JP7430867B2 - A scavenger for thiol group-containing compounds containing an organic germanium compound as an active ingredient - Google Patents

Description

The present invention relates to a scavenger for thiol group-containing compounds, which contains an organic germanium compound as an active ingredient.

Germanium (Ge) is an element that has long been the subject of research as a semiconductor, but research into its organic compounds has also been actively conducted, and various organic germanium compounds have been synthesized.

For example, Ge-132 (poly-trans-[(2-carboxyethyl)germasesquioxane], also called repagermanium, asaigermanium) has immunostimulatory, antitumor, anti-inflammatory, analgesic, and morphine It is a water-soluble organic germanium compound that has various physiological effects such as synergistic effects with Ge-132 is hydrolyzed in water to form the monomer 3-(trihydroxygermyl)propanoic acid (THGP). Since living bodies are rich in water, Ge-132 is thought to undergo hydrolysis and function as THGP or its salts.

One of the mechanisms by which Ge-132 exerts various physiological effects is the interaction between THGP and biological components. For example, THGP forms a lactone-type THGP-cis-diol complex through dehydration condensation with a cis-diol-containing compound, and is thought to control the physiological functions of the cis-diol-containing compound (non-patent Reference 1 etc.). As an example of physiological function control through interaction, it has been reported that THGP forms a complex with adenosine and ATP, inhibiting their binding to P1 or P2 receptors, and may be involved in pain suppression ( Non-patent document 2).

Nakamura et al., Future. Med. Chem., 2015, 7 (10), 1233-1246. Shimada et al., Biol. Trace Elem. Res., 2018, 181 (1), 164-172.

The present invention aims to provide new uses for organogermanium compounds.

The present inventors have discovered that THGP, a type of organogermanium compound, interacts with compounds containing thiol groups, that this interaction suppresses pain and allodynia caused by hydrogen sulfide, and that the thiol group-containing compounds are volatile. The following inventions were completed.

(1) General formula (I)
A compound of
In the formula, R ¹ and R ² are each independently hydrogen, halogen, nitro, hydroxy, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _2-4 alkenyl, C _2-4 haloalkenyl, C _3-4 alkynyl, C _3-4 haloalkynyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-4 alkylthio, C _1-4 alkylsulfinyl or C _1-4 alkylsulfonyl, or together with the two carbon atoms to which is attached, a 4- to 10-membered monocyclic or polycyclic saturated ring, a 4- to 10-membered monocyclic or polycyclic partially saturated ring, a 6- to 10-membered monocyclic or polycyclic partially saturated ring, forming a monocyclic or polycyclic aromatic ring, or a 5- to 10-membered monocyclic or polycyclic heterocycle containing 1 to 4 atoms selected from nitrogen, oxygen, and sulfur;
These rings are unsubstituted or halogen, nitro, hydroxy, cyano, oxo, C _1-4 alkyl, C _1-4 haloalkyl, C _2-4 alkenyl, C _2-4 haloalkenyl, C _{3- 4} alkynyl, C _3-4 haloalkynyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-4 alkylthio, C _1-4 alkylsulfinyl, and C _1-4 alkylsulfonyl. is substituted with a substituent of
^R3 is hydrogen, halogen, nitro, hydroxy, cyano, _C1-4 alkyl, C1-4 haloalkyl, _C2-4 alkenyl, _C2-4 haloalkenyl, _C3-4 alkynyl, _{C3-4 halo} is alkynyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-4 alkylthio, C _1-4 alkylsulfinyl or C _1-4 alkylsulfonyl,
A scavenger for a thiol group-containing compound, which contains the above compound, a pharmaceutically acceptable salt or ester thereof, or a polymer thereof as an active ingredient.
(2) In general formula (I), R ¹ , R ² and R ³ are independently hydrogen, halogen, nitro, hydroxy, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _2-4 Alkenyl, C _2-4 haloalkenyl, C _3-4 alkynyl, C _3-4 haloalkynyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-4 alkylthio, C _1-4 alkylsulfinyl or C _1- The scavenger according to (1), which contains _{a 4-} alkylsulfonyl compound, a pharmaceutically acceptable salt or ester thereof, or a polymer thereof as an active ingredient.
(3) Contains a compound in general formula (I) in which R ¹ , R ² and R ³ are all hydrogen, a pharmaceutically acceptable salt or ester thereof, or a polymer thereof as an active ingredient; (1) The scavenger described in .
(4) The scavenger according to any one of (1) to (3) for protecting a thiol group.
(5) A pharmaceutical composition for suppressing pain caused by hydrogen sulfide, comprising the scavenger according to any one of (1) to (3).
(6) The pharmaceutical composition according to (5) for suppressing allodynia.
(7) A pharmaceutical composition for suppressing itching caused by hydrogen sulfide, comprising the scavenger according to any one of (1) to (3).
(8) A deodorizing or deodorizing composition comprising the scavenger according to any one of (1) to (3).
(9) The deodorizing or deodorizing composition according to (8), for suppressing bad breath, body odor, urine odor, or stool odor.

