WO2014175713A1

WO2014175713A1 - 5-membered heterocyclic derivative, preparation method therefor and pharmaceutical composition comprising same

Info

Publication number: WO2014175713A1
Application number: PCT/KR2014/003733
Authority: WO
Inventors: 서홍원; 임순성; 박수현
Original assignee: (주) 프론트바이오; 한림대학교 산학협력단; (주) 와이디생명과학
Priority date: 2013-04-25
Filing date: 2014-04-25
Publication date: 2014-10-30
Also published as: KR20140127587A

Abstract

The present invention relates to a pharmaceutical composition comprising a 5-membered heterocyclic compound, having an analgesic effect, and a derivative thereof. More particularly, the present invention relates to a preparation method for a 5-membered heterocyclic compound having fewer side effects and having analgesic effects on a broad range of pain including neuropathic pain, and a pharmaceutical composition comprising same.

Description

[Specification J

[Name of invention]

5-membered heterocyclic derivatives, a method for their preparation and pharmaceutical compositions containing them [Technical ^minutes: -

The present invention relates to a pharmaceutical composition comprising a 5-membered heterocyclic compound having an analgesic effect and a derivative thereof. More specifically, the present invention has fewer side effects and has a wide range of analgesic effects, including neuropathic pain. It relates to a process for preparing a five-membered heterocyclic compound and a pharmaceutical composition comprising the same.

Assignment Technology

Currently, analgesics include aspirin-induced anti-inflammatory drugs such as tylenol, and in the case of severe pain, most morphine-based drugs are used. As a new pain inhibitor that has recently been developed, the roots are developed in the form of pain medications developed as narcotic analgesics. In moderate to severe postoperative pain, it was found to have an analgesic effect comparable to that of intravenous morphine. In China, Shanghai Xingtong Biotech Pharmaceutical Co., Ltd. New effect effective for pain caused by drift ice, lung and kidney-related cancer ^: "Achilles" has been developed. In addition, a new analgesic "Pi-ialt" from sea snails has been developed by K lan, an Irish pharmaceutical company, and was the first in the UK.

In Korea, there was an example of a joint research and licensing agreement with Schwarz Pharma, a German multinational pharmaceutical company, in February 2004 for a ¾ saicin antagonist developed as a non-narcotic analgesic.

As the society continues to age as well as chronic malignant neoplastic pain ^■ Patients with degenerative arthritis and low back pain are on the rise every year, but existing opiates such as morphine have been used for drug use by the general public. It is regarded as a disease, and the interest in it is increasing more than ever, and the demand for pain relief is expected to increase much in the future, and it is a time when the development of painkillers for pain that does not meet the existing painkillers is required.

In addition, not only to see a lot of you do not banung to existing drugs, sex and Bima yakseong analgesic pain is not pain hyogoe-existing opiates are known to be relatively large ^{volunteer-agent} due to its narcotic and issue of serious side effects The use of these drugs has been limited, so we are developing natural resources that have new analgesic effects without narcotic and no side effects. Currently, acetaminophen and aspirin have been used as anti-analgesic drugs. 1 day Iggi: lg to 4g should be administered in high doses, which causes side effects such as gastrointestinal disorders, allergies and hepatotoxicity. Therefore, there is an urgent need for the development of new analgesic drugs with excellent analgesic ^efficacy at low doses and no side effects.

[Detailed Description of the Invention]

ί Technical task; S

One embodiment of the invention is a compound of formula (I) or a hydrate thereof Pharmaceutically acceptable salts include:

[Formula 1]

At singular ceremony

X is 0. S, or NH.

R 'is H. Substituted or unsubstituted linear or branched d-; Alkyl. Substituted or unsubstituted C ₂ -C ₆ alkenyl ᅳ substituted or unsubstituted C _:; -C ₃ cycloalkyl. Substituted-unsubstituted C _G -C ₂₀ aryl, selected from the group consisting of N, 0, and S or H- or at least heteroatomic- and monocyclic or bicyclic forms having from 1 to 9 carbon ring members Substituted or unsubstituted heterocyclyl 해 selected from the group consisting of substituted or unsubstituted heteroaryl having one or more heteroatoms and 1 to 9 carbon ring members selected from the group consisting of N. 0 and S Become,

R ² is 0, NI-1, ᅳ (X0H)-, or -OC (O) 一,

R ³ is II, substituted or unsubstituted linear or branched CrC _in al¾, substituted or unsubstituted c ₂ -c _L0 alkenyl. Substituted or unsubstituted c _::厂 c ₁₀ cycloalkyl ᅳ substituted or unsubstituted C (;-C ₂₀ aryl, hyphenylating selected from the group consisting of N, 0 and S— and heteroatoms of 1 to 1 to nine to carbon that is not a monocycle or substituted by-cycle hyeongte having ring members for interrogating or substituted heterocyclyl. N. 0 and S to interrogating atoms and 1 to 9 carbon ring members, the more do ⁱ Suntec from the group consisting of Or substituted from unsubstituted heteroaryl,

π is an integer of ◦ to 3,

here. Substituted alkyl. Substituted alkanyls. Substituted cycloalkyl. Substituted aryl, substituted heterocyclyl and substituted heteroaryl. Alkyl, alkanyl. Cycloalkyl. Aryl, heterocyclyl and heteroaryl are each independently C 厂 C _G alkyl; C3-C2 cycloalkyl; C ₂ -C ( _; alkanyl: C ₅ -C ₁₂ heteroaryl, characterized in that the carbon constituting the ring is substituted with one or more heteroatoms selected from the group consisting of N. 0 and S: C _r Ce alkylsul Phonyl; C _G -C, 2 arylsulfonyl; C-CG alkylthio; mercapto; -011; C, -C _(; alkoxy; Ct-Qs haloalkoxy; -N¾; halo; -C00I-I;- CH0; -CN; -CC _G alkylcarbonyl; -CrCe alkyloxycarbonyl; -Nll ₂ ; -C0NH ₂ ; mono or di Cr alkylyi-mino; and mono or di Cr-Q; alkyl carbamoyl Is substituted with a substituent of hy- nicing selected from.

