Polycyclic amines for opioid receptor modulation

Abstract

The present invention discloses a number of polycyclic amines useful as opioid receptor modulators. The compounds of the present invention are useful in both therapeutic and diagnostic methods, including the treatment of pain, neurological disorders, cardiac disorders, intestinal disorders, drug and alcohol addiction, drug overdose, urinary disorders, respiratory disorders, sexual dysfunction, psoriasis, transplant rejection, or cancer.

Description

[Background technology]

[0001] There continues to be a need for new opioid receptor modulators for pain management with reduced or mitigated side effects. There also continues to be a need for opioid receptor modulators for treating migraine, depression, cognitive impairment, Parkinson's disease, locomotor disorders, pruritus, diarrhea, irritable bowel syndrome and gastrointestinal disorders, bladder dysfunction, overactive bladder, urinary incontinence, neurogenic bladder, interstitial cystitis, drug addiction, alcoholism, drug overdose, premature ejaculation, cough, pulmonary edema, heart disease, cardioprotection, and respiratory depression, as well as for immunomodulators and antitumor agents. Many such opioid receptor modulators are disclosed in U.S. Patent No. 10,676,456 (incorporated by reference). Some additional new compounds are listed below. Summary of the Invention [Means for solving the problem]

[0002] The present invention provides polycyclic amines, prodrugs and pharmaceutically acceptable salts thereof ("compounds of the invention") useful in the treatment of diseases through modulation of opioid receptors, similar to the compounds and uses thereof disclosed in U.S. Patent No. 10,676,456. The processes for making the compounds described below are either disclosed in U.S. Patent No. 10,676,456 or are similar to the processes for making the compounds disclosed therein.

[0003] The compounds of the present invention are useful for preventing or treating diseases or conditions selected from the group consisting of cardioprotection, heart disease, analgesia, functional pain, inflammatory pain, peripherally mediated and neuropathic pain, non-somatic pain, arthritis, psychiatric disorders, cognitive impairment, depression, Parkinson's disease, motor dysfunction, genitourinary disorders, bladder dysfunction, overactive bladder, urinary incontinence, neurogenic bladder, psoriasis, pruritus, vomiting, acne, skin lesions, non-ulcer dyspepsia, gastrointestinal disorders, functional bowel disorders, diarrhea, inflammatory bowel disease, irritable bowel syndrome, interstitial cystitis, sexual dysfunction, drug addiction, alcoholism, drug overdose, premature ejaculation, asthma, cough, pulmonary edema, respiratory dysfunction, respiratory depression, functional bloating, and motility or secretory disorders.These compounds are also useful for immunomodulation, suppressing or preventing rejection of organ transplants or skin grafts, or treating tumors or cancer.All such treatments include administering to patients an effective amount of one or more compounds of the present invention.

[0004] The present invention also includes pharmaceutical compositions comprising a pharmaceutically acceptable carrier and one or more of the compounds of the present invention. These and other aspects and embodiments of the present invention will become apparent from the detailed description that follows. DETAILED DESCRIPTION OF THE INVENTION

[0005] Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

[0006] The compounds of the present invention or their pharmaceutically acceptable salts may have asymmetric carbon atoms or double bonds in their structure.Thus, the compounds of the present invention and their pharmaceutically acceptable salts may exist as single stereoisomers, racemates, and mixtures of enantiomers, diastereoisomers, and geometric isomers.All such single stereoisomers, racemates, and mixtures thereof are intended to be within the scope of the present invention.When the absolute configuration of a particular carbon atom in a compound is known, it is indicated by the appropriate absolute descriptor R or S.

[0007] The compounds of the present invention may be synthesized in the form of a racemic mixture of enantiomers that can be separated from each other according to resolution procedures well known in the art. The racemic compounds of the present invention may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. The diastereomeric salt forms are then separated, for example, by selective or fractional crystallization, and the enantiomers are liberated therefrom by alkali. Another method for separating the optical isomers of the compounds of the present invention includes liquid chromatography using a chiral stationary phase. The pure stereochemically isomers may also be derived from the corresponding pure stereochemically isomers of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably, when a specific stereoisomer is desired, the compound is synthesized by a stereospecific preparation method. These methods advantageously use enantiomerically pure starting materials.

[0008] The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as tritium (H), iodine-125 (I), or carbon-14 (C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0009] As used herein, "treatment" includes prophylactic, therapeutic and / or preventative treatment for humans and other animals.

[0010] A "pharmaceutically or therapeutically effective dose or amount" refers to a dosage level sufficient to induce a desired biological result. That result can be the alleviation of the signs, symptoms, or causes of a disease, or any other alteration of a biological system that is desired. The exact dose will vary depending on various factors, including, but not limited to, the age and size of the subject, the disease, and any treatment being performed.

[0011] A "recipient" or "patient" or "subject" is a living mammal, human or animal, for whom treatment is desired. A "recipient," "patient," or "subject" generally refers to the recipient of treatment administered according to the methods of the present invention. It should be noted that the invention described herein can be used in veterinary as well as human applications, and the term "recipient" should not be construed as limiting. For veterinary applications, the dose range can be determined as described below, taking into account the animal's body weight.

