阅读说明：本技术 医药品、抗癌剂、药物中间体及环式羧酸化合物或其衍生物的制造方法 (Pharmaceutical, anticancer agent, pharmaceutical intermediate, and process for producing cyclic carboxylic acid compound or derivative thereof ) 是由 井上雄介 藤原大辅 橘贤也 宫内启行 于 2019-08-14 设计创作，主要内容包括：本发明的医药品,作为有效成分含有以源自植物的糖类及微生物为来源的环式羧酸化合物及其衍生物中的至少一种。并且,所述环式羧酸化合物优选为由下述式(1)表示的化合物(The pharmaceutical product of the present invention contains, as an active ingredient, at least one of a cyclic carboxylic acid compound derived from a plant-derived saccharide and a microorganism and a derivative thereof. Also, the cyclic carboxylic acid compound is preferably a compound represented by the following formula (1))

1. A pharmaceutical composition is characterized in that,

the active ingredient contains at least one of a cyclic carboxylic acid compound derived from a plant-derived saccharide and a microorganism and a derivative thereof.

2. The pharmaceutical product according to claim 1, wherein,

the cyclic carboxylic acid compound is a compound represented by the following formula (1),

in the formula (1), the ring A is a saturated, partially saturated or aromatic 5-membered ring or a saturated, partially saturated or aromatic 6-membered ring, X is a single bond or a bond containing one or more carbon atoms, R is²～R⁶Independently a hydrogen atom, a hydroxyl group, an amino group, an alkoxy group, a carboxyl group or a carbonyl group, wherein, when ring A is a 5-membered ring, R is²～R⁵Independently a hydrogen atom, a hydroxyl group, an amino group, an alkoxy group, a carboxyl group or a carbonyl group.

3. The pharmaceutical product according to claim 2, wherein,

the cyclic carboxylic acid compound is at least one selected from the group consisting of 2-hydroxybenzoic acid, 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, 2, 3-dihydroxybenzoic acid, 2, 4-dihydroxybenzoic acid, 2, 5-dihydroxybenzoic acid, 2, 6-dihydroxybenzoic acid, 3, 4-dihydroxybenzoic acid and 3, 5-dihydroxybenzoic acid.

4. The pharmaceutical product according to claim 2, wherein,

when ring A of the cyclic carboxylic acid compound is a saturated or partially saturated 5-membered ring in which all the atoms constituting the ring are carbon atoms, R is²～R⁵And one or more of the carbon atoms of the ring A to which X is bonded are asymmetric carbon atoms, and in the case where the ring A of the cyclic carboxylic acid compound is a saturated or partially saturated 6-membered ring in which all the atoms constituting the ring are carbon atoms, R is a substituent²～R⁶And at least one of the carbon atoms of ring A to which X is bonded is an asymmetric carbon atom.

5. The pharmaceutical product according to claim 4, wherein,

in the cyclic carboxylic acid compound, when the carbon atom of the ring A to which X is bonded is C¹R is to be²Having carbon atoms of the bonded ring A as C²R is to be³Having carbon atoms of the bonded ring A as C³R is to be⁴Having carbon atoms of the bonded ring A as C⁴R is to be⁵Having carbon atoms of the bonded ring A as C⁵R is to be⁶Having carbon atoms of the bonded ring A as C⁶Wherein the combination of the asymmetric carbon atoms is one selected from the group consisting of (a) to (h),

(a)C¹

(b)C²

(c)C³

(d)C⁴

(e)C¹and C⁴

(f)C³And C⁴

(g)C¹、C³And C⁴

(h)C³、C⁴And C⁵。

6. The pharmaceutical product according to claim 1, wherein,

the cyclic carboxylic acid compound or derivative thereof is 3-dehydroquinic acid, 3-dehydroshikimic acid, shikimic acid, chorismic acid or prephenate.

7. The medicine according to any one of claims 1 to 6,

the microorganism is Escherichia coli, Bacillus subtilis, Staphylococcus aureus, Corynebacterium, radiobacter, cyanobacteria, methanogen, halophilic bacteria, thermophilic acidophilic bacteria, acid-fast bacteria, mold, yeast or their transformant.

8. The medicine according to any one of claims 1 to 7,

the plant-derived saccharide is a non-edible biomass resource.

9. An anticancer agent characterized by comprising, in a main component,

the active ingredient contains at least one of a cyclic carboxylic acid compound derived from a plant-derived saccharide and a microorganism and a derivative thereof.

10. A pharmaceutical intermediate characterized in that,

contains at least one of a cyclic carboxylic acid compound derived from a plant-derived saccharide and a microorganism and a derivative thereof.

11. A method for producing a cyclic carboxylic acid compound or a derivative thereof, which is useful as an active ingredient of a pharmaceutical or anticancer agent, comprising:

a step of preparing a culture solution containing a plant-derived saccharide and a microorganism to produce at least one of the cyclic carboxylic acid compound and a derivative thereof;

concentrating the culture solution to obtain a concentrated solution; and

and a step of recovering at least one of the cyclic carboxylic acid compound and the derivative thereof from the concentrated solution by a crystallization method, a precipitation method, an extraction method, a sublimation purification method, or a distillation method.

Technical Field

The present invention relates to a pharmaceutical, an anticancer agent, a pharmaceutical intermediate, and a method for producing a cyclic carboxylic acid compound or a derivative thereof.

Background

Aromatic compounds having a specific structure are known as one of pharmaceutical ingredients. For example, patent document 1 describes that an aromatic hydroxycarboxylic acid is important as a raw material or an intermediate for a pharmaceutical.

Documents of the prior art

Patent document

Patent document 1: japanese patent laid-open No. 2007-238469.

Disclosure of Invention

Problems to be solved by the invention

However, the aromatic compounds as described above are generally obtained from petroleum. In this case, petroleum-derived aromatic compounds (chemical products) recovered by purifying petroleum by fractional distillation are so-called core compounds having a simple chemical structure. On the other hand, high value-added compounds with more complex chemical structures must be derived from the core compound through synthetic processes. In this case, unless petroleum is highly fractionated and purified without considering the production cost, raw materials, various isomers derived from a synthesis process, trace components derived from a catalyst, ionic components, mineral components, and the like may remain in petroleum-derived chemical products. These impurities contained in petroleum-derived chemical products are not preferable from the viewpoint of safety to the human body.

The purpose of the present invention is to provide a pharmaceutical, an anticancer agent, and an intermediate thereof, that is, a pharmaceutical intermediate, which contains at least one of a cyclic carboxylic acid compound and a derivative thereof as an active ingredient, does not contain petroleum-derived impurities, and is safer. Also disclosed is a method for producing a cyclic carboxylic acid compound or a derivative thereof, which is useful as an active ingredient of a pharmaceutical or anticancer agent.

Means for solving the problems

This object is achieved by the present invention described in (1) to (11) below.

(1) A pharmaceutical comprising, as an active ingredient, at least one of a cyclic carboxylic acid compound derived from a plant-derived saccharide and a microorganism and a derivative thereof.

(2) The pharmaceutical agent according to the above (1), wherein the cyclic carboxylic acid compound is a compound represented by the following formula (1).

[ in the formula (1), the ring A is a saturated, partially saturated or aromatic 5-membered ring or a saturated, partially saturated or aromatic 6-membered ring, X is a single bond or a bond containing one or more carbon atoms, R is²～R⁶(R when Ring A is a 5-membered ring²～R⁵) Independently of hydrogen atomA hydroxyl, amino, alkoxy, carboxyl or carbonyl group.]

(3) The pharmaceutical product according to the above (2), wherein the cyclic carboxylic acid compound is at least one selected from the group consisting of 2-hydroxybenzoic acid, 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, 2, 3-dihydroxybenzoic acid, 2, 4-dihydroxybenzoic acid, 2, 5-dihydroxybenzoic acid, 2, 6-dihydroxybenzoic acid, 3, 4-dihydroxybenzoic acid and 3, 5-dihydroxybenzoic acid.

(4) The pharmaceutical product according to the above (2), wherein, when ring A of the cyclic carboxylic acid compound is a saturated or partially saturated 5-membered ring in which all the atoms constituting the ring are carbon atoms, R is²～R⁵And one or more of the carbon atoms of the ring A to which X is bonded are asymmetric carbon atoms, and in the case where the ring A of the cyclic carboxylic acid compound is a saturated or partially saturated 6-membered ring in which all the atoms constituting the ring are carbon atoms, R is a substituent²～R⁶And at least one of the carbon atoms of ring A to which X is bonded is an asymmetric carbon atom.

(5) The pharmaceutical product according to the above (4), wherein in the cyclic carboxylic acid compound, when the carbon atom of the ring A to which X is bonded is C¹R is to be²Having carbon atoms of the bonded ring A as C²R is to be³Having carbon atoms of the bonded ring A as C³R is to be⁴Having carbon atoms of the bonded ring A as C⁴R is to be⁵Having carbon atoms of the bonded ring A as C⁵R is to be⁶Having carbon atoms of the bonded ring A as C⁶In the case where the carbon atom is an asymmetric carbon atom, the combination is one selected from the group consisting of the following (a) to (h).

(a)C¹

(b)C²

(c)C³

(d)C⁴

(e)C¹And C⁴

(f)C³And C⁴

(g)C¹、C³And C⁴

(h)C³、C⁴And C⁵。

(6) The pharmaceutical product according to the above (1), wherein the cyclic carboxylic acid compound or the derivative thereof is 3-dehydroquinate (3-dehydroquinate), 3-dehydroshikimic acid (3-dehydroshikimate), shikimic acid (shikimic acid), chorismic acid or prephenate.

(7) The pharmaceutical product according to any one of the above (1) to (6), wherein the microorganism is Escherichia coli, Bacillus subtilis, Staphylococcus aureus, Corynebacterium, actinomycetes, cyanobacteria, methanogen, halophilic, thermoacidophilic bacteria, acid-fast bacteria, mold, yeast or a transformant thereof.

(8) The pharmaceutical product according to any one of the above (1) to (7), wherein the raw material of the plant-derived saccharide is a non-edible biomass resource.

(9) An anticancer agent characterized by containing, as an active ingredient, at least one of a cyclic carboxylic acid compound derived from a plant-derived saccharide and a microorganism, and a derivative thereof.

(10) A pharmaceutical intermediate characterized by containing at least one of a cyclic carboxylic acid compound derived from a plant-derived saccharide and a microorganism and a derivative thereof.

(11) A method for producing a cyclic carboxylic acid compound or a derivative thereof, which is useful as an active ingredient of a pharmaceutical or anticancer agent, comprising:

a step of preparing a culture solution containing a plant-derived saccharide and a microorganism to produce at least one of the cyclic carboxylic acid compound and a derivative thereof;

concentrating the culture solution to obtain a concentrated solution; and

and recovering at least one of the cyclic carboxylic acid compound and the derivative thereof from the concentrated solution by crystallization, precipitation, extraction, sublimation purification, or distillation.

ADVANTAGEOUS EFFECTS OF INVENTION

According to the present invention, a pharmaceutical and an anticancer agent containing at least one of a cyclic carboxylic acid compound and a derivative thereof as an active ingredient and containing no petroleum-derived impurities, and a pharmaceutical intermediate containing at least one of a cyclic carboxylic acid compound and a derivative thereof can be provided. Therefore, a more safe drug, anticancer agent and drug intermediate can be produced more efficiently than a drug, anticancer agent and drug intermediate containing petroleum-derived impurities.

Detailed Description

Hereinafter, the pharmaceutical product, the anticancer agent, the pharmaceutical intermediate, and the process for producing the cyclic carboxylic acid compound or the derivative thereof according to the present invention will be described in detail based on preferred embodiments.

Medicine for treating diabetes

The inventors of the present invention have conducted extensive studies and, as a result, found that: a pharmaceutical agent containing no petroleum-derived impurities can be provided by using, as an active ingredient, at least one of a cyclic carboxylic acid compound derived from a plant-derived saccharide and a microorganism and a derivative thereof. At this time, it was found that: the cyclic carboxylic acid compound or a derivative thereof is preferably produced by a biological process using a plant-derived saccharide (raw material) and a microorganism.

That is, the pharmaceutical of the present invention contains, as an active ingredient, at least one of a cyclic carboxylic acid compound derived from a plant-derived saccharide and a microorganism, and a derivative thereof. In other words, the pharmaceutical of the present invention contains, as an active ingredient, at least one of a cyclic carboxylic acid compound produced by a reaction (bioprocess) between a plant-derived saccharide and a microorganism, and a derivative thereof.

Thus, a pharmaceutical product containing no petroleum-derived impurities can be provided. Such a pharmaceutical is more safe than a pharmaceutical containing an impurity derived from petroleum.

At least one of cyclic carboxylic acid compounds derived from plant-derived saccharides and microorganisms and derivatives thereof can be used as a raw material (pharmaceutical intermediate) for producing a pharmaceutical product.

Thus, a pharmaceutical raw material containing at least one of a cyclic carboxylic acid compound and a derivative thereof as an active ingredient and containing no petroleum-derived impurities can be provided. This drug intermediate enables the production of a pharmaceutical product with higher safety than a drug intermediate containing an impurity derived from petroleum.

As described above, the cyclic carboxylic acid compound contained in the pharmaceutical or the raw material thereof is not particularly limited, but is preferably a compound represented by the following formula (1).

[ in the formula (1), the ring A is a saturated, partially saturated or aromatic 5-membered ring or a saturated, partially saturated or aromatic 6-membered ring, X is a single bond or a bond containing one or more carbon atoms, R is²～R⁶(R when Ring A is a 5-membered ring²～R⁵) Independently a hydrogen atom, a hydroxyl group, an amino group, an alkoxy group, a carboxyl group or a carbonyl group.]

Examples of the saturated, partially saturated or aromatic 5-membered ring include a furan structure, a thiophene structure, a pyrrole structure, a pyrrolidine structure, a tetrahydrofuran structure, a 2, 3-dihydrofuran structure, a pyrazole structure, an imidazole structure, an oxazole structure, an isoxazole structure, a thiazole structure, and an isothiazole structure.

Examples of the saturated ring having a 6-membered ring include: a hydrocarbon-based saturated ring such as a cyclohexane structure; nitrogen-containing saturated rings such as piperidine structure, piperazine structure, triazinane structure, tetrazinane structure, pentazinane structure, quinuclidine structure; oxygen-containing saturated rings such as tetrahydropyran structure, morpholine structure; and sulfur-containing saturated rings such as tetrahydrothiopyran structure, and the like.

Examples of the 6-membered ring of the partially saturated ring include: partially saturated hydrocarbon rings such as cyclohexene structure and cyclohexadiene structure; nitrogen-containing partially saturated rings such as piperidine structures; an oxygen-containing partially saturated ring such as a pyran structure; and sulfur-containing partially saturated rings such as thiazine structures, and the like.

Examples of the 6-membered ring of the aromatic ring include: hydrocarbon aromatic rings such as benzene structure; and nitrogen-containing aromatic rings (nitrogen-containing unsaturated rings) such as pyridine structures, pyridazine structures, pyrimidine structures, pyrazine structures, triazine structures, tetrazine structures, pentazine structures, and the like.

X is a single bond or a bond containing one or more carbon atoms.

When X is a single bond, the carboxyl group is directly bonded to the ring-constituting atom of the ring a.

On the other hand, examples of the bond having one or more carbon atoms include a hydrocarbon group having 1 to 4 carbon atoms, an ether bond, an ester bond, an amide bond, a carbonyl group, a vinylene group, and the like, and one or two or more kinds of bonds are combined.

The hydrocarbon group having 1 to 4 carbon atoms may be either a straight chain or a branched chain, or may be either saturated or unsaturated. The hydrogen atom of the hydrocarbon group may be substituted with a substituent such as an alkyl group having 1 to 2 carbon atoms, a hydroxyl group, an amino group, a carboxyl group, a halogen atom or the like.

In the case where ring A is a 6-membered ring, R²～R⁶Independently a hydrogen atom, a hydroxyl group, an amino group, an alkoxy group, a carboxyl group or a carbonyl group. Further, in the case where ring A is a 5-membered ring, R²～R⁵Independently a hydrogen atom, a hydroxyl group, an amino group, an alkoxy group, a carboxyl group or a carbonyl group.

R when ring A is a 6-membered ring²～R⁶R when any one of them is a carbonyl group or when ring A is a 5-membered ring²～R⁵When any of them is a carbonyl group, a structure in which the atom constituting the ring of ring a is a carbon atom and a double bond is formed between the carbon atom and an oxygen atom is referred to as a carbonyl group.

Specific examples of the cyclic carboxylic acid compound represented by the formula (1) include benzoic acid, phthalic acid, isophthalic acid, terephthalic acid, hemimellitic acid, trimellitic acid, trimesic acid, pyromellitic acid, phenylacetic acid, hydroxyphenylacetic acid, phenylbutyric acid (phenyllactic acid), hydroxyphenylbutyric acid, phenylpyruvic acid, phenyllactic acid, hydroxyphenyllactic acid, anthranilic acid, hydroarthrotic acid, atropic acid, hydrocinnamic acid (coumaric acid), cinnamic acid, salicylic acid (2-hydroxybenzoic acid), m-salicylic acid (3-hydroxybenzoic acid), p-salicylic acid (4-hydroxybenzoic acid), methoxybenzoic acid, aminobenzoic acid, hydroxybenzoic acid, pyrocatechoic acid (2, 3-dihydroxybenzoic acid), β -dihydroxybenzoic acid (2, 4-dihydroxybenzoic acid), Gentisic acid (2, 5-dihydroxybenzoic acid), gamma-dihydroxybenzoic acid (2, 6-dihydroxybenzoic acid), protocatechuic acid (3, 4-dihydroxybenzoic acid), alpha-dihydroxybenzoic acid (3, 5-dihydroxybenzoic acid), trihydroxybenzoic acid, vanillic acid (4-hydroxy-3-methoxybenzoic acid), isovanillic acid (3-hydroxy-4-methoxybenzoic acid), veratric acid, gallic acid, syringic acid, asarone acid, mandelic acid, vanillylmandelic acid, anisic acid, homopartaric acid, plateau catechuic acid, homovanillic acid, homoisovanillic acid, homoveratric acid, homophthalic acid, phthalic acid, isophthalic acid, terephthalic acid, atropine acid, melilotic acid, phloroglucinic acid (melilotic acid), phloroglucic acid, phloroglucinic acid, Dihydrocaffeic Acid, hydrogenated ferulic Acid, hydrogenated isoferulic Acid, umbellic Acid, Caffeic Acid (Caffeic Acid), ferulic Acid, isoferulic Acid, sinapic Acid, syringic Acid, dehydroquinic Acid, dehydroshikimic Acid, shikimic Acid, chorismic Acid, L-tryptophan, L-tyrosine, prephenate, aronic Acid, L-phenylalanine, etc.

Examples of the derivative of the cyclic carboxylic acid compound include esters, acid anhydrides, amides, acid halides (acid halides), salts and the like of the above compounds, and all compounds derived from the cyclic carboxylic acid compound.

Among them, the cyclic carboxylic acid compound represented by the above formula (1) is particularly preferably at least one selected from the group consisting of 2-hydroxybenzoic acid, 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, 2, 3-dihydroxybenzoic acid, 2, 4-dihydroxybenzoic acid, 2, 5-dihydroxybenzoic acid, 2, 6-dihydroxybenzoic acid, 3, 4-dihydroxybenzoic acid and 3, 5-dihydroxybenzoic acid. By using these substances, a more safe pharmaceutical product having various effects can be realized.

Also, the derivative of the cyclic carboxylic acid compound represented by the above formula (1) is particularly preferably erlotinib, itopride hydrochloride, veratridine, hydrochloric acid Mai Pi skin Lin or Picatin II. By using these substances, a more safe pharmaceutical product having various effects can be realized.

Among these derivatives, erlotinib, itopride hydrochloride and veratridine are all compounds derived from the cyclic carboxylic acid compound represented by the above formula (1), and the structures thereof are represented by the following formulae.

Erlotinib

Itopride hydrochloride

Veratridine

Meanwhile, the hydrochloric acid Mai Pi skin Lin and Picatin II are compounds derived from a cyclic carboxylic acid compound represented by the above formula (1), and are described as examples of pharmaceutical products in the following documents.

Global Protocatechuic Acid (CAS 99-50-3) Market Research Report (Market Research Report)2018

The molecular weight of the cyclic carboxylic acid compound or its derivative is not particularly limited, but is preferably 120 to 1000, more preferably 130 to 800.

When ring A of the cyclic carboxylic acid compound represented by the above formula (1) is a saturated or partially saturated ring having all the atoms constituting the ring carbon atoms, R is a 5-membered ring²～R⁵And the carbon atom of ring A to which X is bonded, preferably at least one is an asymmetric carbon atom. When ring A of the cyclic carboxylic acid compound represented by the above formula (1) is a saturated or partially saturated 6-membered ring in which all the atoms constituting the ring are carbon atoms, R is²～R⁶And the carbon atom of ring A to which X is bonded, preferably at least one is an asymmetric carbon atom.

In this case, the cyclic carboxylic acid compound becomes a stereoisomer, and thus a significant pharmaceutical product or a raw material for producing the pharmaceutical product can be realized. By producing such a cyclic carboxylic acid compound from a plant-derived saccharide, a pharmaceutical product containing a specific stereoisomer at high purity or a raw material thereof can be obtained. That is, a drug or a raw material thereof can be obtained which contains a specific stereoisomer at high purity and has a low content of other stereoisomers. Such a drug or a raw material thereof is useful from the viewpoint that a drug having excellent safety and efficacy can be realized. Further, since a complicated production process accompanied by removal of an unnecessary stereoisomer is not required, the production cost can be reduced.

In the cyclic carboxylic acid compound represented by the above formula (1), when the carbon atom of the ring A to which X is bonded is C¹R is to be²Having carbon atoms of the bonded ring A as C²R is to be³Having carbon atoms of the bonded ring A as C³R is to be⁴Having carbon atoms of the bonded ring A as C⁴R is to be⁵Having carbon atoms of the bonded ring A as C⁵R is to be⁶Having carbon atoms of the bonded ring A as C⁶In the case where these carbon atoms are asymmetric carbon atoms, the combination is preferably one selected from the group consisting of the following (a) to (h).

(a)C¹

(b)C²

(c)C³

(d)C⁴

(e)C¹And C⁴

(f)C³And C⁴

(g)C¹、C³And C⁴

(h)C³、C⁴And C⁵。

Further, the following formula (2) is a cyclic carboxylic acid compound represented by the formula (1) and supplemented with C¹～C⁶General formula (iv) of the label (c).

[ in the formula (2), the ring A is a saturated, partially saturated or aromatic 5-membered ring or a saturated, partially saturated or aromatic 6-membered ring, X is a single bond or a bond containing one or more carbon atoms, R is²～R⁶(R when Ring A is a 5-membered ring²～R⁵) Independently a hydrogen atom, a hydroxyl group, an amino group, an alkoxy group, a carboxyl group or a carbonyl group. And, C¹～C⁶Each is a carbon atom as an atom constituting the ring of ring A.]

In this case, the cyclic carboxylic acid compound becomes a stereoisomer, and thus a particularly significant pharmaceutical product or a raw material for producing the pharmaceutical product can be realized. By producing such a cyclic carboxylic acid compound from a plant-derived saccharide, a pharmaceutical product containing a specific stereoisomer selected from one of the groups (a) to (h) above at high purity or a raw material thereof can be obtained. That is, a drug or a raw material thereof can be obtained which contains a specific stereoisomer at high purity and has a low content of other stereoisomers. Such a drug or a raw material thereof is useful from the viewpoint of realizing a drug having excellent safety and efficacy. Further, since the complicated production steps involved in the removal of unnecessary stereoisomers can be reduced, the production cost can be reduced.

The cyclic carboxylic acid compound and the derivative thereof according to the present invention are compounds represented by the above formula (2), and particularly preferably 3-dehydroquinic acid, 3-dehydroshikimic acid, shikimic acid, chorismic acid, or prephenate. These compounds can be produced from plant-derived saccharides, and are useful as active ingredients of pharmaceuticals or pharmaceutical raw materials (pharmaceutical intermediates). Therefore, by using these compounds produced from plant-derived saccharides, a more safe pharmaceutical product having more excellent potency can be realized.

The structures of these cyclic carboxylic acid compounds are represented by the following formulae.

3-dehydroquinic acid

3-dehydroshikimic acid

Shikimic acid

Branched acids

Prephenate

In addition to the above, examples of the cyclic carboxylic acid compound or the derivative thereof according to the present invention include compounds represented by the following formulae (a) to (y).

[ in formulae (a) to (h), R⁷Represents a linear or branched alkyl group having 1 to 12 carbon atoms, and Ms represents a methanesulfonyl group (Mesyl).]

[ in formulae (i) to (o), R⁷Represents a linear or branched alkyl group having 1 to 12 carbon atoms, Ms represents a methanesulfonyl group, and Ph representsRepresents phenyl and Ac represents acryloyl.]

[ in formulae (p) to (u), R⁷Represents a linear or branched alkyl group having 1 to 12 carbon atoms, R⁸And R^8’Independently represents a linear or branched alkyl group having 1 to 12 carbon atoms, R⁹And R¹⁰Independently represents a linear or branched alkyl group having 1 to 12 carbon atoms, and Ms represents a methanesulfonyl group.]

[ in formulae (v) to (y), R⁷Represents a linear or branched alkyl group having 1 to 12 carbon atoms, R⁸And R^8’Independently represents a linear or branched alkyl group having 1 to 12 carbon atoms, R¹¹And R¹²Independently of one another, represents a hydrogen atom or an alkanoyl group, and Ms represents a methanesulfonyl group.]

Examples of the alkanoyl group include a hexanoyl group, a pentanoyl group, a butanoyl group, a propanoyl group, an Acetyl (Ethanoyl) group, and a formyl group.

In the formulae (a) to (y), the compound represented by the formula (o) is Oseltamivir (Oseltamivir). Oseltamivir phosphate is useful as an active ingredient of an influenza therapeutic agent.

Therefore, by producing such a compound from a plant-derived saccharide, a safer influenza therapeutic agent free from petroleum-derived impurities can be provided at low cost.

Examples of the pharmaceutical product containing at least one of the above cyclic carboxylic acid compound and its derivative as an active ingredient include, in addition to influenza therapeutic drugs, anticancer agents, antiulcer agents, antidiabetic agents, antifibrosis agents, antiaging agents, antiviral agents, antiinflammatory agents, analgesic agents, antiarteriosclerotic agents, antilipidemic agents, cardiotonic agents, hepatoprotective agents, neuroprotective agents, kidney protectants, antibionzoxic agents, antiasthmic agents, and anticonvulsant agents.

The anticancer agent of the present invention contains, as active ingredients, at least one of a cyclic carboxylic acid compound derived from a plant-derived saccharide and a microorganism, and a derivative thereof. In other words, the anticancer agent of the present invention contains, as an active ingredient, at least one of a cyclic carboxylic acid compound produced by a reaction (biotechnology) between a plant-derived saccharide and a microorganism, and a derivative thereof.

Thus, an anticancer agent free from petroleum-derived impurities can be provided. Such anticancer agents are respectively higher in safety than anticancer agents containing petroleum-derived impurities.

On the other hand, as a pharmaceutical raw material (pharmaceutical intermediate) containing at least one of a cyclic carboxylic acid compound and a derivative thereof, an intermediate for producing the above-mentioned pharmaceutical is exemplified.

The cyclic carboxylic acid compound and/or the derivative thereof can be used in applications other than pharmaceuticals and pharmaceutical raw materials (pharmaceutical intermediates). Examples of such applications include health supplement compositions, food additives, perfumes, foods, cosmetics, daily necessities, detergents, non-pharmaceutical products, and the like.

Among them, examples of the food include oral compositions (chewing gum, candy, etc.), processed aquatic fish foods such as fish cake and tubular fish roll, livestock products such as sausage and ham, western-style snacks, japanese snacks, noodles such as chinese noodles, udon noodles and buckwheat noodles, seasonings such as sauce, soy sauce and sauce, side dish, fruit juice, soup, and the like.

Examples of the cosmetic include a lotion, a milky lotion, a cream (lotion), a foundation, an eye shadow, a lipstick, a blush, a hair care product, a skin cream (lotion), a skin lotion (lotion), a cream (cream), a nourishing hair lotion (cream ring), a cold cream (cold ring), a vanishing cream (whitening ring), a skin lotion (deposition), a face pack, a gel, a face pack, a soap, a body wash (body soap), a shampoo, an essence (conditioner), a hair conditioner (ring), a bath preparation, a face cleanser, a shaving cream, a hair cream (hair ring), a hair lotion (hair deposition), a hair care solution, a hair mask, a lip gloss (gloss), and a lip balm.

Process for producing cyclic carboxylic acid compound or derivative thereof

The cyclic carboxylic acid compound or the derivative thereof is produced by a biological process using a microorganism using a plant-derived saccharide as a raw material. That is, the cyclic carboxylic acid compound or the derivative thereof is derived from a plant-derived saccharide and a microorganism.

The plant-derived saccharide is not particularly limited, and examples thereof include monosaccharides, polysaccharides, and mixtures thereof.

The monosaccharide is not particularly limited, and examples thereof include saccharides that can be treated with a transformant of a microorganism described later. Examples of such sugars (monosaccharides) include, from the viewpoint of improving the phenol productivity of the transformant, tetroses (C4 sugars), pentoses (C5 sugars), hexoses (C6 sugars), and heptoses (C7 sugars). Among these, as the monosaccharide, at least one selected from the group consisting of arabinose, xylose, glucose, mannitol, fructose, mannose, galactose and sucrose is particularly preferable. Further, such a saccharide may be used in one kind, or may be used in the form of a mixed saccharide by combining a plurality of kinds.

Polysaccharides are polymers of monosaccharides. The average polymerization degree of the polysaccharide is not particularly limited, but is preferably 2 or more and 100 or less, and more preferably 2 or more and 50 or less, from the viewpoint of improving productivity in a biological process using a microorganism. Further, the polysaccharide may be used in one kind, or in combination of plural kinds. Examples of the polysaccharide include maltose, lactose, cellobiose, xylobiose, trehalose, acarbose, stachyose, fructooligosaccharide, galactooligosaccharide, and mannooligosaccharide.

Plant-derived sugars are preferably produced from non-edible biomass resources. In other words, the raw material of the plant-derived saccharide is preferably a non-edible biomass resource.

As the biomass resource, various biomass resources can be used as long as they contain at least a monosaccharide or a polysaccharide from the viewpoint of obtaining the above-described saccharide. The biomass resources include, in addition to grass resources represented by weeds produced from urban areas or cultivated lands, and grass and wood resources represented by intermediate cuts in forestry production areas, waste cellulose, waste starch, waste molasses, sugar cane press residues in the sugar industry, distiller grains in the wine industry, and the like, which are generally recovered as engineering residues or waste products in the food industry, and these can be used in one kind or in combination of plural kinds. Further, as a biomass resource, a processed product can also be used.

By saccharifying such a biomass resource, the plant-derived saccharide can be obtained. The plant-derived saccharide is preferably a cellulose-derived saccharide obtained by saccharifying waste cellulose, and more preferably a mixed saccharide derived from cellulose. Hereinafter, a process using a microorganism using a plant-derived saccharide as a raw material will be described in detail.

The process using the microorganism using the plant-derived saccharide as a raw material includes: a step of obtaining a culture solution containing at least one of the cyclic carboxylic acid compound and a derivative thereof produced by a microorganism (produced by converting a plant-derived saccharide with a microorganism) using the plant-derived saccharide as a raw material; concentrating the culture solution to obtain a concentrated solution; and recovering at least one of the cyclic carboxylic acid compound and the derivative thereof from the concentrated solution by a crystallization method, a precipitation method, an extraction method, a sublimation purification method, or a distillation method. By performing such a process, at least one of the cyclic carboxylic acid compound and the derivative thereof can be efficiently obtained. According to the process using such a microorganism, the active ingredient can be produced (produced) as a result of the reaction between the raw material and the microorganism. Therefore, by limiting the types of the raw material and the microorganism (for example, by limiting the raw material to a saccharide derived from a plant and limiting the type of the microorganism to a bacterial species), only one active ingredient (cyclic carboxylic acid compound or derivative thereof) can be efficiently obtained. Such an effect can be remarkably exhibited by further limiting the types of raw materials and microorganisms (for example, limiting raw materials to mixed sugars derived from cellulose and limiting the types of bacteria). In this regard, it is different from a process that does not use microorganisms (for example, a process that uses an extract from a plant). From this viewpoint, cyclic carboxylic acid compounds and derivatives thereof derived from plant-derived saccharides and microorganisms can be referred to as cyclic carboxylic acid compounds and derivatives thereof (excluding cyclic carboxylic acid compounds and derivatives thereof derived from plant extracts).

In the bioprocess, the recovery rate of the cyclic carboxylic acid compound and the derivative thereof can be improved by appropriately selecting the microorganism, the culture medium, the culture apparatus, and the culture conditions.

< procedure for preparation of culture solution >

First, a culture solution containing a raw material, a microorganism, a culture medium, and the like is prepared. In this culture solution, a microorganism is cultured, and a raw material or the like is allowed to react with the microorganism (by a bioprocess), thereby producing at least one of a cyclic carboxylic acid compound and a derivative thereof.

The microorganism is not particularly limited as long as it can efficiently produce the cyclic carboxylic acid compound and the derivative thereof. Conventionally, microorganisms selected from Escherichia coli (Escherichia coli), bacteria such as Bacillus subtilis, Staphylococcus aureus (Staphylococcus aureus), Corynebacterium glutamicum (Corynebacterium glutamicum), bacteria such as Streptomyces griseus, bacteria such as actinomycetes such as Streptomyces griseus, cyanobacteria such as Microcystis aeruginosa, methanogen (Methanobacterium thermoautotrophicum), halophilic bacteria (Halobacterium salinum), thermophilic bacteria (sulfobacillus acidocaldarius), thermophilic bacteria (Acid-fast bacteria), fungi such as Aspergillus oryzae (Aspergillus oryzae), Saccharomyces cerevisiae (Saccharomyces cerevisiae), and bacteria such as Saccharomyces cerevisiae have been used for transformation according to the purpose.

As the medium, a medium generally used for culturing microorganisms may be used. The medium contains medium components to adjust the environment required for the growth of the microorganism. The medium components preferably contain appropriate amounts of carbon sources, nitrogen sources, inorganic salts, other nutrients, and the like, depending on the type of microorganism used. Therefore, the culture solution before the bioprocess is preferably composed of raw materials, microorganisms, and medium components.

Examples of the carbon source include saccharides or sugar alcohols such as glucose, fructose, sucrose, mannose, maltose, mannitol, xylose, arabinose, galactose, starch, molasses, sorbitol, and glycerol; organic acids such as acetic acid, citric acid, lactic acid, fumaric acid, maleic acid, and gluconic acid; alcohols such as ethanol and propanol. One of these carbon sources may be used alone, or two or more of them may be used in combination.

Examples of the nitrogen source include inorganic or organic ammonium compounds such as ammonium chloride, ammonium sulfate, ammonium nitrate and ammonium acetate, urea, aqueous ammonia, sodium nitrate and potassium nitrate. Furthermore, nitrogen-containing organic compounds such as corn steep liquor, meat extract, peptone, NZ-amine, protein hydrolysate, amino acids, and the like can also be used. As the nitrogen source, one kind may be used alone, or two or more kinds may be used in combination.

Examples of the inorganic salts include potassium dihydrogen phosphate (リン acid first カリウム), dipotassium hydrogen phosphate (リン acid second カリウム), magnesium sulfate, sodium chloride, ferrous nitrate, manganese sulfate, zinc sulfate, cobalt sulfate, and calcium carbonate. As the inorganic salts, one kind may be used alone, or two or more kinds may be used in combination.

Examples of the nutrient components include meat extract, peptone, polypeptone, yeast extract, dry yeast, corn steep liquor, skim milk powder, defatted soybean hydrochloric acid hydrolysate, and extracts and decomposed products of animals, plants, and microbial cells. Further, vitamins may be added to the medium as necessary. Examples of the vitamins include biotin, thiamine (vitamin B1), pyridoxine (vitamin B6), pantothenic acid, inositol, and nicotinic acid.

The culture apparatus may be any of a batch type, a fed-batch type, and a continuous type, but when production of a plurality of species is assumed, the batch type is preferable. In addition, a seed culture system in which scale-up culture is performed stepwise from flask-scale culture is often used, and groups of culture vessels different in size in several stages depending on the production scale are used as one group. The culture conditions are preferably such that the temperature of the medium is about 15 to 45 ℃ and the pH of the medium is about 6 to 8. In addition, parameters such as the aeration method and aeration amount to the culture vessel, the stirring method and rotation speed, the shape of the stirring blade, and the culture time are appropriately set in accordance with the scale and specification of the culture apparatus, the type and concentration of the microorganism used, and the culture process is appropriately adjusted by real-time monitoring.

< concentration step and separation and purification step >

The culture solution obtained by the bioprocess can be prepared in a state of containing the cyclic carboxylic acid compound or the derivative thereof at an appropriate concentration as long as the environment for the growth of the microorganism is appropriately selected. For the purpose of selectively and efficiently recovering the cyclic carboxylic acid compound or its derivative from the thus-prepared culture solution, a recovery process including a concentration step and a separation and purification step of the culture solution is applied. According to this method, a cyclic carboxylic acid compound or a derivative thereof can be efficiently produced.

The concentration step is performed for the following purposes: increasing the concentration of at least one of a cyclic carboxylic acid compound and a derivative thereof in a culture solution obtained after a bioprocess; in the subsequent separation and purification step, the target compound is recovered in high yield and high purity. The concentration step will be described below.

The culture solution after the bioprocess contains a carbon source, a nitrogen source, inorganic salts, nutrients, and the like as components of the medium, in addition to at least one of the cyclic carboxylic acid compound and the derivative thereof produced by the bioprocess, and further contains an organic acid, an amino acid, and salts thereof additionally produced in the bioprocess. In addition, 70-99% of the total weight of the culture solution after the biological process is usually water. Therefore, in the concentration step, it is desired that the water can be efficiently removed without deteriorating or losing the cyclic carboxylic acid compound or its derivative and without further increasing the amount of by-products accompanying the concentration. In order to achieve this object, chemical engineering methods such as heat concentration, reduced pressure distillation, solvent extraction, solid extraction, and membrane separation can be applied, but it is particularly preferable to use reduced pressure concentration in order to avoid deterioration and loss of the cyclic carboxylic acid compound or its derivative due to heat or oxidation in the concentration step and to reduce the amount of heat energy input accompanying the removal of water.

The separation and purification step is performed for the purpose of selectively recovering at least one of a cyclic carboxylic acid compound and a derivative thereof from the concentrated solution obtained in the concentration step.

In the separation and purification step, various chemical engineering methods such as steam distillation, precision fractionation, temperature crystallization, acid crystallization, salting out, reprecipitation, sublimation, column purification, extraction, and membrane separation can be applied. A suitable method is selected in consideration of the properties of the target compound and the properties of impurities or byproducts to be removed. The properties of the cyclic carboxylic acid compound vary depending on the kind and number of the substituents, but when the cyclic carboxylic acid compound or its derivative is solid at room temperature and the water solubility of impurities or by-products is high, a crystallization method (temperature crystallization or acid crystallization) is preferably used.

< processing of pharmaceuticals >

The pharmaceutical of the present invention may contain any other component within a range not impairing the effects of the present invention.

Examples of the other ingredients include granulated sugar, condensed milk, wheat flour, shortening, common salt, glucose, eggs, butter, margarine, maltose, calcium, iron, seasonings, flavors or oils (animal and vegetable oils, mineral oils, ester oils, wax oils, silicone oils, higher alcohols, phospholipids, fatty acids, etc.), surfactants (anionic, cationic, amphoteric or nonionic surfactants), vitamins (vitamin a group, vitamin B group, folic acids, nicotinic acids, pantothenic acids, biotin groups, vitamin C group, vitamin D group, vitamin E group, other ferulic acids, γ -oryzanol, etc.), ultraviolet absorbers (p-aminobenzoic acid, anthranilic acid, salicylic acid, coumarin, benzotriazole, tetrazole, imidazoline, pyrimidine, dioxane, furan, pyrone, camphor, nucleic acids, allantoin or its derivatives, and the like, Amino acid compounds, alkannin, baicalin, baicalein, berberine, and the like), antioxidants (stearate, nordihydroguaiaretic acid, dibutylhydroxytoluene, butylhydroxyanisole, p-hydroxyanisole, propyl gallate, sesamol, sesamolin, gossypol, and the like), thickeners (hydroxyethyl cellulose, ethyl cellulose, carboxyethyl cellulose, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, nitrocellulose, polyvinyl alcohol, polyvinyl methyl ether, polyvinyl pyrrolidone, polyvinyl methacrylate, polyacrylate, carboxyvinyl polymer, Gum arabic, Tragacanth (Gum Tragacanth), agar, casein, dextrin, gelatin, pectin, starch, alginic acid or a salt thereof, and the like), humectants (propylene glycol, 1, 3-butylene glycol, and the like), humectants, Polyethylene glycol, glycerin, 1, 2-pentanediol, hexanediol, octanediol, chondroitin sulfate or a salt thereof, hyaluronic acid or a salt thereof, sodium lactate, and the like), a lower alcohol, a polyhydric alcohol, a water-soluble polymer, a pH adjuster, a preservative/antifungal agent, a coloring agent, a perfume, a refreshing agent, a stabilizer, an animal or plant extract, an animal or plant protein or a decomposition product thereof, an animal or plant polysaccharide or a decomposition product thereof, an animal or plant glycoprotein or a decomposition product thereof, a microbial culture metabolic component, a blood flow promoter, an anti-inflammatory agent, an antiallergic agent, a cell activator, an amino acid or a salt thereof, a keratolytic agent, an astringent, a wound healing agent, a foam booster, an oral agent, a deodorant/deodorant agent, an emulsifier, and the like. These can be used alone or in combination of two or more.

The form of the pharmaceutical product of the present invention is arbitrary, but for example, it is in the form of a solution, a paste (cream), a paste (paste), a gel, a foam, a solid, a powder, or the like.

Further, depending on the purpose, use and use of the drug of the present invention, spraying or transpiration can also be applied to the method of using the drug of the present invention.

The pharmaceutical product of the present invention or a raw material (pharmaceutical intermediate) thereof has been described above, but specific examples of the pharmaceutical product are not limited to the above-mentioned ones, and any product may be used.

Examples

The present invention will be described more specifically below with reference to examples.

(example 1)

Production of 3, 4-dihydroxybenzoic acid by means of a biological process

A culture solution obtained by a biological process using plant-derived sugars and microorganisms is concentrated under reduced pressure so that the total solid content concentration is 15 to 30 mass%. The concentration treatment is carried out by a reduced pressure distillation apparatus while the reduced pressure is set to 100 to 5000Pa and the liquid temperature is set to 30 to 80 ℃. The concentration degree depends on the treatment time, but a concentrated solution having a total solid content of 15 to 30 mass% is recovered by the concentration treatment for 6 to 8 hours. Hydrochloric acid is added to the concentrated solution to adjust the pH to 4 or less, and the solution is cooled to 0 to room temperature. The crystal was recovered by filtration, washed appropriately, and dried under reduced pressure, whereby high-purity 3, 4-dihydroxybenzoic acid having a purity of 99% or more was recovered.

Also, the high-purity 3, 4-dihydroxybenzoic acid, i.e., cyclic carboxylic acid compound, does not contain petroleum-derived impurities.

(example 2)

Production of shikimic acid by bioprocess

Activated carbon was added to a culture solution obtained by a biological process using plant-derived sugars and microorganisms, and activated carbon treatment was performed. Then, a column packed with an ion exchange resin was prepared and treated with a 2mol/L aqueous solution of sodium hydroxide. In addition, the ion exchange resin used is a strongly basic anion exchange resin. Pure water was passed through the column until the effluent water was neutral, and then the raw material liquid subjected to the activated carbon treatment was passed through the column and then the pure water was passed through. Then, as an eluent, 2mol/L of an aqueous acetic acid solution was passed, and an acidic component was recovered. For each fraction recovered, the concentration of shikimic acid is determined and the eluent is passed until elution of shikimic acid is completed. And (4) concentrating and crystallizing the eluent to separate out a solid, thereby obtaining the solid shikimic acid. The concentration crystallization is a treatment of precipitating solid shikimic acid by sequentially performing a concentration treatment and a cooling crystallization treatment.

Also, the high-purity shikimic acid, i.e., the cyclic carboxylic acid compound, does not contain petroleum-derived impurities.

Industrial applicability

According to the present invention, a pharmaceutical and an anticancer agent containing at least one of a cyclic carboxylic acid compound and a derivative thereof as an active ingredient and containing no petroleum-derived impurities, and a pharmaceutical intermediate containing at least one of a cyclic carboxylic acid compound and a derivative thereof can be provided. Therefore, a more safe drug, anticancer agent and drug intermediate can be produced more efficiently than a drug, anticancer agent and drug intermediate containing petroleum-derived impurities. Therefore, the present invention has industrial applicability.