Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/06—Antipsoriatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/10—Anti-acne agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D215/20—Oxygen atoms
  • C07D215/22—Oxygen atoms attached in position 2 or 4
  • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
  • C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
  • C07D335/06—Benzothiopyrans; Hydrogenated benzothiopyrans

Definitions

• retinoid-like activity is well known in the art, and are described in numerous United States and other patents and in scientific publications. It is generally known and accepted in the art that retinoid-like activity is useful for treating animals of the mammalian species, including humans, for curing or alleviating the symptoms and conditions of numerous diseases and conditions. It is now general knowledge in the art that two main types of retinoid receptors exist in mammals (and other organisms). The two main types or families of receptors are respectively designated the RARs and RXRs.
• each type there are subtypes; in the RAR family the subtypes are designated RAR ⁇ , RAR ⁇ and RAR ⁇ , in RXR the subtypes are: RXR ⁇ , RXRp and RXR ⁇ . It has also been established in the art that the distribution of the two main retinoid receptor types, and of the several subtypes is not uniform in the various tissues and organs of mammalian organisms. Moreover, it is generally accepted in the art that many unwanted side effects of retmoids are mediated by one or more of the RAR receptor subtypes.
• retinoid compounds which are disubstituted "chalcone" compounds: U. S. Patent Nos. 6,455,701; 6,469,028; 6,225,494; 5,723,666; 5,739,338 and 5,760,276. United States Patent Nos. 5,723,666; 5,599,967; and 5,605,915 disclose 5 retinoid compounds which include an oxime moiety.
• the present invention is directed to compounds having specific or selective activity as agonists of RAR ⁇ retinoid receptors. More specifically, the present 10 invention is directed to disubstituted chalcone oximes that have specific or selective activity as agonists of RAR ⁇ retinoid receptors.
• the present invention relates to compounds of Formula 1
• R is selected from the groups consisting of the radicals defined by formulas (a) through (g)
• Ri is independently alkyl of 1 to 6 carbons, COOR3, F, Cl, Br or I;
• R 2 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, OH, SH, alkoxy having 1 to 6 carbons, alkylthio having 1 to 6 carbons, NH 2 , Ci- ⁇ alkylamino or di(C ⁇ - 6 alkyl)amino;
• 5 R 3 is H or alkyl of 1 to 10 carbons;
• R 4 is independently halogen, alkyl of 1 to 10 carbons, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 10 carbons, or alkylthio of 1 to 10 carbons;
• A is (CH 2 ) q where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, 10 or alkynyl having 2-6 carbons and 1 or
• the present invention also relates to pharmaceutical compositions incorporating the compounds of Formula 1 and to methods of treatment of emphysema and related pulmonary conditions, for example, bronchiopulmonary 25 dysplasia (BPD),of mammals with pharmaceutical compositions containing one or more compounds of Formula 1.
• BPD bronchiopulmonary 25 dysplasia
• the present invention also relates to the methods of using the compounds of the invention to treat diseases and conditions which are responsive to treatment by RAR ⁇ agonist retinoids, such as skin related diseases including but not being limited 30 to acne and psoriasis.
• the invention also relates to the use of a RAR ⁇ agonist retinoids for the preparation of a medicament for therapy or diagnosis. For example for treatment of diseases and conditions which are responsive to treatment by RAR ⁇ agonist retinoids.
• alkyl refers to and covers any and all groups which are known as 10 normal alkyl and branched-chain alkyl.
• a pharmaceutically acceptable salt may be prepared for any compound in this invention having a functionality capable of forming a salt, for example an acid functionality.
• a pharmaceutically acceptable salt is any salt that retains the activity of the parent compound and does not impart any deleterious or untoward effect on 15 the subject to which it is administered and in the context in which it is administered.
• Pharmaceutically acceptable salts may be derived from organic or inorganic bases.
• the salt may be a mono or polyvalent ion.
• Organic salts may be made with amines, particularly ammonium salts such as mono-, di- and trialkyl 20 amines or ethanol amines. Salts may also be formed with caffeine, tromethamine and similar molecules.
• the compounds of the present invention include at least one olephinic double bond about which trans and cis (E and Z) stereoisomerism can exist.
• the compounds of the present invention have the specific orientations of substituents 25 relative to the double bond or double bonds, as is indicated in the name of the respective compound, and/or by specific showing in the structural formula of the orientation of the substituents relative to the double bond or double bonds.
• the compounds of the invention also include an oxime function that is attached to the adjacent carbon by a double bond about which syn and anti 30 stereoisomerism exists.
• the scope of the invention is intended to cover oximes in both syn and anti configuration.