Another embodiment of the invention. A pharmaceutical composition comprising a compound of Formula 1, or a hydrate or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

Another di-another of the present invention is a compound of formula [or a hydrate thereof or Comprising pharmaceutically acceptable salts. Pain, acute pain. Chronic pain. Neuropathic pain, postoperative pain. migraine. Pharmaceutical compositions for treating or alleviating arthralgia.

Another embodiment of the present invention includes a method of treating or alleviating a symptom of a patient with severe pain. The method is a compound of formula (I). Or administering a hydrate or pharmaceutically acceptable salt thereof to the patient in a therapeutically effective amount.

Another embodiment of the present invention includes the anesthetic use of a compound of Formula 1, or a hydrate or pharmaceutically acceptable salt thereof.

Another embodiment of the invention provides a compound of formula [, or a hydrate thereof or

It includes a method for preparing a pharmaceutically acceptable salt.

Technical Solution

^· Yihi. It will be described in detail with reference to certain embodiments of the invention. Examples thereof are illustrated by the attached structural formulas and formulas. The invention will be described in conjunction with the enumerated embodiments. It is intended that all alternatives be included within the scope of the invention as defined in the claims. Variations and equivalents. Those skilled in the art will recognize many of the reagents used in the methods and synthesis similar or similar to those described herein, which can be used in the practice of the present invention.

Justice

The term "alkyl ', as used herein, refers to a saturated linear or branched monovalent hydrocarbon radical, wherein the alkyl radicals can be optionally substituted independently with one of the substituents described herein. in the alkyl radical has 1 to 18 carbon atoms (dC) in another example, the alkyl radical is _{CrCi 2 Ci-do C, -C} 8 CrC 6 C, -..... Cs CC, or CrC _It may have a carbon atom of _3. Examples of alkyl groups include methyl, ethyl, L-propyl, 2—propyl, 1-butyl, 2-methyl-1-propyl, 2-butyl, 2-methyl-2 ᅳ propyl , 1-pentyl.

2-pentyl (-CH (ai ₃ ) CH ₂ CH ₂ CH ₃ ). 3-pentyl (-CH ((¾CH ₃ ) ₂ ), 2-methyl- 2-butyl.

3-methyl-1 ᅳ butyl, 2-methyl-1-butyl. 1-nuclear chamber, 2-nuclear chamber, 3-nuclear chamber. 2-methyl-2-pentyl, 3-methyl-2-pentyl ᅳ 4—methyl-2—pentyl. 3 ᅳ methyl-3-pentyl, 2-meryl-3-pentyl, 2, 3-dimethyl-2—butyl. 3.3- The methyl 2-butyl may contain 1-heptyl and 1-octylol.

As used herein, the term "alkenyl" refers to a honeycomb or more of an impurity-position. That is, a linear or branched monovalent hydrocarbon radical containing carbon-carbon double grains ¾. Wherein the alkenyl radical may be optionally substituted independently with one or more substituents as defined herein. “Cis” and “trans” backings: ᅳ or alternatively, include radicals having a Έ and a 향 direction. In one example, the alkenyl radical has 2 to 18 carbon atoms (C ₂ -C). In another example. Alkanyl radicals are C ₂ -C, ₂ , C ₂ -C ₀ , c ₂ -c ₈ . c _2- c _(i or c _2-

It may have a carbon atom of < ₃ . Erotic of these. Without limitation. Ethenyl or vinyl. Prop-1-enyl, prop-2-enyl, 2—methylprop-1-enyl, boot-1-enyl, boot-2-enyl, boot— 3—enyl. Buta-1,3-dieneyl, 2-methylbutyene 1,3-diene. Nucleus—L-enyl, nux-2-enyl, nux-3-enyl, nux-4-enyl and nucleus 1.3-dienyl.

As used herein, the term “cycloalkyl” 'refers to a non-aromatic, saturated or partially unsaturated hydrocarbon ring group, wherein the single-group cycloalkyl group is optionally It may be independently substituted with a substituent or more than one described. In one example. Said cycloalkyl group has 3 to 12 carbon atoms (C ₃ -C ₁₂ ). In another. Cycloalkyl is C ₃ -C ₃ . It may have a carbon atom of C: rC, ₀ or C ₅ -C ₁₀ . In another example. As monocycle, the cycloalkyl group is C ₃ -C !. C ₃ -C ₆ or CfrC _c> may have a carbon atom. In another example. As a by-cycle itdi cycloalkyl groups may have a carbon atom of the C ₇ -C _l2 -. Examples of monocyclic cycloalkyl are cyclopropyl. Cy-ecylburyl, cyclopentyl, 1-cyclopent-1-enyl. 1-cyclopent-2-enyl ᅳ 1-cyclopent-3-enyl, cyclonuclear chamber. 1—cyclonuclear-nuil. 1-cyclonux-2i yen, 1-cyclonux-3-enyl, cyclonuclear dienyl. Cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclodecyl and cyclododecyl. Bicyclic cycloalkyl having 7 to 12 ring atoms is not limited to [4,4]. 1: 4, 5: 1. [5,5: 1, [5.6] or [6.6] ring system. Ethysically crosslinked bicyclic cycloalkyls can include, but are not limited to, bicyclo [2.2.1] heptinyl, bicyclo [2.2.2] octane and bicyclo [3.2.2] nonane.