[0012] As used herein, the term "pharmaceutically acceptable" means approved by a federal or state regulatory agency or listed in the United States Pharmacopoeia or other generally recognized pharmacopoeias approved for use in animals, especially humans. The term "carrier" refers to a diluent, adjuvant, excipient, or dispersion medium with which the therapeutic is administered, including, but not limited to, sterile liquids such as water and oils.

[0013] The term "pharmaceutically acceptable salts" is intended to include salts of active compounds prepared with relatively non-toxic acids or bases, depending on the particular substituents found on the compounds described herein. When a compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts. When a compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like. Also included are salts of amino acids such as arginates, and salts of organic acids such as glucuronic acid or galacturonic acid (see, e.g., Berge et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science 66:1-19 (1997)). Certain compounds of the present invention contain both basic and acidic functional groups that allow the compounds to be converted into either base or acid addition salts.

[0014] Other examples of pharmaceutically acceptable salts of the present invention include salts derived from appropriate bases, such as alkali metals (e.g., sodium, potassium), alkaline earth metals (e.g., calcium, magnesium), ammonium, and NR'4 (where R' is C1-C4 alkyl). Pharmaceutically acceptable salts of the present invention having an amino group include salts of organic carboxylic acids such as acetic acid, lactic acid, tartaric acid, malic acid, lactobionic acid, fumaric acid, and succinic acid, organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, isethionic acid, benzenesulfonic acid, and p-toluenesulfonic acid, and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and sulfamic acid. Pharmaceutically acceptable salts of the present invention having a hydroxyl group include salts of Na + , NH4 + , or NR'4 + The compound may comprise the anion of such a compound in combination with a suitable cation such as, for example, where R' is a C1-C4 group.

[0015] The neutral forms of the compounds of the invention are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0016] In addition to salt forms, the present invention provides compounds in prodrug form. Prodrugs of the compounds described herein are such compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention.

[0017] Additionally, prodrugs may be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. For example, they may be bioavailable by oral administration while the parent drug is not. Prodrugs may also have improved solubility in pharmaceutical compositions over the parent drug. A wide variety of prodrug derivatives are known in the art, including those that rely on hydrolysis or oxidative activation of the prodrug. A non-limiting example of a prodrug is a compound of the present invention that is administered as an ester ("prodrug"), which is then metabolically hydrolyzed to the carboxylic acid, the active agent. Further examples include peptidyl derivatives of the compounds of the present invention. Certain compounds of the present invention may exist in solvated forms, including unsolvated forms as well as hydrated forms. In general, solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

[0018] A "pharmaceutical composition" is a formulation containing the disclosed compounds in a form suitable for administration to a subject. Pharmaceutical compositions of the present invention are preferably formulated to be compatible with their intended route of administration. Examples of routes of administration include, but are not limited to, oral and parenteral, e.g., intravenous, intradermal, subcutaneous, inhalation, topical, transdermal, transmucosal, and rectal administration.

[0019] The compounds of the present invention may be combined with exogenous receptors or used as complexing compounds and may be used to bind opioid receptors. Additionally, the compounds may be used as conjugates in agonist / antagonist pairs for specific applications in transduction assays of neurotransmitter function in relevant cell lines or differentiated tissue systems, as well as receptor assays, differential binding, and cellular, histological, and physical monitoring and evaluation purposes.

[0020] For therapeutic intervention, the compounds of the invention can be administered in a pharmaceutical composition containing the compound and a pharmaceutically acceptable carrier. The present invention contemplates the use of any means and / or mode of administration of the compositions of the invention.

[0021] The compounds of the present invention include physiologically functional derivatives thereof. "Physiologically functional derivatives" include pharmaceutically acceptable salts, ethers, esters, or salts of ethers or esters of the compounds of the present invention, or any other compounds that, upon administration to a recipient, can provide (directly or indirectly) the compounds of the present invention, or active metabolites or residues thereof. Phenol C1-C6 alkyl ethers are a subclass of physiologically functional derivatives of the compounds of the present invention.

[0022] When used in pharmaceutical or diagnostic applications, the compounds of the present invention are preferably prepared in racemic mixture or essentially pure enantiomeric form, having an enantiomeric purity of at least 90% enantiomeric excess (EE), preferably at least 95% EE, more preferably at least 98% EE, and most preferably at least 99% EE. Enantiomeric excess provides a quantitative measure of the excess of the percentage amount of a major isomer over the percentage amount of minor isomers present therewith, and can be readily determined by suitable methods well known and established in the art, such as, for example, chiral high-pressure liquid chromatography (HPLC), chiral gas chromatography (GC), nuclear magnetic resonance (NMR) using chiral shift reagents, and the like.

[0023] The subjects treated by administration of the compounds of the invention are preferably human subjects, but also include non-human mammals and other animals (eg, birds, dogs, cats, cows, horses).

