JP2006016319A - Prodrug - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a compound free from the problems of 2-propyloctanoic acid. <P>SOLUTION: The invention provides a prodrug of 2-propyloctanoic acid. A 2-propyloctanoic acid prodrug, especially a compound expressed by general formula (I), its salt, its N-oxide, its quaternary ammonium salt or its solvate, etc., is useful as a medicine because the substance has improved physical properties, dispositions (absorption through digestive tracts, concentration in blood, tissue distribution, etc.), etc., compared with 2-propyloctanoic acid and has high therapeutic value to various neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and cerebral infarction. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a prodrug of 2-propyloctanoic acid useful as a pharmaceutical product. More specifically, some problems that may occur when 2-propyloctanoic acid or its optically active substance (2R) -2-propyloctanoic acid is administered to a living body, particularly oral absorption and persistence in blood. The present invention relates to a prodrug for solving problems in oral irritation and the like.

  In general, even a compound showing excellent drug efficacy in an in vitro test system often does not achieve the desired effect when administered to humans. This is because the compound is not absorbed in the human body, or even if it is absorbed, it is rapidly metabolized and decomposed in the liver or blood. In the development of pharmaceuticals, in order to avoid these problems, a method of chemically modifying a compound to form a prodrug is used. In addition, prodrugs may also be used when active compounds have properties that cause problems when administered orally, such as bitterness and irritation.

  On the other hand, 2-propyloctanoic acid is useful as a therapeutic and / or prophylactic agent for neurodegenerative diseases, neurological dysfunction after stroke or cerebrospinal trauma, brain tumors, cerebrospinal diseases associated with infections, and the like. It is known as a derivative (see, for example, Patent Document 1).

  In addition, 2-propyloctanoic acid is known to be useful as a therapeutic and / or prophylactic agent for Parkinson's disease or Parkinson's syndrome (see, for example, Patent Document 2).

  Furthermore, these actions of (2R) -2-propyloctanoic acid, which is an optically active form of 2-propyloctanoic acid, are due to the function improving action of abnormally activated astrocytes based on the action of reducing intracellular S100β content. (For example, refer nonpatent literature 1).

  However, these patent documents do not describe a prodrug of 2-propyloctanoic acid, and 2-propyloctanoic acid or its optically active substance (2R) -2-propyloctanoic acid was administered as a pharmaceutical. There is no description or suggestion about problems that may occur and how to solve them.

European Patent Publication No. 06322088 European Patent Publication No. 1174131 Tateishi. N, 8 others, Journal of cerebral blood flow & metabolism, 2002, Vol. 22, p. 723-734

  (2R) -2-propyloctanoic acid has a short blood half-life of about 2 to 2.5 hours in humans, and (2R) -2-propyloctanoic acid is irritating to the oral cavity. In addition, it is difficult to administer orally as it is, and since (2R) -2-propyloctanoic acid is an acid, it may irritate the blood vessel by rapid injection into the blood vessel. There are points that need to be improved. In general, a drug having a short blood half-life is repeatedly administered to a living body several times a day in order to obtain the desired drug effect. It is not desirable from the patient's point of view to take many times a day, even if it is an oral preparation, as well as an injection with physical pain for each administration. Even more so, if the drug is irritating to the oral cavity. In addition, drugs that stimulate the blood vessels by being rapidly administered into blood vessels, for example, can only be administered continuously, such as infusion, resulting in the patient being restrained in the hospital for a long time. Therefore, it is not desirable from the patient side or the hospital side. That is, the object of the present invention is to reduce blood vessel irritation of (2R) -2-propyloctanoic acid, such as to give (2R) -2-propyloctanoic acid blood persistence, and (2R) (2) To provide a prodrug of (2R) -2-propyloctanoic acid that reduces irritation to the oral cavity of 2-propyloctanoic acid.

  As a result of intensive studies to solve the above problems, the present inventors have found that the compound of the present invention represented by the following general formula (I) achieves the object, and further studies based on the findings. The invention was completed by the addition.

  That is, the present invention provides a prodrug of [1] 2-propyloctanoic acid; a prodrug of [2] (2R) -2-propyloctanoic acid; [3] 2-propyl Compared with octanoic acid, (1) improved blood persistence, (2) improved oral absorption, (3) improved intestinal stability, (4 The prodrug according to [1] above, wherein the prodrug is one or more selected from: (1) reduced oral irritation, and (5) reduced vascular irritation; [4] General formula (I)

[Wherein, A represents an oxygen atom or an optionally substituted nitrogen atom, ring B represents a cyclic group which may further have a substituent, and D and E are each independently substituted. Represents an optionally substituted C1-8 alkylene group, an optionally substituted C2-8 alkenylene group, an optionally substituted C2-8 alkynylene group or a bond, and M represents an oxygen atom, nitrogen atom, sulfur in the main chain. Represents a spacer or a bond containing an atom and / or a phosphorus atom, R represents a hydrogen atom or a substituent, m represents an integer of 1 to 3, and when m is 2 or more, a plurality of D and a plurality of M are Each may be the same or different, n represents 0 or an integer of 1 to 2, and when n is 2, the plurality of rings B may be the same or different;

Represents an α configuration, a β configuration or a mixture thereof in any ratio. However,

Is (1) a hydroxyl group, (2) a C1-4 alkoxy group optionally substituted with one phenyl group, or (3) an NR ^A R ^B group (in which R ^A and R ^B are each independently (A) a hydrogen atom, (b) a phenyl group optionally substituted with a C1-4 alkoxy group or a carboxy group, (c) a 4- to 7-membered heterocycle containing one nitrogen atom, (d) C1-4 alkyl group optionally substituted with a phenyl group optionally substituted with a C1-4 alkoxy group or a carboxy group, (e) substituted with a 4-7 membered heterocyclic ring containing one nitrogen atom (1) a 4- to 7-membered saturated heterocyclic ring containing 1 to 2 nitrogen atoms, together with the nitrogen atom to which C 1-4 alkyl group or ( ^A ) R ^A and R ^B are bonded, 2) 4-7 membered saturated heterocycle containing one nitrogen atom and one oxygen atom Or (3) represents an amino acid residue). Or a salt or solvate thereof; a prodrug according to the above [1]; [5] a general formula (I-1)

[Wherein, D ¹ represents an optionally substituted C1-4 alkylene group or an optionally substituted C2-4 alkenylene group, Q represents an oxygen atom or an optionally substituted nitrogen atom, The symbol of represents the same meaning as described in [4] above. ], General formula (I-2)

[Wherein, D ¹ represents an optionally substituted C1-4 alkylene group or an optionally substituted C2-4 alkenylene group, Q represents an oxygen atom or an optionally substituted nitrogen atom, The symbol of represents the same meaning as described in [4] above. ], General formula (I-3)

[In the formula, G represents a hydroxyl group which may be protected, and other symbols represent the same meaning as described in the above [4]. ], General formula (I-4)

[In the formula, G represents a hydroxyl group which may be protected, and other symbols represent the same meaning as described in the above [4]. ], General formula (I-5)

[Wherein, D ¹ represents an optionally substituted C1-4 alkylene group or an optionally substituted C2-4 alkenylene group, Q represents an oxygen atom or an optionally substituted nitrogen atom, The symbol of represents the same meaning as described in [4] above. Or general formula (I-6)

[Wherein all symbols have the same meaning as described in [4] above. The compound of the above-mentioned [4], which is a compound represented by the formula: [6] General formula (I-6-1)

[Wherein all symbols have the same meaning as described in [4] above. ], General formula (I-6-2)

[Wherein all symbols have the same meaning as described in [4] above. Or a general formula (I-6-3)

[Wherein all symbols have the same meaning as described in [4] above. The compound according to the above [5], which is a compound represented by the formula: [7] Cyclic ring, benzene, naphthalene, pyrrolidine, piperidine, piperazine, imidazole, pyridine, dihydropyridine, which ring B may have a substituent, The compound according to the above [4], which is a dioxolane, tetrahydropyran, dioxane ring or steroid skeleton; [8] D is an optionally substituted C1-4 alkylene group, an optionally substituted C2-4 alkenylene group or The compound according to the above [4], which is a bond; [9] The above [4], wherein E is an optionally substituted C1-4 alkylene group, an optionally substituted C2-4 alkenylene group or a bond. a compound according; [10] M ^{is, -COO -, - CONR X -} , - O -, - OCO -, - OCOO -, - OCONR ^{-, - NR X -, -} NR X CO -, - NR X COO -, - NR X CONR Y -, - S (O) -, - SO 2 -, - SO 2 NR X -, - NR X SO 2 ^{-, - OP (= O)} (R Z) O- [ wherein, ^{R X} and ^{R Y} each independently represent a hydrogen atom or a substituent, ^{R Z} hydroxyl which may be protected or "O ^- ". Or a compound of the above-mentioned [4], which is a bond; [11] R is (1) a hydrogen atom, (2) an optionally substituted methyl group, (3) an optionally substituted cyclic group, (4) an oxo group, (5) a hydroxyl group, (6) a methoxy group, (7) an optionally substituted C1-20 acyloxy group, (8) an optionally substituted carbonyl group, (9) a methyl group. The compound according to [4] above, which is an optionally substituted carbamoyl group, (10) a nitro group, (11) an amino group optionally substituted with a methyl group, or (12) a chlorine atom; [12] 2- A pharmaceutical composition comprising a prodrug of propyloctanoic acid; [13] the composition according to [12] above, which is an astrocyte function improving agent; [14] the above agent which is a prophylactic and / or therapeutic agent for neurodegenerative diseases [12] The composition according to [12]; 5] Prodrug of 2-propyloctanoic acid, acetylcholinesterase inhibitor, nicotine receptor modulator, β secretase inhibitor, γ secretase inhibitor, β amyloid protein aggregation inhibitor, β amyloid vaccine, β amyloid degrading enzyme, brain Function Activator, Cerebral Circulatory Metabolizer, Dopamine Receptor Agonist, Monoamine Oxidase Inhibitor, Anticholinergic, Catechol-O-Methyltransferase Inhibitor, Amyotrophic Lateral Sclerosis, Neurotrophic Factor, Apoptosis Inhibitor, antidepressant, anxiolytic, antiepileptic, antihypertensive, calcium receptor antagonist, antidiabetic, hyperlipidemic, aldose reductase inhibitor, non-steroidal anti-inflammatory, disease modification Antirheumatic drug, anti-cytokine drug, steroid drug, antithrombotic drug, factor Xa inhibitor, factor VII A pharmaceutical comprising a combination of one or more selected from an inhibitor, an antioxidant and a glycerin preparation; [16] An effective amount of a 2-doctanoic acid prodrug is administered to a mammal A method for preventing and / or treating a neurodegenerative disease in the mammal; [17] use of a prodrug of 2-propyloctanoic acid for the manufacture of a prophylactic and / or therapeutic agent for a neurodegenerative disease; [18] (IR)

[Where:

Represents a β configuration, and other symbols have the same meanings as described in the above [4]. Or a salt or solvate thereof; a prodrug according to the above [2]; [19] a general formula (I)

[Wherein all symbols have the same meaning as described in [4] above. And general formula (IR)

[Wherein all symbols have the same meanings as described in [4] and [18]. ] [20] 2-propyloctanoic acid has (1) blood persistence by using 2-propyloctanoic acid as a prodrug, (2) The present invention relates to a method for improving one or more selected from (a) oral absorbability, (3) gastrointestinal stability, (4) oral irritation and (5) vascular irritation.

  The present invention relates to a prodrug of 2-propyloctanoic acid, particularly a prodrug of (2R) -2-propyloctanoic acid, which is useful as a preventive and / or therapeutic agent for various diseases including neurodegenerative diseases. . According to the present invention, blood persistence can be imparted to 2-propyloctanoic acid, preferably (2R) -2-propyloctanoic acid, so that a desired medicinal effect can be obtained with a smaller number of administrations. In addition, since the carboxy group in the structure is masked by forming a prodrug, there is no risk of irritation to the blood vessel even if it is rapidly administered into the blood vessel, and the blood persistence is increased, so it is necessary to make an infusion There is no. Furthermore, since the oral absorption of 2-propyloctanoic acid, preferably (2R) -2-propyloctanoic acid, can be increased by the present invention, the dose per administration can be reduced, and the preparation can be reduced in size. Can be Furthermore, according to the present invention, the problem of oral irritation of 2-propyloctanoic acid, particularly (2R) -2-propyloctanoic acid, can be avoided, so that it is useful when formulating for oral administration. It is. For example, it can be used as a liquid agent, and there is no problem that (2R) -2-propyloctanoic acid flows out even when the capsule is chewed by mistake, and there is no irritation such as bitterness or burning sensation in the oral cavity. Moreover, since the prodrugs of the present invention become 2-propyloctanoic acid, preferably (2R) -2-propyloctanoic acid, and exhibit pharmacological effects when administered in vivo, they are used. Similarly, it can be used as a preventive and / or therapeutic agent for neurodegenerative diseases and the like.

  In this specification, 2-propyloctanoic acid includes all of (2R) -2-propyloctanoic acid, (2S) -2-propyloctanoic acid, and mixtures in any ratio thereof.

  In the present specification, (2R) -2-propyloctanoic acid refers to the formula (A)

(Where

Represents the β configuration. )
Unless otherwise specified, represents a substantially pure (preferably 90% ee or higher) (2R) -2-propyloctanoic acid.