The term "aryl," as used herein, refers to a cyclic aromatic hydrocarbon group, optionally substituted independently with one or more substituents described herein. In one example. Aryl groups of 6 to 20 carbon atoms (C (;... Has a一C ₂₀₎ In yet another example may have a carbon atom of the aryl group aeseo another example aryl groups C (;.. An aryl group ^Edie, aryl May include bicyclic groups including aromatic rings including fused non-aromatic or partially saturated rings, Exemplary aryl groups include, but are not limited to, phenyl.naphthalenyl, anthracenyl.indenyl, indanyl. Hydronaphthalenyl and 1.2.4-tetrahydronaphthyl In one example, aryl includes phenyl Substituted petroleum or substituted aryl is selected from 1,2, and 3. selected from the group specified herein. Or aryl group substituted with 1 to 2, 1 to 3 or 1 to 4 substituents. In one aryl, the aryl sine-A optional substituent is halogen (F. CI, Br. (), Hydroxy, protected under . De ethoxy, Shi, no nitro-alkyl (e.g. d-;. Alkyl), alkoxy (e.g., (-C _G-alkoxy), benzyloxy carboxy, protected carboxy, carboxymethyl protected carboxymethyl, hydroxymethyl... the protected hydroxymethyl. aminomethyl. protected aminomethyl. trifluoromethoxy ^1. alkylsulfonyl amino, alkylsulfonyl amino alkyl. aryl sulfone ilah furnace, an aryl sulfonyl amino al ¾, by interrogating cycle rilseol sulfonyl amino. Heterocyclylsulfonylaminoalkyl ᅳ Heterocyclyl, selected from aryl or other groups specified .. One or more methine (cn) and / or methylene (CH ₂ ) groups in such substituents are in turn as shown above. And fused aryl rings may be substituted with any of the substituents specified herein, such as 1. 2 or 3, in the same manner in which the alkyl group is substituted.

As used herein, the terms “heterocycle” “heterocyclyl” and “heterocyclic ring” are used interchangeably herein and include (i) saturated or partially unsaturated cyclic groups (ie. One or more in the ring Having a double and / or triple bond) (“heterocycloalkyl”), or (ii) an aromatic cyclic group (“heteroaryl”), in which case at least one ring atom is nitrogen, oxygen. A hetero atom independently selected from phosphorus and sulfur, and the remaining ring atoms are carbonidi-. Heterocyclyl groups may be optionally substituted with hyphena or more substituents described below. In one embodiment. Heterocyclyl includes monocycles or bicycles having from 1 to 9 carbon ring members (d-), with the remaining ring atoms being heteroatomide selected from N. S and P. In the De-Ran example. Heterocyclyls include monocycles or bicycles with carbon atoms of d— C ₅ , C: rC ₅ or C ₄ -C ₅ , the remaining ring atoms being heteroatoms selected from N. 0. S and P Edie-. In certain embodiments, the heterocyclyl is a 3 to 10 membered ring containing one or more heteroatoms independently selected from N, 0, S and P. 3 to 7 membered rings or 3 to 6 membered rings. In another example. Heterocyclyls include monocyclic 3-, 4-, 5-, 6- or membered rings containing the heteroatoms of one Ishing-independently selected from N, 0. S and P. In another embodiment, heterocyclyl is a bi- or poly—cy-cyclic, spiro or bridged 4-, 5-, 6 containing one or more heteroatoms independently selected from N. 0. S and P. -, 7-, 8-, 9- or 10-membered ring systems. Examples of the bicycle system include, but are not limited to, [3,5], [4,5], [5,5]. [3.6: 1. [4.6], [5,6], or [6.6] systems. Examples of bridged ring systems are: [2.2.1] without limitation.

[2.2.2], [3.2.2] and [4.1.0] alignment. Having 1 to 3 heteroatoms selected from N, 0, S and P. In another embodiment, heterocyclyl includes a spiro group having 1 to 4 heteroatoms selected from N, 0, S and P. The heterocyclyl group may be a carbon-linked or hetero atom-linked group. "Heterocyclyl" 'includes heterocyclyl groups fused to cycloalkyl groups.