[0024] Depending on the particular condition being treated, subjects may be administered the compounds of the present invention at any suitable, therapeutically effective and safe dosage, which can be readily determined within the skill of the art and extrapolated without undue experimentation from the animal dosages described in the Examples herein. Compounds of the present invention demonstrate efficacy in in vivo tests for agonist / antagonist activity, such as receptor binding affinity tests and tests for inhibiting muscle contractions induced by electrical stimulation.

[0025] Generally, effective dosages of the compounds of the invention for therapeutic use will vary widely in the broad practice of the invention depending on the particular use, condition, or disease state involved, as can be readily determined by one of skill in the art, but suitable therapeutic dosages of the compounds of the invention to achieve a therapeutic effect for each of the relevant compositions described herein and in the treatment of each of the conditions described herein are in the range of 10 micrograms (μg) to 100 milligrams (mg) per kg of recipient body weight per day, preferably in the range of 50 μg to 75 mg per kg of recipient body weight per day, and most preferably in the range of 100 μg to 50 mg per kg of recipient body weight per day. The desired dosage is preferably presented as one, two, three, four, five, six, or more subdoses administered at appropriate intervals throughout the day. These sub-doses may be administered in unit dosage forms, for example, containing 10 μg to 1000 mg, preferably 50 μg to 500 mg, more preferably 50 μg to 250 mg, and most preferably 50 μg to 10 mg of active ingredient per unit dosage form, or, if the recipient's condition requires it, the dosages may be administered as a continuous infusion.

[0026] The mode of administration and dosage form affect the therapeutic amount of compound that is desirable and effective for a given therapeutic application.

[0027] For example, oral dosages are typically at least twice, e.g., 2 to 10 times, the dosage levels of the same active ingredient used in parenteral administration. For oral administration, the dosage level of the delta receptor binding compounds of the present invention may be about 5 to 200 mg / 70 kg body weight / day. For tablet dosage forms, typical dosage levels of the active ingredient are about 10 to 100 mg per tablet.

[0028] The compounds of the present invention may be administered per se as well as in the form of pharmaceutically acceptable esters, salts, and ethers, and other physiologically functional derivatives of such compounds.

[0029] The present invention also contemplates pharmaceutical compositions for both veterinary and human medical use that contain one or more compound(s) of the invention as an active agent.

[0030] In such pharmaceutical compositions, the active agent is preferably utilized together with one or more pharmaceutically acceptable carrier(s) therefor and, optionally, any other therapeutic ingredients. The carrier(s) preferably will be compatible with the other ingredients of the formulation and not unduly deleterious to the recipient thereof. The active agent is preferably in a pharmaceutically acceptable amount effective to achieve the desired pharmacological effect.

[0031] Formulations include those suitable for parenteral as well as parenteral administration, with specific modes of administration including oral, rectal, topical, sublingual, mucosal, transdermal, nasal, ophthalmic, subcutaneous, intramuscular, intravenous, transdermal, spinal, intrathecal, intraarticular, intraarterial, intrathecal, bronchial, lymphatic, and intrauterine administration. Formulations suitable for oral administration are preferred.

[0032] When the active agent is utilized in a formulation comprising a liquid solution, the formulation may be advantageously administered parenterally. When the active agent is used in a liquid suspension formulation or as a powder in a biocompatible carrier formulation, the formulation may be advantageously administered orally, rectally, or bronchially.

[0033] When the active agent is utilized directly in powdered solid form, it may be advantageously administered orally, or alternatively, it may be administered intrabronchially via nebulization of the powder in a carrier gas to form a gaseous dispersion of the powder that is inhaled by the patient from a breathing circuit containing a suitable nebulizer device.

[0034] In some applications, it may be advantageous to utilize the active agent in a "vectorized" form, such as by encapsulating the active agent in a liposome or other encapsulation vehicle, or by immobilizing the active agent by covalent bonding, chelation, or associated coordination on a suitable biomolecule, such as, for example, one selected from proteins, lipoproteins, glycoproteins, and polysaccharides.

[0035] The compound of the present invention can be conveniently provided in unit dosage form, and can be prepared by any method well known in the field of pharmacy.This method generally comprises the step of associating compound(s) with carrier, which constitutes one or more accessory ingredients.Typically, the compound is prepared by uniformly and intimately associating active compound(s) with liquid carrier, finely divided solid carrier, or both, and then, if necessary, shaping the product into the dosage form of the desired compound.

[0036] Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets, lozenges, etc., each containing a predetermined amount of the active ingredient as a powder or granules, or as a suspension in an aqueous liquid such as a syrup, elixir, emulsion, or draft, or in a non-aqueous liquid.

[0037] Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active compound in a free-flowing form, such as a powder or granules, optionally mixed with a binder, disintegrant, lubricant, inert compound, surfactant, or discharging agent. Molded tablets consisting of a mixture of the powdered active compound and the compound with a suitable carrier may be made by molding in a suitable machine.

[0038] A syrup may be made by adding the active compound to a concentrated, aqueous solution of a sugar, for example, sucrose, to which may also be added any accessory ingredient(s), such as flavorings, suitable preservatives, agents which retard sugar crystallization, and agents which increase the solubility of other ingredients, such as, for example, polyhydroxy alcohols, such as glycerol or sorbitol.