  In the present invention, a prodrug of 2-propyloctanoic acid (hereinafter sometimes abbreviated as a prodrug of the present invention or simply a prodrug) is usually 2-propyloctane as used by those skilled in the art. It is a derivative of an acid and may be any compound that becomes 2-propyloctanoic acid by enzymatic or chemical conversion in the body, and its structure is not particularly limited. The prodrug of the present invention is characterized by improved physical properties, pharmacokinetics (gastrointestinal absorption, blood concentration, tissue distribution, etc.) and the like, as compared with 2-propyloctanoic acid, and high therapeutic value. Specifically, (1) 2-propyloctanoic acid can be improved in blood persistence compared to the case where 2-propyloctanoic acid is administered as it is, (2) compared with 2-propyloctanoic acid. Excellent oral absorption, (3) increased intestinal stability compared to 2-propyloctanoic acid, (4) reduced oral irritation compared to 2-propyloctanoic acid, (5) What is necessary is just to show at least one property that intravascular irritation is reduced as compared with 2-propyloctanoic acid. As will be apparent to those skilled in the art, these properties can be easily confirmed by kinetic analysis, pharmacological tests, safety tests, etc., which are usually performed in pharmaceutical research and development. As a prodrug satisfying such conditions, the general formula (I)

[Wherein all symbols have the same meaning as described above. Or a salt thereof or a solvate thereof.

  In the present specification, examples of the “cyclic group” in the “cyclic group optionally having substituent (s)” represented by ring B include, for example, “carbocycle”, “heterocycle”, “steroid skeleton” and the like. Examples thereof include a divalent group formed by removing any two hydrogen atoms.

  Examples of the “carbocycle” include “C3-15 carbocycle”. "C3-15 carbocycle" includes "C3-15 monocyclic, bicyclic or tricyclic carbocycle" and "C3-15 spiro-linked bicyclic carbocycle and bridged bicyclic carbocycle" And the like. Examples of the “C3-15 monocyclic, bicyclic or tricyclic carbocycle” include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cycloundecane, cyclododecane, cyclotridecane, and the like. Dodecane, cyclotetradecane, cyclopentadecane, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, benzene, pentalene, perhydropentalene, azulene, perhydroazulene, indene, perhydro Indene, indane, naphthalene, dihydronaphthalene, tetrahydronaphthalene, perhydronaphthalene, 6,7-dihydro-5H-benzo [7] annulene, 5H- Down zone [7] annulene, heptalene, perhydropentalene hept, biphenylene, as-indacene, s- indacene, acenaphthylene, acenaphthene, fluorene, phenalene, phenanthrene, anthracene ring, and the like. Examples of the “C 3-15 spiro-linked bicyclic carbocycle and bridged bicyclic carbocycle” include, for example, spiro [4.4] nonane, spiro [4.5] decane, spiro [5.5] undecane. , Bicyclo [2.2.1] heptane, bicyclo [2.2.1] hept-2-ene, bicyclo [3.1.1] heptane, bicyclo [3.1.1] hept-2-ene, bicyclo [3.2.1] octane, bicyclo [2.2.2] octane, bicyclo [2.2.2] oct-2-ene, adamantane, noradamantane ring and the like.

  Examples of the “heterocycle” include “3 to 15 membered heterocycle containing 1 to 5 nitrogen atoms, 1 to 2 oxygen atoms and / or 1 sulfur atom”. “1 to 5 nitrogen atoms, 1 to 2 oxygen atoms and / or 3 to 15 membered heterocyclic ring containing 1 sulfur atom” includes “1 to 5 nitrogen atoms, 1 to 2 3 to 15-membered monocyclic, bicyclic or tricyclic heterocycle containing oxygen atoms and / or 1 sulfur atom ”and“ 1 to 5 nitrogen atoms, 1 to 2 oxygen atoms and / or 3 to 15-membered spiro-linked bicyclic heterocycles and bridged bicyclic heterocycles containing one sulfur atom ”and the like. Examples of the “3- to 15-membered monocyclic, bicyclic or tricyclic heterocycle containing 1 to 5 nitrogen atoms, 1 to 2 oxygen atoms and / or 1 sulfur atom” include pyrrole, Imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepin, thiophene, thiopyran, thiepine, oxazole, isoxazole, thiazole, isothiazole, furazane, oxadiazole, oxazine, Oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, indole, isoindole, indolizine, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, dithianaf Len, indazole, quinoline, isoquinoline, quinolidine, purine, phthalazine, pteridine, naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole, chromene, benzoxepin, benzoxazepine, benzooxadiazepine, benzothiepine, benzo Thiazepine, benzothiadiazepine, benzoazepine, benzodiazepine, benzofurazan, benzothiadiazole, benzotriazole, carbazole, β-carboline, acridine, phenazine, dibenzofuran, xanthene, dibenzothiophene, phenothiazine, phenoxazine, phenoxathiin, thianthrene, fe Nanthridine, phenanthroline, perimidine, aziridine, azetidine, pyrroline, Pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, Perhydropyridazine, dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, oxirane, oxetane, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxepin, tetrahydrooxe Pin, perhydrooxepin, thiirane, thie , Dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydrothiepine, tetrahydrothiepine, perhydrothiepine, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), Dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydro Oxadiazine, tetrahydrooxadiazine, dihydrooxazepine, Torahydrooxazepine, perhydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine, perhydrooxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine, tetrahydrothiazine, dihydrothiadia Gin, Tetrahydrothiadiazine, Dihydrothiazepine, Tetrahydrothiazepine, Perhydrothiazepine, Dihydrothiadiazepine, Tetrahydrothiadiazepine, Perhydrothiadiazepine, Morpholine, Thiomorpholine, Oxanthian, Indoline, Isoindoline, Dihydrobenzofuran , Perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydride Loisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, perhydroindazole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine , Dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, benzooxathiane, dihydrobenzo Oxazine, dihydrobenzothiazine, pyrazinomorpholine, Hydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenzimidazole, dihydrobenzoazepine, tetrahydrobenzoazepine, dihydrobenzodiazepine, tetrahydrobenzodiazepine, benzodioxepane, dihydrobenzoxaze Pin, tetrahydrobenzoxazepine, dihydrocarbazole, tetrahydrocarbazole, perhydrocarbazole, dihydroacridine, tetrahydroacridine, perhydroacridine, dihydrodibenzofuran, dihydrodibenzothiophene, tetrahydrodibenzofuran, tetrahydrodibenzothiophene, perhydrodibenzofuran, perhydrodibenzothiophene The Kisoran, dioxane, dithiolane, dithiane, dioxaindan, benzodioxane, chromene, chroman, benzothiophene dithiolane, Benzojichian ring and the like. “3- to 15-membered spiro-bonded bicyclic heterocycles and bridged bicyclic heterocycles containing 1 to 5 nitrogen atoms, 1 to 2 oxygen atoms and / or 1 sulfur atom” For example, azaspiro [4.4] nonane, oxazaspiro [4.4] nonane, oxaazaspiro [2.5] octane, azaspiro [4.5] decane, 1,3,8-triazaspiro [4.5] decane, 2 , 7-diazaspiro [4.5] decane, 1,4,9-triazaspiro [5.5] undecane, oxazaspiro [4.5] decane, azaspiro [5.5] undecane, azabicyclo [2.2.1] heptane , Azabicyclo [3.1.1] heptane, azabicyclo [3.2.1] octane (such as 8-azabicyclo [3.2.1] octane ring), azabicyclo [2.2.2] octane ( - azabicyclo [2.2.2] octane ring), azabicyclo [2.1.1] hexane (5-azabicyclo [2.1.1] hexane ring) ring, and the like.

In the present specification, the “substituent” in the “cyclic group optionally having substituent (s)” represented by ring B is not particularly limited as long as it is a substituent. Examples of the “substituent” include (1) an optionally substituted C1-20 alkyl group, (2) an optionally substituted C2-20 alkenyl group, and (3) an optionally substituted C2 -20 alkynyl groups, (4) optionally substituted C1-20 alkylidene groups, (5) optionally substituted cyclic groups, (6) oxo groups, (7) hydroxyl groups, (8) substituted May be a C1-20 alkyloxy group, (9) an optionally substituted C2-20 alkenyloxy group, (10) an optionally substituted C2-20 alkynyloxy group, (11) optionally substituted. A hydroxyl group optionally protected by a cyclic group, (12) an optionally substituted C1-20 acyloxy group, (13) a thioxo group, (14) a mercapto group, (15) an optionally substituted C1-20 Archi Substituted with a thio group, (16) an optionally substituted C2-20 alkenylthio group, (17) an optionally substituted C2-20 alkynylthio group, (18) an optionally substituted cyclic group A mercapto group, (19) an optionally substituted C1-20 alkylsulfinyl group (for example, a methylsulfinyl group, an ethylsulfinyl group, etc.), (20) an optionally substituted C2-20 alkenylsulfinyl group, (21) An optionally substituted C2-20 alkynylsulfinyl group, (22) a sulfinyl group substituted with an optionally substituted cyclic group (for example, a phenylsulfinyl group), (23) an optionally substituted C1— 20 alkylsulfonyl groups (for example, methylsulfonyl group, ethylsulfonyl group, etc.), (24) optionally substituted 2-20 alkenylsulfonyl groups, (25) optionally substituted C2-20 alkynylsulfonyl groups, (26) sulfonyl groups substituted with optionally substituted cyclic groups (eg, phenylsulfonyl groups), ( 27) an optionally substituted sulfino group, (28) an optionally substituted sulfo group, (29) an optionally substituted sulfamoyl group (for example, an unsubstituted sulfamoyl group, N-mono or di- ( Optionally substituted C1-20 alkyl) sulfamoyl group (eg N-mono-C1-6 alkylsulfamoyl group (eg N-methylsulfamoyl group, N-ethylsulfamoyl group, N-propyl) Sulfamoyl group, N-isopropylsulfamoyl group, N-butylsulfamoyl group, N-isobutylsulfamoyl group, N- (tert-butyl) sulfamoyl group, N-pentylsulfamoyl group, N-hexylsulfamoyl group, etc.), N, N-diC1-6 alkylsulfamoyl group (for example, N, N-dimethylsulfuryl group) Famoyl group, N, N-diethylsulfamoyl group, N, N-dipropylsulfamoyl group, N, N-dibutylsulfamoyl group, N, N-dipentylsulfamoyl group, N, N-dihexylsulfur Famoyl group, N-methyl-N-ethylsulfamoyl group, etc.))), (30) optionally substituted carbonyl group (for example, methoxycarbonyl group, ethoxycarbonyl group, t-butoxycarbonyl group, etc.) C1-6 alkoxycarbonyl group, for example, C3-8 cycloalkanoyl such as cyclopentylcarbonyl group, cyclohexylcarbonyl group, etc. A substituent, such as a C6-10 arylcarbonyl group such as a benzoyl group, such as a morpholin-4-ylcarbonyl group, a piperidin-1-ylcarbonyl group, or a 1-methylpiperazin-4-ylcarbonyl group An optionally substituted heterocyclic carbonyl group, etc.), (31) an optionally substituted C1-20 acyl group (for example, a formyl group, an acetyl group, a propanoyl group, a pivaloyl group, etc.), and (32) an optionally substituted group. Good carbamoyl groups (eg, unsubstituted carbamoyl groups, N-mono or di- (optionally substituted C1-20 alkyl) carbamoyl groups (eg, N-mono-C1-6 alkylcarbamoyl groups (eg, N- Methylcarbamoyl group, N-ethylcarbamoyl group, N-propylcarbamoyl group, N-isopropylcarbamoyl group N-butylcarbamoyl group, N-isobutylcarbamoyl group, N- (tert-butyl) carbamoyl group, N-pentylcarbamoyl group, N-hexylcarbamoyl group, etc.), N-mono-C1-6 alkylcarbamoyl group substituted by hydroxyl group (For example, N-hydroxymethylcarbamoyl group, N- (2-hydroxyethyl) carbamoyl group, N- (3-hydroxypropyl) carbamoyl group, N- (4-hydroxybutyl) carbamoyl group, etc.), amino group or dimethylamino N-mono-C1-6 alkylcarbamoyl group substituted with a group (for example, N-aminomethylcarbamoyl group, N- (2-aminoethyl) carbamoyl group, N- (3-aminopropyl) carbamoyl group, N- (4 -Aminobutyl) carbamoyl group, N- (dimethylamino) methyl Rucarbamoyl group, N- (2-dimethylaminoethyl) carbamoyl group, N- (3-dimethylaminopropyl) carbamoyl group, N- (4-dimethylaminobutyl) carbamoyl group, etc.), N, N-diC1-6 alkyl Carbamoyl group (for example, N, N-dimethylcarbamoyl group, N, N-diethylcarbamoyl group, N, N-dipropylcarbamoyl group, N, N-dibutylcarbamoyl group, N, N-dipentylcarbamoyl group, N, N- Dihexylcarbamoyl group, N-methyl-N-ethylcarbamoyl group, etc.), N-mono or di- (optionally substituted carbocyclic or heterocyclic) carbamoyl group (for example, N-mono (substituted) Carbamoyl group (for example, N-cyclopropylcarbamoyl group, N-cyclopentylcarba) Yl group, N-cyclohexylcarbamoyl group, N-phenylcarbamoyl group, etc.))), (33) cyano group, (34) optionally substituted amidino group, (35) nitro group, (36) nitroso group (37) an optionally substituted imino group (for example, an unsubstituted imino group, an imino group substituted with a C1-6 alkyl group (for example, a methylimino group, an ethylimino group, etc.)), or a substituent. A good C6-10 aryl group-substituted imino group (for example, a phenylimino group, p-fluorophenylimino group, p-chlorophenylimino group, etc.), a hydroxyimino group-substituted imino group, etc.), (38) Optionally substituted amino groups (eg mono- or di-C1-6 alkylamino groups (eg methylamino, ethylamino, propyl Mino group, dimethylamino group, diethylamino group, etc.), mono- or di-C6-10 arylamino group (eg, phenylamino group, diphenylamino group, etc.), mono-C1-6 alkyl-mono-C6-10 arylamino Groups (for example, N-phenyl-N-methylamino group, N-phenyl-N-ethylamino group, etc.), (39) halogen atom, (40) carboxy group, (41) phosphono group (-PO (OH ₂ ), (42) dihydroxyboryl group (—B (OH) ₂ ), (43) C1-20 alkylcarbonylhydrazino group (for example, methylcarbonylhydrazino group, ethylcarbonylhydrazino group, etc.), (44) For example, C6-10 which may have a substituent such as a benzaldehyde hydrazone group or a p-methoxybenzaldehyde hydrazone group An aryl hydrazone group and the like can be mentioned, and these optional substituents may be substituted by any number that can be substituted at any substitutable position. The “optionally substituted sulfamoyl group”, “optionally substituted carbamoyl group”, “optionally substituted amidino” exemplified in (29), (32), (34), and (38) Group ”and“ optionally substituted amino group ”means that when there are two substituents, together with the nitrogen atom to which they are bonded, 1 to 5 nitrogen atoms, 1 oxygen atom and / or Alternatively, a 5- to 7-membered monocyclic heterocyclic ring containing one sulfur atom may be formed, and the formed heterocyclic ring may be substituted with a C1-8 alkyl group, a hydroxyl group or an amino group.