According to the present invention, it is possible to capture a thiol group-containing compound using an organogermanium compound that is highly safe for living organisms, thereby suppressing pain and allodynia caused, for example, by hydrogen sulfide, and also suppressing thiol group-containing compounds. Undesirable odors caused by the contained compounds can be suppressed.

The results of ¹ H NMR analysis of a mixed aqueous solution of THGP and NaHS (sodium salt of H ₂ S) or Na ₂ S ₂ (sodium salt of H ₂ S ₂ ) are shown. The results of ¹ H NMR analysis of a mixed aqueous solution of THGP and L-cysteine are shown. The results of ¹ H NMR analysis of a mixed aqueous solution of THGP, 1,2-ethanedithiol, aminoethanethiol, homocysteine, and glutathione are shown. The results of evaluating the degree of mechanical allodynia in mice to which a mixed aqueous solution of Na ₂ S and THGP was administered plantarly using the von Frey test are shown. The results are shown in which the degree of occurrence of mechanical allodynia was evaluated using the von Frey test in Na ₂ S plantar-administered mice that had previously been intraperitoneally administered with a THGP aqueous solution. The results are shown in which Ca _v 3.2 inhibitor (TTA-A2) was administered intraperitoneally and evaluated using the von Frey test for mechanical allodynia that occurs after burn stimulation in the hind paws of mice. To treat mechanical allodynia that occurs after burn stimulation of mouse hind paws, H ₂ S synthase CSE inhibitors (β-cyano-L-alanine (BCA) and DL-propargylglycine (PPG)) were administered intraperitoneally, and von Frey Shows the results evaluated with test. The results are shown in which a THGP aqueous solution was intraperitoneally administered and evaluated using the von Frey test against mechanical allodynia that occurs after burn stimulation in the hind paws of mice. The figure shows the amount of H ₂ S gas generated when 100 μM or 200 μM THGP is added to a NaHS aqueous solution. The figure shows the amount of H ₂ S gas generated when 200 μM THGP is added to a NaHS aqueous solution.

A first aspect of the present invention is a scavenger for a thiol group-containing compound, which contains as an active ingredient at least one of the compound of general formula (I), a pharmaceutically acceptable salt or ester thereof, or a polymer thereof. Regarding. Here, the polymer is a polymer that yields the compound of general formula (I) or a pharmaceutically acceptable salt or ester thereof upon hydrolysis.
In the formula, R ¹ and R ² are each independently hydrogen, halogen, nitro, hydroxy, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _2-4 alkenyl, C _2-4 haloalkenyl, C _3-4 alkynyl, C _3-4 haloalkynyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-4 alkylthio, C _1-4 alkylsulfinyl or C _1-4 alkylsulfonyl, or together with the two carbon atoms to which is attached, a 4- to 10-membered monocyclic or polycyclic saturated ring, a 4- to 10-membered monocyclic or polycyclic partially saturated ring, a 6- to 10-membered monocyclic or polycyclic partially saturated ring, forming a monocyclic or polycyclic aromatic ring, or a 5- to 10-membered monocyclic or polycyclic heterocycle containing 1 to 4 atoms selected from nitrogen, oxygen, and sulfur;
These rings are unsubstituted or halogen, nitro, hydroxy, cyano, oxo, C _1-4 alkyl, C _1-4 haloalkyl, C _2-4 alkenyl, C _2-4 haloalkenyl, C _{3- 4} alkynyl, C _3-4 haloalkynyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-4 alkylthio, C _1-4 alkylsulfinyl, and C _1-4 alkylsulfonyl. is substituted with a substituent of
^R3 is hydrogen, halogen, nitro, hydroxy, cyano, _C1-4 alkyl, C1-4 haloalkyl, _C2-4 alkenyl, _C2-4 haloalkenyl, _C3-4 alkynyl, _{C3-4 halo} Alkynyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-4 alkylthio, C _1-4 alkylsulfinyl or C _1-4 alkylsulfonyl.

