; alkoxy of from one to twelve carbon atoms; phenyl; and phenoxy; in which the phenyl or phenoxy groups are optionally substituted with alkyl of from one to six carbon atoms, haloalkyl of from one to six carbon atoms, alkoxy of from one to six carbon atoms, hydroxy, or halogen.
In another embodiment of this invention, there are provided pharmaceutical compositions which comprise a therapeutically effective amount of a compound as defined above in combination with a pharmaceutically acceptable carrier.
In yet another embodiment of this invention, there is provided a method of inhibiting lipoxygenase enzymes in a mammal in need of such treatment comprising administering a therapeutically effective amount of a compound as defined above.
DETAILED DESCRIPTION AND PREFERRED EMBODIMENTS
As used throughout this specification and the appended claims, the term "alkyl" refers to a monovalent group derived from a straight or branched chain saturated hydrocarbon by the removal of a single hydrogen atom. Alkyl groups are exemplified by methyl, ethyl, n- and iso-propyl, n-, sec-, iso- and tert-butyl, and the like.
The term "alkylene" denotes a divalent group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms, for example methylene, 1,2-ethylene, 1,1-ethylene, 1,3-propylene, and the like.
The term "alkenyl" denotes a monovalent group derived from a hydrocarbon containing at least one carbon-carbon double bond by the removal of a single hydrogen atom. Alkenyl groups include, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl and the like.
The term "alkenylene" denotes a divalent group derived from a straight or branched chain hydrocarbon containing at least one carbon-carbon double bond. Examples of alkenylene include --CH.dbd.CH--, --CH.sub.2 CH.dbd.CH--, --C(CH.sub.3).dbd.CH--, --CH.sub.2 CH.dbd.CHCH.sub.2 --, and the like.
The term "cycloalkylene" refers to a divalent group derived from a saturated carbocyclic hydrocarbon by the removal of two hydrogen atoms, for example cyclopropylene, cyclopentylene, cyclohexylene, and the like.
The term "alkylthio" denotes an alkyl group, as defined above, attached to the parent molecular moiety through a sulfur atom.
The terms "heterocyclic aryl" and "heteroaryl" as used herein refers to substituted or unsubstituted 5- or 6-membered ring aromatic groups containing one, two or three nitrogen atoms, one nitrogen and one sulfur atom, or one nitrogen and one oxygen atom. The term heteroaryl also includes bi- or tricyclic groups in which the aromatic heterocyclic ring is fused to one or two benzene rings. Representative heteroaryl groups are pyridyl, thienyl, furyl, indolyl, pyrazinyl, isoquinolyl, quinolyl, imidazolyl, pyrrolyl, pyrimidyl, benzofuryl, benzothienyl, carbazolyl, and the like.
The term "metabolically cleavable group" denotes a group which is cleaved in vivo to yield the parent molecule in which M is hydrogen. Examples of metabolically cleavable groups include --COR, --COOR, --CONRR and --CH.sub.2 OR radicals where R is selected independently at each occurrence from alkyl, trialkylsilyl, carbocyclic aryl or carbocyclic aryl substituted with one or more of C.sub.1 -C.sub.4 alkyl, halogen, hydroxy or C.sub.1 -C.sub.4 alkoxy. Representative metabolically cleavable groups include acetyl, methoxycarbonyl, benzoyl, methoxymethyl and trimethylsilyl groups.
The term "hydroxyalkyl" means an alkyl group as defined above, having one, two or three hydrogen atoms replaced by hydroxyl groups, with the proviso that no more than one hydroxy group may be attached to a single carbon atom of the alkyl group.
The term "phenylalkyl" denotes a phenyl group attached to the parent molecular moiety through an alkylene group.
"Alkoxy" means an alkyl group, as defined above, attached to the parent molecular moiety through an oxygen atom. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like.
"Alkoxyalkyl" means an alkoxy group, as defined above, attached to the parent molecular moiety through an alkylene group.
The term "phenoxy" represents a phenyl group attached to the parent molecular moiety through an oxygen atom.
The term "phenoxyalkyl" denotes a phenoxy group attached to the parent molecular moiety through an alkylene group. Typical phenoxyalkyl groups include phenoxymethyl, phenoxyethyl, and the like.
"(Alkoxyalkoxy)alkyl stands for a group in which an alkoxy group, as defined above is attached through its oxygen atom to a second alkoxy group which, in turn, is attached through an alkylene group to the parent molecular moiety. Representative (alkoxyalkoxy)alkyl groups include methoxymethoxymethyl, methylethoxymethyl, ethoxyethoxymethyl, and the like.
The term "(alkoxycarbonyl)alkyl denotes an ester group (--COOalkyl)) attached through an alkylene group to the parent molecular moiety, for example, ethoxycarbonylmethyl, ethoxycarbonylethyl, and the like.
The terms "(aminocarbonyl)alkyl," "(alkylaminocarbonyl)alkyl," and "(dialkylaminocarbonyl)Alkyl" mean, respectively, an amino group, or an amino group substituted by one or two alkyl groups, as defined above, attached through a carbonyl group and thence through an alkylene group to the parent molecular moiety. Representative groups of this type include --(CH.sub.2)C(O)NH.sub.2, --(CH.sub.2)C(O)NHCH.sub.3, --(CH.sub.2)C(O)N(CH.sub.3).sub.2 and the like.
The term "(C-malanato)alkyl" represents a malonic acid group, attached through its methylene carbon to the parent molecular moiety through an alkylene group; i.e. a group of the formula ##STR5## Similarly, the term "(C-(dialkylmalanato))alkyl represents a malonic acid group in which the two acid functional groups have been esterified with alkyl groups, attached to the parent molecular moiety at its methylene carbon through an alkylene group.
The term "((N-alkyl-N-hydroxyamino)carbonyl)alkyl" stands for a group of the formula ##STR6## in which "alkylene" and "alkyl" are as defined above.
The compounds of the present invention comprise a class of substituted indoles in which the 3-position is substituted by an alkylthio group or an ##STR7## (N-hydroxyamido)alkylcarbonyl group of the formula ##STR8## in which n is an integer of from one to four, M is as previously defined, and R.sup.5 is hydrogen or lower alkyl. Preferred compounds of the present invention are those in which the 3-position substituent is alkylthio.
The 2-position of the indole nucleus of the compounds of the present invention is substituted with a urea, N-hydroxyurea, hydroxamate, guanidyl, or hydroximino group, any of which may be further substituted. These groups are attached to the indole nucleus through an alkylene, alkenylene, or cycloalkylene spacing group. Preferred compounds of the present invention are those in which the substituent at the 2-position of the indole nucleus is selected from N-hydroxyurea groups of the structures ##STR9##
The 1-position of the indole nucleus of compounds of this invention is substituted by an alkyl-substituted carbocyclic aromatic group, an alkyl-substituted heteroaryl group, an N-hydroxyurea of the structure --(CH.sub.2).sub.n N(OH)C(O)NR.sup.5 R.sup.6 or --CH.sub.2).sub.n N(R.sup.5)C(O)N(OH)R.sup.6, where R.sup.5 at each occurrence selected from hydrogen and lower alkyl and R.sup.6 has the values defined above. The integer, n, is 1 to 4, inclusive. Preferred compounds of the present invention are those where the substituent at position 1 of the indole nucleus is benzyl or benzyl substituted by C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, phenoxy, halogen, or hydroxy.
Specific examples of compounds contemplated as falling within the scope of this invention include, but are not limited to the following examples:
N'-hydroxy-N'-methyl-N-2-[2-methyl-3-(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl)]propyl urea
2,2-dimethyl-3-[1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl]propionaldehyde oxime
N-hydroxy-N-2,2-dimethyl-3-[(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl))indol-2-yl]propyl urea
N'-hydroxy-N'methyl-N-2-[(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl))indol-2-yl]ethyl urea
N-2,2-dimethyl-3-[(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethyl-thio)-5-(1-methylethyl))indol-2-yl]propyl urea
N'-hydroxy-N'-methyl-N-2-[3-(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl)-2,2-dimethylpropionylamino]ethyl urea
1-(4-chlorophenylmethyl)-2-[2,2-dimethyl-3-((3-hydroxypropyl)-amino)propyl]-3-(1.1-dimethylethylthio)-5-(1-methylethyl)indole
N-2-[2-methyl-3-(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl)]propyl urea
3-[3-(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl)-2-aminocarbonylamino-2-methylpropyl]propanoic acid, ethyl ester
3-[3-(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl)-2-aminocarbonylamino-2-methylpropyl]propanoic acid
N'-hydroxy-N'-methyl-N-[1-(4-chlorophenylmethyl)-5-(1-methylethyl)-2-((2-methyl-2-ethoxycarbonyl)propyl)indol-2-yl]-3-oxopropylurea
1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-2-[3-(2,2-dimethyl-1-guanidinylimino)propyl]-5-(1-methylethyl)indole
3-[3-(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl)-2-aminocarbonylamino-2-methylpropyl]propanoic acid, sodium salt
N-hydroxy-N-[trans-2-(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl)cyclopropyl]methylurea
3-[3-(1,1-dimethylethylthio)-5-(1-methylethyl)-1-(4-pyridinylmethyl)indol-2-yl]-2,2-dimethylpropanoic acid
3-[3-(1,1-dimethylethylthio)-5-(1-methylethyl)-1-(2-thienylmethyl)indol-2-yl]-2,2-dimethylpropanoic acid
N-hydroxy-N-trans-[3-(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl)]prop-2-enylurea
N-[3-(1-(4-chorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl)-2,2-dimethylpropyl]acetohydroxamic acid
N-hydroxy-N-3-[3-(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl)-2,2-dimethylpropionylamino]propyl urea
3-[1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl]-2,2-dimethylpropionaldehyde oxime-O-2-acetic acid
2-(3-amino-2,2-dimethylpropyl)-1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indole
N-[3-(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl)-2,2-dimethylpropyl]acetamide
N-[trans-2-(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl)cyclopropyl]methyl urea
N'-hydroxy-N-3-[3-(1,1-dimethylethylthio)-5-(1-methylethyl)-2-((2-methyl-2-ethoxycarbonyl)propyl)indol-1-yl]propyl urea
Certain compounds of this invention may exist in geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis-and trans- geometric isomers, R- and S-enantiomers, diastereomers, and mixtures thereof as falling within the scope of the invention. If a particular enantiomer is desired, it may be prepared by chiral synthesis or by derivatization with a chiral auxiliary where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group such as amino or an acidic functional group such as carboxyl, diastereomeric salts are formed with an appropriate optically active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art and subsequent recovery of the pure enantiomers.
Certain compounds of the present invention may contain a basic functional group such as amino, alkylamino, or dialkylamino and are thus capable of forming salts with pharmaceutically acceptable acids. The term "pharmaceutically acceptable salts" in this respect, refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, laurylsulphonate salts and the like. (See, for example S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 66: 1-19 (1977) which is incorporated herein by reference.)
In other cases, the compounds may contain one or more acidic functional groups such as carboxyl and the like and are capable of forming salts with pharmaceutically acceptable bases. The term "pharmaceutically acceptable salts" in these instances refers to the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention. These salts can be likewise prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free acid form with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia, or an organic primary, secondary, or tertiary amine. Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. (See, for example S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 66: 1-19 (1977) which is incorporated herein by reference.)