The term “heteroaryl” refers to an aromatic carbocyclic radical, wherein one or more ring atoms are heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the remaining ring atoms are carbon. The heteroaryl group may be optionally substituted with one or more substituents described herein. In one example, the heteroaryl group contains 1 to 9 carbon ring atoms (d-Cf)). From to another. Heteroaryl groups are dC ₅ . C3-C5 or C ₄ — has a carbon atom of ¾. In one embodiment, exemplary heteroaryl groups contain one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur

5-10 membered rings, 5-6 membered rings or monocyclic aromatic 5 ′. 6- and its ring. In another embodiment. Examples of heteroaryl groups include up to 10 carbon atoms or in another embodiment a ring system of 9 carbon atoms. In this case, the aromatic ring of hy- naising- is nitrogen. It contains one or more heteroatoms independently selected from oxygen and sulfur. "Heteroaryl" includes heteroaryl groups fused to aryl, cycloalkyl or other heterocyclyl groups. Of heteroaryl groups. Pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl. Pyrazine. Tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl. Oxazolyl. Isothiazolyl, Pylyl. Quinolinyl. Isoquinolineyl, indolyl. Benzimidazole. Benzofuranyl. Cynolinyl, indazole, indolizinyl. Phthalazine. Pyridazine. Triazine, isoindole. Pteridylyl. Furinyl, oxadiazolyl, triazolyl. Thiadiazolyl; furazanyl, benzofurazyl, banjothiophenyl, banjothiazolyl, benzoxazolyl. Quinazolinyl, quinoxalinyl, naphthyridinyl, pirlopyrimidinyl. Pyrazolopyrimidinyl and furopyridinyl. As used herein, the expression "pharmaceutically acceptable salts" refers to pharmaceutically acceptable organic or inorganic salts of the compounds of the formula-. Eci salt is sulfate, citrate and acetate. Oxalate, chloride, bromide, iodide. Nitrate. Thiosulfates, phosphates. Acid Phosphates, Isonicolinates. Lactate. Salicylate, citrate. Tartrate. Uretate, tannins. Pantothenate, Heavy Tartrate. Ascorbate. Succinate. Maleate. Gentisate, fumarate. Gluconate ᅳ Glucuronate. Saccharides. Formate. Benzoate. Glutamate, methanesulfonate. Ethane sulfonate, benzene sulfonate. p—luluenesulfonic acid salts and pamolates (ie, 1,1′-methylene-bis— (2-hydroxy-3-naphtholate)). Pharmaceutically acceptable salts are the salts itdi may involve the inclusion of another molecule such as acetates followed, followed by succinic acid salt or other ^subsequent, opposite. Opposite it may be any organic or inorganic moiety that stabilizes the charge on the parent compound. Furthermore, pharmaceutically acceptable salts may have atoms that charge the charge of hyssina-is in its structure. If multiple charges are present, they may have multiple counterparts if they are part of a pharmaceutically acceptable salt. Thus / a pharmaceutically acceptable salt may have a hy- or more charged atom and / or one or more opposite silver. The term “compound of the present invention” _, unless stated otherwise _, includes compounds of formula (I), or stereoisomers, tautomers, solvates, prodrugs and salts (eg, pharmaceutically acceptable salts) thereof. Unless stated otherwise. The structures depicted herein also mean that the compound comprises compounds that differ only in the presence of at least one isotope-rich atom. For example. Compounds of Formula 1 wherein one or more hydrogen atoms are replaced with dihydrogen or tritium—or one or more carbon supports—are replaced with ¹³ c- or “c-carbon atoms are within the scope of the present invention.

In one embodiment, a chronic malignant tumor. Degenerative arthritis. A compound of formula 1 useful for treating or alleviating pain in a patient who does not have a back pain related disease. Or hydrates or pharmaceutically acceptable salts thereof, and pharmaceutical compositions.

One embodiment of the present invention includes a compound of Formula 1 or a hydrate or pharmaceutically acceptable salt thereof:

[Formula I]

From the Singh-Kee

X is 0, S. or Nil,

R ¹ is H. Substituted-unsubstituted linear or branched d-alkyl. Substituted or unsubstituted C ₂ -C _G alkanyl, substituted or unsubstituted C.rC _s cycloalkyl. Substituted or unsubstituted C ₆ -C ₂₀ aryl, selected from the group consisting of N. 0 and S, hetero- or heterocyclic forms having 1 to 9 carbon ring members Substituted or unsubstituted heterocyclyl. Hateroji and L to 9 carbons of Honey-Ixing- selected from the group consisting of N. 0 and S Selected from the group consisting of substituted or unsubstituted heteroaryl having a ring member _,

R ² is 0. Nil. -C (0) -0-. Or -0-C (0) -, ^and,

R ³ is H. Substituted or unsubstituted linear or branched CrC ₁₀ alkyl. Substituted or unsubstituted C ₂ -C, o alkanyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted C ₆ -C ₂₀ aryl. N. mono- or bicycle-type substituted or non-substituted heterocyclyls having at least one heteroatom and 1 to 9 carbon ring members selected from the group consisting of 0 and S, N, 0 and Is selected from the group consisting of at least one heteroatomic-selected from the group consisting of S and substituted or unsubstituted heteroaryl having from 9 to 9 carbon ring members,

n is an integer of 0 to 3,

here. Substituted alkyl. Substituted alkenyl, substituted cycloalkyl. Substituted aryl. Substituted heterocyclyl and substituted heteroaryl are alkyl, alkanyl. Cycloalkyl, aryl, heterocyclyl and heteroaryl are each independently Ci-C alkyl; C: rC _l2 cycloalkyl; C ₂ — C _G alkenyl; Wherein the carbon constituting the ring is substituted with one or more hetero atoms prepacked from the group consisting of N, 0 and S, C-C ₁₂ heteroaryl: CrQ; Alkylsulfonyl: C _G -C ₁₂ arylsulfonyl; C _L —C (; alkylthio; mercapto; -0H: CI-CG alkoxy; C 厂 C _G haloalkoxy; -ΝΌ ₂ ; halo; -C00H; — CHO; -CN; -C, -C _G alkyl carbonyl; -C, -C _G alkyloxycarbonyl: NH _{_2;} - C0NH _2: mono- or di-d- C (; alkylamino; and mono- or di-d-; do the Suntec from the group consisting of alkyl carbamoyl ^■ Di- which means substituted by the above substituents.