[0039] Formulations suitable for parenteral administration conveniently comprise a sterile aqueous preparation of the active compound, which is preferably isotonic with the recipient's blood (e.g., physiological saline). Such formulations may also contain suspending agents and thickening agents, as well as liposomes or other microparticulate systems designed to target the compound to blood components or one or more organs. Formulations may be provided in unit-dose or multi-dose form.

[0040] Nasal spray formulations comprise purified aqueous solutions of the active compounds containing preservatives and isotonic agents. Such formulations are preferably adjusted to a pH and isotonic state compatible with the nasal mucous membranes.

[0041] Formulations for rectal administration may be presented as a suppository with a suitable carrier such as cocoa butter, hydrogenated fats, or hydrogenated fatty carboxylic acids.

[0042] Ophthalmic formulations are prepared in a similar manner to the nasal spray, except that the pH and isotonicity factors are preferably adjusted to match that of the eye.

[0043] Topical formulations contain the active compound dissolved or suspended in one or more vehicles such as mineral oil, petroleum, polyhydroxy alcohols, or other bases used in topical formulations.

[0044] Transdermal formulations may be prepared by incorporating the active agent into a thixotropic or gelatinous carrier such as a cellulosic medium, e.g., methylcellulose or hydroxyethylcellulose, and the resulting formulation is then loaded into a transdermal device adapted to be secured in transdermal contact with the skin of the wearer.

[0045] In addition to the aforementioned ingredients, the formulations of the present invention may further comprise one or more accessory ingredient(s) selected from diluents, buffers, flavoring agents, binders, disintegrants, surfactants, thickeners, lubricants, preservatives (including antioxidants), and the like.

[0046] The disease state or physiological condition involved in such therapeutic intervention may be of any type or kind described above, for example, centrally mediated disorders such as pain, depression, drug addiction and drug dependency, alcoholism and peripheral neuropathic pain, cough, pulmonary edema, gastrointestinal disorders, arthritis, psoriasis, asthma, inflammatory bowel disease, respiratory dysfunction, functional bowel disease, irritable bowel syndrome, diarrhea, functional bloating, pain (functional pain, traumatic pain, etc.), non-ulcer dyspepsia, genitourinary disorders, premature ejaculation, overactive bladder, urinary incontinence, organ transplant rejection, skin transplant rejection, cardiac disease, cardioprotection, vomiting, acne and skin lesions.

[0047] The compounds of the present invention may be readily synthesized within the purview of those skilled in the art and in view of the illustrative synthetic examples set forth below.

[0048] The present invention is further illustrated by the following non-limiting preparative schemes and other examples.

[0049] Preparation of Opioid Receptor Modulators

[0050] The following exemplary schemes show methods of preparing compounds of the present invention, wherein the compounds have a structure according to Formula I, including pharmaceutically acceptable salts and other derivatives of this structure. JPEG0007680053000001.jpg74122 During the ceremony, A includes substituted or unsubstituted alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and arylalkyl; Y includes substituted or unsubstituted alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl; Q includes substituted or unsubstituted aryl, heteroaryl, and null; W is substituted or unsubstituted, saturated or unsaturated (i) a 4- to 8-membered heterocycle containing an N-substituent as a ring atom; (ii) each ring has 4 to 10 members; a fused bicyclic or fused heterobicyclic ring in which at least one of the rings contains an N-substituent as a ring atom; G comprises a substituted or unsubstituted alkyl or N atom; Z includes substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and null; If Z is null, then T is null, but if Z is not null, then T is (i) the moieties H, OH, NH2, NO2, -SO2NH2, halogens; (ii) substituted or unsubstituted alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; When G is alkyl, n is an integer of 1 to 4, and when G is a N atom, n is 1; R 1 and R3 is a member independently selected from H and substituted or unsubstituted alkyl, heteroalkyl, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, aryl, and heteroaryl; m is an integer from 0 to 8, and R 2 , R 4 , R 5 and R 6 may be the same or different, and R 2 , R 4 , R 5 and R 6 are each independently selected from H and substituted or unsubstituted alkyl, heteroalkyl, 3- to 7-membered cycloalkyl, and 3- to 7-membered heterocycloalkyl; R 2 , R 4 , R 5 and R 6 If m is greater than 1 for any of these, then 2 , R 4 , R 5 and R 6 Each member in the chain may be the same or different, and furthermore, R 2 , R 4 , R 5 and R 6 is always less than or equal to the number of W ring positions available for covalent bonding, R 1 and R 3 , or R 1 or R 3 and Z or R 2 and A or R 2 and Y, together with the group to which they may be attached, optionally form a substituted or unsubstituted 3- to 7-membered ring.

[0051] <Scheme 1> Compounds of Formula I where "A" is an alkyl or heteroalkyl moiety are synthesized as shown in Scheme 1. The synthesis of compounds 1-6 is illustrated. JPEG0007680053000002.jpg109152 wherein, for Scheme I above, X is selected from Cl, BR, I, p-toluenesulfonyl (ToS), methanesulfonyl (MS), and trifluoromethanesulfonyl (Tf).