• the specific examples have the specific 3774.1064003
• the compounds of the present invention may also contain one or more chiral centers and therefore may exist in enantiomeric and diastereomeric forms. With 5 regard to the chiral centers in the compounds, the scope of the invention is intended to cover all possible orientations of the substituents, thus including pure enantiomers (optical isomers), diastereomers, mixtures of diastereomers and racemic mixtures of enantiomers. Generally speaking the compounds of the invention can be obtained by the 10 synthetic route shown in Reaction Scheme 1.
• the starting compound in Reaction Scheme 1 is a methyl ketone of Formula 2 where the variable R is defined as in connection with Formula 1.
• the methyl ketone of Formula 2 is reacted with an aldehyde of Formula 3 in the presence of strong base, such as sodium hydroxide, in a suitable polar solvent, such 5 as methanol.
• a suitable polar solvent such as methanol.
• the compound of Formula 4 is then reacted in a suitable polar solvent, such as ethyl alcohol, with hydroxylamine in the presence of pyridine to provide the oxime compounds of the 10 invention of Formula 1.
• oximes of both syn and anti (or cis and trans) configuration are formed in the last reaction, but not necessarily in equal amounts. In most instances the isomeric oximes can be separated from each other by crystallization and/or chromatography.
• the A-B 15 group of Formula 3 is replaced with a bromo group as shown in Formula 5.
• the product (Formula 6) is converted to a compound of Formula 7 by reaction with carbon monoxide in the presence of l,3-bis(diphenylphosphino)propane (dppp) and palladium acetate in dimethylformamide (DMF), triethylamine (TEA) and anhydrous ethanol.
• the 20 chalcone compound of Formula 7 is then converted to the oxime of Formula 8 by reaction with hydroxylamine in the presence of pyridine or other base.
• the compounds of Formula 8 are within the scope of the invention and within the scope of Formula 1.
• methyl ketones of Formula 2 are usually available in accordance with 25 the chemical patent and/or scientific literature, or can be obtained by such modifications of known synthetic methods which are readily within the skill of the practicing organic chemist.
• Reaction Schemes 2 and 3 disclose general synthetic routes that provide the methyl ketone of Formula 2. 3774.1064003
• Reaction Scheme 3 In accordance with Reaction Scheme 2 a compound of Formula 9 is 5 subjected to a Friedel Crafts reaction with acetyl chloride in a suitable aprotic solvent, such as methylene chloride, to provide the methyl ketone of Formula 2.
• a bromo compound of Formula 10 is reacted in a suitable aprotic solvent, such as tetrahydrofuran (THF), under a protective blanket of an inert gas, such as argon, with tributyl(l-ethoxyvinyl)tin in the presence 10 of a palladium catalyst (PdCl 2 (PPh 3 ) 2 ), and thereafter with acid to provide the methyl ketone of Formula 2.
• a palladium catalyst PdCl 2 (PPh 3 ) 2
• -11- with Formula 1 are also available in accordance with the chemical patent and/or scientific literature, or can be obtained by such modifications of known synthetic methods which are readily within the skill of the practicing organic chemist.
• Examples for the aromatic or heteroaromatic aldehyde reagents of Formulas 5 3 and 5 usable in Reaction Scheme 3 are methyl-4-formylbenzoate, methyl 4- formyl-2-fluoro-benzoate, 4-bromo-2-fluoro-benzaladehyde, 4-bromobenzaldehyde, methyl-3-formylbenzoate, methyl 3-formyl-2-fluoro-benzoate, 3-bromo-2-fluoro- benzaladehyde, 3-bromobenzaldehyde, methyl-5-formyl-naphthoate, methyl-6- formyl-naphthoate, methyl-5-formyl-thiophene-2 ⁇ carboxylate, methyl-5-formyl- 10
• BIOLOGICAL ACTIVITY, MODES OF ADMINISTRATION The compounds of the invention were tested in certain assays for activity as agonists of RAR and RXR retinoid receptors.
• one such assay is a chimeric receptor transactivation assay which tests for agonist-like activity in the RAR ⁇ , RAR ⁇ and RAR ⁇ receptor subtypes, and which is based on work published by Feigner P. L. and Holm M. (1989) Focus, 112 is described in detail in United States Patent No. 5,455,265. The specification of United States Patent No. 5,455,265 is hereby expressly incorporated by reference.
• Efficacy in a transactivation assay is expressed as a percentage of the maximum potency attained by the compound compared to a standard which, in this 10 case, is the compound 4-[(lE)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2- naphthalenyl)-l-propenyl]-benzoic acid.
• TNPB This standard compound is described in PCT Publication WO 2002077169 A2.
• Table 1 discloses the activity of certain exemplary compounds of the invention in the above-described chimeric RAR receptor transactivation and 15 binding assays. In the holoreceptor transactivation assay the compounds were relatively inactive in activating RXR ⁇ , RXRp and RXR ⁇ receptors.