In a preferred embodiment of the invention, X is 0-di.

In a preferred embodiment of the invention R 'is H-.

In a preferred embodiment of the invention π is 0 or 1di-.

In a preferred embodiment of the invention is linear d-do alkyl. In addition, the alkyl may be substituted with-圆.

In a preferred embodiment of the invention R ² is linear C ₂ -Q; Alkenyidi ·. Again. The alkanyl may be substituted with phenyl or aryl.

Another embodiment is a compound of Formula [, or a hydrate or pharmaceutically acceptable salt thereof, selected from:

5'acetoxy MF (5-acetoxymethylperfural);

5-propionoxy MF;

5 one butyoxy MF;

5-lauxy MF:

5-succinoxi MF (FY-304);

5-glutaoxy Ml '^'; And

5-thinner M.

Compounds of formula (t) of the present invention contain achiral or chiral cores and, therefore, may exist in different-stereoisomeric forms. But not limited to diastereomers. Mirroring ^and isomers as well as mixtures thereof. All stereoisomers of the compounds of formula (NB), including, for example, racemic mixtures, are intended to form part of the present invention. Also. The present invention includes all geometric and positional isomers. for example. Where the compounds of the formula [comprise a double-binding ring or a fused ring, both cis and trans form as well as combinations thereof are included in the scope of the present invention. Compounds of the present invention are in unsolvated form as well as pharmaceutically acceptable solvents. For example, present in solvated form with water, ethanol and the present invention is intended to include both solvated and unsolvated forms.

Another di- other embodiment of the present invention is a compound of formula (I). Or a hydrate or pharmaceutically acceptable salt thereof. And pharmaceutical compositions comprising a pharmaceutically acceptable carrier, adjuvant or vehicle. Another embodiment of the present invention comprises pain of a compound of the formula [, or a hydrate or pharmaceutically acceptable salt thereof. Acute pain. Chronic pain. Neuropathic pain, post-operative mass. Pharmaceutical compositions for treating or alleviating migraine, arthralgia.

Another embodiment of the present invention includes a method of treating or alleviating pain in a patient with severe ^■ pain. The method is a compound of formula (I). Or administering a therapeutically effective amount to a hydrate or pharmaceutically acceptable salt thereof thereof.

Another embodiment of the present invention includes the anesthetic use of a compound of the formula [, or a hydrate or pharmaceutically acceptable salt thereof.

Another embodiment of the present invention includes a process for preparing a compound of Formula ί., Or a hydrate or pharmaceutically acceptable salt thereof. More specifically, the method for preparing a compound of formula (I) according to the present invention is an enzymatic synthesis method for synthesizing the compound of formula (1) through enzymatic synthesis using lipase with 5-hydroxy MF as a starting material. As a starting material, a strong base is used to remove a hydrogen atom of a hydroxyl group and reacts with a succinic anhydride, which is broadly divided into a chemical synthesis method for synthesizing a compound of the formula [. D-.

One embodiment of the present invention includes the enzymatic preparation of a compound of formula (I), or a hydrate or pharmaceutically acceptable salt thereof. The single-phase method includes the step of reacting aliphatic divalent and lipase with 5-hydroxy MF as a starting material. here. Aliphatic diacids mean aliphatic compounds containing two or more -C0 () H. Specifically formin-, butycin-. Propionic acid. Glutarcin-, succinic acid. Or it can be selected from the lauric acid Dung. Not limited to these.

Another embodiment of the invention is a compound of formula 1. Or chemical preparation of hydrates or pharmaceutically acceptable salts thereof. The method comprises the steps of removing hydrogen atoms of the hydroxy group with a strong base such as sodium hydride using 5-hydroxy MF as a starting material; And adding an acid anhydride or a new chloride to the solvent to cause a substitution reaction. Wherein the acid anhydride is oxalic anhydride. Maleic anhydride, or succinic anhydride, etc., but are not limited to these.

Also. Compounds of the formulas of the present invention, or hydrates or pharmaceutically acceptable salts thereof, are described in 5-llydroxyniethyl furfural (HMP) as a building block platform: Biological properties, synthesis and synthetic applications; Andrei a A. Rosatel la, Sv i en P. Simeonov, Raquel l * \ M. FYacle ancl Carlos A. M. Afonso. Green Chem .. 2011, ^' 1.3. 754) or Synthesis, chemistry ancl applications of 5-hyd r ox yme t hy I furfura I and its derivatives, Jaroslaw Lewkowsk i. ARK I V0C 2001. (i) 17-54).