[0052] In Scheme I, substituted cyclic ester 1-1 is deprotonated in the presence of a strong base such as LDA or LHMDS, followed by alkylation to give 1-2a. Reduction of 1-2a followed by alkylation affords ether 1-4. Deprotection of the Boc group in 1-4 is carried out in the presence of an acid such as TFA or HCl. Reductive amination of 1-5 with a suitable aldehyde or ketone 1-5a, or alkylation of 1-5 with 1-5b under basic conditions, affords 1-6. R 1 Compounds with moieties different from 1-2b are exemplified by the synthesis of intermediates such as 1-2b, 1-2c, or 1-2d. Reaction of 1-1 with an appropriate ketone or aldehyde 1-7 provides intermediate 1-2b. Activation of the hydroxyl group of 1-2b using MSCl, followed by elimination in the presence of a base such as DBU, generates unsaturated intermediate 1-2c. Hydrogenation of 1-2c provides intermediate 1-2d.

[0053] <Scheme 2> Compounds of formula I where "A" is a cyclic alkyl or cyclic heteroalkyl moiety are synthesized as shown in Scheme 2. The synthesis of compounds 2-6 is used as an example. JPEG0007680053000003.jpg151140

[0054] Oxidation of 1-3 to 2-1 can be achieved by Swern oxidation or other oxidizing agents such as Dess-Martin periodinane. Grignard reaction of aldehyde 2-1 with unsaturated or saturated Grignard reagents, followed by alkylation with unsaturated or saturated alkylating agents under basic conditions, affords 2-3. Ring-closing metathesis (Ring-cloSing metatheSiS, RCM) of 2-3 catalyzed by a catalyst such as Grubb's ruthenium-carbene complex affords unsaturated or saturated oxygen-containing heterocycles 2-4 after hydrogenation. Alternatively, synthesis of 2-4 can be achieved by Grignard reaction of 2-1 with 2-1a or 2-1b, followed by either deprotection of intermediate 2-7 or hydroboration of the double bond of intermediate 2-9 to afford the corresponding diol 2-8. Diol 2-8 is converted to 2-4 by intramolecular cyclization under Mitsunobu reaction conditions or by displacement of the corresponding mesylate, tosylate, etc.

[0055] Finally, the synthesis of 2-6 from 2-4 is accomplished using the same methodology as the conversion of 1-4 to 1-6 in Scheme 1.

[0056] <Scheme 3> Compounds of Formula I where "A" is a heteroaryl moiety are synthesized as shown in Scheme 3, and are exemplified by the synthesis of 3-8. JPEG0007680053000004.jpg203147

[0057] The cyano intermediate 3-3 and the ester intermediate 3-5 are prepared by cyanation from substituted 3-2 and alkylation from 3-4, respectively, as described in Scheme 1. Using the general method illustrated in Scheme 3, the cyano group in 3-3 and the ester group in 3-5 were converted to heterocycles such as imidazoles, thiazoles, thiadiazoles, and oxadiazoles 3-6 (3-6a, 3-6b, 3-6c, and 3-6d) via the corresponding intermediates, such as amides, thioamides, hydrazides, thiohydrazides, or N-hydroxyimide amides. Conversion of 3-6 to 3-8 is achieved using the methodology shown in Scheme 1.

[0058] <Scheme 4> Compounds of Formula I where "A" is a heteroalkyl moiety are synthesized as shown in Scheme 4, and are exemplified by the synthesis of 4-6. JPEG0007680053000005.jpg87140

[0059] Suitable substituted cyclic amides 4-3 are prepared from the corresponding esters 4-1 by hydrolysis using a base such as NaOH, LiOH, KOH, etc., followed by coupling with an amine in the presence of a coupling reagent such as EDCI / HOBt, DCC, HATU, etc. Reduction of 4-3 using BH3 or LiAlH4, followed by deprotection of the Boc group of 4-4 and alkylation of 4-5 as described in Scheme 1, gives compounds 4-6.

[0060] <Scheme 5> As shown in Scheme 5, compounds of formula I where Y and Q are specific moieties are synthesized. JPEG0007680053000006.jpg108150

[0061] Reduction of the CN group to an aldehyde 5-1, followed by a Wittig reaction with a quaternary phosphonium salt such as 5-1a, affords compound 5-2. Hydrogenation of the double bond of 5-2, followed by deprotection or deprotection of 5-2, followed by alkylation, affords the unsaturated or saturated compound 5-8. The quaternary phosphonium salt 5-1a is prepared from the appropriate bromide 5-9. Conversion of the appropriate bromide 5-9 to the corresponding aldehyde 5-10, followed by reduction of the aldehyde with a suitable reducing agent such as NaBH4, affords the alcohol 5-11. Halogenation of the alcohol 5-11, followed by treatment with PPh3, affords the quaternary phosphonium salt 5-1a.

[0062] <Scheme 6> As shown in Scheme 6, compounds of Formula I in which Y and Q are other moieties than those in Scheme 5 are synthesized. JPEG0007680053000007.jpg49149 Alcohol 2-2 is oxidized with an oxidizing agent such as Dess-Martin Periodiane, PCC, etc. to form ketone 6-1. Deprotection of the Boc group in 6-1 followed by alkylation affords 6-3.