• the compounds of the invention are specific or selective agonists of the RAR ⁇ retinoid receptors, and as such they are capable of preventing 3774.1064003
• the compounds of the invention are useful for the prevention or treatment of emphysema and other related pulmonary 5 insufficiency diseases or conditions such as bronchiopulmonary dysplasia (BPD) of mammals, including human beings.
• BPD bronchiopulmonary dysplasia
• the compounds are also useful for treating those diseases or conditions which are responsive to RAR ⁇ agonist retinoids, for example skin related diseases including but not being limited to acne and psoriasis.
• the data for Compounds 9a, 9b, 13a, and 13b are provided in Table 1 for comparison only. 10
• These 4 compounds have a substituent in the 3 position of the tetrahydronaphthalene moiety and are not in the scope of the invention because they are less selective to the RAR ⁇ receptors than the compounds of the invention.
• a pharmaceutical composition containing one or more compounds of the invention is 20 administered to the mammal in daily doses in the range of 1 to 100 mg per kg body weight of the mammal.
• the daily dose is between 5 to 20 mg per kg body weight of the mammal.
• the compounds of the invention being agonist of RAR ⁇ retinoid receptors are also useful for preventing or treating diseases and conditions 25 that are responsive to compounds that promote the expression of or bind to RAR y retinoid receptors.
• the compounds of the invention can be used for preventing or treating skin-related diseases, including, without limitation, actinic keratoses, arsenic keratoses, inflammatory and non-inflammatory acne, psoriasis, ichthyoses and other keratinization and hyperproliferative disorders of the skin, 30 eczema and atopic dermatitis Darriers disease, lichen planus, prevention and reversal of glucocorticoid damage (steroid atrophy), as a topical anti-microbial, as skin 3774.10641)03
• the compounds of this invention are preferably administered, orally or directly to the lung by inhalation 5 through an inhaler (See, e.g. Raleigh et al., Proc. Amer. Assoc. Cancer Research Annual Meeting, 1999, 40, 397, which is herein incorporated by reference).
• an inhaler See, e.g. Raleigh et al., Proc. Amer. Assoc. Cancer Research Annual Meeting, 1999, 40, 397, which is herein incorporated by reference.
• the compounds of the invention may be administered systemically or topically, depending on such considerations as the condition to be treated, need for 10 site-specific treatment, quantity of drug to be administered, and numerous other considerations.
• any common topical formulation such as a solution, suspension, gel, ointment, or salve and the like may 15 be used. Preparation of such topical formulations are well described in the art of pharmaceutical formulations as exemplified, for example, by Remington's Pharmaceutical Science, Edition 17, Mack Publishing Company, Easton, Pennsylvania. For topical application, these compounds could also be administered as a powder or spray, particularly in aerosol form.
• the drug may be confected as a powder, pill, tablet or the like or as a syrup or elixir suitable for oral administration.
• the compound will be prepared as a solution or suspension capable of being administered by injection.
• it may be useful to formulate these compounds by injection.
• it may be useful to formulate these 25 compounds in suppository form or as extended release formulation for deposit under the skin or intramuscular injection.
• Other medicaments can be added to such topical formulation for such secondary purposes as treating skin dryness; providing protection against light; other medications for treating dermatoses; medicaments for preventing infection, reducing 30 irritation, inflammation and the like.
• Treatment of dermatoses or any other indications known or discovered to be susceptible to treatment by RAR ⁇ agonist compounds will be effected by administration of the therapeutically effective dose of one or more compounds of the instant invention.
• a therapeutic concentration will be that concentration which 5 effects reduction of the particular condition, or retards its expansion.
• the compound potentially may be used in prophylactic manner to prevent onset of a particular condition.
• a useful therapeutic or prophylactic concentration will vary from condition to condition and in certain instances may vary with the severity of the condition 10 being treated and the patient's susceptibility to treatment. Accordingly, no single concentration will be uniformly useful, but will require modification depending on the particularities of the disease being treated. Such concentrations can be arrived at through routine experimentation.
• variable R represents a substituted 5,6,7,8-tetrahydronapthalen-2-yl radical, a substituted thiochroman-6-yl radical, a substituted l,2,3,4-tetrahydroquinolin-6-yl 25 radical, a substituted chroman-6-yl radical, a substituted 7,8-dihydronapthalen-2-yl radical, a substituted-indan-6-yl radical, or a substituted 5,6,7,8- tetrahydroquinoxalin-2-yl radical.
• R independently represents alkyl of 1 to 6 carbons, more preferably alkyl of 1 to 3 carbons, and even more 30 preferably methyl, and the variable m is preferably an integer having the value of 2 to 4. 3774.1064003
• the aromatic portion of the moiety designated R is either unsubstituted with and R 2 group (n is zero) or substimted with one or two R 2 groups which are preferably alkyl of 1 to 6 carbons, more preferably alkyl of 1 to 3 carbons.