SYNTHESIS OF THE COMPOUNDS
The compounds of the present invention are synthesized by the following general synthetic routes. One general method for the synthesis of intermediate indoles used to prepare compounds of this invention, shown in Reaction Scheme 1, employs the Fischer indole synthesis (cf. Advanced Organic Chemistry, Reactions, Mechanisms, and Structure, 3rd Ed. by J. March, John Wiley and Sons, 1985, p. 1032). In this method a hydrazine I is reacted with ketone II in a suitable solvent at a temperature between 20.degree. C. and the refluxing temperature of the chosen solvent to provide the indole product III. The intermediate indole III is subsequently transformed by the procedures described for individual examples to provide the final products of this invention. ##STR10##
Another general method illustrated in Reaction Scheme 2, involves the reaction of hydrazine intermediate IV with the ketone intermediate V to provide the indole intermediate VI. The intermediate VI is then treated under basic conditions with a halogenated alkylaryl compound VII, where aryl is a heteroaryl group such as furanyl, thienyl, pyridyl, pyrimidyl, thiazoyl, benzothiazolyl, benzothiophenyl, benzofuranyl, or substituted phenyl. ##STR11##
INHIBITION OF LEUKOTRIENE BIOSYNTHESIS IN VITRO
Inhibition of leukotriene biosynthesis by representative compounds of the present invention was evaluated in assays involving calcium ionophore-induced LTB.sub.4 biosynthesis expressed by human polymorphonuclear leukocytes (PMNL) or human whole blood. Human PMNL were isolated from heparinized (20 USP units/mL) venous blood using Ficoll-Hypaque Mono-Poly Resolving Medium. Human PMNL suspensions (5.times.10.sup.6 cells/250 .mu.L) were preincubated with test compounds or vehicle for 15 min at 37.degree. C. followed by calcium ionophore A23187 challenge (final concentration of 8.3 .mu.M) and the reaction terminated after 10 min by adding two volumes of methanol containing prostaglandin B.sub.2 as an internal recovery standard. The methanol extracts were analyzed for LTB.sub.4 content by HPLC or radioimmunoassay.
The assay using human heparinized whole blood was incubated for 30 minutes at 37.degree. C. after adding 50 .mu.M of ionophore A23187. The plasma layer was obtained by centrifugation and deproteinized by the addition of four volumes of methanol. The methanol extract was analyzed for LTB.sub.4 by HPLC or radioimmunoassay.
The inhibitory activity of representative examples is shown in Table 1.
TABLE 1______________________________________Inhibition of LTB.sub.4 Biosynthesis in Human PMNL andHuman Whole Blood Human PMNL Human Whole BloodExample IC.sub.50 (.mu.M) IC.sub.50 (.mu.M)______________________________________ 1 0.15 1.3 2 0.27 2.2 3 0.17 1.6 4 0.57 6.7 5 0.18 0.71 6 0.15 1.2 6.2 0.31 1.4 7 4.2 6.9 8 0.4 5.2 9 77% @ 1.6 5.610 70% @ 1.6 2.511 1.5 6.912 100% @ 3.1 1.313 -- 3.014 40% @ 0.78 2.515 0.09 0.916 -- 5.520 -- 0.6821 -- 1.122 -- 2.123 0.4 2.724 1.1 --______________________________________
INHIBITION OF LEUKOTRIENE BIOSYNTHESIS IN VIVO
Inhibition of the biosynthesis of leukotrienes in vivo after oral administration of compound was determined using a rat peritoneal anaphylaxis model in a similar manner as that described by Young and coworkers (Young, P. R.; Dyer, R. D.; Carter, G. W. Fed. Proc., Fed. Am. Soc. Exp. Biol. 1985, 44, 1185). In this model rats were injected intraperitoneally (ip) with rabbit antibody to bovine serum albumin (BSA) and three hours later injected ip with BSA to induce an antigen-antibody response. Rats were sacrificed 15 minutes after this challenge and the peritoneal fluids were collected and analyzed for leukotriene levels. Test compounds were administered by gavage one hour prior to the antigen challenge. Percent inhibition values were determined by comparing the treatment group to the mean of the control group. Compounds of this invention are orally effective in preventing the in vivo biosynthesis of leukotrienes as illustrated for representative examples shown in Table 2.
TABLE 2______________________________________Inhibition of Leukotriene (LT) Biosynthesis In Vivo Percent Leukotriene inhibition atExample 100 .mu.mol/kg oral dose______________________________________2 46%3 68%5 86%6 86%20 99%______________________________________
PHARMACEUTICAL COMPOSITIONS
The present invention also provides pharmaceutical compositions which comprise one or more of the compounds of formula I above formulated together with one or more non-toxic pharmaceutically acceptable carriers. The pharmaceutical compositions may be specially formulated for oral administration in solid or liquid form, for parenteral injection, or for rectal or vaginal administration.
The pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, or as an oral or nasal spray. The term "parenteral" administration as used herein refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.
Pharmaceutical compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
These compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like, Prologned absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
In some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides) Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.
Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers, or propellants which may be required. Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active compound(s) that is effective to achieve the desired therapeutic response for a particular patient, compositions, and mode of administration. The selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated, and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required for to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
Generally dosage levels of about 1 to about 50, more preferably of about 5 to about 20 mg of active compound per kilogram of body weight per day are administered orally to a mammalian patient. If desired, the effective daily dose may be divided into multiple doses for purposes of administration, e.g. two to four separate doses per day.

The following examples are presented to enable one skilled in the art to practice the present invention. These examples are merely illustrative and should not be read as limiting the invention as it is defined by the appended claims.
EXAMPLE 1
Preparation of N'-hydroxy-N'-methyl-N-2-[2-methyl-3-(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl)]propyl urea ##STR12##
Compound 1.1 was prepared by adaptation of the procedure reported in EPA 87311031.6. To a stirring benzene (7.4 mL) solution of Compound 1.1 (525 mg, 1.11 mmol), triethylamine (0.16 mL, 1.17 mmol) and diphenylphosphorylazide (0.25 mL, 1.11 mmol) were added. The reaction was refluxed for one hour; N-methylhydroxylamine hydrochloride (96 mg, 1.12 mmol) in triethylamine (0.16 mL, 1.13 mmol) and H.sub.2 O (0.25 mL) was added, and the reaction stirred two hours at reflux. The cooled reaction mixture was poured into aq. sat'd NH.sub.4 Cl and extracted with EtOAc (2.times.). The combined organic extracts were washed (sat'd, aq NaHCO.sub.3, H.sub.2 O, and brine), dried (MgSO.sub.4), and concentrated in vacuo to yield 362 mg of desired product 1 as a cream-colored amorphous solid, after purification by chromatography (silica gel, 35% EtOAc/hexanes). m.p. 95.degree.-100.degree. C.; .sup.1 H NMR (300 MHz, DMSO-d.sub.6); 1.20 (9H, s), 1.23 (6H, d, 7.5 Hz), 1.3 (6H, s), 2.95 (4H, m), 3.38 (2H, s), 5.57 (2H, s), 6.35 (1H, s), 6.87 (2H, d, J=8.4 Hz), 6.97 (1H, dd, J=8.4, 1.5 Hz), 7.27 (1H, d, J=9 Hz), 7.34 (2H, d, J=9 Hz), 7.48 (1H, d, J=1.5 Hz), 9.42 (1H, s); MS (M+H).sup.+ =516. Analysis calc'd for C.sub.28 H.sub.38 ClN.sub.3 O.sub.2 S: C, 65.16; H, 7.42; N, 8.14; Found: C, 64.87; H, 7.45; N, 7.94.
EXAMPLE 2
Preparation of 2,2-dimethyl-3-[1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl]propionaldehyde oxime ##STR13##
Compound 2.1 was prepared by reduction of compound 1.1 as follows. To a 0.degree. C. solution of Compound 1.1 (2.61 g, 5.53 mmol) in 50 mL of dry THF, a 2.0M (THF) borane dimethylsulfide solution was added dropwise (5.80 mL, 11.6 mmol). The reaction was stirred 17 hours at room temperature; methanol (10 mL) was added, and it was then concentrated in vacuo, filtered through a silica gel pad, and purified by chromatography (silica gel, 20% EtOAc/hexanes) to obtain 1.69 g of compound 2.1 as a white, amorphous solid. m.p. 67.degree.-70.degree. C.; .sup.1 H NMR (300 MHz, DMSO-d.sub.6); 0.82 (6H, s), 1.18 (9H, s), 1.22 (6H, d, J=7.75 Hz), 2.93 (3H, m), 3.15 (2H, d, J=6 Hz), 4.82 (1H, t, J=6 Hz), 5.58 (2H, s), 6.87 (2H, d, J=8.25 Hz), 6.97 (1H, dd, J=8.25 and 1.5 Hz), 7.25 (1H, d, J=8.25), 7.33 (2H, d, J=8.25 Hz), 7.47 (1H, d, J=1.5 Hz); MS (M+H).sup.+ =458.
To a -63.degree. C. solution of oxalylchloride (0.41 mL, 4.66 mmol) in dry methylene chloride (4.7 mL), the following reagents were added: DMSO (0.41 mL, 5.32 mmol) in dry methylene chloride (5.32 mL) (dropwise over a five minute period) and Compound 2 (1.22 g, 2.66 mmol) in dry methylene chloride (18 mL) (also dropwise over a five minute period). The reaction was stirred ten minutes after the addition of Compound 2 was completed, and then triethylamine (1.67 mL, 12.0 mmol) in dry methylene chloride (4.0 mL) was added dropwise over a five minute period and stirred one hour before quenching the cold reaction mixture with 10% KHSO.sub.4 (aq). This solution was poured into a separatory funnel containing hexanes. The layers were separated, and the aqueous back extracted with ether. The organic layers were combined, washed (1.times.sat'd, aq NaHCO.sub.3 ; 1.times.H.sub.2 O; and 3.times.brine), dried (MgSO.sub.4), and concentrated in vacuo to yield 1.16 g of a yellow, amorphous solid aldehyde intermediate 2.2.
To a stirring solution of Compound 2.2 (1.16 g, 2.54 mmol) in ethanol (8.5 mL), under N.sub.2 (g), pyridine (0.26 mL, 3.18 mmol) and hydroxylamine hydrochloride (210 mg, 3.05 mmol) were added neat and sequentially. The reaction was stirred 16 hours before concentrating in vacuo to yield 1.20 g of Compound 2 as a pale, yellow amorphous solid. A portion of oxime was purified by flash chromatography (silica gel, 10% EtOAc/hexanes) to yield 179 mg of the title compound as an amorphous white solid. m.p. 80.degree.-85.degree. C.; .sup.1 H NMR (300 MHz, DMSO-d.sub.6); 1.08 (6H, s), 1.20 (9H, s), 1.23 (6H, d, J=6.75 Hz), 2.95 (1H, septet, J=6.75 Hz), 3.08 (2H, br s), 5.45 (2H, s), 6.88 (2H, d, J=8.25 Hz), 6.97 (1H, dd, J=1.5 and 8.25 Hz), 7.26 (1H, d, J=8.25 Hz), 7.32 (2H, d, J=8.25 Hz), 7.39 (1H, s), 7.46 (1H, d, J=1.5 Hz), 10.43 (1H, s); MS (M+H).sup.+ =471. Analysis calc'd for C.sub.27 H.sub.35 ClN.sub.2 OS: C, 68.84; H, 7.49; N, 5.95; Found: C, 68.56; H, 7.58; N, 5.70.