[0063] <Scheme 7> As shown in Scheme 7, compounds of formula I where Z and T are specific moieties are synthesized. JPEG0007680053000008.jpg59150

[0064] Starting material 7-1 is a group of intermediates prepared according to Schemes 1 to 6. The aryl group of 7-1 is a substituted or unsubstituted aryl group such as benzene, thiazolyl, thiophenyl, furanyl, imidazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, etc. R 4 is a functional group such as BR, I, CN, COOH, COOEt, boric acid, etc. 4 From R 6Conversion to is achieved by Suzuki coupling of boronic acid with BR or I, or by cyclization of hydrazides of esters with acids, or cyclization of N-hydroxyimidamides with acyl chlorides.

[0065] <Scheme 8> Scheme 8 shows one approach to the synthesis of stereoisomers. Furthermore, the synthesis of two enantiomerically pure isomers can also be achieved by chiral separation by chiral HPLC or by column chromatography. JPEG0007680053000009.jpg153145

[0066] In Scheme 8, ester 8-2, prepared according to Scheme 1, is hydrolyzed to acid 8-3 using an inorganic base such as LiOH, NaOH, or KOH. Activation of acid 8-3 to the corresponding acid chloride or mixed anhydride, followed by reaction with a lithiated chiral auxiliary salt, affords a mixture of diastereoisomers 8-4 and 8-5. Separation of the diastereoisomeric mixture affords the single enantiomers 8-4 and 8-5.

[0067] Enantiomerically pure intermediates such as 8-4 and 8-5 are further converted in enantiomerically pure form to various key intermediates such as 8-8 and 8-10 using the methodology shown in Schemes 1-7. Some examples are shown in Schemes 9 and 10 below.

[0068] <Scheme 9> Scheme 9 shows an example of the synthesis of enantiomerically pure compound 9-8 starting from 8-4. JPEG0007680053000010.jpg97149

[0069] The enantiomerically pure intermediate 8-4 described in Scheme 8 is reduced to the chiral alcohol 9-1 using NaBH4. The conversion of alcohol 9-1 to 9-8 is carried out according to the methodology described in Schemes 1-5. The same methodology as demonstrated in Scheme 9 is used to synthesize the enantiomers of 9-8 starting from the enantiomerically pure intermediate 8-5.

[0070] <Scheme 10> Scheme 10 shows an example of the synthesis of enantiomerically pure compound 10-8 starting from 8-5. JPEG0007680053000011.jpg96136

[0071] Enantiomerically pure compound 10-8 is synthesized starting from 8-5 according to the methodology described in Scheme 9. The same methodology as demonstrated in Scheme 10 is used to synthesize the enantiomers of 10-8 starting from enantiomerically pure intermediate 8-4.

[0072] <Scheme 11> Scheme 11 shows an example of the synthesis of enantiomeric intermediates 10-3 and 9-1 starting from 8-3 by chiral resolution. JPEG0007680053000012.jpg128150

[0073] Enantiomeric intermediates 10-3 and 9-1 were synthesized starting from 8-3 according to the methodology described in Scheme 9 and Scheme 10. The same methodology as demonstrated in Scheme 11 was used to synthesize the enantiomers of 10-3 and 9-1 starting from enantiomerically pure intermediate 11-2.

[0074] Compound (composition) formulation

[0075] For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be either solid or liquid.Solid preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.Solid carriers can be one or more substances that can also function as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or encapsulating materials.

[0076] In powders, the carrier is a finely divided solid, which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

[0077] Powders and tablets preferably contain 5% or 10% to 70% of the active compound. Suitable carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting waxes, cocoa butter, and the like. The term "formulation" is intended to include formulations of the active compound with an encapsulating material as a carrier, in which the active ingredient, with or without other carriers, is surrounded by a carrier, thus providing a capsule in which it is associated with the carrier. Cachets and lozenges are also included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0078] For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active ingredient is dispersed homogeneously therein, as by stirring, etc. The molten homogeneous mixture is then poured into suitable sized molds, allowed to cool and thereby solidify.

[0079] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water / propylene glycol solutions.For parenteral injection, liquid preparations can be formulated in solution in polyethylene glycol solution.

[0080] Aqueous solutions suitable for oral use can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active ingredient in water containing viscous materials such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.

[0081] Also included are solid form preparations which are intended to be converted, shortly before use, to liquid preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions, which may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

[0082] Pharmaceutical preparations are preferably in unit dosage form.In this form, the preparation is divided into unit doses containing appropriate amounts of active ingredients.The unit dosage form can be a packaged preparation, and the package contains individual amounts of preparations, such as packets of tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

[0083] The quantity of active ingredient in a unit dosage preparation may be varied or adjusted to provide a pharmaceutically acceptable dose of the active ingredient.

[0084] The compounds of the present invention and their properties for some of them are listed in Tables I to VI below.