  Among the substituents exemplified in (1) to (44) as the substituent of ring B, the “cyclic group” is a monovalent group formed by removing any one hydrogen atom from the “carbocycle” or “heterocycle”. Means a group or the like.

  Among the substituents exemplified in (1) to (44) as the substituent of ring B, the description “optionally substituted” includes, for example, (1) C1-20 alkyl group, (2) C2-20 alkenyl. Group, (3) C2-20 alkynyl group, (4) C1-20 alkylidene group, (5) cyclic group, (6) C1-20 alkyl group substituted with cyclic group, (7) oxo group, (8) A hydroxyl group, (9) a C1-20 alkyloxy group, (10) a C2-20 alkenyloxy group, (11) a C2-20 alkynyloxy group, (12) a hydroxyl group optionally protected by a cyclic group, (13) C1 -20 acyloxy group, (14) thioxo group, (15) mercapto group, (16) C1-20 alkylthio group, (17) C2-20 alkenylthio group, (18) C2-20 alkynylthio group, (19) cyclic Replace with group Mercapto groups, (20) C1-20 alkylsulfinyl groups, (21) C2-20 alkenylsulfinyl groups, (22) C2-20 alkynylsulfinyl groups, (23) sulfinyl groups substituted with cyclic groups, (24) A C1-20 alkylsulfonyl group, (25) a C2-20 alkenylsulfonyl group, (26) a C2-20 alkynylsulfonyl group, (27) a sulfonyl group substituted with a cyclic group, and (28) a C1 substituted with a cyclic group. 20 alkylsulfonyl groups, (29) sulfino groups, (30) sulfo groups, (31) sulfamoyl groups, (32) C1-20 acyl groups, (33) C1-20 acyl groups substituted with cyclic groups, (34) A carbonyl group substituted with a cyclic group, (35) a carbamoyl group, (36) a cyano group, (37) an amidino group, (38) B group, (39) a nitroso group, it means that (40) imino group, (41) amino group, (42) a halogen atom, that may be substituted with a substituent such as (43) a carboxy group. These optional substituents may be substituted in any number that can be substituted at any substitutable position. In these substituents, “cyclic group” means a monovalent group formed by removing any one hydrogen atom from the “carbocycle” or “heterocycle”.

  In the present specification, "C1-20 alkyl group" means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl , Nonadecyl, icosyl groups and isomer groups thereof.

  In the present specification, the “C2-20 alkenyl group” refers to ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, , An icosenyl group and isomer groups thereof.

  In the present specification, “C2-20 alkynyl group” refers to ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, undecynyl, dodecynyl, tridecynyl, tetradecynyl, pentadecynyl, hexadecynyl, heptadecynyl, octadecynyl, nonadecynyl, , Icosinyl groups and their isomer groups.

  In the present specification, the “C1-20 alkylidene group” means methylidene, ethylidene, propylidene, butylidene, pentylidene, hexylidene, heptylidene, octylidene, nonylidene, decylidene, undecylidene, dodecylidene, tridecylidene, tetradecylidene, pentadecylidene, hexadecidene, , Nonadecylidene, icosilidene groups and isomer groups thereof.

  In the present specification, “C1-20 alkyloxy group” means methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, tridecyloxy , Tetradecyloxy, pentadecyloxy, hexadecyloxy, heptadecyloxy, octadecyloxy, nonadecyloxy, icosyloxy groups and isomers thereof.

  In the present specification, “C2-20 alkenyloxy group” means ethenyloxy, propenyloxy, butenyloxy, pentenyloxy, hexenyloxy, heptenyloxy, octenyloxy, nonenyloxy, decenyloxy, undecenyloxy, dodecenyloxy, tridecenyloxy , Tetradecenyloxy, pentadecenyloxy, hexadecenyloxy, heptadecenyloxy, octadecenyloxy, nonadecenyloxy, icocenyloxy groups and isomer groups thereof.

  In the present specification, “C2-20 alkynyloxy group” means ethynyloxy, propynyloxy, butynyloxy, pentynyloxy, hexynyloxy, heptynyloxy, octynyloxy, nonynyloxy, decynyloxy, undecynyloxy, dodecynyloxy, tridecynyloxy, tetradecyloxy It means nyloxy, pentadecynyloxy, hexadecynyloxy, heptadecynyloxy, octadecynyloxy, nonadecynyloxy, icosinyloxy groups and isomer groups thereof.

  In the present specification, “C1-20 alkylthio group” means methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, heptylthio, octylthio, nonylthio, decylthio, undecylthio, dodecylthio, tridecylthio, tetradecylthio, pentadecylthio, hexadecylthio , Heptadecylthio, octadecylthio, nonadecylthio, icosylthio groups and isomer groups thereof.

  In the present specification, “C2-20 alkenylthio group” means ethenylthio, propenylthio, butenylthio, pentenylthio, hexenylthio, heptenylthio, octenylthio, nonenylthio, decenylthio, undecenylthio, dodecenylthio, tridecenylthio, tetradecenylthio, pentadecyl It means senylthio, hexadecenylthio, heptadecenylthio, octadecenylthio, nonadecenylthio, icocenylthio groups and isomer groups thereof.

  In the present specification, "C2-20 alkynylthio group" means ethynylthio, propynylthio, butynylthio, pentynylthio, hexynylthio, heptynylthio, octynylthio, nonynylthio, decynylthio, undecynylthio, dodecynylthio, tridecynylthio, tetradecynylthio, pentadecynylthio , Hexadecynylthio, heptadecylthio, octadecynylthio, nonadecynylthio, icosinylthio groups and isomer groups thereof.

  In the present specification, the “C1-20 alkylsulfinyl group” means methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, pentylsulfinyl, hexylsulfinyl, heptylsulfinyl, octylsulfinyl, nonylsulfinyl, decylsulfinyl, undecylsulfinyl, It means dodecylsulfinyl, tridecylsulfinyl, tetradecylsulfinyl, pentadecylsulfinyl, hexadecylsulfinyl, heptadecylsulfinyl, octadecylsulfinyl, nonadecylsulfinyl, icosylsulfinyl groups and their isomeric groups.

  In the present specification, the “C2-20 alkenylsulfinyl group” means ethenylsulfinyl, propenylsulfinyl, butenylsulfinyl, pentenylsulfinyl, hexenylsulfinyl, heptenylsulfinyl, octenylsulfinyl, nonenylsulfinyl, decenylsulfinyl, Undecenylsulfinyl, dodecenylsulfinyl, tridecenylsulfinyl, tetradecenylsulfinyl, pentadecenylsulfinyl, hexadecenylsulfinyl, heptadecenylsulfinyl, octadecenylsulfinyl, nonadecenyl It means sulfinyl, icosenylsulfinyl group and isomer groups thereof.

  In the present specification, “C2-20 alkynylsulfinyl group” means ethynylsulfinyl, propynylsulfinyl, butynylsulfinyl, pentynylsulfinyl, hexynylsulfinyl, heptynylsulfinyl, octynylsulfinyl, nonynylsulfinyl, decynylsulfinyl , Undecynylsulfinyl, dodecynylsulfinyl, tridecynylsulfinyl, tetradecynylsulfinyl, pentadecynylsulfinyl, hexadecynylsulfinyl, heptadecylsulfinyl, octadecynylsulfinyl, nonadecynylsulfinyl, icosinylsulfinyl group and those Means an isomeric group of

  In the present specification, the “C1-20 alkylsulfonyl group” means methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, pentylsulfonyl, hexylsulfonyl, heptylsulfonyl, octylsulfonyl, nonylsulfonyl, decylsulfonyl, undecylsulfonyl, It means dodecylsulfonyl, tridecylsulfonyl, tetradecylsulfonyl, pentadecylsulfonyl, hexadecylsulfonyl, heptadecylsulfonyl, octadecylsulfonyl, nonadecylsulfonyl, icosylsulfonyl groups and isomer groups thereof.

  In the present specification, the “C2-20 alkenylsulfonyl group” means ethenylsulfonyl, propenylsulfonyl, butenylsulfonyl, pentenylsulfonyl, hexenylsulfonyl, heptenylsulfonyl, octenylsulfonyl, nonenylsulfonyl, decenylsulfonyl, Undecenylsulfonyl, dodecenylsulfonyl, tridecenylsulfonyl, tetradecenylsulfonyl, pentadecenylsulfonyl, hexadecenylsulfonyl, heptadecenylsulfonyl, octadecenylsulfonyl, nonadecenyl It means sulfonyl, icosenylsulfonyl group and isomer groups thereof.

  In the present specification, “C2-20 alkynylsulfonyl group” means ethynylsulfonyl, propynylsulfonyl, butynylsulfonyl, pentynylsulfonyl, hexynylsulfonyl, heptynylsulfonyl, octynylsulfonyl, noninylsulfonyl, decynylsulfonyl. , Undecynylsulfonyl, dodecynylsulfonyl, tridecynylsulfonyl, tetradecynylsulfonyl, pentadecynylsulfonyl, hexadecynylsulfonyl, heptadecylsulfonyl, octadecynylsulfonyl, nonadecynylsulfonyl, icosinylsulfonyl group and the like Means an isomeric group of

  In the present specification, “C1-20 acyl group” means methanoyl, ethanoyl, propanoyl, butanoyl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexa It means decanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, icosanoyl group and isomer groups thereof.

  In the present specification, “C1-20 acyloxy group” means methanoyloxy, ethanoyloxy, propanoyloxy, butanoyloxy, pentanoyloxy, hexanoyloxy, heptanoyloxy, octanoyloxy, nonanoyloxy, decayloxy Noyloxy, undecanoyloxy, dodecanoyloxy, tridecanoyloxy, tetradecanoyloxy, pentadecanoyloxy, hexadecanoyloxy, heptadecanoyloxy, octadecanoyloxy, nonadecanoyloxy, icosanoyl It means an oxy group and isomer groups thereof.

  In the present specification, the “optionally substituted nitrogen atom” represented by A and Q is an unsubstituted nitrogen atom, that is, —NH—, and an arbitrary substituent is bonded instead of the hydrogen atom. Nitrogen atom. Examples of such a substituent include those similar to those exemplified above as the “substituent” in the “cyclic group optionally having substituent (s)” represented by ring B.

  In the present specification, examples of the “protecting” group in the “optionally protected hydroxyl group” represented by G include “substitution” in the “cyclic group optionally having substituent (s)” represented by ring B, for example. Examples of the “group” include those similar to those exemplified above.

  In the present specification, the “optionally substituted C1-8 alkylene group” represented by D and E means an arbitrary substituent bonded to any carbon atom of the C1-8 alkylene group. . Examples of such a “substituent” include those similar to those exemplified above as the “substituent” in the “cyclic group optionally having substituent (s)” represented by ring B. It is done.

  In the present specification, the “optionally substituted C2-8 alkenylene group” represented by D and E means an arbitrary substituent bonded to any carbon atom of the C2-8 alkenylene group. . Examples of such a “substituent” include those similar to those exemplified above as the “substituent” in the “cyclic group optionally having substituent (s)” represented by ring B. It is done.

  In the present specification, the “optionally substituted C 2-8 alkynylene group” represented by D and E means an arbitrary substituent bonded to any carbon atom of the C 2-8 alkynylene group. . Examples of such a “substituent” include those similar to those exemplified above as the “substituent” in the “cyclic group optionally having substituent (s)” represented by ring B. It is done.

Herein, D, as the "substituent" group in the "optionally substituted by C1~4 alkylene group or an optionally substituted C2~4 alkenylene group" represented by D ¹ and E, for example, Examples of the “substituent” in the “cyclic group optionally having substituent (s)” represented by ring B include the same as those exemplified above.

In the present specification, the “spacer containing an oxygen atom, nitrogen atom, sulfur atom and / or phosphorus atom in the main chain” represented by M means an oxygen atom, nitrogen atom, sulfur atom and / or phosphorus atom in the main chain. This represents a spacer containing at least one, and the type and number of other constituent atoms are not limited. The spacer includes a main chain oxygen atom, nitrogen atom, sulfur atom and / or a phosphorus atom, for ^{example, -COO -, - COOCO -,} - CONR X -, - CONR X CO -, - O -, - OCO- ^{, -OCOO -, - OCONR X -} , - NR X -, - NR X CO -, - NR X COO -, - NR X CONR Y -, - S -, - S (O) -, - SO 2 -, —SO ₂ NR ^X —, —NR ^X SO ₂ —, —OSO ₃ — and —OP (═O) (R ^Z ) O— wherein R ^X and R ^Y are each independently a hydrogen atom or a substituent. the stands, R ^Z is a hydroxyl group may be protected or ^- represent "O". ] Etc. are mentioned.