In the compound of general formula (I), R ¹ and R ² each independently represent hydrogen: halogen such as fluorine, chlorine or bromine; nitro; hydroxy; cyano; linear, branched or cyclic carbon number 1 to C _1-4 alkyl which is 4 alkyls; C _1-4 haloalkyl which is linear, branched or cyclic alkyl having 1 to 4 carbon atoms substituted with one or more halogens; straight chain, branched chain or C _2-4 alkenyl which is a cyclic alkenyl having 2 to 4 carbon atoms; C _2-4 which is a linear, branched or cyclic alkenyl having 2 to 4 carbon atoms substituted with one or more halogens Haloalkenyl; C _3-4 alkynyl, which is a straight-chain or branched alkynyl having 3 to 4 carbon atoms; A straight-chain or branched alkynyl, having 3 to 4 carbon atoms, substituted with one or more halogens C _3-4 haloalkynyl; C _1-4 alkoxy represented by -OC _1-4 alkyl; C _1-4 haloalkoxy represented by -OC _1-4 haloalkyl; represented by -SC _1-4 alkyl C _1-4 alkylthio; C _1-4 alkylsulfinyl represented by -SO-C _1-4 alkyl; or C _1-4 alkylsulfonyl represented by -SO ₂ -C _1-4 alkyl .

In addition, R ¹ and R ² together with the two carbon atoms to which they are bonded represent a 4- to 10-membered monocyclic or polycyclic saturated ring, a 4- to 10-membered monocyclic or polycyclic ring, a partially saturated ring, a 6- to 10-membered monocyclic or polycyclic aromatic ring, or a 5- to 10-membered monocyclic or polycyclic ring with 1 to 4 atoms selected from nitrogen, oxygen, and sulfur. You may form a heterocycle containing.

A 4- to 10-membered monocyclic or polycyclic saturated ring is a saturated carbocyclic ring having one or more ring structures having 4 to 10 carbon atoms as ring constituent atoms, such as cyclobutyl. , cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclooctyl, spirooctyl, and the like.

A 4- to 10-membered monocyclic or polycyclic partially saturated ring is a partially saturated carbocyclic ring having one or more ring structures having 4 to 10 carbon atoms as ring constituent atoms, for example: , cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclooctenyl, and the like.

A 6- to 10-membered monocyclic or polycyclic aromatic ring is an aromatic ring having one or more ring structures having 6 to 10 carbon atoms as ring constituent atoms, and includes, for example, phenyl, Examples include naphthyl and indyl.

A 5- to 10-membered monocyclic or polycyclic heterocycle containing 1 to 4 atoms selected from the group consisting of nitrogen, oxygen, and sulfur has 6 to 10 atoms as ring members. , a saturated ring, partially saturated ring or aromatic ring having one or more ring structures, in which 1 to 4 ring atoms are heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur. , and the other ring constituent atoms are carbon atoms. Examples include furanyl, thiophenyl, pyrrolyl, imidazolyl, pyranyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, indolyl, quinolyl, isoquinolyl, and the like.

The ring formed by R ¹ and R ² is halogen, nitro, hydroxy, cyano, oxo, C _1-4 alkyl, C _1-4 haloalkyl, C _2-4 alkenyl, C _2-4 haloalkenyl, C _3- One or more of the group consisting of ₄ alkynyl, C _3-4 haloalkynyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-4 alkylthio, C _1-4 alkylsulfinyl, and C _1-4 alkylsulfonyl. may be substituted with a substituent. Details of each group are as described in the explanation of R ¹ and R ² .

In the compound of general formula (I), R ³ is hydrogen, halogen, nitro, hydroxy, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _2-4 alkenyl, C _2-4 haloalkenyl, C _{3 -4} alkynyl, C _3-4 haloalkynyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-4 alkylthio, C _1-4 alkylsulfinyl or C _1-4 alkylsulfonyl. Details of each group are as described in the explanation of R ¹ and R ² .

Compounds suitably used in the present invention include general formula (I) in which R ¹ , R ² and R ³ are independently hydrogen, halogen, nitro, hydroxy, cyano, C _1-4 alkyl, C _{1 -4} haloalkyl, C _2-4 alkenyl, C _2-4 haloalkenyl, C _3-4 alkynyl, C _3-4 haloalkynyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-4 alkylthio, C ₁ A compound that is _-4 alkylsulfinyl or C _1-4 alkylsulfonyl, a pharmaceutically acceptable salt or ester thereof, or a polymer thereof.

A particularly preferred compound is a compound in which R ¹ , R ² and R ³ are all hydrogen in the general formula (I), that is, THGP (3-(trihydroxygermyl)propanoic acid). , or a pharmaceutically acceptable salt or ester thereof, or a polymer thereof.

The present invention encompasses the use of pharmaceutically acceptable salts or esters of compounds of general formula (I). Such salts include salts with customary bases, for example alkali metal salts (e.g. sodium and potassium salts), alkaline earth metal salts (e.g. calcium and magnesium salts), ammonium salts, or organic amines ( Examples include ethylamine, diethylamine, triethylamine, DIPEA, monoethanolamine, diethanolamine, triethanolamine, dimethylaminoethanol, diethylaminoethanol, tris(hydroxymethyl)aminomethane, choline (2-hydroxy-N,N,N-trimethylethaneamine). procaine, dicyclohexylamine, dibenzylamine, N-methylmorpholine, N-methylpiperidine, arginine, lysine and 1,2-ethylenediamine).