The pharmaceutical compositions herein can be formulated in a variety of oral or parenteral dosage forms. As a dosage form for oral administration, for example, a tablet. Pills, hard soft capsules. Liquids, suspensions. Emulsifier. Syrup. Granules, these formulations are in addition to the active ingredient Diluents (e.g. lactose.extrose.sucrose.mannie, sorbitol celrose and / or glycine). Glidants such as silky-, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols. The tablets also contain magnesium aluminum silicate, starch paste, gelatin, tragacanth. And may contain binders such as methylcellose, sodium key-boxymethylcellulose and / or polyvinylpyridine, in the case of thi-la starch _, agar. Disintegrants or boiling mixtures such as alginic acid or its sodium salt and / or absorbents, colorants. Flavor. And sweeteners. Singh-based formulations can be prepared by conventional common-, granular- or coating methods. Also representative of formulations for parenteral administration is an ocular formulation, preferably an isotonic aqueous solution or suspension. The singe-based compositions may contain sterile and / or adjuvants, stabilizing agents, hydrating or emulsifying accelerators, auxiliaries such as salts and / or buffers for osmotic-control, and kiti-therapeutically useful substances, and Can be formulated according to the method.

The compounds of formula I: of the present invention may be administered by any route suitable for the condition to be treated. Suitable route is oral. Parenteral (eg Fi.- intramuscular, intravenous, intraarterial. Finney 1. Intradural and epidural). Percutaneous, weaving, nasal. Local (eg buccal and sublingual). Vaginal, boxing-including intra, pulmonary and intranasal administration. In the treatment of local pain. Compounds may be administered to a ^heel, administered in the lesion. For example, extra-inhibitor grafts can be administered prior to perfusion or implantation. The preferred route is di'll be able to symptoms vary Dali ⁱ round of beneficiaries.

ΐ in my Dosage Ding-A pharmaceutically effective amount of a compound of the invention administered parenterally is: About 0.01-100 nig / kg of the patient's body weight per day, alternatively about 0.1 to

Will range from 20 nig / kg, with a typical initial range of 0.3 to L5 mg / l <g / yldi-.

In another embodiment, the oral unit dosage form. For example, tablets and capsules preferably contain about 5 to about 100 mg of the compound of the present invention. Dosages administered to patients may range from about 5 mg to about 100 mg of the compound of Formula 1. Typical dosages can be from about 5 mg to about 300 mg of a compound of Formula ί-. Dosage is the absorption of certain compounds. Distribution. Dash-and outlet coming stirring ^Huck, and pharmacodynamic properties of a day diluent (Q1D) depending on, twice a day, including (β |: 1)), or more frequently itdi be administered. Also. Virulence factors can affect the dosage and administration regimen. Also, band 1. Pills to be administered orally. Capsules or tablets may be administered daily or more rarely for a specific time period. The regimen may be repeated in various treatment cycles.

Dose levels for patients with talk tablets are congested. Age, gender. Health-can vary depending on the diet, diet, time of administration, method of administration and excretion, and drug mix and ^severity of disease.

Advantageous Effects

The present invention has less side effects and excellent analgesic effect as a non-narcotic analgesic.

A pharmaceutical composition comprising a five-membered heterocyclic derivative is provided.

Also. The present invention provides a process for preparing 5-membered heterocyclic derivatives having excellent analgesic effects.

ί brief description of the drawings] 1 is a 5-i and 5彌⁷ won by oral administration of the test gyeolgoe Tero cyclic derivative is (wr i thing test).

2 shows the results of oral administration of 5-HMF and 5-membered heterocyclic derivatives (formalin test).

3 shows the results of oral administration (formalin test) according to the concentration of 5—succinoxi MF derivative.

4 is a neuropathy induced by the abdominal administration of vincristine in mice two weeks a week for 6 weeks, the degree of neuropathy was confirmed by the tan-f lick test-.

5 and 6 are graphs showing the analgesic effect of 5—succinoxi MF derivatives by concentration and time in the neuropathic pain induced by vincristine shown in FIG. 4 over time. ;

The present invention will be described in more detail with reference to hihi-hi-gi-Handi-. only. The following examples are intended to illustrate the invention but are not limited to the scope of the invention.

Synthesis of 5-membered heterocyclic derivatives

1) Tasting ^:

5-hydroxy MF and Novozynie 435 (l ipase acrylic resin from Candida Antrcita) used to synthesize derivatives. Butyric acid and propiic acid. Glutarcin-. Succinic acid, lauric acid and other solvents were purchased from Sigma-Aldrich.

2) Melting Point (MP) and FT-IR Measurements

The MP of the synthesized five-membered heterocyclic derivative was applied by Melting Point tester (b-540. L'lLichi), and VI- [R analysis was performed by Fourier-transform infrared spectroscopy (T-IR-4I00, .iasco). )use with . Measured in the range of 3000-500 cnf ^1- .

3) Electron impact / mass spectrometer (El -MS) and NMR ('[I, ⁱ C)

Electron impact / mass spectrometer (K [/ MS) of the heap-formed five-membered heterocyclic derivatives showed ionization energy of 70 eV. It has a source temperature of 280 ° C and a trap current of 300 μ. Conditional measurements were made on the scan range 50-550 and the R spectra was measured with the DPX-400.

AVANCI ':-Measured using 600 (Bi-ucker).

Example 1 Enzymatic Synthesis of Five-membered Heterocyclic Derivatives

Synthesis conditions of the compound used in synthesizing the 5-membered heterocyclic derivatives (selected from formic acid-.butyric acid.propynecin-.glutarsin-, succinic acid, or lauric acid) are shown in Table 1. In a glass vial, 5-IIMF (2.4 nimol. 3 g), 2, 2, 4 ᅳ trimethylpentane (isooctane) 0.1 L, lipase 2.8 g. 5 g of molecular sieves and formcin. Butyricin-. Peuropieun new ^and. Glutarcin-. Succinity-. Alternatively, a compound selected from lauric acid is added at a molar concentration of 2-5 times that of 5 ᅳ I 画 'ᅳ, and then reacted at 200 rpm, 60 ° C for 2 hours in a Jinting ᅳ incubator, followed by thin membrane chromatography (TLC). Confirmed the synthesis of 5-membered heterocyclic derivatives. Nucleic acid / ethyl acetate (1: 0.5, v / v) was used as a developing solvent for ΊΊΧ-.