• the aromatic or heteroaromatic radical represented by Y is preferably phenyl, pyridyl, thienyl or furyl. Even more preferably Y is phenyl, and more preferably the phenyl group is substimted by the chalcone oxime linker and the A-B group in the 1,4 (para) position.
• Y When Y is pyridyl, it is preferably substimted by the chalcone oxime linker and the A-B group in the 2,5 position.
• the thienyl or 10 furyl groups are preferably substitated by the chalcone oxime linker and the A-B group in the 2,4 or 2,5 positions.
• the fluoro group is preferably attached in the 1,2 (ortho) position relative to the chalcone 15 oxime linker.
• the A-B group preferably represents (CH 2 ) q -COOH, (CH 2 ) q -COOR 8 , or (CH 2 ) q -CONR 9 R ⁇ o. More preferably q is zero (0) and B is COOH, the cation of a pharmaceutically acceptable salt, or Rs is alkyl of 1 to 3 carbons, or methoxymethyl. In the most preferred compounds of the invention R 8 is H or the cation of a 20 pharmaceutically acceptable salt.
• Table 1 The structures of the presently most preferred compounds of the invention are shown in Table 1, and the experimental procedures for their syntheses are described below.
• ketone 1 (5.78 g, 98 % yield) as a white solid :
• reaction mixture was acidified with IN HC1 and extracted with ethyl acetate (3 x 10 mL). The combined organic layer was washed with brine (1 10 mL), dried (MgS0 4 ) and concentrated at reduced pressure.
• N-Heptyl-6-acetyl -4,4-dimethyl-3 ,4-dihydro-7H-quinolin-2-one (Compound 29) Sodium hydride (21.0 mg, 90.0 mmol) was slowly added into a solution of 6- acetyl-4,4-dimethyl-3,4-dihydro-iH-quinolin-2-one (Compound 28, 98.0 mg, 45.0 mmol) in 3 mL of DMF at 0 °C. After stirring at 0 °C for 10 min, 1-iodoheptane (30.5 mg, 135.0 mmol) was added to the reaction mixture and the ice-bath was removed.
• reaction mixture was allowed to stir for 2 h and then quenched with ice water.
• the resulting solution was then extracted with ether (3 x 10 mL), washed with brine (1 10 mL), dried (MgS0 ) and concentrated at reduced pressure.
• Reaction Scheme 14 serves as an example for preparing compounds of the invention which are benzodihydrofuran derivatives, that is where the variable R of 20 Formula 1 is represented by Formula (c) or Formula (d). More specifically, Reaction Scheme 14 and the following reaction schemes illustrate the synthesis of bromo compounds within the scope of Formula 10 from which compounds of the invention can be obtained by the steps shown in Reaction Scheme 3b.
• Reaction Scheme 14 illustrates the synthesis of 25 the compounds of the invention where the variable (R m represents geminal dimethyl groups substituting one or two carbons of the non-aromatic portion of the dihydrobenzofuran nucleus.
• R m represents geminal dimethyl groups substituting one or two carbons of the non-aromatic portion of the dihydrobenzofuran nucleus.
• N-bromosuccinimide ⁇ BS
• THF tetrahydrofuran
• 4-bromo-2,2,7,7- tetramethyl-dihydro- ⁇ o-benzofuran of Formula 12 4-bromo-2,2,7,7- tetramethyl-dihydro- ⁇ o-benzofuran of Formula 12.
• 4-bromophenol is reacted with 3-chloro-2-methyl-prop-l-ene in the presence of strong acid (H 2 S0 4 ), and thereafter 5 with strong base ( ⁇ aH) to provide 3,3-dimethyl-5-bromo-dihydrobenzofuran of Formula 13.
• the bromo compounds of Formulas 12 and 13 are subjected to the same sequence of reactions (not shown in Scheme 14) as the bromo compounds of Formula 10 in Reaction Scheme 3 to provide compounds of the invention in accordance with Formula 1 where the variable R is dihydro-z ' s ⁇ -berizofuran or 10 dihydrobenzofuran radical.
• Reaction Scheme 15 provides examples for preparing compounds of the . invention which are chromene or thiochromene derivatives, that is where the variable R of Formula 1 is represented by Formula (f) and where the dashed line represents presence of a bond.
• the scheme illustrates the synthesis of the compounds of the invention where the variable (R ⁇ ) m 20 represents geminal dimethyl groups substituting carbon 2 of the non-aromatic 3774.1064003
• the compound of Formula 15 is reacted with a Grignard reagent of the formula RiMgX (where X is halogen and Ri is defined as in connection with Formula 1) and then with acid to provide the 7-bromo-2,2-dimethyl-thio-chromene or corresponding chromene derivative of Formula 16.
• a Grignard reagent of the formula RiMgX where X is halogen and Ri is defined as in connection with Formula 1

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