[0085] The pyrrolidine ring and pyridine or pyridine-like molecule are pyrrolidine N-structures. Compounds bound to constituents JPEG0007680053000013.jpg245157JPEG0007680053000014.jpg246157JPEG0007680053000015.jpg240157JPEG0007680053000016.jpg245157JPEG0007680053000017.jpg245157JPEG0007680053000018.jpg244157JPEG0007680053000019.jpg245158JPEG0007680053000020.jpg229158JPEG0007680053000021.jpg245157JPEG0007680053000022.jpg245157JPEG0007680053000023.jpg234157JPEG0007680053000024.jpg238158JPEG0007680053000025.jpg229157JPEG0007680053000026.jpg231157JPEG0007680053000027.jpg246157JPEG0007680053000028.jpg245157JPEG0007680053000029.jpg245158JPEG0007680053000030.jpg244157JPEG0007680053000031.jpg248157JPEG0007680053000032.jpg245157JPEG0007680053000033.jpg235157JPEG0007680053000034.jpg246157JPEG0007680053000035.jpg227157JPEG0007680053000036.jpg219158JPEG0007680053000037.jpg232158JPEG0007680053000038.jpg245156JPEG0007680053000039.jpg245158JPEG0007680053000040.jpg245156JPEG0007680053000041.jpg223157JPEG0007680053000042.jpg223157JPEG0007680053000043.jpg235157JPEG0007680053000044.jpg235157JPEG0007680053000045.jpg244157JPEG0007680053000046.jpg243157JPEG0007680053000047.jpg243157JPEG0007680053000048.jpg244157JPEG0007680053000049.jpg246157JPEG0007680053000050.jpg245157JPEG0007680053000051.jpg246157JPEG0007680053000052.jpg240158JPEG0007680053000053.jpg245157JPEG0007680053000054.jpg244157JPEG0007680053000055.jpg243157JPEG0007680053000056.jpg231158JPEG0007680053000057.jpg244157JPEG0007680053000058.jpg244157JPEG0007680053000059.jpg225158JPEG0007680053000060.jpg245156JPEG0007680053000061.jpg240157JPEG0007680053000062.jpg235157JPEG0007680053000063.jpg224157JPEG0007680053000064.jpg229157JPEG0007680053000065.jpg218157JPEG0007680053000066.jpg234157JPEG0007680053000067.jpg245157JPEG0007680053000068.jpg229157JPEG0007680053000069.jpg245157JPEG0007680053000070.jpg230157JPEG0007680053000071.jpg225158JPEG0007680053000072.jpg245157JPEG0007680053000073.jpg246156JPEG0007680053000074.jpg245157JPEG0007680053000075.jpg229157JPEG0007680053000076.jpg245157JPEG0007680053000077.jpg240157JPEG0007680053000078.jpg234158JPEG0007680053000079.jpg245157JPEG0007680053000080.jpg235157JPEG0007680 053000081.jpg241157JPEG0007680053000082.jpg236157JPEG0007680053000083.jpg246157J PEG0007680053000084.jpg245157JPEG0007680053000085.jpg235158JPEG0007680053000086. jpg245157JPEG0007680053000087.jpg245157JPEG0007680053000088.jpg245156JPEG0007680 053000089.jpg240157JPEG0007680053000090.jpg245157JPEG0007680053000091.jpg240156J PEG0007680053000092.jpg246157JPEG0007680053000093.jpg235156JPEG0007680053000094. jpg246157JPEG0007680053000095.jpg245156JPEG0007680053000096.jpg245156JPEG0007680 053000097.jpg246157JPEG0007680053000098.jpg246157JPEG0007680053000099.jpg194157.

[0086] Explanation of columns 4 and 5 of Tables I, III, and V: Electrospin ionization (ESI) was used for mass analysis of the compounds, and the measured mass results are shown in column 4. The rightmost (fifth) column shows the H NMR of such compounds in MeOD at 300 MHz.

[0087] Enantiomeric and in vivo testing of selected compounds of Table I JPEG0007680053000100.jpg245148JPEG0007680053000101.jpg243149JPEG0007680053000102.jpg191149

[0088] Explanation of Table II, center column:

[0089] "S" means that the S enantiomer was tested and the results are shown in the right-most column.

[0090] "R" means that the R enantiomer was tested and the results are shown in the right-most column.

[0091] "R&S" means that the racemate was tested.

[0092] "S, S or R" means that the compound has two chiral centers and can potentially have four diastereoisomers. Compounds with S at the first chiral center and S or R at the second chiral center were tested.

[0093] "R, R&S" means that the compound has two chiral centers and can have four diastereoisomers. Compounds with R at the first chiral center and racemic at the second chiral center were tested.

[0094] "S, R&S" means that the compound has two chiral centers and can have four diastereoisomers. Compounds with S at the first chiral center and racemic at the second chiral center were tested.