In the present specification, the “substituent” represented by R, R ^X and R ^Y is not particularly limited as long as it is a substituent. For example, examples of the “substituent” in the “cyclic group which may further have a substituent” represented by ring B include the same as those exemplified above.

In the present specification, examples of the “protected” group in the “optionally protected hydroxyl group” represented by R ^Z include, for example, “in the cyclic group optionally having substituents” represented by ring B, Examples of the “substituent” are the same as those exemplified above.

In the present specification, “O ⁻ ” represented by R ^Z represents an oxygen anion, but when R ^Z represents “O ⁻ ”, a cation part (for example, quaternized nitrogen) must be present in the molecule. Atoms).

  In the present specification, the “bond” represented by D, E, and M refers to a direct bond without interposing another atom therebetween.

  In the present specification, the “halogen atom” means fluorine, chlorine, bromine and iodine.

  In the present specification, the “C1-8 alkylene group” means, for example, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene group and isomer groups thereof.

  In the present specification, the “C1-4 alkylene group” means, for example, methylene, ethylene, trimethylene, tetramethylene group and isomer groups thereof.

  In the present specification, the “C2-8 alkenylene group” means, for example, ethenylene, propenylene, butenylene, butadienylene, pentenylene, pentadienylene, hexenylene, hexadienylene, heptenylene, heptadienylene, octenylene, octadielenylene group and their isomer groups To do.

  In the present specification, the “C2-4 alkenylene group” means, for example, ethenylene, propenylene, butenylene groups and isomer groups thereof.

  In the present specification, the “C2-8 alkynylene group” means, for example, ethynylene, propynylene, butynylene, butadinylene, pentynylene, pentadiinylene, hexynylene, hexadiinylene, heptynylene, heptadinylene, octynylene, octadiinylene group and isomer groups thereof. To do.

  In the present specification, the “steroid skeleton” in the “steroid skeleton optionally having substituent (s)” represented by ring B is what is generally referred to as a steroid skeleton. Ordinarily, it refers to a perhydro-1H-cyclopenta [a] phenanthrene skeleton. Examples of the “steroid skeleton optionally having a substituent” include structures derived from cholic acid, deoxycholic acid, chenodeoxycholic acid, ursocholic acid, and ursodeoxycholic acid represented by the formula (B).

  In the present specification, the compounds excluded from the proviso in the general formula (I) are those disclosed in EP 0632088. Hereinafter, description of the group described in this proviso will be described.

  A C1-4 alkoxy group represents a methoxy, ethoxy, propoxy, butoxy group and isomer groups thereof.

  The 4- to 7-membered heterocyclic ring containing one nitrogen atom represents, for example, pyrrole, pyridine, azepine, a ring saturated with a part thereof or a ring saturated with all (pyrrolidine, piperidine, etc.).

  A C1-4 alkyl group represents a methyl, ethyl, propyl, butyl group and isomers thereof.

^A 4- to 7-membered saturated heterocyclic ring containing 1 to 2 nitrogen atoms formed together with the nitrogen atom to which R ^A and R ^B are bonded is azetidine, pyrrolidine, piperidine, perhydroazepine, pyrazolidine , Imidazolidine, perhydrodiazine (such as piperazine), and perhydrodiazepine ring.

^A 4- to 7-membered saturated heterocyclic ring containing one nitrogen atom and one oxygen atom formed together with the nitrogen atom to which R ^A and R ^B are bonded includes oxazolidine, perhydrooxazine (morpholine Etc.), and represents a perhydrooxazepine ring.

The amino acid residue formed together with the nitrogen atom to which R ^A and R ^B bind is glycine, alanine, serine, cysteine, cystine, threonine, valine, methionine, leucine, isoleucine, norleucine, phenylalanine, tyrosine, Represents thyronine, proline, hydroxyproline, tryptophan, aspartic acid, glutamic acid, arginine, lysine, ornithine, histidine residues and esters thereof (such as C1-4 alkyl ester or benzyl ester).

  In the present invention, A is preferably an oxygen atom, for example.

  In the present invention, the “cyclic group” in the “cyclic group optionally having substituent (s)” represented by ring B is preferably, for example, a C3-10 monocyclic or bicyclic carbocyclic ring, 1-5 Any two hydrogen atoms are removed from a 3 to 10-membered monocyclic or bicyclic heterocyclic ring, steroid skeleton, etc. containing 1 nitrogen atom, 1 to 2 oxygen atoms and / or 1 sulfur atom A divalent group that can be formed, and more preferably, any two of, for example, cyclohexane, benzene, naphthalene, pyrrolidine, piperidine, piperazine, imidazole, pyridine, dihydropyridine, dioxolane, tetrahydropyran, dioxane ring, steroid skeleton, etc. Examples thereof include a divalent group formed by removing a hydrogen atom.

  In the present invention, the “substituent” in the “cyclic group optionally having substituent (s)” represented by ring B is preferably, for example, C 1 to C 1 which may be substituted with 1 to 3 halogen atoms. 4 alkyl group, oxo group, optionally protected hydroxyl group, carboxy group, optionally substituted carbonyl group, halogen atom and the like, more preferably, for example, methyl group, trifluoromethyl group, oxo group , Hydroxy group, carboxy group, methoxycarbonyl group, chlorine atom and the like.

  In the present invention, D preferably includes, for example, an optionally substituted C1-8 alkylene group, an optionally substituted C2-8 alkenylene group, a bond, and the like, and more preferably, for example, a substituted group. A C1-4 alkylene group which may be substituted, a C2-4 alkenylene group which may be substituted, a bond, etc. are mentioned, and particularly preferably, for example, a methylene group which may be substituted or a substituent may be substituted. Examples thereof include an ethylene group, an optionally substituted trimethylene group, an optionally substituted propenylene group, and a bond. In addition, the substituent at this time is preferably, for example, an oxo group, an optionally protected hydroxyl group, an optionally substituted nitrogen atom, etc., for example, an oxo group, a hydroxyl group optionally protected by a benzyl group , A hydroxyl group protected with a C14-17 acyl group, a nitrogen atom substituted with a C14-17 acyl group, and the like are more preferable.

  In the present invention, E is preferably a C1-8 alkylene group which may be substituted, a C2-8 alkenylene group which may be substituted, a bond, etc., more preferably, for example, a substituted group. A C1-4 alkylene group which may be substituted, a C2-4 alkenylene group which may be substituted, a bond, etc. are mentioned, and particularly preferably, for example, a methylene group which may be substituted or a substituent may be substituted. Examples thereof include an ethylene group, an optionally substituted trimethylene group, an optionally substituted propenylene group, and a bond. In addition, as the substituent at this time, for example, an oxo group, an optionally protected hydroxyl group, an optionally substituted nitrogen atom, and the like are preferable, and for example, an oxo group is more preferable.

In the present invention, preferably as M, for ^{example, -COO -, - CONR X -} , - O -, - OCO -, - OCOO -, - OCONR X -, - NR X -, - NR X CO -, - NR _{^{X COO -, - NR X CONR}} Y -, - S (O) -, - SO 2 -, - SO 2 NR X -, - NR X SO 2 -, - OP (= O) (R Z) O- [ In the formula, all symbols have the same meaning as described above. And a bond, etc., more preferably, for example, —COO—, —CONR ^X —, —O—, —OCO—, —OCOO—, —OCONH—, —NHCO—, —NHCOO—, —OP (= O) (R ^Z ) O— [wherein all symbols have the same meanings as described above. ] And a bond. Further, the substituent in this case, for example, the R ^X, R ^Y, for example, a hydrogen atom, preferably also may C1~8 alkyl group which may be substituted, for example, a hydrogen atom, preferably more and methyl group . Further, as ^RZ , for example, a hydroxyl group protected with a methyl group (that is, a methoxy group), [O ⁻ ] and the like are preferable, and for example, [O ⁻ ] and the like are more preferable.

  In the present invention, R is preferably a hydrogen atom, an optionally substituted C1-20 alkyl group, an optionally substituted C2-20 alkenyl group, an optionally substituted C1-20 alkylidene group, A cyclic group that may be substituted, an oxo group, a hydroxyl group, a C1-20 alkyloxy group that may be substituted, a hydroxyl group that may be protected with a cyclic group that may be substituted, and a substituent that may be substituted. C1-20 acyloxy group, mercapto group, C1-20 alkylthio group which may be substituted, carbonyl group which may be substituted, C1-20 acyl group which may be substituted, carbamoyl group which may be substituted (When there are two substituents, together with the nitrogen atom to which they are attached, 1 to 5 nitrogen atoms, 1 oxygen atom and / or 1 A 5- to 7-membered monocyclic heterocyclic ring containing a yellow atom may be formed (this heterocyclic ring may be substituted by a C1-8 alkyl group, a hydroxyl group, or an amino group)), a cyano group , A nitro group, an optionally substituted amino group (when there are two substituents, together with the nitrogen atom to which they are attached, 1 to 5 nitrogen atoms, 1 oxygen atom and / or 1 A 5- to 7-membered monocyclic heterocyclic ring containing 1 sulfur atom (this heterocyclic ring may be substituted by a C1-8 alkyl group, a hydroxyl group, or an amino group)), A halogen atom, and the like. More preferably, for example, a hydrogen atom, an optionally substituted C1-4 alkyl group, an optionally substituted cyclic group, an oxo group, a hydroxyl group, an optionally substituted C1— 4 alkyloxy groups, may be substituted A hydroxyl group which may be protected by a cyclic group, an optionally substituted C1-20 acyloxy group, a mercapto group, an optionally substituted carbonyl group, an optionally substituted carbamoyl group (two substituents Sometimes, together with the nitrogen atom to which they are attached, a 5-7 membered monocyclic heterocycle containing 1-5 nitrogen atoms, 1 oxygen atom and / or 1 sulfur atom is formed. (This heterocyclic ring may be substituted by a C1-8 alkyl group, a hydroxyl group, or an amino group)), a nitro group, an optionally substituted amino group (when there are two substituents) Together with the nitrogen atom to which they are attached, may form a 5-7 membered monocyclic heterocycle containing 1-5 nitrogen atoms, 1 oxygen atom and / or 1 sulfur atom. (This heterocycle is a C1-8 alkyl group. , A hydroxyl group, or an amino group. )), Halogen atoms and the like, and particularly preferably, for example, a hydrogen atom, an optionally substituted methyl group, an optionally substituted cyclic group, an oxo group, a hydroxyl group, a methoxy group, or an optionally substituted group. Examples thereof include a C1-20 acyloxy group, an optionally substituted carbonyl group, a carbamoyl group optionally substituted with a methyl group, a nitro group, an amino group optionally substituted with a methyl group, and a chlorine atom. Moreover, as a substituent at this time, for example, a C1-20 alkyl group, a cyclic group, a C1-20 alkyl group substituted with a cyclic group, an oxo group, a hydroxyl group, a C1-20 alkyloxy group, a C1-20 acyloxy group C1-20 acyl group and halogen atom are preferable, for example, methyl group, ethyl group, propyl group, butyl group, cyclic group, benzyl group, oxo group, hydroxyl group, C1-8 alkyloxy group, chlorine atom and the like are more preferable. . Here, as the “cyclic group”, for example, a C3-10 monocyclic or bicyclic carbocyclic ring which may have a substituent, or 1 to 5 nitrogen atoms which may have a substituent Any hydrogen atom from a 3- to 10-membered monocyclic or bicyclic heterocyclic ring containing 1 to 2 oxygen atoms and / or 1 sulfur atom, a steroid skeleton optionally having a substituent, etc. Monovalent groups that can be removed are preferable, for example, optionally having cyclohexane, benzene, naphthalene, pyrrolidine, piperidine, imidazole, pyridine, dihydropyridine, dioxolane, tetrahydropyran, dioxane ring, and substituents. A monovalent group formed by removing any hydrogen atom from the steroid skeleton or the like which may be present is more preferable.

  In the present invention, m is preferably 1, for example.

  In the present invention, n is preferably 0, 1, 2, or the like, and more preferably, 0, 1, or the like.

  In the present invention, the compounds of the general formula (I) containing the combinations of the meanings listed above as preferable are preferable. More preferably, for example, the general formula (I-1)

[Wherein, D ¹ represents an optionally substituted C1-4 alkylene group or an optionally substituted C2-4 alkenylene group, Q represents an oxygen atom or an optionally substituted nitrogen atom, The symbol represents the same meaning as described above. ], General formula (I-2)

[Wherein all symbols have the same meaning as described above. ], General formula (I-3)

[In formula, G represents the hydroxyl group which may be protected, and other symbols represent the same meaning as the above. ], General formula (I-4)

[Wherein all symbols have the same meaning as described above. ], General formula (I-5)

[Wherein all symbols have the same meaning as described above. ], General formula (I-6)

[Wherein all symbols have the same meaning as described above. Or a salt thereof or a solvate thereof. Particularly preferred compounds include, for example, the general formula (I-6-1)

[Wherein all symbols have the same meaning as described above. ], General formula (I-6-2)

[Wherein all symbols have the same meaning as described above. Or a general formula (I-6-3)

[Wherein all symbols have the same meaning as described above. Or a salt thereof or a solvate thereof.