Pharmaceutically acceptable esters of compounds of general formula (I) are in vivo hydrolyzable esters of carboxylic acids of general formula (I). Such esters are preferably C _1-4 alkyl esters such as methyl, ethyl, and tert-butyl esters.

The compound of general formula (I) is an acrylic acid derivative of general formula (II) (wherein R ¹ to R ³ are as described in the description of the compound of general formula (I)), as shown below. ) and trichlorogermane, followed by hydrolysis.

Hydrogelmylation and hydrolysis may be carried out under common reaction conditions known to those skilled in the art. For example, hydrogelmylation can be carried out at a temperature of about 25 to 40°C using concentrated hydrochloric acid, diethyl ether, chloroform, or the like as a solvent. Hydrolysis can be carried out by allowing the compound obtained by hydrogelmylation to coexist with water, preferably in a neutral to alkaline aqueous solvent, for example in an alkaline aqueous solution such as an aqueous sodium hydroxide solution.

The polymer of the compound of general formula (I) has the general formula (III)
It can be expressed as R ¹ to R ³ in general formula (III) are as explained in general formula (I), and n is an integer of 2 or more. Similar to the production of Ge-132 from THGP, the polymer is produced by drying the compound of general formula (I) or a pharmaceutically acceptable salt or ester thereof dissolved in an aqueous solution, and conducting dehydration condensation between molecules. It can be obtained by a polymerization reaction that produces. All structural units of the polymers may be the same or different. The former polymer can be obtained by drying an aqueous solution in which one kind of the compound of general formula (I) or a pharmaceutically acceptable salt or ester thereof is dissolved. Since the polymerization reaction is reversible, by dissolving the polymer in an aqueous medium such as water, the polymer is hydrolyzed and the compound of general formula (I) or a pharmaceutically acceptable salt or ester thereof is produced. can get.

Examples of polymers of the compound of general formula (I) include Ge-132 and Poly-[( 2-carboxyethyl-hydroxygermanium)oxide], Tsutsui et al. (J. Am. Chem. Soc., 1976, 98 (25), 8287-8289.) and Mizuno et al. (J. Pharm. Sci., 2015, 104 (8) One example is Propagermanium (3-oxygermylpropionic acid polymer), which is a water-soluble organic germanium compound having a ladder-like structure (a cyclic structure composed of 8 atoms of germanium and oxygen) described in , 2482-2488.).

In the present invention, the thiol group-containing compound captured by the compound of general formula (I) or a pharmaceutically acceptable salt or ester thereof or a polymer thereof is a compound having at least one thiol group in its structure. If so, there are no particular limitations. In addition to the thiol group -SH, the thiol group in the thiol group-containing compound may be -S ^- in which the proton of the thiol group is dissociated, or a mercaptide group in which the proton of the thiol group is replaced with a metal atom.

Without being bound by theory, the compound of general formula (I) is capable of producing thiol through the bond between the Ge-bonded hydroxyl group (Ge-OH) present therein and the thiol group of the thiol group-containing compound. It is thought that it traps group-containing compounds.