[0095] The rightmost column of Table II: Antinociception and warm-water tail-flick test results are shown for male C57BL / 6 mice (20-30 g, 6-12 weeks) maintained on a 12-h light / dark cycle with rodent chow and water ad libitum and housed individually until testing. Antinociception was assessed using the 55°C warm-water tail-flick test. The latency to the first sign of a rapid tail flick was used as the behavioral endpoint. Each mouse was first tested for baseline latency by immersing its tail in water and recording the time to respond. Mice that did not respond within 2 seconds were excluded from further testing. Responding mice were then administered the test compound by subcutaneous application and subsequently tested for antinociception at 30, 60, 90, and 120 minutes. Antinociception was calculated using the following formula: percentage antinociception = 100 x (test latency - control latency) / (20 - control latency). To avoid tissue damage, animals that did not respond within 20 seconds were assigned the maximum score (100%).

[0096] Novel compounds with pyrrolidine rings and non-pyridine-like molecules attached to the pyrrolidine N-unit JPEG0007680053000103.jpg245159JPEG0007680053000104.jpg245159JPEG00076800530 00105.jpg223159JPEG0007680053000106.jpg246159JPEG0007680053000107.jpg246159 JPEG0007680053000108.jpg245159JPEG0007680053000109.jpg245159JPEG00076800530 00110.jpg230159JPEG0007680053000111.jpg240160JPEG0007680053000112.jpg168159 *The explanations for the fourth and fifth columns of Table III are the same as those in Table I.

[0097] Enantiomeric and in vivo testing of compounds Nos. 1 to 25 in Table III JPEG0007680053000113.jpg187153

[0098] Legend to Table IV, center column: "S, S&R" means that the compound has two chiral centers and has four possible diastereoisomers. Compounds with S at the first chiral center and racemic at the second chiral center were tested.

[0099] Novel compounds with pyridine rings and other groups attached to the pyridine N-building block thing JPEG0007680053000114.jpg245162JPEG0007680053000115.jpg244160JPEG0007680053000116.jpg233163JPEG0007680053000117.jpg222162 JPEG0007680053000118.jpg223162JPEG0007680053000119.jpg236163JPEG0007680053000120.jpg247162JPEG0007680053000121.jpg241162 JPEG0007680053000122.jpg246162JPEG0007680053000123.jpg241162JPEG0007680053000124.jpg226162JPEG0007680053000125.jpg236162 JPEG0007680053000126.jpg246163JPEG0007680053000127.jpg235162JPEG0007680053000128.jpg229162JPEG0007680053000129.jpg175162 *The explanations for the fourth and fifth columns of Table V are the same as those in Table I.

[0100] In vivo testing of compounds Nos. 1 to 36 in Table V JPEG0007680053000130.jpg221148

[0101] The specific methods, processes, compounds, and compositions described herein are representative of preferred and other embodiments and are illustrative only and do not limit the scope of the invention. Other objects, aspects, and embodiments will occur to those skilled in the art in light of this specification and are encompassed within the spirit of the invention as defined by the claims. It will be readily apparent to those skilled in the art that various substitutions and modifications can be made to the invention disclosed herein without departing from the scope and spirit of the invention. The invention illustratively described herein may suitably be practiced in the absence of any element or elements or limitation or limitations not specifically disclosed herein as essential. Thus, for example, in each example herein, in embodiments or examples of the invention, any use of terms such as "comprising," "including," "containing," "having," etc. should be read expansively and without limitation. The methods and processes illustratively described herein may suitably be practiced with different orders of steps and are not necessarily limited to the order of steps set forth in the specification or claims. It should also be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references, and the plural includes the singular, unless the content clearly dictates otherwise. Under no circumstances should this patent be construed as limited to the particular examples or embodiments or methods specifically disclosed herein. Under no circumstances should this patent be construed as limited by any statements made by examiners or other officials or employees of the Patent and Trademark Office, unless such statements are specifically and without limitation or reservation expressly adopted in the applicant's responsive description.

[0102] The present invention has been described broadly and generically herein. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the present invention. The terms and expressions used are used as terms of description and not of limitation, and the use of such terms and expressions is not intended to exclude equivalents of the functions shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention as defined by the appended claims. Thus, while the present invention has been specifically disclosed by preferred embodiments and optional features, it will be understood that those skilled in the art may resort to modifications and variations of the concepts disclosed herein, and that such modifications and variations are considered to be within the scope of the invention, as defined by the appended claims.

Claims

1. A compound selected from compounds having any one of the following formulas, or a pharma- ceutically acceptable salt thereof, wherein, unless otherwise indicated, each of the following chiral compounds is in either the R or S configuration, or a pharma- ceutically acceptable salt thereof.

2. 10. Any one of compound numbers 1 to 16 according to claim 1 or a pharma- ceutically acceptable salt thereof.

3. 2. Any one of compound numbers 18 to 44 according to claim 1 or a pharma- ceutically acceptable salt thereof.

4. 2. Any one of compound numbers 82 to 109 according to claim 1 or a pharma- ceutically acceptable salt thereof.

5. 2. Any one of compound numbers 111 to 123 according to claim 1 or a pharma- ceutically acceptable salt thereof.

6. 2. Any one of compound numbers 126, 127, 280-282, 313, and 319-322 according to claim 1, or a pharma- ceutically acceptable salt thereof.

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