More specific embodiments include the following compounds, salts thereof, or solvates thereof.
(1) (2R) -2-propyloctanoic acid 1- (acetyloxy) ethyl ester, (2) (2R) -2-propyloctanoic acid 1- (acetyloxy) -1-methylethyl ester,
(3) (2R) -2-propyloctanoic acid 1-{[(cyclohexyloxy) carbonyl] oxy} ethyl ester,
(4) ethane-1,2-diyl (2R, 2′R) bis (2-propyloctanoate),
(5) Palmitic acid 2-{[(2R) -2-propyloctanoyl] oxy} ethyl ester,
(6) 4-oxo-4- (2-{[(2R) -2-propyloctanoyl] oxy} ethoxy) butanoic acid sodium,
(7) Piperidine-3-carboxylic acid 2-{[(2R) -2-propyloctanoyl] oxy} ethyl ester,
(8) 1,4-dihydropyridine-3-carboxylic acid 2-{[(2R) -2-propyloctanoyl] oxy} ethyl ester,
(9) 3-hydroxy-2-naphthoic acid 2-{[(2R) -2-propyloctanoyl] oxy} ethyl ester,
(10) 3-{[(2R) -2-propyloctanoyl] oxy} propane-1,2-diyl dioctadecanoate,
(11) 2-{[(2R) -2-propyloctanoyl] oxy} propane-1,3-diyl dipentadecanoate,
(12) (2R) -2-propyloctanoic anhydride,
(13) (2R) -2-propyloctanoic acid 3-oxo-1,3-dihydro-2-benzofuran-1-yl ester,
(14) (2R) -2-propyloctanoic acid (5-methyl-2-oxo-1,3-dioxola-4-yl) methyl ester,
(15) (2R) -2-propyloctanoic acid [(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] methyl ester,
(16) (2R) -2-propyloctanoic acid 3-ethoxy-1-methyl-3-oxopropyl ester,
(17) (4R) -4-((3R, 5R, 7R, 8R, 9S, 10S, 12S, 13R, 14S, 17R) -7,12-dihydroxy-10,13-dimethyl-3-{[(1 -{[(2R) -2-propyloctanoyl] oxy} ethoxy) carbonyl] oxy} hexadecahydro-1H-cyclopenta [a] phenanthren-17-yl) pentanoic acid,
(18) Cholic acid 2-{[(2R) -2-propyloctanoyl] oxy} ethyl ester, and (19) (2R) -2-propyloctanoic acid 2- (dimethylamino) -2-oxoethyl ester.

[Isomer]
In the present invention, all isomers are included unless otherwise specified. For example, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an alkylthio group, an alkylene group, an alkenylene group, and an alkynylene group include straight-chain and branched-chain groups. Furthermore, isomers (E, Z, cis, trans isomers) in double bonds, rings, condensed rings, isomers due to the presence of asymmetric carbon, etc. (R, S isomers, α, β configuration, enantiomers, diastereomers) , Optically active substances having optical activity (D, L, d, l form), polar bodies (high polar bodies, low polar bodies) by chromatographic separation, equilibrium compounds, rotamers, mixtures of these in any proportions, All racemic mixtures are included in the present invention.

  In the present invention, unless otherwise specified, the symbols are apparent to those skilled in the art.

Represents the α configuration,

Represents the β configuration,

Represents α configuration, β configuration or a mixture thereof,

Represents a mixture of α configuration and β configuration.

In addition, the compound of the present invention represented by the general formula (I) may be labeled with an isotope (eg, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I) or the like.

[Salts, solvates, etc.]
The salts of the compounds of the present invention represented by the general formula (I) include all pharmacologically acceptable salts. The pharmacologically acceptable salt is preferably non-toxic and water-soluble. Suitable salts include, for example, alkali metal (eg, potassium, sodium, lithium, etc.) salts, alkaline earth metal (eg, calcium, magnesium, etc.) salts, ammonium salts (eg, tetramethylammonium salt, tetrabutyl). Ammonium salts), organic amines (for example, triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) methylamine, lysine, arginine, N-methyl- Salt of D-glucamine, etc., acid adduct salt (eg, inorganic acid salt (eg, hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, etc.), organic acid salt (E.g. acetate, trifluoroacetate, lactate, Isartrate, oxalate, fumarate, maleate, benzoate, citrate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, glucuronic acid Salt, gluconate, etc.)).

  The salt of the compound of the present invention represented by the general formula (I) includes an N-oxide form. The N-oxide form of the compound of the present invention represented by the general formula (I) refers to the nitrogen atom when a nitrogen atom is present in the substituent represented by R in the compound of the present invention represented by the general formula (I). Represents an oxidized product. Moreover, the N-oxide form of the compound of the present invention represented by the general formula (I) may further form the above salt.

The salt of the compound of the present invention represented by the general formula (I) includes a quaternary ammonium salt. The quaternary ammonium salt of the compound of the present invention represented by the general formula (I) is the nitrogen atom in the compound represented by the general formula (I) when a nitrogen atom is present in the substituent represented by R. Is quaternized by R ⁰ group (R ⁰ group represents a C 1-8 alkyl group, a C 1-8 alkyl group substituted by a phenyl group, etc.). Further, the quaternary ammonium salt of the compound of the present invention represented by the general formula (I) may further be the above-mentioned salt or N-oxide.

  Examples of the solvate of the compound of the present invention represented by the general formula (I) include solvates such as water and alcohol solvents (for example, ethanol). The solvate is preferably non-toxic and water-soluble. Moreover, the solvate of the compound of the present invention represented by the general formula (I) includes the solvates of the above salts, N-oxides and quaternary ammonium salts.

  The compound of the present invention represented by the general formula (I) can be converted into the above salt, the above N-oxide, the above quaternary ammonium salt and the above solvate by a known method.

[Production method]
The compound of the present invention represented by the general formula (I) can be produced by a known method such as the method described in International Publication WO02 / 092068, Comprehensive Organic Transformations (A Guide to Functional Group Preparations). , 2nd edition) (Richard C. Larock, John Wiley & Sons Inc, 1999) be able to. In each of the following production methods, the raw material compound may be used as a salt. As such a salt, those described as the salt of the general formula (I) are used.

  It should be noted that, for those skilled in the art, the production raw material and intermediate compound of the present invention compound represented by the general formula (I) shown below have a hydroxyl group, a carboxyl group, an amino group, or a mercapto group. In this case, the production of the compound of the present invention represented by the general formula (I) can be facilitated by subjecting them to a protection / deprotection reaction as appropriate.

  Examples of hydroxyl protecting groups include methyl, trityl, methoxymethyl (MOM), 1-ethoxyethyl (EE), methoxyethoxymethyl (MEM), 2-tetrahydropyranyl (THP), and trimethylsilyl. (TMS) group, triethylsilyl (TES) group, t-butyldimethylsilyl (TBDMS) group, t-butyldiphenylsilyl (TBDPS) group, acetyl (Ac) group, pivaloyl group, benzoyl group, benzyl (Bn) group, Examples include a p-methoxybenzyl group, an allyloxycarbonyl (Alloc) group, and a 2,2,2-trichloroethoxycarbonyl (Troc) group.

  Examples of the protecting group for the carboxy group include a methyl group, an ethyl group, a t-butyl group, an allyl group, a phenacyl group, and a benzyl group.

  Examples of amino-protecting groups include benzyloxycarbonyl group, t-butoxycarbonyl group, allyloxycarbonyl (Alloc) group, 1-methyl-1- (4-biphenyl) ethoxycarbonyl (Bpoc) group, trifluoroacetyl group , 9-fluorenylmethoxycarbonyl group, benzyl (Bn) group, p-methoxybenzyl group, benzyloxymethyl (BOM) group, 2- (trimethylsilyl) ethoxymethyl (SEM) group and the like.

  Examples of the mercapto group-protecting group include a benzyl group, a methoxybenzyl group, a methoxymethyl (MOM) group, a 2-tetrahydropyranyl (THP) group, a diphenylmethyl group, and an acetyl (Ac) group.

  The protecting group for the hydroxyl group, carboxyl group, amino group, or mercapto group is not particularly limited as long as it is a group that can be easily and selectively eliminated other than those described above. For example, those described in Protective Groups in Organic Synthesis (T.W. Greene, John Wiley & Sons Inc, 1999) can also be used.

Deprotection reactions for protecting groups of hydroxyl, carboxyl, amino or mercapto groups are well known, for example,
(1) alkaline hydrolysis,
(2) Deprotection reaction under acidic conditions,
(3) Deprotection reaction by hydrogenolysis,
(4) Deprotection reaction using a metal complex,
(5) Deprotection reaction using metal,
(6) Deprotection reaction of silyl group.

Specifically explaining these methods,
(1) The deprotection reaction (for example, trifluoroacetyl group and the like) by alkali hydrolysis is carried out, for example, in an organic solvent (methanol, tetrahydrofuran, 1,4-dioxane and the like) in an alkali metal hydroxide (sodium hydroxide, Potassium hydroxide, lithium hydroxide, etc.), alkaline earth metal hydroxides (barium hydroxide, calcium hydroxide, etc.) or carbonates (sodium carbonate, potassium carbonate, etc.) or their aqueous solutions or mixtures thereof, It is carried out at a temperature of 0 to 40 ° C.

  (2) Deprotection reaction under acid conditions (for example, deprotection reaction of t-butoxycarbonyl group, trityl group, etc.) is, for example, water or an organic solvent (dichloromethane, chloroform, 1,4-dioxane, ethyl acetate, Anisole, etc.), in an organic acid (acetic acid, trifluoroacetic acid, methanesulfonic acid, etc.), or in an inorganic acid (hydrochloric acid, sulfuric acid, etc.) or a mixture thereof (hydrogen bromide / acetic acid, etc.) Done.

  (3) Deprotection reaction by hydrogenolysis (for example, deprotection reaction of benzyl group, benzhydryl group, benzyloxycarbonyl group, allyloxycarbonyl group, etc.) is carried out, for example, with a solvent (ether type (tetrahydrofuran, 1,4-dioxane). , Dimethoxyethane, diethyl ether, etc.), alcohol (methanol, ethanol, etc.), benzene (benzene, toluene, etc.), ketone (acetone, methyl ethyl ketone, etc.), nitrile (acetonitrile, etc.), amide (N, N- Dimethylformamide), water, ethyl acetate, acetic acid or a mixed solvent of two or more thereof) in the presence of a catalyst (palladium-carbon, palladium black, palladium hydroxide, platinum oxide, Raney nickel, etc.) at atmospheric pressure or under pressure. Under hydrogen atmosphere under pressure or ammonium formate Presence, at a temperature of 0 to 200 ° C..

  (4) Deprotection reaction using a metal complex (for example, deprotection reaction of allyloxycarbonyl group or the like) is, for example, an organic solvent (dichloromethane, N, N-dimethylformamide, tetrahydrofuran, ethyl acetate, acetonitrile, 1,4- Dioxane, ethanol, etc.), water or mixed solvents thereof, trap reagents (tributyltin hydride, triethylsilane, dimedone, morpholine, diethylamine, pyrrolidine, etc.), organic acids (acetic acid, formic acid, 2-ethylhexanoic acid, etc.) and / or Alternatively, in the presence of an organic acid salt (sodium 2-ethylhexanoate, potassium 2-ethylhexanoate, etc.), in the presence or absence of a phosphine reagent (triphenylphosphine, etc.), a metal complex (tetrakistriphenylphosphine palladium ( 0), bis (triphenylphosphate) Fin) palladium (II), palladium (II), with tris (triphenylphosphine) rhodium (I) etc.), at a temperature of 0 to 40 ° C..

  (5) The deprotection reaction using a metal is carried out, for example, in an acidic solvent (acetic acid, a buffer solution of pH 4.2 to 7.2 or a mixed solution of these solutions and an organic solvent such as tetrahydrofuran) in the presence of powdered zinc. If necessary, it is performed at a temperature of 0 ° C. to 40 ° C. while applying ultrasonic waves.

  (6) The deprotection reaction of the silyl group is carried out at a temperature of 0 to 40 ° C. using tetrabutylammonium fluoride in an organic solvent miscible with water (tetrahydrofuran, acetonitrile, etc.).

  [1] Among the compounds of the present invention represented by the general formula (I), a compound in which A is an oxygen atom, that is, the general formula (IA)

[Wherein all symbols have the same meaning as described above. The compound represented by the formula is 2-propyloctanoic acid and general formula (II)

[Wherein all symbols have the same meaning as described above. ]
It can manufacture by attaching | subjecting the compound shown by esterification reaction. This esterification reaction is known, for example
(1) Method using a condensing agent (2) Method using a mixed acid anhydride,
(3) a method using an acid halide,
Etc.

Specifically explaining these methods,
(1) The method using a condensing agent is, for example, using 2-propyloctanoic acid as an organic solvent (for example, halogenated hydrocarbons such as chloroform and dichloromethane, for example, ethers such as diethyl ether, tetrahydrofuran and 1,4-dioxane). For example, acid amides such as N, N-dimethylformamide, etc. These solvents can be used singly or, if necessary, two or more kinds can be used in an appropriate ratio, for example, In a ratio of 1: 1 to 1:10) or in the absence of solvent, a base (for example, an alkylamine such as triethylamine, tributylamine, diisopropylethylamine, such as N, N-dimethylaniline, In the presence or absence of aromatic amines such as pyridine and 4- (dimethylamino) pyridine). Agents (eg, 1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- [3- (dimethylamino) propyl] carbodiimide (EDC), 1,1′-carbonyldiimidazole (CDI), 2-chloro- 1-methylpyridinium iodine, 1-propylphosphonic acid cyclic anhydride (PPA), etc.) and with or without 1-hydroxybenztriazole (HOBt) It is carried out by reacting the compound shown at 0 to 40 ° C.

  (2) The method using a mixed acid anhydride is, for example, using 2-propyloctanoic acid as an organic solvent (for example, halogenated hydrocarbons such as chloroform and dichloromethane, for example, diethyl ether, tetrahydrofuran, 1,4-dioxane and the like). Ethers, for example, acid amides such as N, N-dimethylformamide, etc. These solvents can be used singly or, if necessary, two or more kinds can be used in an appropriate ratio, For example, it may be used by mixing at a ratio of 1: 1 to 1:10.) Or without a solvent, in a base (for example, pyridine, triethylamine, dimethylaniline, N, N-dimethylaminopyridine, diisopropylethylamine, etc.) In the presence, acid halides (eg pivaloyl chloride, p-toluenesulfonyl chloride, methanesulfuric acid) Nyl chloride, etc.) or an acid derivative (eg, ethyl chloroformate, isobutyl chloroformate, etc.) at 0 to 40 ° C., and the resulting mixed acid anhydride is subjected to halogenated carbonization such as chloroform, dichloromethane, etc. Hydrogen, for example, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, for example, acid amides such as N, N-dimethylformamide, etc. These solvents can be used alone, In addition, if necessary, two or more kinds may be mixed and used in an appropriate ratio, for example, a ratio of 1: 1 to 1:10.) In the compound represented by the general formula (II) The reaction is carried out at 0 to 40 ° C.