Table 1. Enzymatic ¾ ^· castle conditions Compound Lipi- ^Second)

Dragon ¹ .S ³ (g)

OC00H, mmol) ω

23.8 acetic anhydride. 119 0.1 2.8 5.0

23.8 Tsu-Peilic anhydride. 47.6 0.1 2.3 5.0

23.8 Butyric anhydride ^' water, 47.6 0.1 2.8 5.0

^' 8.0 Sacrutartic acid superior, 15.8 0.033 1.65 1.65

8.0 Succinic anhydride 15.8 0.033 1.65 1..65

1.8 lauric acid ,. 8.98 0.005 0.14 0.25

8.0 Non ¾ Thinner "1 1 8.0 0.033 1.65 1.65

2,2 (Isooctane)

.435 Candida Anlrdii)) Example 2J-Synthesis of 5-membered heterocyclic derivatives

2-1. Place 5-HMF and anhydrous ^' HIF (5-HMF W, 1 g 10 iiiL) in a two-neck equipotential bottom flask, layering with N ₂ gas on a magnetic stir bar and force-to-ice ice bath (0 ° C) Stirring was carried out. After completion of N ₂ gas filling, the cap was opened and sodium hydride (NaH. 6.25 ι ol) was added while continuously blowing N ₂ gas. After the addition was completed, the N ₂ gas balloon was attached and stirred for 20-30 minutes. Succinic anhydride (10.4 () 1) was added and stirred at room temperature for 24 hours to react. After completion of reaction, the solvent was removed, the material was fractionated using methylene chloride (MC) and 1½0, and the MC layer was washed 2-3 times with 1½0 ^. . The remaining ᅡ 1 ₂ 0 of the C layer was removed with Na ₂ S0 ^ and concentrated to give the final derivative.

Table 2. Analytical data of synthesized five-membered heterocyclic derivatives

Example 3: rideithK inhibition test of 5-H and 5-membered heterocyclic derivatives

5-IIMF and 5-membered heterocyclic derivatives were administered to 4 week old ICR mice (approximately 25 g body weight). ^Kim, spinal cord. Intraventricular administration. It was then treated with acetic acid 0.25% ί ^η in the abdominal cavity of the mouse was irradiated for 30 minutes and then di-driver riding banung (writhing response) .. At this time, the 5-1側^'' and the 5-membered heterocyclic derivatives of the present invention administered as a control Not The same test was done using mice.

1 is an oral administration test of 5—HMF and a 5-membered heterocyclic derivative of the present invention (writhing test). After 30 minutes of oral administration of 5-HMF and the 5-membered heterocyclic derivative of the present invention to the mice at a concentration of 10 mg / kg, 1% acetic acid was administered intraperitoneally to conduct a wri hing test. It was confirmed to show-. Example 4 Formalin Test of 5-HMF and 5-membered Heterocyclic Derivatives

5-IIMF and the 5-membered heterocyclic derivatives of the present invention were administered orally, spinal cavity, intraventricularly to 4 week old ICR mice (about 25 g in weight). Thirty minutes later, after the 5% formalin aqueous solution was administered to the hind paws of each gig-each mouse _. . The first phase during the first 5 minutes and. The time of showing pain response such as licking or shaking the mouse paws during the second phase for 20 to 40 minutes was measured. In this case, the same test was performed using mice that were not administered 5-HMF and the 5-membered heterocyclic derivative of the present invention as a control group.

2 shows the results of oral administration experiments of 5-HMF and 5-membered heterocyclic derivatives (formalin test). 30 minutes after oral administration of the 5-membered heterocyclic derivative to the mice at a concentration of 10 mg / kg. 5% formalin was administered to the left paw of the mouse, which showed an analgesic effect on the ^nodules , Ls, and 5-HMF and -acetoxy MF derivatives in the 2nd phase. In particular, in the 2nd phase, it was confirmed that the analgesic effect was better in the acetyl derivative MF than 5-HMP.

Figure 3 shows 30 minutes after oral administration of 5-IF 10 mg / kg or 5-succinoxi MF derivatives to mice at concentrations of 5, 1.0 and 20 nig / kg, 5% formalin was administered to the left foot of the mice. In experimental nodules, _Ist ph _ase showed significant analgesic effects at concentrations of 20 mg / kg of 5-HMF and 5 succinoxi MF derivatives, and in the 2nd phase, 5-HMF and 5-succinoxi. Significant analgesic effects were observed at all concentrations of MF-derived vegetables. In particular, it was confirmed that 5-succinoxi MF derivatives were superior in analgesic effect in both 1st and 2nd phases than 5-HMF.

Figure 4 induces neuropathy by intraperitoneal administration of vincrisine in mice two weeks per week for 6 weeks, and the degree of induction of neuropathy was confirmed by ii 卜 flick test-.