EXAMPLE 3
Preparation of N-hydroxy-N-2,2-dimethyl-3-[(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl))indol-2-yl]propyl urea ##STR14##
To a stirring solution of Compound 2 (1.16 g, 2.46 mmol) in ethanol (5.0 mL), under N.sub.2 (g) atmosphere, borane pyridine complex (0.84 mL, 8.33 mmol) was added neat. The reaction was stirred for two hours, cooled to 0.degree. C., and 12M HCl (1.4 mL, 16.7 mmol) in ethanol (1.0 mL) added dropwise over a 30 minute period. After stirring 16 hours at room temperature, 50 mL of H.sub.2 O was added to the reaction, and 4N NaOH(aq) added to raise the pH to 14. The basic solution was extracted with ether. The organic layer was washed (brine), dried (MgSO.sub.4), and concentrated in vacuo. The crude material was purified by chromatography (silica gel, 50% EtOAc/hexanes), yielding 898 mg of hydroxylamine intermediate 3.1 as an amorphous, white solid.
To a stirring solution of 3.1 (642 mg, 1.36 mmol) in THF (5 mL) was added trimethylsilyl isocyanate (0.24 mL, 1.5 mmol). After stirring 90 minutes, additional trimethylsilyl isocyanate(TMSNCO) (0.10 mL, 0.73 mmol) was added. The reaction was stirred for one hour then poured into a separatory funnel containing NH.sub.4 Cl (sat'd, aq) and extracted with ethyl acetate. The organic layer was washed (brine), dried (MgSO.sub.4), concentrated in vacuo, and purified by chromatography (silica gel, 50-75% EtOAc/hexane) to yield 427 mg of desired product 3 as a white amorphous solid. m.p. 95.degree.-100.degree. C.; .sup.1 H NMR (300 MHz, DMSO-d.sub.6); 0.90 (6H, s), 1.18 (9H, s), 1.22 (6H, d, J=6.75 Hz), 2.95 (3H, m), 3.35 (2H, s), 5.52 (2H, s), 6.25 (2H, s), 6.90 (2H, d, J=9 Hz), 6.95 (1H, dd, J=1.5, 9 Hz), 7.23 (1H, d, J=9 Hz), 7.33 (2H, d, J=9 Hz), 7.47 (1H, d, 1.5 Hz), 9.28 (1H, s); MS (M+H).sup.+ =516. Analysis calc'd for C.sub.28 H.sub.38 ClN.sub.3 O.sub.2 S (0.25 H.sub.2 O): C, 64.59; H, 7.45; N, 8.07; Found: C, 64.58; H, 7.45; N, 7.95.
EXAMPLE 4
Preparation of N'-hydroxy-N'methyl-N-2-[(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl))indol-2-yl]ethyl urea ##STR15##
To a solution of diisopropylamine (11.5 mL, 81.1 mmol) in dry THF (175 mL) at 0.degree. C., under N.sub.2 (g) atmosphere, n-BuLi (2.5M in hexanes) (31.0 mL, 77 mmol) was added over a fifteen minute interval. The reaction was stirred for 15 additional minutes at both 0.degree. C. and -78.degree. C.; t-butyl acetate (10.0 mL, 69.9 mmol) in dry THF (15 mL) was added dropwise over a 15 minute period. After stirring 45 minutes at -78.degree. C., 2-chloro, 3-iodo-1-propene (15.8 g, 78 mmol) was added, and the reaction stirred for 15 minutes at -78.degree. C. and 15 minutes at 0.degree. C. before quenching with excess NH.sub.4 Cl (sat'd, aq). The quenched reaction mixture was poured into a separatory funnel and extracted with EtOAc (2.times.). The combined organic layers were washed (10% aq HCl, H.sub.2 O, and brine), dried (MgSO.sub.4), and concentrated in vacuo to yield 18.87 g of a dark red oil. 10.18 g of intermediate 4.1, as a pale red oil, was obtained after distillation (b.p. 79.5.degree.-83.degree. C.).
Starting with Compound 4.1 (2.5 g, 13.11 mmol) and adapting the procedure reported in EPA 87311031.6 used in Example 1, 1.09 g of the Fischer-Indole product 4.2, was obtained as a yellow waxy solid after purification by chromatography (silica gel, 5% EtOAc/hexane). Compound 4.2 (293 mg, 0.586 mmol) was stirred in CH.sub.2 Cl.sub.2 (2.5 mL), TFA 0.45 mL (5.86 mmol), and anisole (0.13 mL, 1.17 mmol) overnight. After purification by chromatography (silica gel, EtOAc and 5-10% MeOH/CHCl.sub.3), 187 mg of the acid intermediate 4.3 was obtained.
Starting with intermediate 4.3 (161 mg, 0.363 mmol) and following the procedure outlined in Example 1, 100 mg of desired product 4 was obtained as a white solid after purification by chromatography (silica gel, 50% EtOAc/hexane). m.p. 87.degree.-93.degree. C.; .sup.1 H NMR (300 MHz, DMSO-d.sub.6); 1.23 (6H, d, J=7.5 Hz), 1.28 (9H, s), 2.95 (4H, m), 3.08 (2H, m), 3.15 (2H, m), 5.62 (2H, s), 6.98 (3H, m), 7.20 (1H, d, J=8.25 Hz), 7.25 (1H, m), 7.37 (2H, m), 7.46 (1H, d, J=1.5 Hz), 9.33 (1H, m); MS (M+H).sup.+ =488, (M+NH.sub.4).sup.+ =505. Analysis calc'd for C.sub.26 H.sub.34 ClN.sub.3 O.sub.2 S: C, 63.98 ; H, 7.02; N, 8.61; Found: C, 63.69; H, 7.13; N, 8.37.
EXAMPLE 5
Preparation of N-2,2-dimethyl-3-[(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl))indol-2-yl]propyl urea ##STR16##
A stirring solution of 3 (632 mg, 1.22 mmol) in methanol (10 mL), under N.sub.2 (g) atmosphere, was warmed to 45.degree. C. (H.sub.2 O bath). To this solution was added NaOAc.times.3H.sub.2 O (2.0 g, 14.64 mmol) in H.sub.2 O (3 mL). After stirring a few minutes the reaction became homogeneous, and 3.1 mL of a 1.2M TiCl.sub.3 aqueous was added dropwise over a few minutes. After stirring 24 hours, the reaction was partially concentrated in vacuo. The resultant concentrate was poured into 50% aq NaCl (100 mL) and extracted carefully with a 2/1 THF/ethyl acetate (2.times.100 mL) solution. The organic extracts were combined, washed (sat'd, aq NaHCO.sub.3 and brine), dried (MgSO.sub.4), concentrated in vacuo, and purified by chromatography (silica gel, 5% MeOH/CH.sub.2 Cl.sub.2) to yield 350 mg of desired product 5 as a white amorphous solid. m.p. 109.degree.-112.degree. C.; .sup.1 H NMR (300 MHz, DMSO-d.sub.6); 0.82 (6H, s), 1.20 (9H, s), 1.23 (6H, d, 6.75 Hz), 2.83-2.98 (5H, m), 5.43 (2H, s), 5.52 (2H, s), 6.06 (1H, br t, J=6 Hz), 6.88 (2H, d, J=8.25 Hz), 6.97 (1H, dd, J=8.25, 1.5 Hz), 7.24 (1H, d, J=8.25 Hz), 7.32 (2H, d, J=8.25 Hz), 7.47 (1H, d, J=1.5 Hz); MS (M+H).sup.+ =500. Analysis calc'd for C.sub.28 H.sub.38 ClN.sub.3 OS: C, 67.24; H, 7.66; N, 8.40; Found: C, 67.11; H, 7.74; N, 8.25.
EXAMPLE 6
Preparation of N'-hydroxy-N'-methyl-N-2-[3-(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl)-2,2-dimethylpropionylamino]ethyl urea ##STR17##
The following reactants were combined in a round-bottom flask: Compound 1.1 (8.0 g, 16.9 mmol), .beta.-alanine ethyl ester hydrochloride (2.65 g, 16.9 mmol), and 1-hydroxybenztriazole hydrate n6.85 g, 50.7 mmol). The vessel was placed under N.sub.2 (g) atmosphere; DMF (43 mL) and N-methyl morpholine (3.70 mL, 33.8 mmol) were then added. The reaction was cooled to -23.degree. C. (CCl.sub.4 /CO.sub.2 bath) and stirred ten minutes before adding 1-ethyl-3-(3-aminomethyl) carbodiimide hydrochloride (3.24 g, 16.9 mmol). The reaction was allowed to slowly warm to room temperature and stir overnight. The reaction mixture was poured into NaHCO.sub.3 (200 mL) (aq, sat'd) and extracted with EtOAc (2.times.500 mL). The combined organic extracts were washed (4.times.H.sub.2 O, 3.times.brine), dried (MgSO.sub.4), concentrated in vacuo, and purified by chromatography (silica gel, 20-35% EtOAc/hexane) to yield 8.83 g of intermediate ester 6.1. m.p. 45.degree.-50.degree. C.; .sup.1 H NMR (300 MHz, DMSO-d.sub.6); 1.08 (6H, s), 1.14 (3H, t, J=6.75 Hz), 1.19 (9H, s), 1.23 (6H, d, J=6.75 Hz), 2.42 (2H, t, J=7.50 Hz), 2.95 (1H, septet, J=6.75 Hz), 3.15 (2H, s), 3.22-3.32 (2H, m), 4.0 (2H, quartet, J=6.75 Hz), 5.45 (2H, s), 6.86 (2H, d, J=8.25 Hz), 6.97 (1H, dd, J=8.25, 1.5 Hz), 7.24 (1H, d, 8.25 Hz), 7.32 (2H, d, J= 8.25 Hz), 7.47 (1H, d, 1.5 Hz), 7.58 (1H, br t, J=5.25 Hz); MS (M+H).sup.+ =571.
To a stirring solution of ester 6.1 (7.31 g, 12.8 mmol) in THF (40 mL), LiOH (880 mg, 21.0 mmol) in H.sub.2 O (23 mL) was added. The reaction was stirred for four hours then acidified with HCl (12M). The aqueous solution was extracted with EtOAc (2.times.300 mL). The combined aqueous extracts were dried (MgSO.sub.4), concentrated in vacuo and purified by chromatography (silica gel, 20-50% EtOAc/hexane/2% HOAc) to yield 6.80 g of acid 6.2 as a white, amorphous solid. m.p. 80.3.degree.-83.0.degree. C.; .sup.1 H NMR (300 MHz, DMSO-d.sub.6); 1.08 (6H, s), 1.20 (9H, s), 1.23 (6H, d, J=6.75 Hz), 2.36 (2H, t, J=7.50 Hz), 2.95 (1H, septet, J=6.75 Hz), 3.17 (2H, s), 3.20-3.30 (2H, m), 5.45 (2 H, s), 6.87 (2H, d, J=8.25 Hz), 6.97 (1H, dd, J=1.5 Hz, 8.25 Hz), 7.24 (1H, d, J=8.25 Hz), 7.32 (2H, d, J=8.25 Hz), 7.47 (1H, d, J=1.5 Hz), 7.57 (1H, br t, J=5.25 Hz); MS (M+H).sup.+ =543.