  (3) The method using an acid halide is, for example, using 2-propyloctanoic acid as an organic solvent (for example, halogenated hydrocarbons such as chloroform and dichloromethane, for example, ethers such as diethyl ether, tetrahydrofuran and 1,4-dioxane). For example, acid amides such as N, N-dimethylformamide, etc. These solvents can be used singly or, if necessary, two or more kinds can be used in an appropriate ratio, for example, (The mixture may be used in a ratio of 1: 1 to 1:10.) In or without a solvent, an acid halide agent (for example, oxalyl chloride, thionyl chloride, phosphorus pentachloride, phosphorus trichloride, etc.) and- The reaction is carried out at 20 ° C. to reflux temperature, and the resulting acid halide is converted into a base (for example, triethylamine, tributylamine, diisopropylethylamine, etc. Reaction with a compound represented by the general formula (II) at 0 to 40 ° C. in the presence of alkylamines such as aromatic amines such as N, N-dimethylaniline, pyridine and 4- (dimethylamino) pyridine). It is done by. In addition, an organic solvent (for example, diethyl ether, 1,4-dioxane, tetrahydrofuran, etc.) is used for the obtained acid halide. These solvents can be used singly or in combination of two or more as required. May be used in an appropriate ratio such as 1: 1 to 1:10.) In an alkaline aqueous solution (for example, sodium bicarbonate water or sodium hydroxide solution), It can also carry out by making it react with the compound shown by (II) at 0-40 degreeC.

  These reactions (1), (2) and (3) are all desirably carried out under anhydrous conditions in an inert gas (argon, nitrogen, etc.) atmosphere.

  If necessary, this reaction may be followed by an operation for conversion to the desired non-toxic salt by a known method.

  [2] Among the compounds of the present invention represented by the general formula (I), a compound in which A is an optionally substituted nitrogen atom, that is, the general formula (IB)

[Wherein, R ^IB represents a hydrogen atom or a substituent (the substituent represents the same meaning as the “substituent” in the optionally substituted nitrogen atom), and the other symbols are as defined above. Represents the same meaning. ]
The compound represented by 2-propyloctanoic acid and general formula (III)

[Wherein all symbols have the same meaning as described above. ]
It can manufacture by attaching | subjecting to the compound shown by amidation reaction. This amidation reaction is known. For example, instead of the alcohol compound represented by the general formula (II), an amine compound represented by the general formula (III) is used, and the method similar to the above esterification reaction is used. Can be done. If necessary, this reaction may be followed by an operation for conversion to the desired non-toxic salt by a known method.

  In the present invention, 2-propyloctanoic acid used as a raw material and the compounds represented by the general formulas (II) and (III) are known per se or known methods, for example, European Patent Publication No. 0632008. , WO 99/58513 pamphlet, WO 00/48982 pamphlet, WO 03/051852 pamphlet, WO 03/097851 pamphlet, etc., Comprehensive Organic Trans The method described in Formations (Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd edition) (by Richard C. Larock, John Wiley & Sons Inc, 1999) and / or a method based on the method are appropriately improved. Can be manufactured in combination.

  In each reaction in the present specification, a solid-phase-supported reagent supported on a high-molecular polymer (for example, polystyrene, polyacrylamide, polypropylene, polyethylene glycol, etc.) may be used as appropriate.

  In each reaction in the present specification, the reaction product is obtained by a conventional purification means such as distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, ion exchange resin, It can be purified by scavenger resin, column chromatography, washing or recrystallization. Purification may be performed for each reaction or after completion of several reactions.

[toxicity]
The toxicity of the prodrug of the present invention is sufficiently low and confirmed to be sufficiently safe for use as a pharmaceutical product. In addition, the prodrug of the present invention is converted to (2R) -2-propyloctanoic acid by enzymatic or chemical conversion in vivo, and exhibits pharmacological activity. ) -2-Propyloctanoic acid has a sufficiently low toxicity. For example, even in a single intravenous administration using a dog, no death was observed at 100 mg / kg.

[Application to pharmaceutical products]
Since the prodrug of the present invention is converted into (2R) -2-propyloctanoic acid by enzymatic or chemical conversion when administered in vivo, it exhibits pharmacological activity. It can be used as a prophylactic and / or therapeutic agent for any disease or patient for whom 2-propyloctanoic acid is effective. Examples of such diseases include neurodegenerative diseases. The “therapeutic agent” in the present invention means not only the so-called “therapeutic agent” that leads the pathological condition toward healing, but also the meaning of the so-called “progression preventing agent” that suppresses the progression and stops the progression of the pathological condition. included.

  Here, the neurodegenerative diseases include all diseases associated with neuronal degeneration and are not limited by the pathogenesis. The neurodegenerative disease in the present invention includes a neurological disorder and a disease requiring nerve regeneration. The nerve cell may be any nerve cell in the living body, for example, a central nerve (eg, cranial nerve, spinal nerve, etc.), a peripheral nerve (eg, autonomic nervous system (eg, sympathetic nerve, parasympathetic nerve, etc.)) Or the like. Preferably, the neurodegenerative disease is, for example, a disease of the central nervous system, such as Parkinson's disease, Parkinson's syndrome, Alzheimer's disease, Down's syndrome, amyotrophic lateral sclerosis, familial amyotrophic lateral sclerosis, progressive nucleus Supraparalysis, Huntington's disease, spinocerebellar ataxia, dentate nucleus red nucleus pallidal atrophy, olive bridge cerebellar atrophy, corticobasal degeneration, familial dementia, frontotemporal dementia, senile Dementia, diffuse Lewy body disease, striatum-substantia nigra degeneration, chorea-ataxia, dystonia, mage syndrome, late-onset cerebellar cortical atrophy, familial spastic paraplegia, motor neuropathy Card Joseph disease, Pick disease, stroke (eg, cerebral hemorrhage (eg, hypertensive intracerebral hemorrhage, etc.), cerebral infarction (eg, cerebral thrombus, cerebral embolism, etc.), transient ischemic attack, subarachnoid hemorrhage, etc. Neurological dysfunction after trauma Associated with demyelinating diseases (eg, multiple sclerosis, Guillain-Barre syndrome, acute disseminated encephalomyelitis, acute cerebellar inflammation, transverse myelitis, etc.), brain tumors (eg, astrocytoma), infection Examples include cerebrospinal diseases (eg meningitis, brain abscess, Creutzfeld-Jakob disease, AIDS dementia, etc.), mental disorders (schizophrenia, manic depression, neurosis, psychosomatic disease, epilepsy, etc.). More preferable examples of the neurodegenerative disease include stroke, and particularly preferable examples include cerebral infarction. In particular, acute cerebral infarction is preferable. Although not to be construed strictly, acute cerebral infarction means cerebral infarction within 2 weeks after onset.

  Neuropathy includes any disorder of nerve function. Examples of neurological disorders include transient blindness (for example, transient cataract), consciousness disorder, contralateral hemiplegia, sensory disorder, homonymous half-blindness, aphasia, alternating hemiplegia, bilateral limb paralysis, Sensory disorders, homonymous half-blindness, dizziness, tinnitus, nystagmus, diplopia, coma and the like are preferable, and those neurological disorders associated with the neurodegenerative diseases are preferable.

  A disease that requires nerve regeneration means a disease in which the absolute number of nerve cells is reduced due to the loss of nerve cells, and normal nerve function is impaired. Can be cited. For such diseases, cells that can form normal nerves (for example, neural stem cells, neural progenitor cells, neural cells, other stem cells, glial cells, etc.) are surgically transplanted, or endogenous these Treatment is performed to activate cells and regenerate nerves. The prodrug of the present invention can promote nerve regeneration by being temporarily or continuously administered when transplanting the above-mentioned cells or activating endogenous cells.

  The prodrug of the present invention can improve the blood persistence of (2R) -2-propyloctanoic acid as compared with the case where (1) (2R) -2-propyloctanoic acid is administered as it is, (2) Excellent oral absorption compared to (2R) -2-propyloctanoic acid, (3) Gastrointestinal stability increased compared to (2R) -2-propyloctanoic acid, (4) Since it exhibits at least one of the properties that oral irritation is reduced compared to (2R) -2-propyloctanoic acid, it is usually used in humans and animals for these purposes. Preferably, it is administered systemically and in an oral form. Of course, however, it can also be administered topically and parenterally.

  The dose varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc. In the case of oral administration, it is usually once per day in the range of 1 μg to 5000 mg per adult per person. It is administered orally twice. In the case of parenteral administration, it is administered parenterally once to several times a day in the range of 0.1 ng to 500 mg per adult per person. The parenteral dosage form is preferably intravenous administration and is continuously administered intravenously in the range of 1 hour to 24 hours per day.

  Of course, as described above, the administration / treatment amount varies depending on various conditions, and therefore an amount smaller than the above-mentioned administration / treatment amount may be sufficient, or administration / treatment may be necessary beyond the range.

  When the prodrug of the present invention is administered orally, it is used as a solid preparation for internal use for oral administration, a liquid preparation for internal use and the like.

  Examples of the solid preparation for internal use for oral administration include tablets, pills, capsules, powders, granules and the like. Capsules include hard capsules and soft capsules. Tablets include sublingual tablets, buccal adhesive tablets, buccal quick disintegrating tablets and the like.

  In such solid preparations for internal use, one or more active substances are left as they are, or excipients (eg, lactose, mannitol, glucose, microcrystalline cellulose, starch, etc.), binders (eg, hydroxypropylcellulose) , Polyvinyl pyrrolidone, magnesium aluminate metasilicate, etc.), disintegrant (eg, calcium calcium glycolate), lubricant (eg, magnesium stearate), stabilizer, solubilizer (eg, glutamic acid, aspartic acid) Etc.) and the like, and formulated into a conventional method. Moreover, you may coat | cover with a coating agent (For example, sucrose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate etc.) as needed, and you may coat | cover with two or more layers. Also included are capsules of absorbable substances such as gelatin.

  The sublingual tablet is prepared according to a known method. For example, one or more active substances with excipients (eg lactose, mannitol, glucose, microcrystalline cellulose, colloidal silica, starch, etc.), binders (eg hydroxypropylcellulose, polyvinylpyrrolidone, magnesium aluminate metasilicate) Etc.), disintegrating agents (for example, starch, L-hydroxypropyl cellulose, carboxymethyl cellulose, croscarmellose sodium, calcium cellulose glycolate, etc.), lubricants (for example, magnesium stearate, etc.), swelling agents (for example, hydroxy Propylcellulose, hydroxypropylmethylcellulose, carbopol, carboxymethylcellulose, polyvinyl alcohol, xanthan gum, guar gum, etc.), swelling aids (eg glucose, fructose) , Mannitol, xylitol, erythritol, maltose, trehalose, phosphate, citrate, silicate, glycine, glutamic acid, arginine, etc., stabilizer, solubilizer (eg, polyethylene glycol, propylene glycol, glutamic acid, asparagine) Acid, etc.), flavoring agents (for example, orange, strawberry, mint, lemon, vanilla, etc.) and the like, and formulated into a conventional method for use. Moreover, you may coat | cover with a coating agent (For example, sucrose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate etc.) as needed, and you may coat | cover with two or more layers. Moreover, additives such as preservatives, antioxidants, colorants, sweeteners and the like that are commonly used can be added as necessary.

  The intraoral patch is prepared according to a known method. For example, one or more active substances with excipients (eg lactose, mannitol, glucose, microcrystalline cellulose, colloidal silica, starch, etc.), binders (eg hydroxypropylcellulose, polyvinylpyrrolidone, magnesium aluminate metasilicate) Etc.), disintegrating agents (for example, starch, L-hydroxypropyl cellulose, carboxymethyl cellulose, croscarmellose sodium, calcium cellulose glycolate, etc.), lubricants (for example, magnesium stearate, etc.), adhesives (for example, hydroxy Propylcellulose, hydroxypropylmethylcellulose, carbopol, carboxymethylcellulose, polyvinyl alcohol, xanthan gum, guar gum, etc.), adhesion aids (eg glucose, fructose) , Mannitol, xylitol, erythritol, maltose, trehalose, phosphate, citrate, silicate, glycine, glutamic acid, arginine, etc.) stabilizer, solubilizer (eg, polyethylene glycol, propylene glycol, glutamic acid, aspartic acid) Etc.), flavoring agents (for example, orange, strawberry, mint, lemon, vanilla, etc.) and the like, and formulated into a conventional method for use. Moreover, you may coat | cover with a coating agent (For example, sucrose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate etc.) as needed, and you may coat | cover with two or more layers. Moreover, additives such as preservatives, antioxidants, colorants, sweeteners and the like that are commonly used can be added as necessary.