Examples of thiol group-containing compounds include hydrogen sulfide ( _H2S ), hydrogen polysulfides such as hydrogen disulfide or hydrogen trisulfide, cysteine, homocysteine, glutathione, 1,2-ethanedithiol, aminoethanethiol, and methyl mercaptan. , ethyl mercaptan, n-propyl mercaptan, isopropyl mercaptan, n-butyl mercaptan, isobutyl mercaptan, sec-butyl mercaptan, tert-butyl mercaptan, n-amyl mercaptan, isoamyl mercaptan, hexyl mercaptan, heptyl mercaptan, octyl mercaptan, nonyl mercaptan, Lauryl mercaptan, 2-methyl-3-butanethiol, allyl mercaptan, isopentenyl marcaptan, thiogeraniol, limonethyl, 8-mercaptomenthone, p-menthene-8-thiol, thiomenthol, thioglycerin, phenylmercaptan, o- Thiocresol, 2-ethylthiophenol, 2-naphthylmercaptan, furfuryl mercaptan, methylfurfuryl mercaptan, 2-methyl-3-furanthiol, thienyl mercaptan, thiofurfuryl mercaptan, 2-mercaptopropionic acid, 4-methoxy- 2-Methyl-2-butanethiol, 4-ethoxy-2-methyl-2-butanethiol, 5-methoxy-3-methyl-3-pentanethiol, 3-mercapto-2-pentanone, 3-mercapto-3-formic acid Methylbutyl, 3-mercaptohexanol, 3-mercaptohexanal, 3-mercaptohexyl acetate, 3-mercaptohexylbutanoate, 3-mercaptohexylpentanoate, 3-mercaptohexylhexanoate, 4-mercapto-4-methylpentane -2-one, 4-mercapto-4-methylpentan-2-ol, 3-mercapto-3-methylbutan-1-ol, 3-mercapto-3-methylbutyl acetate, 3-mercapto-3-methylbutyl Propanoate, 1,1-ethanedithiol, 1,2-ethanedithiol, 1,3-propanedithiol, 1,4-butanedithiol, 1,5-pentanedithiol, 1,6-hexanedithiol, 1-methylthio- Ethanethiol, 2-mercaptoethanol, 1-mercapto-2-propanol, 3-mercapto-2-methylpentanol, 3-mercapto-2-methylpentanal, 3-mercapto-2-methylbutanol, 3-mercapto-2 -Methylbutanal, 3-mercapto-3-methylhexanol, 1-methoxy-3-hexanethiol, 1-ethoxy-3-hexanethiol, mercaptoacetaldehyde, 1-mercapto-2-propanone, 1-mercapto-2-butanone , 3-mercapto-2-butanone, 1-mercapto-3-pentanone, 2-mercapto-3-pentanone, 5-methyl-4-mercapto-2-hexanone, 2-mercaptoethyl acetate, ethyl 3-mercaptopropanoate , ethyl 2-mercaptopropanoate, ethyl 3-mercaptobutanoate, ethyl 3-mercapto-2-methylpropanoate, 3-mercapto-2-methylpentanal, ethyl 2-mercaptopropionate, 3-mercapto Propyl acetate, 2,5-dimethyl-3-furanthiol, 2-methyl-3-thiophenethiol, 2-(thiophene-2)-ethanethiol, 3,4-dimethyl-2,3-dihydrothiophene-2-thiol , 4-mercapto-2,5-dimethylthiophen-3-one, 5-methyl-2-furfurylthiol, 3-methyl-3-sulfanylhexan-1-ol, and the like.

H ₂ S, a thiol group-containing compound, is known as a highly toxic gas and also acts as a gaseous information transmitter in vivo, increasing the activity of Ca _v 3.2 T-type Ca ²⁺ channels expressed in primary sensory nerves. It has been reported that elevated levels induce colon pain, pancreatic pain, visceral pain including bladder pain, hyperalgesia, allodynia, itching, etc. (Maho Tsubota et al., Pharmaceutical Journal, 134(12), 1245-1252 (2014); Wang, X.-L. et al., Sci. Rep. 5, 16768 (2015)). Allodynia is a hypersensitivity abnormality in which pain is caused by non-noxious stimuli that normally do not cause pain (touch, mild pressure, non-noxious hot and cold stimuli, etc.), and its onset mechanism is still unknown. It is.

As shown in the Examples below, the present inventors have found that THGP, a compound of general formula (I), interacts with H ₂ S and suppresses allodynia caused by H ₂ S in a concentration-dependent manner. Confirmed experimentally. It was also confirmed that THGP suppressed allodynia induced by burn stimulation, which is thought to be related to endogenous H ₂ S, in a concentration-dependent manner. Therefore, the thiol group-containing compound scavenger of this embodiment can be used to treat and/or prevent diseases or symptoms caused by thiol group-containing compounds, such as H ₂ S, such as allodynia, hyperalgesia, colon pain, pancreatic pain, and bladder pain. It can be used for the treatment and/or prevention of pain, including visceral pain, and pruritus. Here, the treatment and/or prevention of diseases or symptoms caused by H ₂ S includes delaying or stopping the progression of these diseases or symptoms, regression or disappearance of lesions, prevention of onset or recurrence, etc. Encompasses medically acceptable interventions for a variety of purposes.

In addition, thiol group-containing compounds are known to cause various odors in living organisms, such as H ₂ S and methyl mercaptan, which cause bad breath, allyl mercaptan, which causes stress odor, and 3-methyl-3-sulfanylhexan-1-ol. 3-mercapto-3-methyl-1-butanol is said to be the cause of cat urine odor. In addition, thiol group-containing compounds are considered to be the cause of bad odors in the living environment, and are listed as regulated substances in the Offensive Odor Prevention Act. The scavenger of this embodiment can suppress odors caused by thiol group-containing compounds by capturing them and suppressing their volatilization. Note that in this specification, odor suppression includes deodorization and deodorization.

For example, the oral cavity of a subject who has or is concerned about halitosis, typically suffering from periodontal disease, is rinsed with a solution containing the scavenger of the present invention, or a solid product containing the scavenger of the present invention. It is possible to suppress bad breath by holding it in the oral cavity and dissolving it with saliva. In the case of mammals other than humans, drinking water or feed containing the scavenger of the present invention may be fed.

Alternatively, a solution in which the scavenger of this embodiment is dissolved may be applied to the excrement of a companion animal such as a dog or a cat by spraying, or a carrier such as a moisture absorbent or sawdust to which the scavenger of this embodiment is attached. By using it as toilet sand or bedding material, it is possible to suppress the odor of excrement caused by thiol group-containing compounds.

Furthermore, the scavenger of this embodiment can be used as a protective agent that protects the SH group from highly reactive functional groups such as epoxy groups and from oxidation by interacting with the SH group. The scavenging agent of this embodiment used as a protecting agent for SH groups has advantages such as being usable in water, being able to be deprotected under mild conditions, and being highly safe.

The compound of general formula (I), its salt or ester, or its polymer may be used as a scavenger in the present invention as it is, and may also be used as a scavenger in the present invention, and may also be used as a buffer, stabilizer, preservative, excipient and other components. It may also be used in the form of pharmaceutical compositions, food compositions, cosmetic compositions, deodorizing or deodorizing compositions, and other compositions containing other active ingredients. Such compositions are yet another aspect of the invention.

Other ingredients permissible in the above compositions are well known to those skilled in the art for each purpose of the composition, and within the ordinary skill of those skilled in the art, for example, in the case of pharmaceutical compositions, the 17th edition Japanese Pharmacopoeia The components can be appropriately selected and used from those listed in other standards.

In the present invention, the dosage form of the scavenger or the composition containing the same is arbitrary as long as the compound of general formula (I) can interact with the thiol group, but when administered to humans or animals, Preferred examples include oral preparations (tablets, capsules, powders, granules, fine granules, pills, suspensions, emulsions, liquids, syrups, etc.), injections, external preparations (sprays, external solutions, (inhalants, ointments, patches, etc.), mouthwashes, etc. Furthermore, if a polar solvent is not present in the environment of use, the scavenger or a composition containing the scavenger is preferably in the form of a solution dissolved in the polar solvent, typically in the form of an aqueous solution.

The method of administering the scavenger and the composition containing the same to a living body is not particularly limited, and is appropriately determined depending on the dosage form. In one preferred embodiment, the route of administration of the scavenger and the composition containing the same is preferably intraperitoneal administration, intravenous administration, oral administration, or transdermal administration.

The dosage of the thiol group-containing compound scavenger and the pharmaceutical composition containing the same is appropriately selected depending on the usage, the age of the subject, the type and site of the disease or symptom, and other conditions. The dose is 10 μg to 2000 μg, preferably 50 μg to 1000 μg, more preferably 100 μg to 500 μg per kg of body weight, and can be administered once a day, divided into multiple doses, or intermittently.

The present invention will be explained in more detail with reference to the following examples, but the present invention is not limited to these examples.

Example 1 Interaction of THGP with NaHS or Na ₂ S ₂ NaHS (sodium salt of H ₂ S) or Na ₂ S ₂ (H ₂ S (sodium salt of ₂ ) and Ge-132 (Asai Germanium Institute) were dissolved to prepare a 5 mM solution of NaHS or Na ₂ S ₂ and THGP at a mixed molar ratio of 1:1, pH 7.0 to 7.5. As a comparison, a solution in which only THGP was dissolved was also prepared. ¹ H NMR spectra were measured at 25° C., 16 integrations, and 300 MHz. The remaining HOD signal was offset to 4.80 ppm.

The ¹ H NMR spectra of each sample are shown in Figure 1. In the ¹ H NMR spectrum of THGP, a signal originating from Ge-CH ₂ was observed as a triplet at 1.56 ppm, and a signal originating from CH ₂ -COO ^- was observed as a triplet at 2.47 ppm. On the other hand, in the mixed solution with NaHS or Na ₂ S ₂ , new signals were observed at 1.40 ppm and 2.39 ppm in addition to the above signals. Since NaHS or Na ₂ S ₂ alone did not have a signal near the above chemical shift, it was inferred that the newly observed signal was derived from a complex of THGP and NaHS or Na ₂ S ₂ .

Example 2 Interaction between THGP and cysteine L-cysteine and Ge-132 were dissolved in heavy water to prepare a 250 mM solution of cysteine and THGP at a mixed molar ratio of 1:1, pH 7.0 to 7.5. ¹ H NMR spectra were measured at 25° C., 16 integrations, and 300 MHz. The remaining HOD signal was offset to 4.80 ppm. As a comparison, a solution containing only cysteine or THGP was prepared.

The ¹ H NMR spectra of each sample are shown in Figure 2a. In the ¹ H NMR spectrum of THGP, a signal originating from Ge-CH ₂ was observed as a triplet at 1.52 ppm, and a signal originating from CH ₂ -COO ^- was observed as a triplet at 2.43 ppm. On the other hand, in the mixed solution with cysteine, new signals were observed at 1.92 ppm and 2.60 ppm in addition to the above signals. Since cysteine alone did not have a signal near the above chemical shift, it was inferred that the newly observed signal was derived from a complex between THGP and cysteine. In addition, similar tests were conducted on 1,2-Ethanedithiol, Aminoethanethiol, Homocysteine, and Glutathione as compounds having SH groups, and their interaction with THGP was confirmed. The NMR spectra of each sample are shown in Figure 2b. In all samples, no signal derived from a single thiol compound was observed in the range of 1 to 2 ppm, but a signal derived from a complex was observed.

Example 3 Inhibitory effect on mechanical allodynia 1) A mixed aqueous solution of Na ₂ S 10 pmol/paw and THGP 100, 1000 or 10000 pmol/paw or physiological saline was administered to the soles of ddY mice by local injection, Mechanical allodynia was evaluated using the von Frey test (n=5). The results are shown in Figure 3a. In the figure, the vertical axis represents the threshold of mechanical stimulation in which the mouse raises its paw, and the lower this value, the more severe the degree of allodynia. Mechanical allodynia was induced 15 minutes after Na ₂ S administration in the V + Na ₂ S group, in which Na ₂ S alone was administered to the plantar region of the mouse foot, whereas mechanical allodynia was induced in the THGP + Na ₂ S group, in which THGP was administered to the plantar region at the same time as Na ₂ S. It was confirmed that _2S- induced allodynia was suppressed in a THGP dose-dependent manner.

Next, we verified the effects of intraperitoneal administration of THGP. 30 or 100 mg/kg of THGP was intraperitoneally administered to ddY mice, and 30 minutes later, 10 pmol/paw of Na ₂ S was administered plantarly to evaluate mechanical allodynia using the von Frey test (n=5). The results are shown in Figure 3b. It was also confirmed that Na ₂ S-induced allodynia was suppressed in a THGP dose-dependent manner by intraperitoneal administration of THGP 30 minutes before the plantar administration of Na ₂ S.

2) A burn stimulus was applied to the hind paws of ddY mice under isoflurane anesthesia at 52.5°C for 25 seconds, and 3 hours later, TTA-A2 (1 mg/kg), a Ca _v 3.2 inhibitor, and H ₂ S synthase were administered. CSE inhibitors BCA (β-cyano-L-alanine, 50 mg/kg) or PPG (DL-propargylglycine, 30 mg/kg), or physiological saline for comparison, were administered intraperitoneally, and von Frey test was conducted. Mechanical allodynia was evaluated using (n=5). The results are shown in Figures 4a and b. Mechanical allodynia that lasts for 24 hours or more develops after 2 hours of burn stimulation (Group V), but TTA-A2, an inhibitor of Ca _v 3.2 involved in the expression of allodynia caused by H ₂ S, and endogenous It was confirmed that burn-induced allodynia was significantly suppressed by administration of BCA and PPG, which are known to suppress the production of H ₂ S. These results indicate that endogenous H ₂ S is involved in burn-induced allodynia.

In the above test, 10, 30 or 100 mg/kg of THGP was administered intraperitoneally to mice in place of TTA-A2, BCA or PPG after burn stimulation, and mechanical allodynia was evaluated by the von Frey test (n=5 ). The results are shown in Figure 4c. It was confirmed that by intraperitoneal administration of the THGP aqueous solution, burn-induced allodynia was significantly suppressed, similar to the above-mentioned inhibitors.

As shown above, THGP was shown to be effective in suppressing allodynia caused by exogenous H ₂ S or endogenous H ₂ S.

Example 4 Volatilization suppressing effect on H ₂ S
248 mL of 100 mM phosphate buffer (pH 7.4) was added to a 500 mL two-necked round-bottomed flask, and an N ₂ gas cylinder equipped with a flow meter and an H ₂ S reading tube (GASTEC, No. 4LK) were attached. Added 1 mL of 10 mM NaHS solution to a round bottom flask and stirred for 3 minutes. Add 1 mL of Ge-132 aqueous solution so that the final concentration of THGP is 100 or 200 μM, and while bubbling N ₂ gas into the solution at a flow rate of 500 mL/min, change the scale of the H ₂ S reading tube over time. It was measured.

In the absence of THGP, the H ₂ S efflux rate was 0.460 divisions/sec, whereas in the presence of THGP concentrations of 100 μM or 200 μM, it was 0.187 or 0.004 divisions/sec, respectively (FIG. 5a). Furthermore, in the presence of 200 μM THGP, the maximum scale of the detection tube was not exceeded even after 4 hours (Figure 5b). From the above, it was confirmed that THGP can capture H ₂ S gas and suppress the volatilization of H ₂ S gas in a concentration-dependent manner.

Example 5 Protection of SH group Aminoethanethiol and 5 times the mole of THGP relative to aminoethanethiol are dissolved in heavy water, propylene oxide is added, and then NMR is measured. The addition of THGP protects the SH group in aminoethanethiol, and the ring-opening reaction between the NH ₂ group and propylene oxide (epoxy group in propylene oxide) proceeds selectively, so we confirmed the difference in NMR spectra depending on the presence or absence of THGP. By doing so, it is possible to confirm the protective effect of SH group by THGP.

Example 6 Sawdust (product name: Super Woody) was used as a cat litter material. When your cat urinates, after urinating, or when you feel a urine odor, spray a 5% or 10%-THGP aqueous solution (pH 5.8-pH 8.5) on the toilet material to eliminate the urine odor. was able to suppress it.

Example 7 Bad breath suppression effect
Ge-132, a THGP polymer, was used as is or dissolved in a small amount of water to treat dogs with periodontal disease (small dogs: Chihuahuas, medium-sized dogs: Shiba Inu, large dogs: Golden Retrievers, total of 3 dogs). The product was applied to the oral gums or inner cheeks of animals with strong bad breath that made it difficult for owners to communicate normally. The amount of Ge-132 used at one time was 125 mg, and as a result of applying it once a day for 8 days, it was confirmed that bad breath was suppressed.

Claims (9)

General formula (I)
A compound of
In the formula, R ¹ and R ² are each independently hydrogen, halogen, nitro, hydroxy, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _2-4 alkenyl, C _2-4 haloalkenyl, C _3-4 alkynyl, C _3-4 haloalkynyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-4 alkylthio, C _1-4 alkylsulfinyl or C _1-4 alkylsulfonyl, or together with the two carbon atoms to which is attached, a 4- to 10-membered monocyclic or polycyclic saturated ring, a 4- to 10-membered monocyclic or polycyclic partially saturated ring , or a 5- to 10-membered monocyclic or polycyclic partially saturated ring. forming a monocyclic or polycyclic saturated or partially unsaturated heterocycle containing 1 to 4 atoms selected from nitrogen, oxygen and sulfur;
These rings are unsubstituted or halogen, nitro, hydroxy, cyano, oxo, C _1-4 alkyl, C _1-4 haloalkyl, C _2-4 alkenyl, C _2-4 haloalkenyl, C _{3- 4} alkynyl, C _3-4 haloalkynyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-4 alkylthio, C _1-4 alkylsulfinyl, and C _1-4 alkylsulfonyl. is substituted with a substituent,
^R3 is hydrogen, halogen, nitro, hydroxy, cyano, _C1-4 alkyl, C1-4 haloalkyl, _C2-4 alkenyl, _C2-4 haloalkenyl, _C3-4 alkynyl, _{C3-4 halo} is alkynyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-4 alkylthio, C _1-4 alkylsulfinyl or C _1-4 alkylsulfonyl,
A compound having an SH group , comprising as an active ingredient the above compound, a pharmaceutically acceptable salt of the above compound, a C _1-4 alkyl ester in the carboxyl group of the above compound, or a polymer thereof in the form of germanium sesquioxide. A scavenger for
However, when the above polymer is an active ingredient, dissolution in an aqueous solvent produces a compound of general formula (I), a pharmaceutically acceptable salt thereof, or a C 1-4 _alkyl ester in its carboxyl group. The scavenging agent used as such . R ¹ , R ² and R ³ are each independently hydrogen, halogen, nitro, hydroxy, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _2-4 alkenyl, C _2-4 haloalkenyl, C General formula (I) which is _3-4 alkynyl, _C3-4 haloalkynyl, _C1-4 alkoxy, _C1-4 haloalkoxy, _C1-4 alkylthio, _C1-4 alkylsulfinyl or _C1-4 alkylsulfonyl 2. A compound according to claim 1, comprising as an active ingredient a compound thereof, a pharmaceutically acceptable salt of said compound, a C _1-4 alkyl ester at the carboxyl group of said compound, or a polymer thereof in the form of germanium sesquioxide. scavenger. A compound of general formula (I) in which R ¹ , R ² and R ³ are all hydrogen , a pharmaceutically acceptable salt of the compound, a C _1-4 alkyl ester in the carboxyl group of the compound, or germanium sesquioxide A scavenger according to claim 1, comprising as an active ingredient these polymers in the form of . Scavenging agent according to any one of claims 1 to 3 for the protection of SH groups . A pharmaceutical composition for suppressing pain caused by hydrogen sulfide, comprising the scavenger according to any one of claims 1 to 3. The pharmaceutical composition according to claim 5, for suppressing allodynia. A pharmaceutical composition for suppressing itching caused by hydrogen sulfide, comprising the scavenger according to any one of claims 1 to 3. A deodorizing or deodorizing composition comprising the scavenger according to any one of claims 1 to 3. The deodorizing or deodorizing composition according to claim 8, for suppressing bad breath, body odor, urine odor, or stool odor.