5 and 6 are concentration-specific analgesic effect of 5-succinoxi MF derivative in the neuropathic pain model induced by vincrisine shown in FIG. It is a graph by time. Referring to the phase τΐ graphs. The 5-succinoxi MF derivative was found to have a concentration-dependent analgesic effect on neuropathic pain, and began to show significant analgesic effect from 60 minutes to 25– U) 0 ms / kg at 120 minutes. It can be seen that it shows an excellent analgesic effect in concentration.

Administered once to 5 g / kg of 5-succinyl rust during MF derivative in the mice a day to gyeonggu youngheong drug on ^mice: looked for. Its nodules. Survival of mice from 3 days to a week. Body weight, bowel movement, behavior, and long-term, vis-à-right. It was confirmed that there was no earing in the internal organs such as the bowel.

Claims

[Range of request]

[Claim 1]

Hi-group compounds of formula (I) or hydrates or pharmaceutically acceptable salts thereof:

In the singular formula _,

X is 0. S, or NH.

R ¹ is H. Substituted-unsubstituted linear or branched dC ^′ G alkyl. Substituted or unsubstituted C ₂ -C _G alkenyl. With substituted or unsubstituted C ₃ -C ₃ cycloalkyl, substituted or unsubstituted C (rC ₂₀ aryl, N, 0 and S, at least one hetero ring-selected from the group consisting of 1 and 9 to 9 carbon ring members) monocycle or are you ^buy-back, to form a substituted cycle which is unsubstituted Tero heterocyclyl, N. 0 and it is optionally substituted from the group consisting of S with at least one heteroatom selected sheet ⁱ and one to nine carbon ring members, Sunpacked from the group consisting of teroaryl,

R ² is 0. NIL -c (o) -o-. Or -ο-αω-.

R ³ is Η. Substituted or unsubstituted linear or branched C, _-C10 alkyl. Substituted or unsubstituted C ₂ -C ₁₀ alkanyl, substituted or unsubstituted C ₃ -C ₁₀ cycloal-gil, substituted or unsubstituted C _G -C ₂₀ is -aryl, N. 0 and S Hy "or more heteroatoms selected from the group consisting of substituted or unsubstituted heterocyclyl, N. 0 and S in monocycle or bicycle form having one or more hetero atoms and 1 to 9 carbon ring members selected from Original and:: 1. Selected from the group consisting of substituted or unsubstituted heteroaryl having from 1 to 9 carbon ring members.

n is an integer from 0 to 3,

Wherein substituted alkyl. Substituted alkanyls. Substituted cycloalkyl. Substituted aryl. Substituted heterocyclyl and substituted heteroaryl are referred to as Xing alkyl? ^"¾ cycloalkenyl, aryl, and heteroaryl cycles by interrogating the _gig-G, each independently CrC alkyl; C ₃ -C ₁₂ cycloalkyl;

C ₂ -C _G alkanyl; The carbon constituting the ring of seonbaek from the group consisting of N. 0 and S do Tero year to C _12, characterized in that the substituted atom or more interrogating ^■ aryl: Cr; Alkylsulfonyl; QrC, ₂ arylsulfonyl; CC ₆ alkylthio; Mercapto; -OH; C 厂 C _G alkoxy; CC _G haloalkoxy; — N0 ₂ ; Halo; -C00H; -01-10: -CN; (: [[; ₍ ; Alkylcarbonyl; (; alkyloxycarbonyl; -NH ₂ ; -C0NH ₂ ; mono or di d-Cc, alkylamino; and mono or di

It is meant to be substituted with one or more substituents selected from the group consisting of C-CG alkyl carbang oil.

[Claim 2]

The compound of claim 1, wherein X is zero. R ¹ is H A compound of formula [, or a hydrate or pharmaceutically acceptable salt thereof. '

[Claim 3] The method of claim 1. or n is 0 or 1, or a hydrate or pharmaceutically acceptable salt thereof.

[Claim 4]

In the first hing. ^ Is a linear C 厂 C ₁₀ alkyl wherein said alkyl is substituted with -C00H, or a hydrate or pharmaceutically acceptable salt thereof.

[Claim 5]

The compound of formula or the hydrate or pharmaceutically thereof of claim ² , wherein R ² is linear C ₂ —C _G alkenyl, and the sing-group sing-group alkanyl is substituted with phenyl or aryl.

Acceptable salts.

[Claim 6]

A process for preparing a compound of formula (I) according to claim 1 comprising reacting together aliphatic diacids and lipases with 5-hydroxymethylperfural as starting material.

[Formula I]

Beyond defined-the same.

[Claim 7]

The aliphatic diacid is formic acid. Butyric acid. Propiic acid. Glutarcin, succinct. Or lauric acid.

[Claim 8]

Removing the hydrogen atom of the hydroxy group with a strong base such as sodium hydride using 5-hydroxymethylperfural as a starting material; And adding an acid anhydride, an acid chloride or the like to the singe-group solvent to cause a substitution reaction.

[Formula I]

It is equal to non-other- defined.

[Claim 9]

The method of claim 8. Acid anhydride is oxalic anhydride. Maleic anhydride. Or a process selected from succinic anhydride.

[Billing 10]

Comprising a compound of the formula ί or a hydrate or pharmaceutically acceptable salt thereof according to the first term. Neuropathic pain. Acute pain. Chronic pain, abdominal pain, toothache. Menstrual pain. lumbago. Fifty pains. Shingles. Trigeminal neuralgia, cancer pain, diabetic neuropathy. Postoperative pain. migraine. Pharmaceutical compositions for treating or alleviating joint pain.