  The intraoral quick disintegrating tablet is prepared according to a known method. For example, one or more active substances can be used as is, or a suitable coating agent (eg, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, acrylic acid / methacrylic acid copolymer, etc.), plasticizer (eg, polyethylene glycol, triethyl citrate). Active substance powder or granulated raw material particles coated with an excipient (for example, lactose, mannitol, glucose, microcrystalline cellulose, colloidal silica, starch, etc.), binder (for example, Hydroxypropylcellulose, polyvinylpyrrolidone, magnesium aluminate metasilicate, etc.), disintegrating agents (eg, starch, L-hydroxypropylcellulose, carboxymethylcellulose, croscarmellose sodium, fibrin grease) Calcium oxalate), lubricant (eg, magnesium stearate), dispersion aid (eg, glucose, fructose, mannitol, xylitol, erythritol, maltose, trehalose, phosphate, citrate, silicate) , Glycine, glutamic acid, arginine, etc.), stabilizers, solubilizers (eg, polyethylene glycol, propylene glycol, glutamic acid, aspartic acid, etc.), flavors (eg, orange, strawberry, mint, lemon, vanilla, etc.) And is formulated and used according to conventional methods. Moreover, you may coat | cover with a coating agent (For example, sucrose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate etc.) as needed, and you may coat | cover with two or more layers. If necessary, additives such as commonly used preservatives, antioxidants, colorants, sweeteners and the like can be added.

  Liquid preparations for internal use for oral administration include pharmaceutically acceptable solutions, suspensions, emulsions, syrups, elixirs and the like. In such a solution, one or more active substances are dissolved, suspended or emulsified in a commonly used diluent (for example, purified water, ethanol or a mixture thereof). Furthermore, this liquid agent may contain a wetting agent, a suspending agent, an emulsifier, a sweetening agent, a flavoring agent, a fragrance, a preservative, a buffering agent and the like.

  In addition, when the prodrug of the present invention is administered parenterally, it is used as an injection, an external preparation, a suppository, an eye drop, an inhalant, a nasal preparation and the like for parenteral administration.

  External dosage forms for parenteral administration include, for example, ointments, gels, creams, poultices, patches, liniments, sprays, inhalants, sprays, aerosols, eye drops, And nasal drops. These contain one or more active substances and are produced by known methods or commonly used formulations.

  The ointment is produced by a known or commonly used formulation. For example, one or more active substances are produced by grinding or melting a base. The ointment base is selected from known or commonly used ones. For example, higher fatty acids or higher fatty acid esters (for example, adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipic acid ester, myristic acid ester, palmitic acid ester, stearic acid ester, oleic acid ester, etc.), waxes (E.g., beeswax, whale wax, ceresin, etc.), surfactants (e.g., polyoxyethylene alkyl ether phosphates, etc.), higher alcohols (e.g., cetanol, stearyl alcohol, cetostearyl alcohol, etc.), silicone oils (e.g., Dimethylpolysiloxane, etc.), hydrocarbons (eg, hydrophilic petrolatum, white petrolatum, purified lanolin, liquid paraffin, etc.), glycols (eg, ethylene glycol, diethylene glycol, propylene glycol, polyethylene) Recall, macrogol, etc.), vegetable oil (eg, castor oil, olive oil, sesame oil, turpentine oil, etc.), animal oil (eg, mink oil, egg yolk oil, squalane, squalene, etc.), water, absorption enhancer, anti-rash agent Can be used alone or in admixture of two or more. Furthermore, a humectant, a preservative, a stabilizer, an antioxidant, a flavoring agent and the like may be included.

  The gel is produced by a known or commonly used formulation. For example, it is produced by melting one or more active substances in a base. The gel base is selected from known or commonly used ones. For example, lower alcohol (eg, ethanol, isopropyl alcohol, etc.), gelling agent (eg, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, ethylcellulose, etc.), neutralizing agent (eg, triethanolamine, diisopropanolamine, etc.), Those selected from surfactants (for example, polyethylene glycol monostearate), gums, water, absorption promoters and anti-rash agents are used alone or in admixture of two or more. Furthermore, a preservative, an antioxidant, a flavoring agent and the like may be included.

  The cream is produced by a known or commonly used formulation. For example, it is prepared by melting or emulsifying one or more active substances in a base. The cream base is selected from known or commonly used ones. For example, higher fatty acid esters, lower alcohols, hydrocarbons, polyhydric alcohols (eg, propylene glycol, 1,3-butylene glycol, etc.), higher alcohols (eg, 2-hexyldecanol, cetanol, etc.), emulsifiers (eg, polyoxy (Ethylene alkyl ethers, fatty acid esters, etc.), water, absorption accelerators, and rash prevention agents may be used alone or in admixture of two or more. Furthermore, a preservative, an antioxidant, a flavoring agent and the like may be included.

  The poultice is produced by a known or commonly used formulation. For example, it is produced by melting one or more active substances in a base material, and applying it as a kneaded product on a support. The poultice base is selected from known or commonly used ones. For example, thickeners (for example, polyacrylic acid, polyvinylpyrrolidone, gum arabic, starch, gelatin, methylcellulose, etc.), wetting agents (for example, urea, glycerin, propylene glycol, etc.), fillers (for example, kaolin, zinc oxide, Talc, calcium, magnesium, etc.), water, solubilizers, tackifiers and anti-rash agents are used alone or in admixture of two or more. Furthermore, a preservative, an antioxidant, a flavoring agent and the like may be included.

  The patch is produced by a known or commonly used formulation. For example, it is produced by melting one or more active substances in a base and spreading and coating them on a support. The base for patch is selected from known or commonly used ones. For example, those selected from polymer bases, oils and fats, higher fatty acids, tackifiers and anti-rash agents may be used alone or in admixture of two or more. Furthermore, a preservative, an antioxidant, a flavoring agent and the like may be included.

  The liniment is produced by a known or commonly used formulation. For example, one or more actives may be selected from water, alcohol (eg, ethanol, polyethylene glycol, etc.), higher fatty acid, glycerin, soap, emulsifier, suspending agent, etc. alone or in combination of two or more. Prepared by dissolving, suspending or emulsifying. Furthermore, a preservative, an antioxidant, a flavoring agent and the like may be included.

  Sprays, inhalants, and sprays are buffers that provide isotonicity with stabilizers such as sodium bisulfite in addition to commonly used diluents, such as sodium chloride, sodium citrate or citric acid. An isotonic agent such as The production method of the spray is described in detail in, for example, US Pat. Nos. 2,868,691 and 3,095,355.

  The injection for parenteral administration includes all injections. For example, an injection for muscle, an injection for intravenous injection, an intravenous infusion, and the like are included.

  Examples of the injection for parenteral administration include solutions, suspensions, emulsions, and solid injections used by dissolving or suspending in a solvent at the time of use. An injection is used by dissolving, suspending or emulsifying one or more active substances in a solvent. Examples of the solvent include distilled water for injection, physiological saline, vegetable oil, propylene glycol, polyethylene glycol, alcohols such as ethanol, and combinations thereof. Furthermore, this injection contains a stabilizer, a solubilizing agent (for example, glutamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.), a suspending agent, an emulsifying agent, a soothing agent, a buffering agent, a preservative and the like. Also good. These are sterilized in the final step or prepared by aseptic manipulation. In addition, an aseptic solid preparation, for example, a lyophilized product can be produced and dissolved in aseptic distilled water for injection or other solvent before use.

  Inhalants for parenteral administration include aerosols, inhalable powders or inhalable solutions, which are used by dissolving or suspending them in water or other suitable media at the time of use. It may be.

  These inhalants are produced according to known methods. For example, in the case of inhalation solutions, preservatives (eg, benzalkonium chloride, parabens, etc.), colorants, buffering agents (eg, sodium phosphate, sodium acetate, etc.), isotonic agents (eg, chloride) Sodium, concentrated glycerin, etc.), thickeners (for example, cariboxyvinyl polymer, etc.), absorption accelerators, and the like are appropriately selected as necessary. In the case of powders for inhalation, lubricants (for example, stearic acid and its salts), binders (for example, starch, dextrin, etc.), excipients (for example, lactose, cellulose, etc.), colorants, antiseptics An agent (for example, benzalkonium chloride, paraben, etc.), an absorption accelerator and the like are appropriately selected as necessary. A nebulizer (for example, an atomizer, a nebulizer, etc.) is usually used when administering an inhalation solution, and an inhalation administration device for powdered drugs is usually used when administering an inhalable powder.

  Other compositions for parenteral administration include suppositories for rectal administration and pessaries for intravaginal administration, which contain one or more active substances and are prescribed by conventional methods.

  Since the prodrug of the present invention is converted into (2R) -2-propyloctanoic acid by enzymatic or chemical conversion when administered in vivo, it exhibits pharmacological activity. ) -2-Propyloctanoic acid for (1) complementation and / or enhancement of preventive and / or therapeutic effects, (2) kinetics / absorption improvement, dose reduction, and / or (3) other side effects to reduce side effects It may be administered as a concomitant drug in combination with these drugs.

  In order to (1) supplement and / or enhance the preventive and / or therapeutic effects of other drugs used in combination, (2) improve kinetics / absorption, reduce dosage, and / or (3) reduce side effects, The prodrugs of the present invention may be combined and administered as a concomitant drug.

  The combination drug of the prodrug of the present invention and other drugs (hereinafter abbreviated as the combination drug of the present invention) may be administered in the form of a combination drug containing both components in one preparation, or separately. It may be in the form of administration in the form of When administered as separate preparations, simultaneous administration and administration by time difference are included. In addition, administration by a time difference may be performed by administering the prodrug of the present invention first and administering another drug later, or administering the other drug first and administering the prodrug of the present invention later. Of course, each administration method may be the same or different.

  The disease that exhibits the preventive and / or therapeutic effect by the combination agent of the present invention is not particularly limited, and the combination agent of the present invention complements and prevents the prevention and / or treatment effect as compared with the case where they are administered alone. Any disease may be used as long as the disease is enhanced.

  Other drugs used in the concomitant drug of the present invention include, for example, acetylcholinesterase inhibitors, nicotine receptor modulators, β amyloid protein production, secretion, accumulation, aggregation and / or deposition inhibitors (eg, β secretase inhibitors) , Γ-secretase inhibitor, β-amyloid protein aggregation inhibitor, β-amyloid vaccine, β-amyloid degrading enzyme, etc.), brain function activator, cerebral circulation metabolism improver, other Parkinson's disease therapeutic agents (for example, dopamine receptor agonist, Monoamine oxidase (MAO) inhibitor, anticholinergic agent, catechol-O-methyltransferase (COMT) inhibitor, etc.), amyotrophic lateral sclerosis drug, neurotrophic factor, abnormal behavior associated with dementia progression, acupuncture Therapeutic agents such as apoptosis inhibitors, nerve differentiation / regeneration promoters, antidepressants, anxiolytics, antiepileptics, antihypertensives, drugs Antihyperlipidemic agents (eg, statin, fibrate, squalene synthase inhibitors, etc.), aldose reductase inhibitors, non-steroidal anti-inflammatory drugs , Disease-modifying anti-rheumatic drugs, anti-cytokine drugs (eg, TNF inhibitors, MAP kinase inhibitors, etc.), steroid drugs, sex hormones or derivatives thereof, parathyroid hormone (eg, PTH), factor Xa inhibitors, factor VIIa Inhibitors, antioxidants, glycerin preparations and the like can be mentioned.

  Examples of the acetylcholinesterase inhibitor include donepezil hydrochloride, rivastigmine, galantamine, and zanapezil (TAK-147).

  Examples of β-secretase inhibitors include 6- (4-biphenylyl) methoxy-2- [2- (N, N-dimethylamino) ethyl] tetralin, 6- (4-biphenylyl) methoxy-2- (N, N -Dimethylamino) methyltetralin, 6- (4-biphenylyl) methoxy-2- (N, N-dipropylamino) methyltetralin, 2- (N, N-dimethylamino) methyl-6- (4'-methoxybiphenyl) -4-yl) methoxytetralin, 6- (4-biphenylyl) methoxy-2- [2- (N, N-diethylamino) ethyl] tetralin, 2- [2- (N, N-dimethylamino) ethyl] -6 -(4'-Methylbiphenyl-4-yl) methoxytetralin, 2- [2- (N, N-dimethylamino) ethyl] -6- (4'-methoxybiphenyl) 4-yl) methoxytetralin, 6- (2 ′, 4′-dimethoxybiphenyl-4-yl) methoxy-2- [2- (N, N-dimethylamino) ethyl] tetralin, 6- [4- (1, 3-benzodioxol-5-yl) phenyl] methoxy-2- [2- (N, N-dimethylamino) ethyl] tetralin, 6- (3 ′, 4′-dimethoxybiphenyl-4-yl) methoxy- 2- [2- (N, N-dimethylamino) ethyl] tetralin, its optically active substance, its salt and its hydrate, OM99-2 (WO01 / 00663).

  β-amyloid protein aggregation inhibitors include, for example, PTI-00703, ALZHEMED (NC-531), PPI-368 (Special Tables Hei 11-514333), PPI-558 (Special Tables Hei 2001-500852), SKF-74652 ( Biochem., J., 340 (1), 283-289, 1999).

  Examples of the brain function activator include aniracetam and nicergoline.

  Examples of drugs for improving cerebral circulation metabolism include idebenone, calcium hopantenate, amantadine hydrochloride, meclofenoxate hydrochloride, dihydroergotoxine mesylate, pyrithioxine hydrochloride, γ-aminobutyric acid, bifemelane hydrochloride, lisuride maleate, indeloxazine hydrochloride , Nicergoline, and propentofylline.

  Examples of dopamine receptor agonists include L-dopa, bromocriptene, pergolide, talipexol, prasipexol, cabergoline, and adamantadine.

  Examples of monoamine oxidase (MAO) inhibitors include safradine, deprenyl, sergiline (selegiline), remacemide, and riluzole.

  Examples of anticholinergic agents include trihexyphenidyl and biperidene.

  Examples of catechol-O-methyltransferase (COMT) inhibitors include entacapone.

  Examples of the therapeutic agent for amyotrophic lateral sclerosis include riluzole and neurotrophic factor (for example, ABS-205).

  Examples of apoptosis inhibitors include CPI-1189, IDN-6556, and CEP-1347.