Starting with acid intermediate 6.2 (746 mg, 1.37 mmol) and following the procedure of Example 1 listed above, 315 mg of desired product 6 was obtained as a white, amorphous solid. m.p. 99.3.degree.-105.degree. C.; .sup.1 H NMR (300 MHz, DMSO-d.sub.6); 1.08 (6H, s), 1.20 (9H, s), 1.23 (6H, d, J=7.5 Hz), 2.88-3.00 (4H, m), 3.05-3.15 (4H, m), 3.17 (2H, s), 5.43 (2H, s), 6.87 (2H, d, J=8.25 Hz), 6.98 (1H, dd, J=1.5, 8.25 Hz), 7.05 (1H, m), 7.25 (1H, d, J=8.25 Hz), 7.32 (2H, d, J=8.25 Hz), 7.47 (1H, d, J=1.5 Hz), 7.59 (1H, m), 9.32 (1H, s); MS (M+H).sup.+ =587. Analysis calc'd for C.sub.31 H.sub.43 ClN.sub.4 O.sub.3 S(0.5 H.sub.2 O): C, 62.45; H, 7.44; N, 9.40; Found: C, 62.71; H, 7.33; N, 9.38.
EXAMPLE 7
Preparation of 1-(4-chlorophenylmethyl)-2-[2,2-dimethyl-3-((3-hydroxypropyl)-amino)propyl]-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indole ##STR18##
To a stirring solution, under N.sub.2 (g) atmosphere, of ester 6.1 (964 mg, 1.69 mmol) in Et.sub.2 O (4 mL) and THF (10 mL), 1.0M LAH (ether) solution (3.38 mL, 3.38 mmol with respect to aluminum) was added dropwise over a 90 second period. After stirring 3 hours, the reaction mixture was quenched with H.sub.2 O (0.2 mL), 15% aqueous NaOH (0.2 mL), and H.sub.2 O (0.6 mL). The resulting aluminum salts were filtered off through a celite pad with EtOAc (200 mL). The filtrate was concentrated in vacuo and purified by chromatography (silica gel, 10-35% EtOAc/hexane/2% isopropylamine) to yield 680 mg of desired product 7 as a clear, colorless oil. .sup.1 H NMR (300 MHz, DMSO-d.sub.6); 0.87 (6H, s), 1.20 (9H, s), 1.23 (6H, d, J=7.5 Hz), 1.55-1.64 (3H, m), 2.27 (2H, br s), 2.58 (2H, br t, J=6.0 Hz), 2.90-3.00 (3H, m), 3.48 (2H, t, J=6.0 Hz), 4.50 (1H, br s), 5.65 (2H, br s), 6.87 (2H, d, J=8.25 Hz), 6.95 (1H, dd, J=1.5, 8.25 Hz), 7.23 (1H, d, J=8.25 Hz), 7.32 (2H, d, J=8.25 Hz), 7.47 (1H, d, J=1.5 Hz); MS (M+H).sup.+ =515. Analysis calc'd for C.sub.30 H.sub.43 ClN.sub.2 OS: C, 69.94; H, 8.41; N, 5.44; Found: C, 70.56; H, 8.57; N, 5.49.
EXAMPLE 8
Preparation of N-2-[2-methyl-3-(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl)]propyl urea ##STR19##
Starting with Compound 1.1 (1.00 g, 2.12 mmol) and 14.8N ammonium hydroxide (0.90 g, 2.23 mmol) and following the procedure outlined in Example 1, 344 mg of desired product 8 was obtained as white, powdery solid after recrystallization (Et.sub.2 O/CH.sub.2 Cl.sub.2 /hexane). m.p. 206.1.degree.-206.5.degree. C.; .sup.1 H NMR (300 MHz, DMSO-d.sub.6); 1.18 (15H, s), 1.23 (6H, d, J=6.75 Hz), 2.95 (1H, septet, J=6.75 Hz), 3.4 (2H, s), 5.41 (2H, s), 5.58 (2H, s), 5.92 (1H, s), 6.90 (2H, d, J=8.25 Hz), 6.97 (1H, dd, J=1.5 and 8.25 Hz), 7.28-7.35 (3H, m), 7.46 (1H, d, J=1.5 Hz); MS (M).sup.+ =485. Analysis calc'd for C.sub.27 H.sub.36 ClN.sub.3 OS: C, 66.71; H, 7.46; N, 8.64; Found: C, 66.89; H, 7.51; N, 8.59.
EXAMPLE 9
Preparation of 3-[3-(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl)-2-aminocarbonylamino-2-methylpropyl]propanoic acid, ethyl ester ##STR20##
Starting with Compound 1.1 (1.34 g, 2.84 mmol) and .beta.-alanine ethyl ester hydrochloride (445 mg, 2.84 mmol) and following the procedure outlined in Example 1, 1.28 g of Compound 9 was obtained as a white, amorphous solid after purification by chromatography (silica gel, 30% EtOAc/hexane). m.p. 131.degree. C.; .sup.1 H NMR (300 MHz, DMSO-d.sub.6); 1.18-1.21 (18H, m), 1.23 (6H, d, J=6.9 Hz), 2.42 (2H, t, J=6.7 Hz), 2.95 (1H, septet, J=7.5 Hz), 3.23 (2H, quartet, J=6.0 Hz), 3.38 (2H, br s), 4.08 (2H, quartet, J=7.2 Hz), 5.52 (2H, s), 5.83 (1H, t, J=6.25 Hz), 5.87 (1H, s), 6.89 (2H, d, J=8.6 Hz), 6.97 (1H, dd, J=1.5 and 8.4 Hz), 7.22 (1H, d, J=8.2 Hz), 7.32 (2H, d, J=8.4 Hz), 7.46 (1H, d, J=1.7 Hz); MS (M+H).sup.+ =586. Analysis calc'd for C.sub.32 H.sub.44 ClN.sub.3 O.sub.3 S: C, 65.56; H, 7.56; N, 7.17; Found: C, 65.76; H, 7.65; N, 7.12.
EXAMPLE 10
Preparation of 3-[3-(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl)-2-aminocarbonylamino-2-methylpropyl]propanoic acid ##STR21##
Starting with Compound 9 (1.00 g, 1.71 mmol) and following the procedure outlined in Example 6, 930 mg of desired product 10 was obtained as white, amorphous solid after purification by chromatography (silica gel, 15-50% EtOAc/2% HOAc/hexane). m.p. 139.degree.-141.degree. C.; .sup.1 H NMR (300 MHz, DMSO-d.sub.6); 1.18 (15H, s), 1.23 (6H, d, J=6.9 Hz), 2.36 (2H, t, J=6.5 Hz), 2.95 (1H, septet, J=6.9 Hz), 3.20 (2H, quartet, J=6.0 Hz), 3.37 (2H, br s), 5.52 (2H, s), 5.83 (1H, t, J=6.25 Hz), 5.89 (1H, s), 6.88 (2H, d, J=8.6 Hz), 6.97 (1H, dd, J=1.7 and 8.6 Hz), 7.22 (1H, d, J=8.2 Hz), 7.32 (2H, d, J=8.2 Hz), 7.46 (1H, J=1.7 Hz); MS (M+H).sup.+ =558/560. Analysis calc'd for C.sub.30 H.sub.40 ClN.sub.3 O.sub.3 S: C, 62.54; H, 7.35; N, 7.29; Found: C, 62.56; H, 7.12; N, 6.97.
EXAMPLE 11
Preparation of N'-hydroxy-N'-methyl-N-[1-(4-chlorophenylmethyl)-5-(1-methylethyl)-2-((2-methyl-2-ethoxycarbonyl)propyl)indol-2-yl]-3-oxopropylurea ##STR22##
Starting with Compound 11.1 (3.60 g, 7.20 mmol), the ethyl ester of Compound 1.1, in benzene (70 mL), AlCl.sub.3 (2.88 g, 21.6 mmol) was added neat. The reaction was stirred for one hour, under N.sub.2 (g) atmosphere. The brown reaction mixture was poured into a separatory funnel containing 10% aqueous HCl and extracted with EtOAc. The combined organic extracts were washed (2.times.H.sub.2 O and 1.times.brine), dried (MgSO.sub.4), and concentrated in vacuo to yield 3.63 g of a dark orange syrup. After purification by chromatography (silica gel, 10-20% Et.sub.2 O/hexane), 1.68 g of Compound 11.2 was obtained as a viscous oil.
To a stirring solution, under N.sub.2 (g) atmosphere, of Compound 11.2 (1.68 g, 4.08 mmol) in distilled CH.sub.2 Cl.sub.2 (35 mL), succinic anhydride (410 mg, 4.10 mmol) was added neat. The reaction was cooled to 0.degree. C., and AlCl.sub.3 (1.25 g, 9.40 mmol) added via a powder addition funnel (over a three minute interval). After stirring overnight at room temperature, the reaction mixture was poured into dilute aqueous HCl and extracted with EtOAc. The combined organic extracts were washed (1.times.brine), dried (MgSO.sub.4), and concentrated in vacuo. The crude concentrate was purified by chromatography (silica gel, 20% EtOAc/2% HOAc/hexane), followed by recrystallization (CH.sub.2 Cl.sub.2 /hexane) to yield 535 mg of Compound 11.3 as a fine white solid. m.p. 172.5.degree.-174.degree. C.
Starting with Compound 11.3 (385 mg, 0.752 mmol) and following the procedure outlined in Example 1, 30 mg of Compound 11 as a salmon-colored solid was obtained after purification by chromatography (silica gel, 20-50% EtOAc/hexane/2% HOAc) and recrystallization (EtOAc/hexane). m.p. 150.5.degree.-152.degree. C.; .sup.1 H NMR (300 MHz, DMSO-d.sub.6); 1.10 (3H, t, J=6.75 Hz), 1.16 (9H, s), 1.25 (6H, d, J=6.75 Hz), 2.95 (3H, s), 3.02 (1H, septet, J=6.75 Hz), 3.23 (2H, t, J=6.75 Hz), 3.45 (2H, quartet, J=6.0 Hz), 3.58 (2H, s), 4.0 (2H, quartet, J=6.75 Hz), 5.50 (2H, br s), 6.92 (3H, m), 7.08 (1H, dd, J=1.5 and 8.25 Hz), 7.32 (1H, d, J=8.25 Hz), 7.35 (2H, d, J=8.25 Hz), 7.76 (1H, br s), 9.39 (1H, s); MS (M+H).sup.+ =556. Analysis calc'd for C.sub.30 H.sub.38 ClN.sub.3 O.sub.5 (0.25 H.sub.2 O): C, 64.28; H, 6.92; N, 7.50; Found: C, 64.33; H, 6.86; N, 7.35.
EXAMPLE 12
Preparation of 1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-2-[3-(2,2-dimethyl-1-guanidinylimino)propyl]-5-(1-methylethyl)indole ##STR23##
Compound 2.2 (676 mg, 1.48 mmol) was suspended in EtOH (3 mL) and stirred under N.sub.2 (g) atmosphere. Aminoguanadinium hydrogen carbonate (205 mg, 1.50 mmol) was suspended in MeOH (3 mL) and 6N HCl aqueous added until all of the solid dissolved. The aminoguanidinium solution was added to the solution of Compound 2.2, and the reaction allowed to stir 16 hours. The reaction was concentrated in vacuo and purified by chromatography (silica gel, 5.5% MeOH/2% isopropylamine/CHCl.sub.3) to yield 374 mg of Compound 12 as a cream-colored amorphous solid. m.p. 105.degree.-107.degree. C.; .sup.1 H NMR (300 MHz, DMSO-d.sub.6); 1.07 (6H, s), 1.20 (9H, s), 1.22 (6H, d, J=6.75 Hz), 2.95 (1H, septet, J=6.75 Hz), 3.05 (2H, br s), 5.22 (2H, br s), 5.40 (2H, s), 5.51 (2H, br s), 6.85 (2H, d, J=8.25 Hz), 6.97 (1H, dd, J=8.25 and 1.5 Hz), 7.27 (1H, d, J=8.25 Hz), 7.32 (3H, m), 7.46 (1H, d, J=1.5 Hz); MS (M+H).sup.+ =512/514. Analysis calc'd for C.sub.28 H.sub.38 ClN.sub.5 S(0.25 H.sub.2 O): C, 65.09; H, 7.51; N, 13.67; Found: C, 64.97; H, 7.51; N, 13.47.
EXAMPLE 13
Preparation of 3-[3-(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl)-2-aminocarbonylamino-2-methylpropyl]propanoic acid, sodium salt ##STR24##
To a stirring THF (2 mL) solution of Compound 10 (314 mg, 0.563 mmol), NaOMe (30.4 mg, 0.563 mmol) was added and the reaction stirred at room temperature. The reaction was carried out under N.sub.2 (g) atmosphere. After one hour the reaction was taken up in 50% EtOAc/THF, washed (2.times.brine), dried (MgSO.sub.4), and purified by chromatography (silica gel, 5% MeOH/CH.sub.2 Cl.sub.2) to yield 236 mg of Compound 13 as an off-white amorphous solid. m.p. 176.degree.-185.degree. C.; .sup.1 H NMR (300 MHz, DMSO-d.sub.6); 1.18 (15H, s), 1.22 (6H, d, J=6.75 Hz), 2.26 (2H, t, J=6.0 Hz), 2.95 (1H, septet, J=6.75 Hz), 3.17 (2H, m), 3.38 (2H, br s), 5.53 (2H, br s), 5.88 (1H, br s), 6.0 (1H, br s), 6.89 (2H, d, J=8.25 Hz), 6.96 (1H, dd, J=8.25 and 1.5 Hz), 7.23 (1H, d, J=8.25 Hz), 7.32 (2H, d, J=8.25 Hz), 7.46 (1H, d, J=1.5 Hz); MS (M+H).sup.+ =580 and (M+Na)=602. Analysis calc'd for C.sub.30 H.sub.39 ClN.sub.3 O.sub.3 : C, 62.12; H, 6.78; N, 7.24; Found: C, 62.21; H, 6.78; N, 7.34.
EXAMPLE 14
Preparation of N-hydroxy-N-[trans-2-(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl)cyclopropyl]methylurea ##STR25##
To a solution of ethyl bromopyruvate (10.00 g, 51.3 mmol) in THF (250 mL) at 0.degree. C., was added 2-methyl-2-propanethiol (4.86 g, 53.87 mmol) followed by the dropwise addition of triethylamine (6.22 g, 61.56 mmol). The cooling bath was removed and the reaction allowed to come to rt and stir for 15 h. The reaction was then diluted with brine (250 mL) and extracted with ethyl acetate (3.times.250 mL). The organics were combined, dried with MgSO.sub.4 and concentrated. Vacuum distillation of the resulting residue (0.7 mm Hg) afforded 6.47 g (62%) of ethyl t-butylthiopyruvate as a colorless oil (b.p. 89.degree.-92.degree. C.) which was used immediately.
To a solution of ethyl t-butylpyruvate (6.46 g, 31.7 mmol) in toluene (120 mL) was added N-(4-isopropylphenyl)-N-(4-chlorobenzyl)-hydrazine (11.43 g, 36.7 mmol), sodium acetate (3.30 g, 40.26 mmol) and acetic acid (60 mL). The reaction was stirred for 24 h in the dark. It was then diluted with brine (200 mL) and extracted with ethyl acetate (3.times.200 mL). The organics were combined, dried with MgSO.sub.4 and concentrated. The resulting residue was chromatographed (silica gel, ether:hexanes, 2:98) to afford 7.53 g (46%) of intermediate 14.1.
To a solution of intermediate 14.1 (7.51 g, 16.91 mmol) in toluene (25 mL) at -78.degree. C., was added diisobutylaluminum hydride (50.73 mL of a 1.0M solution in hexanes, 50.73 mmol) dropwise. Upon completion of addition, the reaction was stirred for 30 min at -78.degree. C. It was then quenched with aqueous 10% HCl (75 mL) and warmed to rt and extracted with ethyl acetate (3.times.75 mL). The organics were combined, dried with MgSO.sub.4 and concentrated. The unpurified residue was taken up in CH.sub.2 Cl.sub.2 (80 mL) and pyridinium dichromate (9.54 g, 25.37 mmol) was added. The reaction was stirred for 15 h, then filtered through Celite. The filtrate was concentrated. The resulting residue was chromatographed (silica gel, ether:hexanes, 3:97) to afford 4.16 g (61% over the two steps) of intermediate 14.2 as an off-white solid.
A solution of intermediate 14.2 (4.15 g, 10.4 mmol) and malonic acid (1.40 g, 13.5 mmol) in pyridine (5 mL) containing piperidine (177 mg, 2.08 mmol) was refluxed for 18 h. It was then cooled to rt and poured into ice/conc. HCl (50 mL). This aqueous solution was then extracted with ethyl acetate (3.times.50 mL). The organics were combined, dried with MgSO.sub.4 and concentrated. The resulting residue was chromatographed (silica gel, ether:hexanes:acetic acid, 30:69:1) to afford 1.06 g (23%) of intermediate 14.3 as a gold foam.
To a solution of intermediate 14.3 (1.05 g, 2.4 mmol) in CH.sub.2 Cl.sub.2 (10 mL) was added oxalyl chloride (362 mg, 2.9 mmol) followed by a drop of N,N-dimethylformamide. The reaction was stirred for 1 hr, then concentrated. The resulting residue was taken up in CH.sub.2 Cl.sub.2 (10 mL) and cooled to 0.degree. C. N,O-Dimethylhydroxylamine hydrochloride (283 mg, 2.9 mmol) was added followed by pyridine (456 mg, 5.76 mmol). The cooling bath was withdrawn and the reaction allowed to warm to rt, diluted with brine (10 mL), and the layers were separated. The aqueous layer was extracted with CH.sub.2 Cl.sub.2 (2.times.10 mL). The organics were combined, dried with MgSO.sub.4 and concentrated. The resulting residue was chromatographed (silica gel, ether:hexanes, 1:1) to afford 1.04 g (89%) of intermediate 14.4 as a brown oil.
To a suspension of trimethylsulfoxonium iodide (514 mg, 2.3 mmol) in DMSO (5 mL) was added sodium hydride (57 mg of 97% dry, 2.3 mmol) and the resulting mixture was stirred for 20 min. Intermediate 14.4 (1.03 g, 2.1 mmol) was then added dropwise as a solution in DMSO (5 mL) and the reaction was stirred for 2 h at rt then brought to 50.degree. C. for 18 h. It was then cooled to rt and diluted with brine (15 mL). This aqueous solution was extracted with ethyl acetate (3.times.20 mL). The organics were combined, dried with MgSO.sub.4 and concentrated. The resulting residue was chromatographed (silica gel, ether:hexanes, 25:75) to afford intermediate 972 mg (93%) of intermediate 14.7 as a colorless oil.
To a solution of intermediate 14.7 (962 mg, 1.93 mmol) in THF (9 mL) at 0.degree. C., was added diisobutylaluminum hydride (2.02 mL of a 1.0M solution in hexanes, 2.02 mmol) dropwise. Upon complete addition, the reaction was stirred for 30 min. It was then diluted with 10% aqueous HCl (10 mL) and extracted with ethyl acetate (3.times.10 mL). The organics were combined, dried with MgSO.sub.4 and concentrated. The resulting residue was chromatographed (silica gel, ether:hexanes, 15:85) to afford 349 mg (41%) of intermediate 14.8 along with 372 mg (44%) of intermediate 14.9. Intermediate 14.9 (362 mg, 0.819 mmol) was recycled to intermediate 14.8 (218 mg, 61%) following the oxidation procedure described for the conversion of 2.1 to 2.2.
A solution of intermediate 14.8 (567 mg, 1.29 mmol) in 1:1 ethanol:pyridine (6 mL) was stirred for 18 h and concentrated. The resulting residue was taken up in brine (5 mL) and extracted with ethyl acetate (3.times.5 mL). The organics were combined, dried with MgSO.sub.4 and concentrated to afford intermediate 14.10.
To a solution of intermediate 14.10 from above in ethanol (6 mL) was added borane-pyridine (264 mg, 2.84 mmol) and the mixture was stirred for 30 min. Aqueous 6N HCl (0.516 mL, 3.10 mmol) was added dropwise and the reaction was stirred for 1 hr. It was then neutralized by the addition of aqueous 2N NaOH, diluted with brine (5 mL) and extracted with ethyl acetate (3.times.10 mL). The organics were combined, dried with MgSO.sub.4 and concentrated to afford intermediate 14.11.
To a solution of intermediate 14.11 in THF (6 mL) was added trimethylsilyl isocyanate (163 mg, 1.42 mmol) and the reaction was stirred for 10 min and concentrated. The resulting residue was chromatographed (silica gel, ether:hexanes to ether:methanol, 70:30 to 90:10) to afford the desired material as a foam. .sup.1 H NMR (300 MHz, DMSO-d.sub.6): 0.98 (m, 1H), 1.22 (d, 6H), 1.24 (s, 9H), 1.31 (m, 1H), 1.62 (m, 1H), 1.72 (m, 1H), 2.95 (septet, 1H), 3.21 (m, 1H), 3.66 (dd, 1H, J=5 Hz, J=14 Hz), 5.58 (br s, 2H), 6.30 (br s, 2H), 6.98 (m, 3H), 7.24 (d, 1H, J=8.5 Hz), 7.35 (m, 2H), 7.46 (m, 1H), 9.30 (s, 1H); MS (M+H).sup.+ =500; Analysis calc'd for C.sub.27 H.sub.34 ClN.sub.3 O.sub.2 S.1/4H.sub.2 O: C, 64.27, H, 6.89, N, 8.33; Found: C, 64.26, H, 6.82, N, 7.92.
EXAMPLE 15
Preparation of 3-[3-(1,1-dimethylethylthio)-5-(1-methylethyl)-1-(4-pyridinylmethyl)indol-2-yl]-2,2-dimethylpropanoic acid ##STR26##
Compound 15.1 was prepared by adaptation of the procedure reported in EPA 87311031.6 using 4-isopropylphenyl hydrazine hydrochloride hydrate. To a -23.degree. C. (CO.sub.2 (s)/CCl.sub.4 bath) stirred THF (80 mL) solution of 4-pyridinemethanol (2.18 g, 20 mmol) under N.sub.2 (g) atmosphere, methanesulfonyl chloride (1.60 mL, 20 mmol) and triethylamine (2.88 mL, 20 6 mmol) were added neat and sequentially. The reaction was stirred at -23.degree. C. one hour to give the corresponding mesylate. To a stirred DMSO (25 mL) solution of 15.1 (5.0 g, 13.3 mmol) under N.sub.2 (g) atmosphere, neat NaH (1.08 g, 35.9 mmol) was added. The above-formed mesylate was cannulated into the reaction mixture within 2 minutes of adding the NaH. The reaction was stirred for 120 minutes before it was quenched with sat'd aqueous NH.sub.4 Cl and extracted with EtOAc (2.times.200 mL) and 1/1 THF/EtOAc (1.times. 100 mL). The combined organic extracts were washed (brine), dried (Na.sub.2 SO.sub.4), and concentrated in vacuo to yield 1.24 g of compound 15.2 as a pale yellow solid.
15.2 (1.24 g, 2.66 mmol) was converted to 15 by adapting the procedure outlined in Example 1, to provide 0.60 g of 15 as a white, fibrous solid after recrystallization from CH.sub.2 Cl.sub.2 /EtOAc/hexane. m.p. 258.degree. C.; .sup.1 H NMR (300 MHz, DMSO-d.sub.6); 1.01 (6H, s), 1.18-1.27 (15H, m), 2.96 (1H, septet, J=6.75 Hz), 3.18 (2H, br s), 5.55 (2H, s), 6.77 (2H, d, J=6.75 Hz), 7.0 (1H, dd, J=8.25 and 1.5 Hz), 7.27 (1H, d, J=8.25 Hz), 7.50 (1H, d, J=1.5 Hz), 8.45 (2H, d, J=6.75 Hz), 12.45 (1H, br s). MS (M+H).sup.+ =439. Analysis calc'd for C.sub.26 H.sub.34 N.sub.2 O.sub.2 S(0.5 H.sub.2 O): C, 70.47; H, 7.85; N, 6.32; Found: C, 70.57; H, 7.82; N, 6.30.
EXAMPLE 16
Preparation of 3-[3-(1,1-dimethylethylthio)-5-(1-methylethyl)-1-(2-thienylmethyl)indol-2-yl]-2,2-dimethylpropanoic acid ##STR27##
Compound 16 was prepared following the procedure described in Example 15 where 2-thiophenemethanol was substituted for 4-pyridinemethanol. Purification by flash chromatography (sg, 5-10% EtOAc/CCl.sub.4 /2% HOAc) afforded 1.95 g of Compound 16 as a pale yellow solid. m.p. 130.5.degree.-132.degree. C.; .sup.1 H NMR (300 MHz, DMSO-d.sub.6); 1.12 (6H, s), 1.18 (9H, s), 1.23 (6H, d, J=7 Hz), 2.95 (1H, septet, J=7 Hz), 3.31 (2H, s), 5.65 (2H, s), 6.91 (1H, dd, J=4 and 5 Hz), 6.97 (1H, dd, J=1.5 and 4 Hz), 7.02 (1H, dd, J=1.5 and 8.25 Hz), 7.33 (1H, dd, J=1.5 and 5 Hz), 7.42-7.48 (2H, m), 12.47 (1H, br s). MS (M+H).sup.+ =444 and (M+NH.sub.4).sup.+ =461. Analysis calc'd for C.sub.25 H.sub.33 NO.sub.2 S.sub.2 : C, 67.68; H, 7.50; N, 3.16; Found: C, 67.45; H, 7.50; N, 3.10.
EXAMPLE 17
Preparation of N-hydroxy-N-trans-[3-(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl)]prop-2-enylurea ##STR28##
Compound 14.3 is converted to the corresponding oxime, 17.1, following the procedures described for the conversion of 1.1 to 2. Subsequently, 17.1 is converted into 17 following the procedures for the conversion of 2 into 3.
EXAMPLE 18
Preparation of N-[3-(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl)-2,2-dimethylpropyl]acetohydroxamic acid ##STR29##
Hydroxylamine 3.1 is converted to 18 by treatment with acetyl chloride (2 equiv) and triethylamine to give the N,O-diacetate 18.1, which is O-deprotected by treatment with aqueous NaOH to provide 18.
EXAMPLE 19
Preparation of N-hydroxy-N-3-[3-(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl)-2,2-dimethylpropionylamino]propyl urea ##STR30##
Compound 7 is reduced to the corresponding alcohol, 19.1, following the procedure employed for the conversion of 1.1 to 2.1, and is subsequently converted to 19 following the procedure employed to transform 15.3 into 15.
EXAMPLE 20
Preparation of 3-[1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl]-2,2-dimethylpropionaldehyde oxime-O-2-acetic acid ##STR31##
Compound 20 was prepared by following the procedure employed for the conversion of 2.2 to 2 where Carboxymethoxylamine hemihydrochloride was used in place of hydroxylamine hydrochloride. After purification by flash chromatography (silica gel, 20/75/5 EtOAc/Hexane/HOAc), 500 mg of a white amorphous solid was obtained. m.p. 65.degree.-75.degree. C.; .sup.1 H NMR (300 MHz, DMSO-d.sub.6); 1.08 (6H, s), 1.20 (9H, s), 1.23 (6H, d, J=7 Hz), 2.95 (1H, septet, J=7 Hz), 3.09 (2H, bs), 4.43 (2H, s), 5.47 (2H, s), 6.88 (2H, d, J=8.25 Hz), 6.98 (1H, dd, J=1.5 and 8.25 Hz), 7.25 (1H, d, J=8.25 Hz), 7.34 (2H, d, J=8.25 Hz), 7.47 (1H, d, J=1.5 Hz), 7.55 (1H, s), 12.67 (1H, bs); MS (M+H).sup.+ =529. Analysis calc'd for C.sub.29 H.sub.37 ClN.sub.2 O.sub.3 S: C, 65.83; H, 7.05; N, 5.29; Found: C, 66.07; H, 7.09; N, 5.15.
EXAMPLE 21
Preparation of 2-(3-amino-2,2-dimethylpropyl)-1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indole ##STR32##
To a stirring solution of Compound 3.1 (10.9 g, 23.1 mmol) in 2/1/1 EtOH/EtOAc/THF, 20 g of an aqueous preparation of RaNi (50% in H.sub.2 O) was added. After stirring for thirty minutes, the reaction was carefully filtered. The catalyst was washed with THF--making sure it was not allowed to go completely dry. The resulting filtrate was concentrated and purified by flash chromatography (silica gel, 3.5/96.5 MeOH/CH.sub.2 Cl.sub.2) to yield 7.84 g of Compound 21 as an amorphous white solid.
M.p. 58.degree.-68.degree. C.; .sup.1 H NMR (300 MHz, DMSO-d.sub.6); 0.82 (6H, s), 1.20 (9H, s), 1.23 (6H, d, J=7 Hz), 1.85 (2H, bs), 2.38 (2H, s), 2.87-3.00 (3H, m), 5.58 (2H, s), 6.88 (2H, d, J=8.25 Hz), 6.96 (1H, dd, J=1.5 and 8.25 Hz), 7.23 (1H, d, J=8.25 Hz), 7.33 (2H, d, J=8.25 Hz), 7.46 (1H, d, J=1.5 Hz); MS (M+H).sup.+ =457. Analysis calc'd for C.sub.27 H.sub.37 ClN.sub.2 S: C, 70.94; H, 8.16; N, 6.13; Found: C, 70.64; H, 8.13; N, 6.11.
EXAMPLE 22
Preparation of N-[3-(1-(4-chlorophenylmethyl)-3-(1,1 -dimethylethylthio)-5-(1-methylethyl)indol-2-yl)-2,2-dimethylpropyl]acetamide ##STR33##
To a 0.degree. C. stirring solution of Compound 21 (525 mg, 1.15 mmol) in CH.sub.3 CN (4 mL), diisopropylethylamine (0.40 mL, 2.3 mmol) and acetic anhydride (0.11 mL, 1.15 mol) were added neat and sequentially. The cooling bath was removed immediately. After five minutes, the reaction was poured into 10% HCl (aq) and extracted with EtOAc (2.times.50 mL). The organic layers were combined, washed (3.times.brine), dried (MgSO.sub.4), and concentrated in vacuo to yield 591 mg of an off-white solid. Recrystallization from Et.sub.2 O/CH.sub.2 CL.sub.2 /EtOAc/Hexane afforded 130 mg of a white solid.
M.p. 137.8.degree.-139.degree. C.; .sup.1 H NMR (300 MHz, DMSO-d.sub.6); 0.82 (6H, s), 1.20 (9H, s), 1.22 (6H, d, J=7 Hz), 1.85 (3H, s), 2.82-3.08 (5H, m), 5.52 (2H, s), 6.87 (2H, d, J=8.25 Hz), 6.97 (1H, dd, J=1.5 and 8.25 Hz), 7.23 (1H, d, J=8.25 Hz), 7.33 (2H, d, J=8.25 Hz), 7.47 (1H, d, J=1.5 Hz), 7.83 (1H, t, J=6 Hz); MS (M+H).sup.+ =499. Analysis calc'd for C.sub.29 H.sub.39 ClN.sub.2 OS: C, 69.78; H, 7.88; N, 5.16; Found: C, 69.87; H, 7.91; N, 5.60.
EXAMPLE 23
Preparation of N-[trans-2-(1-(4-chlorophenylmethyl)-3-(1,1-dimethylethylthio)-5-(1-methylethyl)indol-2-yl)cyclopropyl]methyl urea ##STR34##
Compound 23 was prepared starting with Compound 14 and following the procedure employed for the conversion of 3 to 5. Purification by flash chromatography (silica gel, 95/5 Et.sub.2 O/MeOH) afforded 20 mg of 23 as an amorphous white solid. .sup.1 H NMR (300 MHz, DMSO-d.sub.6); 0.89 (1H, m), 1.18 (1H, m), 1.21 (6H, d, J=7 Hz), 1.24 (9H, s), 1.45 (1H, m), 1.68 (1H, m), 2.94 (2H, m), 3.30 (1H, m), 5.44 (2H, bs), 5.58 (2H, bs), 6.06 (1H, J=6 Hz); MS (M+H).sup.+ =484 and (M+NH4)=501.
EXAMPLE 24
Preparation of N'-hydroxy-N-3-[3-(1,1-dimethylethylthio)-5-(1-methylethyl)-2-((2-methyl-2-ethoxycarbonyl)propyl)indol-1-yl]propyl urea ##STR35##
To a stirring DMSO solution (15 mL) of 15.1 (2.91 g, 8.22 mmol), NaH (271 mg, 9.05 mmol) and allyl bromide (0.78 mL, 9.05 mmol) were added neat and sequentially. The reaction was stirred under N.sub.2 (g) for 18 hours then poured into 50% aqueous NH.sub.4 Cl and extracted with EtOAc (2.times.50 mL). The combined organic extracts were washed (2.times.H.sub.2 O and 3.times.brine), dried (MgSO.sub.4), and concentrated in vacuo to yield 273 mg of a viscous, yellow oil. This was purified by chromatography (silica gel, 2% EtOAc/CCl.sub.4) to yield 214 mg of allyl intermediate 24.1 as a viscous oil.
To a stirring THF (17 mL) solution of 24.1 (1.80 g, 4.33 mmol) under N.sub.2 (g), a 0.5M solution of 9-BBN in THF (43.3 mL, 21.7 mmol) was added rapidly, and the reaction allowed to stir 18 hours at room temperature. NaOH (868 mg, 21.7 mmol) in H.sub.2 O (7 mL) was added all at once. The reaction was cooled to 0.degree. C. (ice/H.sub.2 O bath) and a 30% aqueous H.sub.2 O.sub.2 solution (7.4 g, 65 mmol) added in three portions over a 5 minute period. The reaction was stirred for 10 minutes at 0.degree. C. before diluting with brine (75 mL) and extracting with Et.sub.2 O (2.times.100 mL). The Et.sub.2 O extracts were combined, washed (2.times.50 mL, brine), dried (Na.sub.2 SO.sub.4), and concentrated in vacuo to yield 1.12 g of hydroxy intermediate 24.2 as an orange, viscous oil after purification by chromatography (silica gel, 35% EtOAc/hexane).
To a stirring THF (10 mL) solution of 24.2 under N.sub.2 (g) atmosphere, triphenylphosphine (810 mg, 3.09 mmol) and bis-N,O-tert-butyloxycarbonylhydroxylamine (665 mg, 2.85 mmol) were added neat and sequentially. The homogeneous solution was cooled to -10.degree. C. (ice/EtOH bath) and diethylazodicarboxylate (0.49 mL, 3.09 mmol) in THF (2 mL) was added dropwise over a 5 minute interval. The reaction was allowed to warm to room temperature and stir 18 hours. The reaction was concentrated in vacuo and purified by chromatography (silica gel, 3% EtOAc/CCl.sub.4) to obtain 702 mg of 24.3 as an amorphous solid.
To a stirring CH.sub.2 Cl.sub.2 (5 mL) solution of 24.3, was added TFA (5 mL). The reaction was stirred 8 minutes and then immediately poured into a sat'd aqueous Na.sub.2 CO.sub.3 solution and extracted with EtOAc (2.times.100 mL). The organic extracts were combined, washed (50% aqueous NaHCO.sub.3, and brine), dried (Na.sub.2 SO.sub.4), and concentrated in vacuo to yield 384 mg of the resulting hydroxylamine, 24.4. This was used without further purification.
To a stirring THF (3 mL) solution of 24.4 (355 mg, 0.791 mmol) under N.sub.2 (g) atmosphere, trimethylsilyl isocyanate (0.63 mL, 3.96 mmol) was added. The reaction was stirred for 90 minutes, concentrated in vacuo, and purified by chromatography (silica gel, 3% MeOH/CH.sub.2 Cl.sub.2) to yield 184 mg of 24 as an amorphous solid. m.p. 64.degree. C.; .sup.1 H NMR (300 MHz, DMSO-d.sub.6); 1.10 (6H, s), 1.13-1.20 (12H, m), 1.25 (6H, d, J=6.9 Hz), 1.81 (2H, quintet, J=6.9 Hz), 2.97 (1H, septet, J=6.9 Hz), 3.22-3.32 (4H, m), 4.06 (2H, quartet, J=6.9 Hz), 4.21 (2H, t, J=6.9 Hz), 6.33 (2H, s), 7.05 (1H, dd, J=1.5 and 8.25 Hz), 7.41 (1H, d, J=8.25 Hz), 7.43 (1H, d, J=1.5 Hz), 9.28 (1H, s); MS (M+H).sup.+ =492 and (M+NH.sub.4).sup.+ =509. Analysis calc'd for C.sub.26 H.sub.41 N.sub.3 O.sub.4 S(0.5 H.sub.2 O): C, 62.94; H, 8.43; N, 8.47; Found: C, 62.99; H, 8.49; N, 8.39.
Substituted indole N-hydroxyureas presented in Table 3 are prepared by the method used for Example 1 substituting N-methylhydroxylamine for the requisite N-substituted hydroxylamine, R.sup.2 NHOH.
TABLE 3______________________________________ ##STR36##Example R.sup.2______________________________________25 CH.sub.2 CH.sub.326 CH.sub.2 CH.sub.2 C.sub.6 H.sub.527 CH.sub.2 CH.sub.2 COOCH.sub.328 CH.sub.2 CH.sub.2 CONH.sub.229 CH.sub.2 CH.sub.2 CH.sub.2 OH30 CH.sub.2 CH.sub.2 OH31 CH.sub.2 CH.sub.2 OCH.sub.332 CH.sub.2 CH.sub.2 OC.sub.6 H.sub.533 CH.sub.2 CH.sub.2 OCOCH.sub.334 CH.sub.2 CH.sub.2 -2-pyridyl35 CH.sub.2 CH.sub.2 -3-pyridyl36 CH.sub.2 CH.sub.2 -4-pyridyl______________________________________
Substituted indole N-hydroxyurea compounds of the present invention presented in Table 4 are prepared by the method used for Example 3 substituting trimethylsilylisocyanate with the requisite N-substituted isocyanate, R.sup.3 --N.dbd.C.dbd.O.
TABLE 4______________________________________ ##STR37##Example R.sup.3______________________________________37 CH.sub.2 CH.sub.338 CH.sub.2 CH.sub.2 C.sub.6 H.sub.539 CH.sub.2 CH.sub.2 COOCH.sub.340 CH.sub.2 CH.sub.2 CONH.sub.241 CH.sub.2 CH.sub.2 CH.sub.2 COOCH.sub.342 (CH.sub.2).sub.4 COOCH.sub.343 CH.sub.2 C.sub.6 H.sub.544 CH.sub.2 CH.sub.2 OCH.sub.345 CH.sub.2 CH.sub.2 OC.sub.6 H.sub.546 CH.sub.2 CH.sub.2 OC(O)CH.sub.347 CH.sub.2 CH.sub.2 -2-pyridyl48 CH.sub.2 CH.sub.2 -3-pyridyl49 CH.sub.2 CH.sub.2 -4-pyridyl50 C.sub.6 H.sub.5513-pyridyl522-furyl533-thienyl542-benzo[b]thienyl552-benzo[b] furyl562-thiazoyl______________________________________
Substituted indole urea compounds in accordance with the present invention presented in Table 5 are prepared by the method used for Example 5 by deoxygenation of the N-hydroxyurea examples shown in Table 4.
TABLE 5______________________________________ ##STR38##Example R.sup.3______________________________________57 CH.sub.2 CH.sub.358 CH.sub.2 CH.sub.2 C.sub.6 H.sub.559 CH.sub.2 CH.sub.2 COOCH.sub.360 CH.sub.2 CH.sub.2 CONH.sub.261 CH.sub.2 CH.sub.2 CH.sub.2 COOCH.sub.362 (CH.sub.2).sub.4 COOCH.sub.363 CH.sub.2 C.sub.6 H.sub.564 CH.sub.2 CH.sub.2 OCH.sub.365 CH.sub.2 CH.sub.2 OC.sub.6 H.sub.566 CH.sub.2 CH.sub.2 OCOCH.sub.367 CH.sub.2 CH.sub.2 -2-pyridyl68 CH.sub.2 CH.sub.2 -3-pyridyl69 CH.sub.2 CH.sub.2 -4-pyridyl70 C.sub.6 H.sub.5713-pyridyl722-furyl733-thienyl742-benzo[b]thienyl752-benzo[b] furyl762-thiazoyl______________________________________
Substituted indole oxime derivatives presented in Table 6 are prepared by the method used for Example 2 substituting hydroxylamine with the requisite O-substituted hydroxylamine R.sup.2 ONH.sub.2.
TABLE 6______________________________________ ##STR39##Example R.sup.2______________________________________77 CH.sub.2 CH.sub.378 CH.sub.2 CH.sub.2 C.sub.6 H.sub.579 CH.sub.2 CH.sub.2 COOCH.sub.380 CH.sub.2 CH.sub.2 CONH.sub.281 CH.sub.2 CONH.sub.282 (CH.sub.2).sub.2 CON(Et).sub.283 CH.sub.2(N-morpholine)84 CH.sub.2(N-piperidine)85 CH.sub.2(N-piperazine)86 CH.sub.2COOCH.sub.2 CH.sub.2 NH.sub.287 CH.sub.2COOCH.sub.2 CH(OH)CH.sub.2 OH88 CH.sub.2COOCH(CH.sub.3)O(O)CC(CH.sub.3).sub.389 CH.sub.2COOCH.sub.2N-succinimide90 (CH.sub.2).sub.3 COOCH.sub.391 (CH.sub.2).sub.4 COOCH.sub.392 (CH.sub.2).sub.2 COOH93 (CH.sub.2).sub.3 COOH94 (CH.sub.2).sub.4 COOH95 (CH.sub.2).sub.2 CH.sub.2 OH96 (CH.sub.2).sub.3 CH.sub.2 OH97 (CH.sub.2).sub.4 CH.sub.2 OH98 CH.sub.2 CON(OH)CH.sub.399 (CH.sub.2).sub.2 CON(OH)CH.sub.3100 CH(COOCH.sub.3).sub.2101 CH(COOH).sub.2102 CH.sub.2 C.sub.6 H.sub.5103 CH.sub.2 CH.sub.2 OCH.sub.3104 CH.sub.2 CH.sub.2 OC.sub.6 H.sub.5105 CH.sub.2 CH.sub.2 OCOCH.sub.3106 CH.sub.2 CH.sub.2 -2-pyridyl107 CH.sub.2 CH.sub.2 -3-pyridyl108 CH.sub.2 CH.sub.2 -4-pyridyl109 CH.sub.2 -3-benzoic acid110 CH.sub.2 -3-pyridyl111 CH.sub.2 -2-furyl112 CH.sub.2 -3-thienyl113 CH.sub.2 -2-benzo[b]thienyl114 CH.sub.2 -2-benzo[b]furyl115 CH.sub.2 -2-thiazoyl116 CH.sub.2 -5-tetrazoyl117 CH.sub.2 -5-triazoyl118 CH.sub.2 -2-imidazoyl119 CH.sub.2 -2-pyrimidyl______________________________________
Substituted indole acid derivatives presented in Table 7 are prepared by the method used for Example 15 substituting 4-pyridylmethanol with the requisite heteroarylmethanol intermediate B--OH.
TABLE 7______________________________________ ##STR40##Example B______________________________________120 CH.sub.2 -2-pyridyl121 CH.sub.2 -3-pyridyl122 CH.sub.2 -4-pyridyl123 CH.sub.2 -2-furyl124 CH.sub.2 -3-furyl125 CH.sub.2 -2-thienyl126 CH.sub.2 -3-thienyl127 CH.sub.2 -2-benzo[b]thienyl128 CH.sub.2 -2-benzo[b]furyl129 CH.sub.2 -2-thiazoyl130 CH.sub.2 -2-imidazoyl131 CH.sub.2 -2-pyrimidyl______________________________________
Substituted indole oxime derivatives as shown in Table 8 are prepared by the method used for Example 2 substituting compound 1.1 with the indole acid compounds described in Table 7 and reaction of the requisite aldehyde with the appropriate hydroxylamine, R.sup.2 ONH.sub.2.
TABLE 8______________________________________ ##STR41##Example B R.sup.2______________________________________132 CH.sub.2 -2-pyridyl CH.sub.2 COOH133 CH.sub.2 -3-pyridyl CH.sub.2 COOH134 CH.sub.2 -4-pyridyl CH.sub.2 COOH135 CH.sub.2 -2-furyl (CH.sub.2).sub.2 COOH136 CH.sub.2 -3-furyl (CH.sub.2).sub.2 COOH137 CH.sub.2 -2-thienyl CH.sub.2 COOH138 CH.sub.2 -3-thienyl CH.sub.2 COOH139 CH.sub.2 -2-benzo[b]thienyl CH.sub.2 COOH140 CH.sub.2 -2-benzo[b]furyl CH.sub.2 COOH141 CH.sub.2 -2-thiazoyl CH.sub.2 COOH142 CH.sub.2 -2-imidazoyl CH.sub.2 COOH143 CH.sub.2 -2-pyrimidyl CH.sub.2 COOH______________________________________
Substituted indole oxime derivatives as shown in Table 9 are prepared by the method used for Example 11 where 11.1 is desulfurized to provide the indole intermediate 11.2 and then 11.2 is converted to various oxime derivatives by the method of Example 2 substituting hydroxylamine with the requisite O-substituted hydroxylamine, R.sup.2 ONH.sub.2.
TABLE 9______________________________________ ##STR42##Example R.sup.2______________________________________144 CH.sub.2 COOH145 CH.sub.2 CH.sub.2 OH146 CH.sub.2 CH.sub.3147 CH.sub.2 CH.sub.2 C.sub.6 H.sub.5148 CH.sub.2 CH.sub.2 COOCH.sub.3149 CH.sub.2 CH.sub.2 CONH.sub.2150 CH.sub.2 CONH.sub.2151 (CH.sub.2).sub.2 CON(Et).sub.2152 CH.sub.2 -morpholinylamide153 CH.sub.2 -piperidinylamide154 CH.sub.2 -1,5-piperizinylamide155 CH.sub.2COOCH.sub.2 CH.sub.2 NH.sub.2156 CH.sub.2COOCH.sub.2 CH(OH)CH.sub.2 OH157 CH.sub.2COOCH(CH.sub.3)OOC(CH.sub.3).sub.3158 CH.sub.2COOCH.sub.2N-succinimide159 (CH.sub.2).sub.3 COOCH.sub.3160 (CH.sub.2).sub.4 COOCH.sub.3161 (CH.sub.2).sub.2 COOH162 (CH.sub.2).sub.3 COOH163 (CH.sub.2).sub.4 COOH164 (CH.sub.2).sub.2 CH.sub.2 OH165 (CH.sub.2).sub.3 CH.sub.2 OH166 (CH.sub.2).sub.4 CH.sub.2 OH167 CH.sub.2 CON(OH)CH.sub.3168 (CH.sub.2).sub.2 CON(OH)CH.sub.3169 CH(COOCH.sub.3).sub.2170 CH(COOH).sub.2171 CH.sub.2 C.sub.6 H.sub.5172 CH.sub.2 CH.sub.2 OCH.sub.3173 CH.sub.2 CH.sub.2 OC.sub.6 H.sub.5174 CH.sub.2 CH.sub.2 OCOCH.sub.3175 CH.sub.2 CH.sub.2 -2-pyridyl176 CH.sub.2 CH.sub.2 -3-pyridyl177 CH.sub.2 CH.sub.2 -4-pyridyl178 CH.sub.2 -3-benzoic acid179 CH.sub.2 -3-pyridyl180 CH.sub.2 -2-furyl181 CH.sub.2 -3-thienyl182 CH.sub.2 -2-benzo[b]thienyl183 CH.sub.2 -2-benzo[b]furyl184 CH.sub.2 -2-thiazoyl185 CH.sub.2 -5-tetrazoyl186 CH.sub.2 -5-triazoyl187 CH.sub.2 -2-imidazoyl188 CH.sub.2 -2-pyrimidyl______________________________________
Substituted indole amine derivatives presented in Table 10 are prepared by reductive amination (with for example sodium cyanoborohydride) of the aldehyde 2.2 using the requisite amine.
TABLE 10______________________________________ ##STR43##Example R.sup.2______________________________________189 CH.sub.2 COOCH.sub.3190 CH.sub.2 CH.sub.2 OH191 CH.sub.2 CH.sub.3192 CH.sub.2 CH.sub.2 C.sub.6 H.sub.5193 CH.sub.2 CH.sub.2 COOCH.sub.3194 CH.sub.2 CH.sub.2 CONH.sub.2195 CH.sub.2 CONH.sub.2196 (CH.sub.2).sub.2 CON(Et).sub.2197 CH.sub.2COOCH.sub.2 CH.sub.2 NH.sub.2198 CH.sub.2COOCH.sub.2 CH(OH)CH.sub.2 OH199 CH.sub.2COOCH(CH.sub.3)OOC(CH.sub.3).sub.3200 CH.sub.2COOCH.sub.2N-succinimide201 (CH.sub.2).sub.3 COOCH.sub.3202 (CH.sub.2).sub.4 COOCH.sub.3203 (CH.sub.2).sub.2 CH.sub.2 OH204 (CH.sub.2).sub.3 CH.sub.2 OH205 (CH.sub.2 ).sub.4 CH.sub.2 OH206 CH.sub.2 CON(OH)CH.sub.3207 (CH.sub.2).sub.2 CON(OH)CH.sub.3208 CH(COOCH.sub.3).sub.2209 CH.sub.2 C.sub.6 H.sub.5210 CH.sub.2 CH.sub.2 OCH.sub.3211 CH.sub.2 CH.sub.2 OC.sub.6 H.sub.5212 CH.sub.2 CH.sub.2 OCOCH.sub.3213 CH.sub.2 CH.sub.2 -2-pyridyl214 CH.sub.2 CH.sub.2 -3-pyridyl215 CH.sub.2 CH.sub.2 -4-pyridyl216 CH.sub.2 -3-benzoic acid217 CH.sub.2 -3-pyridyl218 CH.sub.2 -2-furyl219 CH.sub.2 -3-thienyl220 CH.sub.2 -2-benzo[b]thienyl221 CH.sub.2 -2-benzo[b]furyl222 CH.sub.2 -2-thiazoyl223 CH.sub.2 -5-tetrazoyl224 CH.sub.2 -5-triazoyl225 CH.sub.2 -2-imidazoyl226 CH.sub.2 -2-pyrimidyl227 C.sub.6 H.sub.52282-furyl2293-thienyl2302-benzo[b]thienyl2312-benzo[b]furyl2322-thiazoyl______________________________________
Substituted indole hydroxamic acid derivatives as shown in Table 11 are prepared by the method of Example 3 substituting trimethylsilylisocyanate with the requisite carboxylic acid chloride or anhydride and suitable base such as pyridine or triethylamine.
TABLE 11______________________________________ ##STR44##Example R.sub.2______________________________________233 CH.sub.2 COOCH.sub.3234 CH(CH.sub.3)OCH.sub.3235 CH.sub.2 CH.sub.3236 CH.sub.2 CH.sub.2 C.sub.6 H.sub.5238 CH(CH.sub.3)COOCH.sub.3238 CH.sub.2 CH.sub.2 CONH.sub.2239 CH.sub.2 CONH.sub.2240 (CH.sub.2).sub.2 CON(Et).sub.2241 CH.sub.2 COOCH(CH.sub.3)O(O)CC(CH.sub.3).sub.3242 CH(CH.sub.3)COOCH.sub.3243 (CH.sub.2).sub.4 COOCH.sub.3244 (CH.sub.2).sub.2 COOCH.sub.3245 (CH.sub.2).sub.2 CH.sub.2 OCH.sub.3246 (CH.sub.2).sub.3 CH.sub.2 OCH.sub.3247 (CH.sub.2).sub.4 CH.sub.2 OCH.sub.3248 CH(COOCH.sub.3).sub.2249 CH.sub.2 C.sub.6 H.sub.5250 CH.sub.2 CH.sub.2 OCH.sub.3251 CH.sub.2 CH.sub.2 OC.sub.6 H.sub.5252 CH.sub.2 CH.sub.2 OCOCH.sub.3253 CH.sub.2 -2-furyl254 CH.sub.2 -3-thienyl255 CH.sub.2 -2-benzo[b]thienyl256 CH.sub.2 -2-benzo[b]furyl257 CH.sub.2 -2-thiazoyl258 CH.sub.2 -5-tetrazoyl259 CH.sub.2 -5-triazoyl260 CH.sub.2 -2-imidazoyl261 CH.sub.2 -2-pyrimidyl262 C.sub.6 H.sub.52632-furyl2643-thienyl2652-benzo[b]thienyl2662-benzo[b]furyl2672-thiazoyl______________________________________
Substituted indole hydroxamic acid derivatives X presented in Table 12 are prepared by the method of Example 4 substituting the intermediate 4.1 with the requisite alpha-substituted ketone intermediate VIII to provide the indole intermediate IX which is then converted to the corresponding oxime derivatives X. ##STR45##
TABLE 12______________________________________Example R R.sup.2______________________________________268 2-pyridyl CH.sub.2 COOH269 3-pyridyl CH.sub.2 COOH270 4-pyridyl CH.sub.2 COOH271 4-fluorophenyl CH.sub.2 COOH272 2-thiazoyl CH.sub.2 COOH273 1-methyl-1-ethylphenyl CH.sub.2 COOH274 benzyl CH.sub.2 COOH275 CH.sub.2 -2-pyridyl CH.sub.2 COOH276 isopropyl CH.sub.2 COOH277 2-thienyl CH.sub.2 COOH278 3-thienyl CH.sub.2 COOH______________________________________
The foregoing examples are provided to enable one skilled in the art to practice the present invention. These examples are merely illustrative, however, and should not be read as limiting the scope of the invention as it is claimed in the appended claims.

Number	Name	Date
3859305	Posselt et al.	Jan 1975
3931229	Zinnes et al.	Jan 1976
4021448	Bell	May 1977
4119638	Ray	Oct 1978
4464379	Betzing et al.	Aug 1984
4654360	Greenhouse et al.	Mar 1987
4814344	Humber et al.	Mar 1989
4873259	Summers, Jr. et al.	Oct 1989

Indole derivatives which inhibit leukotriene biosynthesis

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