  Examples of the neuronal differentiation / regeneration promoting agent include Leteprinim, Xaliproden (SR-57746-A), and SB-216763.

  Examples of antiepileptic drugs include phenobarbital, mehobarbital, metalbital, primidone, phenytoin, ethotoin, trimetadione, ethosuximide, acetylphenetride, carbamazepine, acetazolamide, diazepam, sodium valproate.

  Examples of statins for treating hyperlipidemia include pravastatin sodium, atorvastatin, simvastatin, and rosuvastatin.

  Examples of the fibrate hyperlipidemia therapeutic agent include clofibrate.

  Examples of the nonsteroidal anti-inflammatory drug include meloxicam, teoxicam, indomethacin, ibuprofen, celecoxib, rofecoxib, and aspirin.

  Examples of the steroid drug include dexamethasone, hexestrol, and cortisone acetate.

  Examples of sex hormones or derivatives thereof include progesterone, estradiol, and estradiol benzoate.

  Examples of the antioxidant include edaravone.

  Examples of the glycerin preparation include glycerol.

  The above drugs are exemplary, and the concomitant drug of the present invention is not limited thereto.

  As the dosage and administration method of the prodrug of the present invention in the concomitant drug of the present invention, the same ones as described above can be used.

  The weight ratio of the prodrug of the present invention to other drugs is not particularly limited. Other drugs may be administered in combination of any two or more. In addition, other drugs that complement and / or enhance the prophylactic and / or therapeutic effects of the prodrug of the present invention are not only those that have been found so far, but those that will be found in the future based on the above-described mechanism. Is also included.

  In addition, the prodrug of the present invention can be administered in combination with an antithrombotic drug (including a thrombolytic drug) to synergistically increase the patient's survival rate or neurological symptoms without suppressing the thrombolytic action of the antithrombotic drug. Can be used to treat cerebral infarction. Antithrombotic drugs include, for example, tissue plasminogen activator (t-PA, alteplase), urobilinogen, urokinase, thisokinase, heparin, oral anticoagulant (warfarin), synthetic antithrombin drug (gabexate mesylate, mesylate) Acid nafamostat, argatroban, etc.) and antiplatelet drugs (aspirin, dipyridamole, ticlopine hydrochloride, beraprost sodium, cilostazol, ozagrel sodium, etc.), more preferably tissue plasminogen activator or warfarin. Cerebral infarction includes cerebral hemorrhage, subarachnoid hemorrhage, and white matter abnormality.

[Pharmacological activity]
When the prodrug of the present invention is administered in vivo, it expresses the same pharmacological effect as (2R) -2-propyloctanoic acid, which is known in the in vivo test, for example, European Patent No. 0632008. And an animal model described in European Patent Publication No. 1174131 and the like, that is, an active condition avoidance experiment in an experimental cerebral ischemia model, an MPTP-induced experimental Parkinson's disease model, and the like.

  In addition, it can be easily determined by performing a human taste test that the prodrug of the present invention has improved oral irritation compared to (2R) -2-propyloctanoic acid. .

  In addition, the prodrug of the present invention is kinetically compared to (2R) -2-propyloctanoic acid, for example, in terms of the length of blood half-life, gastrointestinal stability, oral absorption, bioavailability, etc. That it is excellent in the method can be easily evaluated by a known method, for example, the method described in “Drug Bioavailability (Evaluation and Improvement Science)”, Hyundai Medical Co., Ltd., issued July 6, 1998, etc. it can.

[Example]
Hereinafter, although an example explains the present invention in detail, the present invention is not limited to these.

  The compound name used in this specification is generally a computer program for naming according to the rules of IUPAC, ACD / Name batch (registered trademark, manufactured by Advanced Chemistry Development Inc.), or IUPAC naming. Named according to the law.

  Hereinafter, although the formulation example of the prodrug of this invention is disclosed, this invention is not limited to these.

[Formulation example]
Formulation Example 1:
Cholic acid 2-{[(2R) -2-propyloctanoyl] oxy} ethyl ester (100 g), carboxymethylcellulose calcium (20.0 g), magnesium stearate (10.0 g) and microcrystalline cellulose (870 g) After mixing by the method, tableting is performed to obtain 10,000 tablets each containing 10 mg of the active ingredient.

Formulation Example 2:
Cholic acid 2-{[(2R) -2-propyloctanoyl] oxy} ethyl ester (200 g), mannitol (2 kg) and distilled water (50 L) were mixed by a conventional method, then filtered through a dust filter, and 5 mL each. Fill ampoules and sterilize by heating in an autoclave to obtain 10,000 ampoules containing 20 mg of active ingredient in one ampule.

  Prodrugs of (2R) -2-propyloctanoic acid according to the invention, in particular of the general formula (I)

[Wherein the symbols have the same meaning as described in the specification. ], A salt thereof, an N-oxide thereof, a quaternary ammonium salt thereof or a solvate thereof, etc. are compared with (2R) -2-propyloctanoic acid in terms of physical properties, pharmacokinetics (gastrointestinal absorption) Parkinson's disease, Parkinson's syndrome, Alzheimer's disease, Down's syndrome, amyotrophic lateral sclerosis, familial amyotrophic lateral sclerosis, progressive nuclei, etc. Supraparalysis, Huntington's disease, spinocerebellar ataxia, dentate nucleus red nucleus pallidal atrophy, olive bridge cerebellar atrophy, corticobasal degeneration, familial dementia, frontotemporal dementia, senile Dementia, diffuse Lewy body disease, striatum-substantia nigra degeneration, chorea-ataxia, dystonia, mage syndrome, late-onset cerebellar cortical atrophy, familial spastic paraplegia, motor neuropathy Card Joseph's disease, Pick's disease, stroke (Eg, cerebral hemorrhage (eg, hypertensive intracerebral hemorrhage), cerebral infarction (eg, cerebral thrombus, cerebral embolism, etc.), transient ischemic attack, subarachnoid hemorrhage, etc., neurological dysfunction after cerebrospinal trauma, prolapse Myelopathy (eg, multiple sclerosis, Guillain-Barre syndrome, acute disseminated encephalomyelitis, acute cerebellar inflammation, transverse myelitis, etc.), brain tumor (eg, astrocytoma, etc.), brain associated with infection Neurodegenerative diseases such as spinal cord diseases (eg meningitis, brain abscess, Creutzfeldt-Jakob disease, AIDS dementia, etc.), mental disorders (schizophrenia, manic depression, neurosis, psychosomatic disorder, epilepsy, etc.) Transient blindness (eg, transient cataract), disturbance of consciousness, contralateral hemiplegia, sensory impairment, homonymous half-blindness, aphasia, alternating hemiplegia, bilateral quadriplegia, sensory impairment, homonymous half-blindness Nervous disorders such as dizziness, tinnitus, nystagmus, double vision, coma, and nerve regeneration are required That has high therapeutic value against diseases such as, useful as pharmaceuticals.

Claims (18)

  Prodrug of 2-propyloctanoic acid.   The prodrug according to claim 1, which is a prodrug of (2R) -2-propyloctanoic acid.   Compared with 2-propyloctanoic acid, (1) blood sustainability is improved, (2) oral absorption is improved, and (3) gastrointestinal stability is improved. The prodrug according to claim 1, wherein the prodrug is selected from the group consisting of (4) reduced irritation in the oral cavity and (5) reduced irritation in blood vessels. Formula (I)

[Wherein, A represents an oxygen atom or an optionally substituted nitrogen atom, ring B represents a cyclic group which may further have a substituent, and D and E are each independently substituted. Represents an optionally substituted C1-8 alkylene group, an optionally substituted C2-8 alkenylene group, an optionally substituted C2-8 alkynylene group or a bond, and M represents an oxygen atom, nitrogen atom, sulfur in the main chain. Represents a spacer or a bond containing an atom and / or a phosphorus atom, R represents a hydrogen atom or a substituent, m represents an integer of 1 to 3, and when m is 2 or more, a plurality of D and a plurality of M are Each may be the same or different, n represents 0 or an integer of 1 to 2, and when n is 2, the plurality of rings B may be the same or different;

Represents an α configuration, a β configuration or a mixture thereof in any ratio.
However,

Is (1) a hydroxyl group, (2) a C1-4 alkoxy group optionally substituted with one phenyl group, or (3) an NR ^A R ^B group (in which R ^A and R ^B are each independently (A) a hydrogen atom, (b) a phenyl group optionally substituted with a C1-4 alkoxy group or a carboxy group, (c) a 4- to 7-membered heterocycle containing one nitrogen atom, (d) C1-4 alkyl group optionally substituted with a phenyl group optionally substituted with a C1-4 alkoxy group or a carboxy group, (e) substituted with a 4-7 membered heterocyclic ring containing one nitrogen atom (1) a 4- to 7-membered saturated heterocyclic ring containing 1 to 2 nitrogen atoms, together with the nitrogen atom to which C 1-4 alkyl group or ( ^A ) R ^A and R ^B are bonded, 2) 4-7 membered saturated heterocycle containing one nitrogen atom and one oxygen atom Or (3) represents an amino acid residue). A prodrug according to claim 1, which is a compound represented by the formula: Formula (I-1)

[Wherein, D ¹ represents an optionally substituted C1-4 alkylene group or an optionally substituted C2-4 alkenylene group, Q represents an oxygen atom or an optionally substituted nitrogen atom, The symbol of represents the same meaning as described in claim 4. ], General formula (I-2)

[Wherein, D ¹ represents an optionally substituted C1-4 alkylene group or an optionally substituted C2-4 alkenylene group, Q represents an oxygen atom or an optionally substituted nitrogen atom, The symbol of represents the same meaning as described in claim 4. ], General formula (I-3)

[In the formula, G represents a hydroxyl group which may be protected, and other symbols represent the same meaning as described in claim 4. ], General formula (I-4)

[In the formula, G represents a hydroxyl group which may be protected, and other symbols represent the same meaning as described in claim 4. ], General formula (I-5)

[Wherein, D ¹ represents an optionally substituted C1-4 alkylene group or an optionally substituted C2-4 alkenylene group, Q represents an oxygen atom or an optionally substituted nitrogen atom, The symbol of represents the same meaning as described in claim 4. Or general formula (I-6)

[Wherein all symbols have the same meaning as described in claim 4. The compound of Claim 4 which is a compound shown by this. Formula (I-6-1)

[Wherein all symbols have the same meaning as described in claim 4. ], General formula (I-6-2)

[Wherein all symbols have the same meaning as described in claim 4. Or a general formula (I-6-3)

[Wherein all symbols have the same meaning as described in claim 4. The compound of Claim 5 which is a compound shown by this.   The compound according to claim 4, wherein the ring B is an optionally substituted cyclohexane, benzene, naphthalene, pyrrolidine, piperidine, piperazine, imidazole, pyridine, dihydropyridine, dioxolane, tetrahydropyran, dioxane ring or a steroid skeleton. .   The compound according to claim 4, wherein D is a C1-4 alkylene group which may be substituted, a C2-4 alkenylene group which may be substituted, or a bond.   The compound according to claim 4, wherein E is an optionally substituted C1-4 alkylene group, an optionally substituted C2-4 alkenylene group, or a bond. M ^{is, -COO -, - CONR X -} , - O -, - OCO -, - OCOO -, - OCONR X -, - NR X -, - NR X CO -, - NR X COO -, - NR X CONR ^Y— , —S (O) —, —SO ₂ —, —SO ₂ NR ^X —, —NR ^X SO ₂ —, —OP (═O) (R ^Z ) O— [wherein R ^X and R ^Y Each independently represents a hydrogen atom or a substituent, and R ^Z represents an optionally protected hydroxyl group or “O ⁻ ”. Or a bond.   R is (1) a hydrogen atom, (2) an optionally substituted methyl group, (3) an optionally substituted cyclic group, (4) an oxo group, (5) a hydroxyl group, (6) a methoxy group, (7) an optionally substituted C1-20 acyloxy group, (8) an optionally substituted carbonyl group, (9) a carbamoyl group optionally substituted with a methyl group, (10) a nitro group, (11 The compound according to claim 4, which is an amino group optionally substituted with a methyl group or (12) a chlorine atom.   A pharmaceutical composition comprising a prodrug of 2-propyloctanoic acid.   The composition according to claim 12, which is an astrocyte function improving agent.   The composition according to claim 12, which is a preventive and / or therapeutic agent for a neurodegenerative disease.   2-Propyloctanoic acid prodrug, acetylcholinesterase inhibitor, nicotine receptor modulator, β-secretase inhibitor, γ-secretase inhibitor, β-amyloid protein aggregation inhibitor, β-amyloid vaccine, β-amyloid degrading enzyme, brain function activation Drugs, cerebral circulation metabolism improving drugs, dopamine receptor agonists, monoamine oxidase inhibitors, anticholinergics, catechol-O-methyltransferase inhibitors, amyotrophic lateral sclerosis drugs, neurotrophic factors, apoptosis inhibitors , Antidepressants, anxiolytics, antiepileptics, antihypertensives, calcium receptor antagonists, antidiabetics, antihyperlipidemics, aldose reductase inhibitors, non-steroidal anti-inflammatory drugs, disease-modifying anti Rheumatic drugs, anti-cytokine drugs, steroid drugs, antithrombotic drugs, factor Xa inhibitors, factor VIIa inhibitors A pharmaceutical comprising a combination of one or more selected from drugs, antioxidants and glycerin preparations.   A method for preventing and / or treating a neurodegenerative disease in a mammal, comprising administering an effective amount of a 2-drugoctanoic acid prodrug to the mammal.   Use of a prodrug of 2-propyloctanoic acid for the manufacture of a prophylactic and / or therapeutic agent for neurodegenerative diseases. General formula (IR)

[Where:

Represents a β configuration, and other symbols have the same meaning as described in claim 4. A prodrug according to claim 2, which is a compound represented by the formula: