WO2006080412A2 - Cyanopyrrolidine derivative-containing composition for solid pharmaceutical preparations, solid pharmaceutical preparation containing the composition, and process for producing the solid pharmaceutical preparation - Google Patents
Cyanopyrrolidine derivative-containing composition for solid pharmaceutical preparations, solid pharmaceutical preparation containing the composition, and process for producing the solid pharmaceutical preparation Download PDFInfo
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- WO2006080412A2 WO2006080412A2 PCT/JP2006/301258 JP2006301258W WO2006080412A2 WO 2006080412 A2 WO2006080412 A2 WO 2006080412A2 JP 2006301258 W JP2006301258 W JP 2006301258W WO 2006080412 A2 WO2006080412 A2 WO 2006080412A2
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- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
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- WLGDAKIJYPIYLR-UHFFFAOYSA-M octane-1-sulfonate Chemical compound CCCCCCCCS([O-])(=O)=O WLGDAKIJYPIYLR-UHFFFAOYSA-M 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates to a composition for solid pharmaceutical preparations consisting of a cyanopyrrolidine derivative, to a solid pharmaceutical preparation containing the composition, and to a process for producing the solid pharmaceutical preparation.
- DPPIV Dipeptidylpeptidase IV
- hydrolysis dipeptides from peptides chain - with proline or alanine at the second position from N-terminal .
- DPPIV is widely distributed in tissues , blood plasma and organs such as kidneys and liver, and is involved in the metabolism of a wide spectrum of physiologically active peptides .
- GLP-I glucagon-like peptide 1
- Known physiological functions of GLP-I include stimulation of insulin secretion from pancreas, extension of gastric evacuation time, and suppression of food intake . For this reason, inhibition of DPPIV enhances the activity of GLP-I, increases insulin activity, and improves sugar metabolism, thereby suggesting that it is effective for the treatment of type 2 diabetes .
- DPPIV is also known to be involved in the metabolism of neuropeptide Y that is a neuropeptide, in the activation of T cells that is cells of the immune system, in the adhesion of cancer cells to endothelium, and in the entry of HIV virus into lymphocytes .
- inhibition of DPPIV is considered to be effective in the treatment of diseases such as autoimmune disease .
- DPPIV is expressed at a high level in fibrocytes taken from the skin of patients suffering from psoriasis, arthritis rheumatoides or lichen planus, and that patients suffering from benign prostate hypertrophy show a high degree of DPPIV activity. It is therefore expected that inhibition of DPPIV is also effective in the treatment of dermatosis and benign prostate hypertrophy.
- the present invention has been accomplished in view of the foregoing problems of the related art, and an obj ect thereof is to provide : a composition for solid pharmaceutical preparations (although it contains a cyanopyrrolidine derivative) capable of ensuring the stability of the cyanopyrrolidine derivative formulated in pharmaceutical preparations and of reducing the decomposition of the cyanopyrrolidine derivative due to the addition of other oral additives ; a solid pharmaceutical preparation containing the composition; and a process for producing the solid pharmaceutical preparation.
- the present inventors have diligently conducted studies to solve the foregoing problems . As a result, they have established that it is possible to ensure the stability of a cyanopyrrolidine derivative formulated in pharmaceutical preparations by mixing a cyanopyrrolidine derivative with at least one stabilizing ingredient selected from the group- consisting of sugars and sugar alcohols to form a composition essentially consisting of the cyanopyrrolidine derivative and the stabilizing ingredient, and that it is possible to reduce the decomposition of the cyanopyrrolidine derivative even when mixed with other oral additives at a later time . Thus, they have completed the present invention .
- composition of the present invention for solid pharmaceutical preparations is a composition essentially consisting of a cyanopyrrolidine derivative represented by the following general formula ( 1 ) or a pharmaceutically acceptable salt thereof, and at least one stabilizing ingredient selected from the group consisting of sugars and sugar alcohols , [ Formula 1 ]
- R 1 represents a halogen atom, a hydroxy1 group, an alkoxy group of 1 to 5 carbon atoms or an alkyl group of 1 to 5 carbon atoms
- R 2 represents a hydrogen atom, a halogen atom, a hydroxyl group / an alkoxy group of 1 to 5 carbon atoms or an alkyl group of 1 to 5 carbon atoms, or R 1 and R 2 bond together to form an - oxo group, a hydroxyimino group, an alkoxyimino group of 1 to 5 carbon atoms or an alkylidene group of 1 to 5 carbon atoms
- R 3 and R 4 may be the same or different, each represents a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxy group of 1 to 5 carbon atoms or an alkyl group of 1 to 5 carbon atoms , or R 3 and R 4 bond together to form an oxo group, a hydroxyimino group, an
- R 11 represents a hydrogen atom, a phenyl group which may be substituted, a pyridyl group which may be substituted, a tert-butoxycarbonyl group or a benzyloxycarbonyl group
- R 12 represents a hydrogen atom or a group represented by - (CH ⁇ ) 1n -R 13 (wherein m represents an integer of 1 to 5, and R 1J represents a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl group)
- R 14 represents a chain alkyl group of 1 to 5 carbon atoms or a benzyl group
- an alkenyl group of 2 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group and a chain alkoxy group of 1 to 5 carbon atoms] , or a group represented by -CRV-CR 9 R 10 -
- R 7 ' R 8 ' R 9 and R l ⁇ may be' the same or different, each represents a hydrogen atom; a halogen atom; or an alkyl group of 1 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a hydroxyalkyl group of 1 to 5 carbon atoms, a carboxyl group, a mercapto group, an alky
- W represents a hydrogen atom, an acyl group derived from naturally occurring amino acids , a group represented by the following general formula ( 2 ) : [ Formula 2 ]
- W 1 represents an alkanoyl group of 1 to 5 carbon atoms, an arylcarbonyl group which may be substituted or an alkyl group of 1 to 5 carbon atoms, and W" " represents a hydrogen atom or an alkyl group of 1 to 5 carbon atoms] , or a group represented by the following general formula ( 3 ) : [ Formula 3]
- W 3 and W 4 may be the same or different, each represents a hydrogen atom or an alkyl group of 1 to 5 carbon atoms] ,
- Z represents a hydrogen atom; an alkyl group of 1 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a hydroxyalkyl group of 1 to 5 carbon atoms, a carboxyl group, a mercapto group, an alkylthio group of 1 to 5 carbon atoms , a guanidyl group, a phenyl group which may be substituted, an imidazolyl group, an indolyl group, a group represented by -NHR 11 (wherein R 11 represents a hydrogen atom, a phenyl group which may be substituted, a pyridyl group which may be substituted, a tert-butoxycarbonyl group or a benzyloxycarbonyl group) , a group represented by -CONHR 1" (wherein R 12 represents a hydrogen atom or a group represented by - (CH;) m
- R 15 and R 16 may be the same or different, each represents a hydrogen atom; an alkyl group of 1 to 6 carbon atoms which may be substituted with one or more substituents selected from the following Y 1 substituent group; a cycloalkyl group of 3 to 6 carbon atoms which may be substituted with one or more substituents selected from the following Y" substituent group; a cycloalkylalkyl group of 4 to 9 carbon atoms which may be substituted with one or more substituents selected from the following Y 2 substituent group; an alkenyl group of 2 to 6 carbon atoms which may be substituted with one or more substituents selected from the following Y 2 substituent group; a cycloalkenyl group- of 3 to 6 carbon atoms which may be substituted with one or more substituents selected from the following Y 2 substituent group; cycloalkenylalkyl group of 4 to 9 carbon atoms which may be substituted with one or more substituents selected from the following
- A represents a single bond or an alkylene group of 1 to 3 carbon atoms
- R 18 and R ⁇ ° may be the same or different, each represents : a hydrogen atom; an alkyl group of 1 to 10 carbon atoms which may be substituted with one or more substituents selected from the following Y 4 substituent group; a cycloalkyl group of 3 to 6 carbon atoms which may be substituted with one or more substituents selected from the following Y" substituent group; a cycloalkylalkyl group of 4 to 9 carbon atoms which may be substituted with one or more substituents selected from the following Y 2 substituent group; or an arylalkyl group which may be substituted with one or more substituents selected from the following Y 3 substituent group,
- R 19 represents : an alkyl group of 1 to 10 carbon atoms which may be substituted with one or more substituents selected from the following Y 4 substituent group; the following Q; or - (C1-3 alkylene) -Q, the C 3. - 3 alkylene may be substituted with one or more substituents selected from a halogen atom and a hydroxyl group, the Q represents an aliphatic or aromatic hydrocarbon selected from the group consisting of a cycloalkyl group of 3 to 10 carbon atoms which may be substituted with one or more substituents selected from the following Y 3 substituent group; a bridged cyclic alkyl group of 4 to 10 carbon atoms which may be substituted with one or more substituents selected from the following Y 3 substituent group; an alkenyl group of 2 to 10 carbon atoms which may be substituted with one or more substituents selected from the following Y 3 substituent group; a cycloalkenyl group of 3 to 10 carbon atoms which may
- R 19 representing an aryl group or heterocyclic ring may form a 5- to 8-membered ring by combining a substituent adj acent to the atom constituting its ring, and may contain one or more heteroatoms in the ring,
- R 18 , R 19 or R 20 may bond to an heteroatom adj acent to R 18 and R 19 , R 18 and R 20 , or R 19 and R ⁇ 0 to form a 4- to 10-membered heterocyclic ring which may be substituted with one or more substituents selected from the following Y 5 substituent group
- R J1 represents a hydrogen atom; an alkyl group of 1 to 6 carbon atoms which may be substituted with one or more substituents selected from the following Y 1 substituent group; an aryl group which may be substituted with one or more substituents selected from the following Y 3 substituent group; or a heteroaryl group which may be substituted with one or more substituents selected from the following Y 3 substituent group) ]
- Y 1 substituent group a group consisting of a halogen atom, a hydroxyl group, a carboxyl group, a cyano group, an amino group', an aminocarbonyl group, a cycloalkyloxy group of 3 to 5 carbon atoms and an alkoxy group of 1 to ⁇ carbon atoms,
- (Y 2 substituent group) a group consisting of a halogen atom, a hydroxyl group, a carboxyl group, a cyano group, an amino group, an aminocarbonyl group, a cycloalkyloxy group of 3 to 5 carbon atoms, an alkoxy group of 1 to 6 carbon atoms and an alkyl group of 1 to 6 carbon atoms,
- the stabilizing ingredient according to the present invention is at least one stabilizing ingredient selected from the group consisting of mannitol, lactose, xylitol, sorbitol, maltitol, maltose, glucose, lactitol and dextrate .
- compositions for solid pharmaceutical preparations of the present invention which contain the cyanopyrrolidine derivative or a pharmaceutically acceptable salt thereof and at least one stabilizing ingredient selected from the group consisting of sugars and sugar alcohols is not particularly limited.
- the content of an oral additive other than the stabilizing ingredient, which is contained in the composition is preferably 70wt% or less .
- the cyanopyrrolidine derivative according to the present invention or a pharmaceutically acceptable salt thereof is a benzenesulfonic acid salt of ( 2S, 4S) -2-cyano-4-fluoro-l- [ (2-hydroxy-l, 1-dimetyl ) ethylami ⁇ no] acetylpyrrolidine .
- the solid pharmaceutical preparation of the present invention contains the composition of the present invention for solid pharmaceutical preparations .
- the composition for solid pharmaceutical preparations contains an oral additive in addition to the composition for solid pharmaceutical preparations, when the composition for solid pharmaceutical preparations is in the form of granulated substance .
- composition of the present invention may be in the form of non-granulated substance .
- the tablet of the present invention may be that obtained by directly compressing, into a tablet form, the composition which is in the form of non-granulated substance .
- the process of the present invention for producing a solid pharmaceutical preparation comprising : a step of producing a composition for solid pharmaceutical preparations by mixing a cyanopyrrolidine derivative represented by the following general formula ( 1 ) or a pharmaceutically acceptable salt thereof with at least one stabilizing ingredient selected from the group consisting of sugars and sugar alcohols, the composition essentially consisting of the cyanopyrrolidine derivative or a pharmaceutically acceptable salt thereof, and at least one stabilizing ingredient selected from the group consisting of ,sugars and sugar alcohols, [Formula 5 ]
- R 1 represents a halogen atom, a hydroxyl group, an alkoxy group of 1 to 5 carbon atoms or an alkyl group of 1 to 5 carbon atoms
- R 2 represents a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxy group of 1 to 5 carbon atoms or an alkyl group of 1 to 5 carbon atoms
- R 1 and R" bond together to form an oxo group
- R J and R 4 may be the same or different, each represents a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxy group of 1 to 5 carbon atoms or an alkyl group of 1 to 5 carbon atoms, or R 3 and R 4 bond together to form an oxo group, a hydroxyimino group, an alkoxyi
- X represents an oxygen atom or a sulfur atom
- Y represents a group represented by -CR 5 R 6 - [wherein R 5 and R 6 may be the same or different, each represents a hydrogen atom; w a halogen atom; an alkyl group of 1 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a hydroxyalkyl group of 1 to 5 carbon atoms, a carboxyl group, a mercapto group, an alkylthio group of 1 to 5 carbon atoms , a guanidyl group, a phenyl group which may be substituted, an imidazolyl group, an indolyl group, a group represented by -NHR 11 (wherein R 11 represents a hydrogen atom, a phenyl group which may be substituted, a pyridyl group which may be substituted, a tert-but
- R 14 represents a chain alkyl group of 1 to 5 carbon atoms or a benzyl group
- an alkenyl group of 2 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group and a chain alkoxy group of 1 to 5 carbon atoms ] , or a group represented by -CR 7 R 8 -CR 9 R 10 -
- R 7 ' R 8 ' R 9 and R 10 may be the same or different, each represents a hydrogen atom; a halogen atom; or an alkyl group of 1 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a hydroxyalkyl group of 1 to 5 carbon atoms, a carboxyl group, a mercapto group, an alkyl group of 1
- R 12 represents a hydrogen atom or a group represented by - (CH 2 ) ra -R 13 (wherein m represents an integer of 1 to 5, and R 13 represents a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl group)
- a group represented by -OR 14 wherein R 14 represents a chain alkyl group of 1 to 5 carbon atoms or a benzyl group
- W represents a hydrogen atom, an acyl group derived from naturally occurring amino acids, a group represented by the following general formula (2 ) : [ Formula 6]
- W 1 represents an alkanoyl group of 1 to 5 carbon atoms, an arylcarbonyl group which may be substituted or an alkyl group of 1 to 5 carbon atoms
- W 2 represents a hydrogen atom or an alkyl group of 1 to 5 carbon atoms
- W 3 and W 4 may be the same or different, each represents a hydrogen atom or an alkyl group of 1 to 5 carbon atoms ] ,
- Z represents a hydrogen atom; an alkyl group of 1 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a hydroxyalkyl group of 1 to 5 carbon atoms, a carboxyl group, a mercapto group, an alkylthio group of 1 to 5 carbon atoms, a guanidyl group, a phenyl group which may be substituted, an imidazolyl group, an indolyl group, a group represented by -NHR 11 (wherein R 11 represents a hydrogen atom, a phenyl group which may be substituted, a pyridyl group which may be substituted, a tert-butoxycarbonyl group or a benzyloxycarbonyl group) , a group represented by -CONHR 1 " (wherein R 1" represents a hydrogen atom or a group represented by - (CHc) 1n
- R 14 represents a chain alkyl group of 1 to 5 carbon atoms or a benzyl group
- R 4 a group represented by the following general formula ( 4 ) :
- R 15 and R l ⁇ may be the same or different, each represents a hydrogen atom; an alkyl group of 1 to 6 carbon atoms which may be substituted with one or more substituents selected from the following Y 1 substituent group; a cycloalkyl group of 3 to 6 carbon atoms which may be substituted with one or more substituents selected from the following Y 2 substituent group; a cycloalkylalkyl group of 4 to 9 carbon atoms which may be substituted with one or more substituents selected from the following Y 2 substituent group; an alkenyl group of 2 to 6 carbon atoms which may be substituted with one or more substituents selected from the following Y 2 substituent group; a cycloalkenyl group of 3 to 6 carbon atoms which may be substituted with one or more substituents selected from the following Y 2 substituent group; cycloalkenylalkyl group of 4 to 9 carbon atoms which may be substituted with one or more substituents selected from the following
- A represents a single bond or an alkylene group of 1 to 3 carbon atoms
- R 18 and R 20 may be the same or different, each represents : a hydrogen atom; an alkyl group of 1 to 10 carbon atoms which may be substituted with one or more substituents selected from the following Y 4 substituent group; a cycloalkyl group of 3 to 6 carbon atoms which may be substituted with one or more substituents selected from the following Y ⁇ substituent group; a cycloalkylalkyl group of 4 to 9 carbon atoms which may be substituted with one or more substituents selected from the following Y 2 substituent group; or an arylalkyl group which may be substituted with one or more substituents selected from the following Y 3 substituent group,
- R iq represents : an alkyl group of 1 to 10 carbon atoms which may be substituted with one or more substituents selected from the following Y 4 substituent group; the following Q; or - (C 1 -S alkylene) -Q, the Ci- 3 alkylene may be substituted with one or more substituents selected from a halogen atom and a hydroxyl group, the Q represents an aliphatic or aromatic hydrocarbon selected from the group consisting of a cycloalkyl group of 3 to 10 carbon atoms which may be substituted with one or more substituents selected from the following Y 3 substituent group; a bridged cyclic alkyl group of 4 to 10 carbon atoms which may be substituted with one or more substituents selected from the following Y 3 substituent group; an alkenyl group of 2 to 10 carbon atoms which may be substituted with one or more substituents selected from the following Y 3 substituent group; a cycloalkenyl group of 3 to 10 carbon atom
- R 19 representing an aryl group or heterocyclic ring may form a 5- to 8-membered ring by combining a substituent adj acent to the atom constituting its ring, and may contain one or more heteroatoms in the ring,
- R 18 , R 19 or R 2 ⁇ may bond to an heteroatom adj acent to R 18 and R 19 , R 18 and R 2 ⁇ , or R 19 and R 2fl to form a 4- to 10-membered heterocyclic ring which may be substituted with one or more substituents selected from the following Y 5 substituent group, and
- R 21 represents a hydrogen atom; an alkyl group of 1 to 6 carbon atoms which may be substituted with one or more substituents selected from the following Y 1 substituent group; an aryl group which may be substituted with one or more substituents selected from the following Y 3 substituent group; - or a heteroaryl group which may be substituted with one or more substituents selected from the following Y 3 substituent group) ] , or Y, Z and an adj acent nitrogen atom bond together to form a cyclic amino group of 2 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, a chain alkyl group of 1 to 5 carbon atoms and a group represented by -OR 22 (wherein R 22 represents a chain alkyl group of 1 to 5 carbon atoms, an aminocarbonylmethyl group or a benzyl group) ] , (Y 1 substituent group) :
- (Y ⁇ substituent group) a group consisting of a halogen atom, a hydroxyl group, a carboxyl group, a cyano group, an amino group, an aminocarbonyl group, a cycloalkyloxy group of 3 to
- Another aspect of the process of the present invention for producing solid pharmaceutical preparations is a process in which the step of producing the composition for solid pharmaceutical preparations further includes a step of mixing the cyanopyrrolidine derivative or a pharmaceutically acceptable salt thereof with at least one stabilizing ingredient selected from the group consisting of sugars and sugar alcohols, and granulating the resultant mixture to produce the composition for solid pharmaceutical preparations .
- the step of producing the composition for solid pharmaceutical preparations be a step in which the cyanopyrrolidine derivative or a pharmaceutically acceptable salt thereof is mixed with the stabilizing ingredient and then the resultant mixture is granulated in the presence of water .
- Another aspect of the process of the present invention for producing solid pharmaceutical preparations is a process in which the step of producing the composition for solid pharmaceutical preparations further includes a step of mixing the cyanopyrrolidine derivative or a pharmaceutically acceptable salt thereof with at least one stabilizing ingredient selected from the group consisting of sugars and sugar alcohols, and directly compressing the resultant mixture into a tablet form.
- a composition for solid pharmaceutical preparations (although it contains a cyanopyrrolidine derivative) capable of ensuring the stability of the cyanopyrrolidine derivative formulated in pharmaceutical preparations and of reducing the decomposition of the cyanopyrrolidine derivative due to the - addition of other oral additives; a solid pharmaceutical preparation containing the composition; and a process for producing the solid pharmaceutical preparation .
- composition of the present invention for solid pharmaceutical preparations is characterized in that it essentially consisted of a cyanopyrrolidine derivative represented by the described above general formula ( 1 ) or a pharmaceutically acceptable salt thereof (hereinafter collectively referred to as "a cyanopyrrolidine derivative or the like” ) and at least one stabilizing ingredient selected from the group consisting of sugars and sugar alcohols .
- Such a cyanopyrrolidine derivative or the like is a compound that shows an excellent DPPIV inhibiting activity.
- Examples of compounds that are suitable for such a cyanopyrrolidine derivative or the like include cyanopyrrolidine derivatives or pharmaceutically acceptable salts thereof, represented by the following general formula (5) : [Formula 9]
- R 41 represents a halogen atom, a hydroxyl group, an alkoxy group of 1 to 5 carbon atoms or an alkyl group of 1 to 5 carbon atoms
- R 42 represents a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxy group of 1 to 5 carbon atoms or an alkyl group of 1 to 5 carbon atoms
- R 41 and R 4 ⁇ bond together to form an oxo group, a hydroxyimino group, an alkoxyimino group of 1 to 5 carbon atoms or an alkylidene group of 1 to 5 carbon atoms
- R 43 and R 44 each represents a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxy group of 1 to 5 carbon atoms or an alkyl group of 1 to 5 carbon atoms, or R 4J and R 44 bond together to form an oxo group, a hydroxyimino group, an alkoxyimino group of 1 to 5 carbon atoms or an alkylidene group of 1 to 5 carbon atoms,
- X 1 represents an oxygen atom or a sulfur atom
- Y 1 represents a group represented by -CR 45 R 46 - [wherein R 45 and R 46 may be the same or different, each represents : a hydrogen atom; a halogen atom; an alkyl group of 1 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a hydroxyalkyl group of 1 to 5 carbon atoms, a carboxyl group, a mercapto group, an alkylthio group of 1 to 5 carbon atoms , a guanidyl group, a phenyl group which may be substituted, an imidazolyl group, an indolyl group, a group represented by -NHR 51 (wherein R 51 represents a hydrogen atom, a phenyl group which may be substituted, a pyridyl group which may be substituted, a tert
- R 54 represents a chain alkyl group of 1 to 5 carbon atoms or a benzyl group
- R 54 represents a chain alkyl group of 1 to 5 carbon atoms or a benzyl group
- an alkenyl group of 2 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group and a chain alkoxy group of 1 to 5 carbon atoms] , or a group represented by -CR 47 R 48 -CR 49 R 5 ⁇ -
- R 47 , R 48 , R 49 and R 50 may be the same or different, each represents : a hydrogen atom; a halogen atom; or an alkyl group of 1 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a hydroxyalkyl group of
- R 51 represents a hydrogen atom, a phenyl group which may be substituted, a pyridyl group which may be substituted, a tert-butoxycarbonyl group or a benzyloxycarbonyl group
- R 52 represents a hydrogen atom or a group represented by - (CH 2 ) m -R 53 (wherein m represents an integer of 1 to 5, and R 5J represents a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl group)
- R 54 represents a chain alkyl group of 1 to 5 carbon atoms or a benzyl group
- Z 1 represents : a hydrogen atom; or an alkyl group of 1 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a hydroxyalkyl group of 1 to 5 carbon atoms, a carboxyl group, a mercapto group, an alkylthio group of 1 to 5 carbon atoms, a guanidyl group, a phenyl group which may be substituted, an imidazolyl group, an indolyl group, a group represented by -NHR 51 (wherein R 51 represents a hydrogen atom, a phenyl group which may be substituted, a pyridyl group which may be substituted, a tert-butoxycarbonyl group or a benzyloxycarbonyl group) , a group represented by -CONHR 5 " (wherein R 5 ⁇ represents a hydrogen atom or a group represented by - (CH
- R 55 represents a chain alkyl group of 1 to 5 carbon atoms, an aminocarbonylmethyl group or a benzyl group
- cyanopyrrolidine derivatives examples include cyanopyrrolidine derivatives and pharmaceutically acceptable salts thereof, represented by the following general formula ( 6) : [ Formula 10]
- B 1 represents an alkanoyl group of 1 to 5 carbon atoms, an arylcarbonyl group which may be substituted or an alkyl group of 1 to 5 carbon atoms
- B 2 represents a hydrogen atom or an alkyl group of 1 to 5 carbon atoms
- B 3 and B 4 may be the same or different, each represents a hydrogen atom or an alkyl group of 1 to 5 carbon atoms
- X represents an oxygen atom or a sulfur atom
- Y represents a group represented by -CR 65 R 66 -
- R 65 and R 66 may be the same or different, each represents : a hydrogen atom; a halogen atom; an alkyl group of 1 to 10 carbon atoms which may be substituted with one or more groups ' selected from the group consisting of a halogen atom, a hydroxyl group, a hydroxyalkyl group of 1 to 5 carbon atoms, a carboxyl group, a mercapto group, an alkylthio group of 1 to 5 carbon atoms , a guanidyl group, a phenyl group which may be substituted, an imidazolyl group, an indolyl group, a group represented by -NHR 71
- R 71 represents a hydrogen atom, a phenyl group which may be substituted, a pyridyl group which may be substituted, a tert-butoxycarbonyl group or a benzyloxycarbonyl group
- R 72 represents a hydrogen atom or a group represented by - (CH 2 ) m -R 73 (wherein m represents an integer of 1 to 5, and R 73 represents a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl group)
- -OR 74 represents a group represented by -OR 74
- R 74 represents a chain alkyl group of 1 to 5 carbon atoms or a benzyl group
- alkenyl group of 2 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group and a chain alkoxy group of 1 to 5 carbon atoms ] , or a group represented by -CR 67 R 68 -CR 69 R 7n -
- R 67 , R 58 , R 69 and R 70 may be the same or different, each represents : a hydrogen atom; a halogen atom; or an alkyl group of 1 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a hydroxyalkyl group of 1 to 5 carbon atoms, a carboxyl group,
- R 71 represents a hydrogen atom, a phenyl group which may be substituted, a pyridyl group which may be substituted, a tert-butoxycarbonyl group or a benzyloxycarbonyl group
- R 7 represents a hydrogen atom or a group represented by - (CH 2 ) m -R 73 (wherein m represents an integer of 1 to 5, and R 73 represents a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl group)
- -OR 74 represents a group represented by -OR 74
- R 74 represents a chain alkyl group of 1 to 5 carbon atoms or a benzyl group
- Z 2 represents : a hydrogen atom; or an alkyl group of 1 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a hydroxyalkyl group of 1 to 5 carbon atoms, a carboxyl group, a mercapto group, an alkylthio group of 1 to 5 carbon atoms, a guanidyl group, a phenyl group which may be substituted, an imidazolyl group, an indolyl group, a group represented by -NHR 71 (wherein R 71 represents a hydrogen atom, a phenyl group which may be substituted, a pyridyl group which may be substituted, a tert-butoxycarbonyl group or a benzyloxycarbonyl group) , a group represented by -CONHR 7" (wherein R /2 represents a hydrogen atom or a group represented by -
- R 75 represents a chain alkyl group of 1 to 5 carbon atoms, an aminocarbonylmethy1 group or a benzyl group
- examples of other compounds that are suitable for such a cyanopyrrolidine derivative or the like include cyanofluoropyrrolidine compounds and pharmaceutically acceptable salts and hydrates thereof, represented by the following general formula ( 9 ) : [ Formula 13 ]
- V represents a hydrogen atom or a fluorine atom
- R 81 and R 82 may be the same or different, each represents : a hydrogen atom; an alkyl group of 1 to 6 carbon atoms which may be substituted with one or more substituents selected from the Y 11 substituent group; a cycloalkyl group of 3 to 6 carbon atoms which may be substituted with one or more substituents selected from the Y 12 substituent group; a cycloalkylalkyl group of 4 to 9 carbon atoms which may be substituted with one or more substituents selected from the Y 12 substituent group; an alkenyl group -of 2 to 6 carbon atoms which may be substituted with one or more substituents selected from the Y 1 " substituent group; a cycloalkenyl group of 3 to 6 carbon atoms which may be substituted with one or more substituents selected from the Y 12 substituent group; or a cycloalkenylalkyl group of 4 to 9 carbon atoms which may be substituted with one or more substituents selected
- R 84 and R 86 may be the same or different, each represents : a hydrogen atom; an alkyl group of 1 to 10 carbon atoms which may be substituted with one or more substituents selected from the Y 14 substituent group; a cycloalkyl group of 3 to 6 carbon atoms which may be substituted with one or more substituents selected from the Y 12 substituent group; a cycloalkylalkyl group of 4 to 9 carbon atoms which may be substituted with one or more - substituents selected from the Y 12 substituent group; or an arylalkyl group which may be substituted with one or more substituents selected from the Y 13 substituent group,
- R 85 represents : an alkyl group of 1 to 10 carbon atoms which may be substituted with one or more substituents selected from the Y 14 substituent group; - (Ci_ 3 alkylene) -Q; or Q, the C1-3 alkylene may be substituted with one or more substituents selected from a halogen atom and a hydroxyl group, the Q represents an aliphatic or aromatic hydrocarbon selected from a group consisting of a cycloalkyl group of 3 to 10 carbon atoms which may be substituted with one or more substituents selected from the Y 13 substituent group; a bridged cyclic alkyl group of 4 to 10 carbon atoms which may be substituted with one or more substituents selected from the Y 13 substituent group; an alkenyl group of 2 to 10 carbon atoms which may be substituted with one or more substituents selected from the Y lj substituent group; a cycloalkenyl group of 3 to 10 carbon atoms which may be substituted with
- an aryl group or heterocyclic ring may form a 5- to 8-membered ring by combining a substituent adj acent to the atom constituting its ring, and may contain one or more heteroatoms in the ring,
- R 84 , R 85 or R 8S may bond to heteroatoms adj acent to R 84 and R 85 , R 84 and R 86 , or R 85 and R 86 to form a 4- to 10-membered heterocyclic ring which may be substituted with one or more substituents selected from the Y 15 substituent group, and
- R represents : a hydrogen atom; an alkyl group of 1 to 6 carbon atoms which may be substituted with one or more substituents selected from the Y 11 substituent group; an aryl group which may be substituted with one or more substituents selected from the Y 13 substituent group; or a heteroaryl group which may be substituted with one or more substituents selected from the Y 13 substituent group) ,
- Y 11 substituent group represents a group consisting of a halogen atom, a hydroxyl group, a carboxyl group, a cyano group, an amino group, an aminocarbonyl group, a cycloalkyloxy group of 3 to 5 carbon atoms and an alkoxy group of 1 to 6 carbon atoms ,
- Y 12 substituent group represents a group consisting of a halogen atom, a hydroxyl group, a carboxyl group, a cyano group, an amino group, an aminocarbonyl group, a cycloalkyloxy group of 3 to 5 carbon atoms, an alkoxy group of 1 to 6 carbon atoms and an alkyl group of 1 to 6 carbon atoms,
- R 89 , R 9 ⁇ and R 91 may be the same or different, each represents : a hydrogen atom; an alkyl group of 1 to 6 carbon atoms which may be substituted with one or more substituents selected from the Y l ⁇ substituent group; a cycloalkyl group of 3 to 6 carbon atoms which may be substituted with one or more substituents selected from the Y 1 " substituent group; a cycloalkylalkyl group of 4 to 9 carbon atoms which may be substituted with one or more substituents selected from the Y 1 " substituent group; or a phenyl group which may be substituted with one or more substituents selected from the Y 1 " substituent group) , an alkyl group of 1 to 6 carbon atoms which may be substituted with one or more substituents selected from the Y 11 substituent group, and a phenyl group which may be substituted with one or more substituents selected from the Y 12 substituent - group] .
- (2S, 4S) -2-cyano-4-fluoro-l- [ (2-hydroxy-1 , 1-dimethyl ) ethylam ino] acetylpyrrolidine is more preferable because it is stable when formulated in pharmaceutical preparations .
- Detailed descriptions (e . g . , optimal conditions and production process ) for such a benzenesulfonic acid salt are disclosed in International Patent Publication No .2004/ 02407 pamphlet .
- mannitol, lactose, xylitol, sorbitol, maltitol, maltose, glucose, lactitol and dextrate are preferable because it is possible to ensure the stability of the cyanopyrrolidine derivative or the like when it is formulated in pharmaceutical preparations .
- These sugars and sugar alcohols may be used singly or in combination of two or more .
- compositions for solid pharmaceutical preparations of the present invention is not particularly limited, the composition is preferably in the form of granulated substance . In so doing it is made possible to ensure the stability of a cyanopyrrolidine derivative or the like when it is formulated in solid pharmaceutical preparations in which the composition for solid pharmaceutical preparations and an oral additive other than the stabilizing ingredient are contained.
- composition of the present invention for solid pharmaceutical preparations is a composition essentially consisting of a cyanopyrrolidine derivative or the like and at least one stabilizing ingredient selected from the group consisting of sugars and sugar alcohols .
- the content of the cyanopyrrolidine derivative or the like in such a composition for solid pharmaceutical preparations is 2-99wt%, preferably 5-99wt%, more preferably 10-90wt%, still more preferably 15-90wt% . This is because if the content of the cyanopyrrolidine derivative or the like is below the lower limit, it becomes difficult to ensure the stability of the cyanopyrrolidine derivative or the like even when mixed with the stabilizing ingredient .
- the content of the sugars and sugar alcohols in such a composition for solid pharmaceutical preparations is l-95wt%.
- the composition of the present invention for solid pharmaceutical preparations essentially consists of a cyanopyrrolidine derivative or the like and at least one stabilizing ingredient selected from the group consisting of sugars and sugar alcohols
- an oral additive other than the sugars and sugar alcohols (or stabilizing ingredients) can be added in a small content unless it influences the stability of the cyanopyrrolidine derivative or the like .
- the content of such a oral additive is 70wt% or less , preferably 60wt% or less , more preferably 50wt% or less , still more preferably 30wt% or less .
- the content of such a oral additive is 10wt% or less, preferably 5wt% or less, more preferably 2wt% or less . If the content exceeds the upper limit, the stability of the cyanopyrrolidine derivative or the like in the composition for solid pharmaceutical preparations tends to be significantly reduced.
- oral additives other than sugars and sugar alcohols ( stabilizing ingredients ) which can be added in the composition for solid pharmaceutical preparations oral additives used for solid pharmaceutical preparations that are generally acceptable as medical drugs can be used appropriately.
- examples of additives that are relatively less likely to cause the decomposition of the cyanopyrrolidine derivative or the like include stearic acid, calcium stearate , talc and pullulan .
- the process for producing such a composition for solid pharmaceutical preparations is not particularly limited; examples of such a process include methods in which the cyanopyrrolidine derivative or the like and the stabilizing ingredient are granulated ( agitation granulation, fluidized bed granulation, extrusion granulation, tumbling fluidized bed- granulation and dry granulation) .
- the process for producing such a composition for solid pharmaceutical preparations is not limited to the foregoing granulation methods, and any publicly known process can be used appropriately, e . g . , a process is used in which a composition for solid pharmaceutical preparations is produced by mixing a cyanopyrrolidine derivative or the like and the stabilizing ingredient , and by directly compressing the resultant mixture into a tablet form.
- the solid pharmaceutical preparation of the present invention is characterized by containing the composition for solid pharmaceutical preparations .
- the composition for solid pharmaceutical preparations contains a cyanopyrrolidine derivative or the like . For this reason, the decomposition of the cyanopyrrolidine derivative or the like due to the presence of other oral additives is prevented to occur when it is formulated in solid pharmaceutical preparations .
- the composition for solid pharmaceutical preparations is preferably present in the form of granulated substance, and the solid pharmaceutical preparation preferably contains additional oral additives . If the composition for solid pharmaceutical preparations is present in the form of granulated substance, it is possible to ensure the stability of the cyanopyrrolidine - derivative or the like formulated in solid pharmaceutical preparations even when it is mixed with oral additives other than the stabilizing ingredients .
- the oral additives added in the solid pharmaceutical preparation of the present invention are not particularly limited, and those used for solid pharmaceutical preparations that are generally acceptable as medical drugs can be used appropriately.
- examples of these oral additives include diluents, binders , disintegrators , plasticizers and lubricants .
- diluents include : sugar- and sugar alcohol-based diluents such as glucose, sucrose, mannitol, lactose, xylitol, sorbitol, maltitol and dextrate; cellulose-based diluents such as microcrystalline cellulose ; starch-based diluents such as cornstarch; and inorganic diluents such as dibasic calcium phosphate anhydrous .
- binders include cellulose-based binders such as methylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose .
- disintegrators examples include cellulose-based disintegrators such as carmellose calcium, low substituted hydroxypropylcellulose and cross carmellose sodium, and starch-based disintegrators such as partially pregelatinized starch and carboxymethyl starch sodium.
- plasticizers include inorganic-based plasticzers such as light sillic acid anhydride .
- lubricants include stearic acid, ' magnesium stearate, calcium stearate, talc and sodium stearyl fumarate . These oral additives may be used singly or in combination of two or more . In addition, the proportion of these oral additives in solid pharmaceutical preparations is not particularly limited . They can be added in an appropriate content .
- composition of the present invention for solid pharmaceutical preparations and the solid pharmaceutical preparation of the present invention have been described.
- the process for producing the solid pharmaceutical preparation of the present invention will be described below.
- the process for producing the composition for solid pharmaceutical preparations of the present invention is characterized in that it includes a step ( i) in which a cyanopyrrolidine derivative represented by the foregoing general formula ( 1) or a pharmaceutically acceptable salt thereof is mixed with at least one stabilizing ingredient selected from the group consisting of sugars and sugar alcohols (and the resultant mixture may be granulated) to form a composition for solid pharmaceutical preparations, which essentially consists of the cyanopyrrolidine derivative and at least one stabilizing ingredient selected from the group consisting of sugars and sugar alcohols .
- the step ( i) is one in which a cyanopyrrolidine derivative or a pharmaceutically acceptable salt thereof ( i . e . , a cyanopyrrolidine derivative or the like) is mixed with at least one stabilizing ingredient selected from the group consisting of sugars and sugar alcohols ( and the resultant mixture may be granulated) to form a composition for solid pharmaceutical preparations , which essentially consists of the cyanopyrrolidine derivative or the like and at least one stabilizing ingredient selected from the group consisting of sugars and sugar alcohols .
- a cyanopyrrolidine derivative or the like used in this step ( i) is similar to the cyanopyrrolidine derivative or a pharmaceutically acceptable salt thereof contained in the foregoing composition of the present invention for solid pharmaceutical preparations .
- the step for producing such a composition is not particularly limited, if the composition formed in the step (i ) is mixed with oral additives used for solid pharmaceutical preparations that are generally acceptable as medical drugs to form a solid pharmaceutical preparation, it is preferable to adopt a step in which the cyanopyrrolidine derivative or the like, and the sugars and sugar alcohols ( stabilizing ingredients) are mixed together followed by granulation process ; in particular, a process (a) in which they are granulated under the presence of water is preferable ..
- Examples of granulation methods adopted in the step ( a) for producing such a composition include agitation granulation, kneading granulation, fluidized bed granulation, extrusion granulation and tumbling fluidized bed granulation. Among these, " agitation granulation or kneading granulation is preferable .
- the granulation step of the present invention can adopt a dry granulation method in addition to the granulation methods in the step (a) .
- composition for solid pharmaceutical preparations can be formulated into solid pharmaceutical preparations using methods that are known in the field of solid pharmaceutical preparations, mixing it with oral additives or without mixing it with them.
- oral additives are similar to those described in the production of the solid pharmaceutical preparation of the present invention .
- Examples of publicly known methods for formulating the composition for solid pharmaceutical preparations into solid pharmaceutical preparations include : a method in which the composition is directly compressed into tablets to form solid pharmaceutical preparations ; a method in which the composition and oral additives are mixed together before compressed into tablets to form solid pharmaceutical preparations ; a method in which the composition is loaded into a capsule; and a method in which the composition and oral additives are mixed together before loaded into a capsule .
- the form of the resultant solid pharmaceutical preparations is not particularly limited. They can be of any form: tablet, powder, granule or capsule .
- compositions for solid pharmaceutical preparations thus produced after a drying process were mixed with other oral additives to produce mix powers .
- the mix powder thus produced was compressed into tablets using a tableting machine (VIRG019, manufactured by Kikusui Seisakusho, Ltd) . In this way tablets ( solid pharmaceutical preparations ) with a diameter of 9mm were obtained.
- Examples 8 to 9 and Comparative Example 1 ingredients were blended together in contents shown in Table 2 to provide solid pharmaceutical preparations .
- the resultant mixture was granulated in an agitation granulator (Vertical Granulator VG5, manufactured by Powrex Corporation) to produce granulated substance .
- the resultant granulated substance were dried in a fluidized bed drier (FL-MINI, manufactured by Freund Corporation) to produce dry powders .
- FL-MINI fluidized bed drier
- the dry powders mixed with Calcium stearate to produce mix powders .
- the mix powders thus produced were processed into solid pharmaceutical preparations .
- the solid pharmaceutical preparations obtained in Examples 1 to 4 , 8 and 9 and Comparative Example 1 were pounded in a mortar . Subsequently, the solid pharmaceutical preparations obtained in Example 8 and Comparative Example 1 were brought to a concentration of 200 ⁇ g/ml with methanol and a mobile phase; those obtained in Examples 1, 2 , 5 to 7 and 9 were brought to a concentration of 400 ⁇ g/ml with methanol and a mobile phase ; and those obtained in Examples 3 and 4 were brought to a concentration of 800 ⁇ g/ml with methanol and a mobile phase .
- Liquid chromatography was carried out in accordance with Japanese Pharmacopoeia, whereby the contents of related substances were determined on the basis of the peak areas derived from the sample and standard solutions .
- the measurement conditions are as follows :
- Example 1 at 65°C . Subsequently, the contents of related substances remained after 2 weeks ( “2W” in Table 4 ) , and 4 weeks
- sample solutions used for the measurement of the contents of related substances were prepared in a similar manner as those used for the measurement for the solid pharmaceutical preparation prepared in Examples 1 and 2. Further, sample solutions were prepared in a similar manner as the sample solutions described above after grinding the solid pharmaceutical preparations .
- Example 10 ingredients were blended together in contents shown in Table 5 to provide solid pharmaceutical preparations .
- the compound (a) and oral additives other than calcium stearate the re ' sultant commixture was mixed with calcium stearate .
- the resultant mixture was compressed into tablet form by the use of a tableting machine to obtain tablets of 5.5mm in diameter .
- a composition for solid pharmaceutical preparations (although it contains a cyanopyrrolidine derivative or the like) capable of ensuring the stability of the cyanopyrrolidine derivative or the like formulated in pharmaceutical preparations and of reducing the decomposition of the cyanopyrrolidine derivative or the like due to the addition of other oral additives; a solid pharmaceutical preparation containing the composition; and a process for producing the solid pharmaceutical preparation .
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Abstract
A composition for solid pharmaceutical preparations, essentially consisting of a cyanopyrrolidine derivative represented by the following general formula (1) or a pharmaceutically acceptable salt thereof, and at least one stabilizing ingredient selected from the group consisting of sugars and sugar alcohols, [Formula 1] [wherein R1 represents, for example, a halogen atom or a hydroxyl group, R3 and R4 may be the same or different, each represents, for example, a hydrogen atom or a halogen atom, X represents an oxygen atom or a sulfur atom, Y represents, for example, a group represented by -CR5R6- (wherein R5 and R6 may be the same or different, each represents, for example, a hydrogen atom or a halogen atom), W represents, for example, a hydrogen atom or an acyl group derived from naturally occurring amino acids, and Z represents, for example, a hydrogen atom or an alkyl group of 1 to 10 carbon atoms which may be substituted with one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a hydroxylalkyl group of 1 to 5 carbon atoms, a carboxyl group, a mercapto group and the like].
Description
DESCRIPTION
CYANOPYRROLIDINE DERIVATIVE-CONTAINING COMPOSITION FOR SOLID PHARMACEUTICAL PREPARATIONS, SOLID PHARMACEUTICAL PREPARATION CONTAINING THE COMPOSITION, AND PROCESS FOR PRODUCING THE SOLID
PHARMACEUTICAL PREPARATION
TECHNICAL FIELD
The present invention relates to a composition for solid pharmaceutical preparations consisting of a cyanopyrrolidine derivative, to a solid pharmaceutical preparation containing the composition, and to a process for producing the solid pharmaceutical preparation.
BACKGROUND ART
Dipeptidylpeptidase IV (DPPIV) is a kind of serine protease that cleaves , by hydrolysis , dipeptides from peptides chain - with proline or alanine at the second position from N-terminal . DPPIV is widely distributed in tissues , blood plasma and organs such as kidneys and liver, and is involved in the metabolism of a wide spectrum of physiologically active peptides .
Recent studies revealed that DPPIVmediates the metabolism of glucagon-like peptide 1 (GLP-I ) ; that is, DPPIV inactivates GLP-I by cleaving, by hydrolysis, dipeptide of a N-terminal His-Ala of GLP-I , and the inactivated GLP-I is allowed to act as an antagonist for the GLP-I receptor .
Known physiological functions of GLP-I include stimulation of insulin secretion from pancreas, extension of gastric evacuation time, and suppression of food intake . For this reason, inhibition of DPPIV enhances the activity of GLP-I, increases insulin activity, and improves sugar metabolism, thereby suggesting that it is effective for the treatment of type 2 diabetes .
DPPIV is also known to be involved in the metabolism of neuropeptide Y that is a neuropeptide, in the activation of T cells that is cells of the immune system, in the adhesion of cancer cells to endothelium, and in the entry of HIV virus into lymphocytes . Thus, inhibition of DPPIV is considered to be effective in the treatment of diseases such as autoimmune disease .
In addition, it has been found that DPPIV is expressed at a high level in fibrocytes taken from the skin of patients suffering from psoriasis, arthritis rheumatoides or lichen planus, and that patients suffering from benign prostate hypertrophy show a high degree of DPPIV activity. It is therefore expected that inhibition of DPPIV is also effective in the treatment of dermatosis and benign prostate hypertrophy.
Examples of conventional compounds for inhibiting DPPIV are as follows : International Patent Publication No .03/095425 pamphlet discloses a cyanopyrrolidine derivative and a salt thereof, which is expressed by a predetermined general formula and which contains , for example,
( 2S, 4S) -I- [ ( 2S , 3S ) -2- [ ( 1-acetoxyethoxycarbonγl ) amino] -3-met ylpentanoyl] -2-cyano-4-fluoropyrrolidine or
(2S, 4S) -1- [ ( 2S ) -2- [ ( 1-acetoxyethoxycarbonyl ) amino] -3-methyl butanoyl] -2-cyano-4-fluoropyrrolidine; International Patent Publication No .2004/101514 pamphletdiscloses a cyanopyrrolidine derivative which is expressed by a predetermined general formula and which contains, for example,
(2S, 4S) -2-cyano-4-fluoro-l- [ [2- ( 3 , 4-methylenedioxybenzoyl ) a mino-1, 1-dimethyl] ethylamino] acetylpyrrolidine; International Patent Publication No .02/38541 pamphlet discloses a cyanopyrrolidine derivative which is expressed by a predetermined general formula and which contains, for example,
( 2S, 4S) -2-cyano-4-fluoro-l- [ [ ( 2S , 3S ) -3-methyl-2-methylamino ] pentanoyl] pyrrolidine; and International Patent Publication No .2004/02407 pamphlet discloses as a highly stable cyanopyrrolidine derivative a benzenesulfonic acid salt of
(2S, 4S) -2-cyano-4-fluoro-l- [ (2-hydroxy-l, 1-dimethyl ) ethylam ino] acetylpyrrolidine . However, addition of oral additives as- solid pharmaceutical preparations to the cyanopyrrolidine derivatives disclosed in the foregoing documents facilitates the production of compounds that results from decomposition of the cyanopyrrolidine derivatives (hereinafter, referred to as "decomposition of the cyanopyrrolidine derivative ( s) " on an appropriate basis) and, therefore, their stability in the solid pharmaceutical preparations is not necessarily satisfactory .
DISCLOSRE OF THE INVENTION
The present invention has been accomplished in view of the foregoing problems of the related art, and an obj ect thereof is to provide : a composition for solid pharmaceutical preparations (although it contains a cyanopyrrolidine derivative) capable of ensuring the stability of the cyanopyrrolidine derivative formulated in pharmaceutical preparations and of reducing the decomposition of the cyanopyrrolidine derivative due to the addition of other oral additives ; a solid pharmaceutical preparation containing the composition; and a process for producing the solid pharmaceutical preparation.
The present inventors have diligently conducted studies to solve the foregoing problems . As a result, they have established that it is possible to ensure the stability of a cyanopyrrolidine derivative formulated in pharmaceutical preparations by mixing a cyanopyrrolidine derivative with at least one stabilizing ingredient selected from the group- consisting of sugars and sugar alcohols to form a composition essentially consisting of the cyanopyrrolidine derivative and the stabilizing ingredient, and that it is possible to reduce the decomposition of the cyanopyrrolidine derivative even when mixed with other oral additives at a later time . Thus, they have completed the present invention .
Specifically, the composition of the present invention for solid pharmaceutical preparations is a composition
essentially consisting of a cyanopyrrolidine derivative represented by the following general formula ( 1 ) or a pharmaceutically acceptable salt thereof, and at least one stabilizing ingredient selected from the group consisting of sugars and sugar alcohols , [ Formula 1 ]
[wherein R1 represents a halogen atom, a hydroxy1 group, an alkoxy group of 1 to 5 carbon atoms or an alkyl group of 1 to 5 carbon atoms , R2 represents a hydrogen atom, a halogen atom, a hydroxyl group/ an alkoxy group of 1 to 5 carbon atoms or an alkyl group of 1 to 5 carbon atoms, or R1 and R2 bond together to form an - oxo group, a hydroxyimino group, an alkoxyimino group of 1 to 5 carbon atoms or an alkylidene group of 1 to 5 carbon atoms, R3 and R4 may be the same or different, each represents a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxy group of 1 to 5 carbon atoms or an alkyl group of 1 to 5 carbon atoms , or R3 and R4 bond together to form an oxo group, a hydroxyimino group, an alkoxyimino group of 1 to 5 carbon atoms or an alkylidene group of 1 to' 5 carbon atoms,
X represents an oxygen atom or a sulfur atom, Y represents a group represented by -CR5R6- [wherein R5 and R6 may be the same or different, each represents a hydrogen atom; a halogen atom; an alkyl group of 1 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a hydroxyalkyl group of 1 to 5 carbon atoms, a carboxyl group, a mercapto group, an alkylthio group of 1 to 5 carbon atoms, a guanidyl group, a phenyl group which may be substituted, an imidazolyl group, an indolyl group, a group represented by -NHR11
(wherein R11 represents a hydrogen atom, a phenyl group which may be substituted, a pyridyl group which may be substituted, a tert-butoxycarbonyl group or a benzyloxycarbonyl group) , a group represented by -CONHR12 (wherein R12 represents a hydrogen atom or a group represented by - (CH^) 1n-R13 (wherein m represents an integer of 1 to 5, and R1J represents a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl group) ) and a group represented by -OR14
(wherein R14 represents a chain alkyl group of 1 to 5 carbon atoms or a benzyl group) ; or an alkenyl group of 2 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group and a chain alkoxy group of 1 to 5 carbon atoms] , or a group represented by -CRV-CR9R10- (wherein R7' R8' R9 and Rlυ may be' the same or different, each represents a hydrogen atom; a halogen atom; or
an alkyl group of 1 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a hydroxyalkyl group of 1 to 5 carbon atoms, a carboxyl group, a mercapto group, an alkylthio group of 1 to 5 carbon atoms, a guanidyl group, a phenyl group which may be substituted, an imidazolyl group, an indolyl group, a group represented by -NHR11 (wherein R11 represents a hydrogen atom, a phenyl group which may be substituted, a pyridyl group which may be substituted, a tert-butoxycarbonyl group or a benzyloxycarbonyl group) , a group represented by -CONHR1" (wherein R12 represents a hydrogen atom or a group represented by - (CH2) m-R^ (wherein m represents an integer of 1 to 5, and R13 represents a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl group) ) and a group represented by -OR14 (wherein R14 represents a chain alkyl group of 1 to 5 carbon atoms or a benzyl group) , or R7, R9 and an adj acent carbon atom bond together to form: a cycloalkyl group of 3 to 8 carbon atoms which may be substituted with one or more groups - selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group, a chain alkyl group of 1 to 5 carbon atoms and a chain alkoxy group of 1 to 5 carbon atoms ; a cycloalkenyl group of 4 to 8 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group, a chain alkyl group of 1 to 5 carbon atoms and a chain alkoxy
group of 1 to 5 carbon atoms ; a bicycloalkyl group of 5 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group, a chain alkyl group of 1 to 5 carbon atoms and a chain alkoxy group of 1 to 5 carbon atoms ; or a bicycloalkenyl group of 5 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group, a chain alkyl group of 1 to 5 carbon atoms and a chain alkoxy group of 1 to 5 carbon atoms) ,
W represents a hydrogen atom, an acyl group derived from naturally occurring amino acids , a group represented by the following general formula ( 2 ) : [ Formula 2 ]
[wherein W1 represents an alkanoyl group of 1 to 5 carbon atoms, an arylcarbonyl group which may be substituted or an alkyl group of 1 to 5 carbon atoms, and W"" represents a hydrogen atom or an alkyl group of 1 to 5 carbon atoms] , or a group represented by the following general formula ( 3 ) : [ Formula 3]
[wherein W3 and W4 may be the same or different, each represents a hydrogen atom or an alkyl group of 1 to 5 carbon atoms] ,
Z represents a hydrogen atom; an alkyl group of 1 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a hydroxyalkyl group of 1 to 5 carbon atoms, a carboxyl group, a mercapto group, an alkylthio group of 1 to 5 carbon atoms , a guanidyl group, a phenyl group which may be substituted, an imidazolyl group, an indolyl group, a group represented by -NHR11 (wherein R11 represents a hydrogen atom, a phenyl group which may be substituted, a pyridyl group which may be substituted, a tert-butoxycarbonyl group or a benzyloxycarbonyl group) , a group represented by -CONHR1" (wherein R12 represents a hydrogen atom or a group represented by - (CH;) m-RlJ (wherein m represents an integer of 1 to 5, and R13 represents a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl group) ) and a group represented by -OR14 (wherein R14 represents a chain alkyl group of 1 to 5 carbon atoms or a benzyl group) ; or a group represented by the following general formula ( 4 ) : [Formula 4 ]
[wherein R15 and R16 may be the same or different, each represents a hydrogen atom; an alkyl group of 1 to 6 carbon atoms which may be substituted with one or more substituents selected from the following Y1 substituent group; a cycloalkyl group of 3 to 6 carbon atoms which may be substituted with one or more substituents selected from the following Y" substituent group; a cycloalkylalkyl group of 4 to 9 carbon atoms which may be substituted with one or more substituents selected from the following Y2 substituent group; an alkenyl group of 2 to 6 carbon atoms which may be substituted with one or more substituents selected from the following Y2 substituent group; a cycloalkenyl group- of 3 to 6 carbon atoms which may be substituted with one or more substituents selected from the following Y2 substituent group; cycloalkenylalkyl group of 4 to 9 carbon atoms which may be substituted with one or more substituents selected from the following Yz substituent group, or R15, R16 and an adj acent carbon atom bond together to form a cycloalkyl group of 3 to 10 carbon atoms which may be substituted with one or more substituents selected from the following Y2 substituent group,
A represents a single bond or an alkylene group of 1 to 3 carbon atoms,
R17 represents a group represented by -N (R18) COR19, -N (R18) SO2R19, -NR18R2υ, -SO2R19, -SO_NR18R19, -OCONR18R19, -CH=CH-R:1 or -C≡C-R21; or a heteroaryl group selected from heteroaryl groups which have at least one oxygen atom and/or one sulfur atom and may also have a nitrogen atom, 6-membered nitrogen containing aromatic rings , and 9- to 11-membered condensate rings thereof (here, the heteroaryl groups may be substituted with one or more substituents selected from the following Y3 substituent group) ,
(wherein R18 and R~° may be the same or different, each represents : a hydrogen atom; an alkyl group of 1 to 10 carbon atoms which may be substituted with one or more substituents selected from the following Y4 substituent group; a cycloalkyl group of 3 to 6 carbon atoms which may be substituted with one or more substituents selected from the following Y" substituent group; a cycloalkylalkyl group of 4 to 9 carbon atoms which may be substituted with one or more substituents selected from the following Y2 substituent group; or an arylalkyl group which may be substituted with one or more substituents selected from the following Y3 substituent group,
R19 represents : an alkyl group of 1 to 10 carbon atoms which may be substituted with one or more substituents selected from the following Y4 substituent group; the following Q; or - (C1-3 alkylene) -Q, the C3.-3 alkylene may be substituted with one or more substituents selected from a halogen atom and a hydroxyl group, the Q represents an aliphatic or aromatic hydrocarbon
selected from the group consisting of a cycloalkyl group of 3 to 10 carbon atoms which may be substituted with one or more substituents selected from the following Y3 substituent group; a bridged cyclic alkyl group of 4 to 10 carbon atoms which may be substituted with one or more substituents selected from the following Y3 substituent group; an alkenyl group of 2 to 10 carbon atoms which may be substituted with one or more substituents selected from the following Y3 substituent group; a cycloalkenyl group of 3 to 10 carbon atoms which may be substituted with one or more substituents selected from the following Y3 substituent group; a bridged cyclic alkenyl group of 4 to 10 carbon atoms which may be substituted with one or more substituents selected from the following YJ substituent group; and aryl groups which may be substituted with one or more substituents selected from the following Y3 substituent group; or a heterocyclic ring which may be substituted with one or more substituents selected from the following Y5 substituent group,
In R19 , representing an aryl group or heterocyclic ring may form a 5- to 8-membered ring by combining a substituent adj acent to the atom constituting its ring, and may contain one or more heteroatoms in the ring,
R18, R19 or R20 may bond to an heteroatom adj acent to R18 and R19, R18 and R20, or R19 and RΞ0 to form a 4- to 10-membered heterocyclic ring which may be substituted with one or more substituents selected from the following Y5 substituent group, and
RJ1 represents a hydrogen atom; an alkyl group of 1 to 6 carbon atoms which may be substituted with one or more substituents selected from the following Y1 substituent group; an aryl group which may be substituted with one or more substituents selected from the following Y3 substituent group; or a heteroaryl group which may be substituted with one or more substituents selected from the following Y3 substituent group) ] , or Y, Z and an adj acent nitrogen atom bond together to form a cyclic amino group of 2 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, a chain alkyl group of 1 to 5 carbon atoms and a group represented by -OR22 (wherein R"" represents a chain alkyl group of 1 to 5 carbon atoms, an aminocarbonylmethyl group or a benzyl group) ] ,
(Y1 substituent group) : a group consisting of a halogen atom, a hydroxyl group, a carboxyl group, a cyano group, an amino group', an aminocarbonyl group, a cycloalkyloxy group of 3 to 5 carbon atoms and an alkoxy group of 1 to β carbon atoms,
(Y2 substituent group) : a group consisting of a halogen atom, a hydroxyl group, a carboxyl group, a cyano group, an amino group, an aminocarbonyl group, a cycloalkyloxy group of 3 to 5 carbon atoms, an alkoxy group of 1 to 6 carbon atoms and an alkyl group of 1 to 6 carbon atoms,
(Y3 substituent group) : a group consisting of a halogen atom, a hydroxyl group, a cyano group, a nitro group, an amino group, groups represented by -OR30, -COR30, -CO2R30, -CONR30R31,
-N (R30) COR31 , -N (R30) CONR31R3:, -N (R30) SO2R31, -NR30R31, -SO2R30, -SO2NR30R31, -SO2N=CHNR30R31 and -OCONR30R31 (wherein R30, R31 and R32 may be the same or different, each represents a hydrogen atom; an alkyl group of 1 to 6 carbon atoms which may be substituted with one or more substituents selected from the Y1 substituent group; a cycloalkyl group of 3 to 6 carbon atoms which may be substituted with one or more substituents selected from the Y" substituent group; a cycloalkylalkyl group of 4 to 9 carbon atoms which may be substituted with one or more substituents selected from the Y2 substituent group; or a phenyl group which may be substituted with one or more substituents selected from the Y2 substituent group) , an alkyl group of 1 to 6 carbon atoms which may be substituted with one or more substituents selected from the Y1 substituent group, and a phenyl group which may be substituted with one or more substituents selected from the Y2 substituent group,
- (Y4 substituent group) : a group consisting of a halogen atom, a hydroxyl group, a cyano group, a nitro group, an amino . group, groups represented by -OR30, -COR30, -CO2R30, -CONR30R31, -N (R30) COR31, -N (R30J CONR31R32, -N (R30) SO2R31, -NR30R31, -SO2R30, -SO2NR30R31, -SO2N=CHNR30R31 and -OCONR30R31 (wherein R30, R31 and R32 may be the same or different, each represents a hydrogen atom; an alkyl group of 1 to 6 carbon atoms which may be substituted with one or more substituents selected from the Y1 substituent group; a cycloalkyl group of 3 to 6 carbon atoms which may be substituted with one or more substituents selected
from the Y" substituent group; a cycloalkylalkyl group of 4 to 9 carbon atoms which may be substituted with one or more substituents selected from the Y2 substituent group; or a phenyl group which may be substituted with one or more substituents selected from the Y2 substituent group) and a phenyl group which may be substituted with one or more substituents selected from the Y~ substituent group, and
(Y5 substituent group) : a group consisting of an oxo group, a halogen atom, a hydroxyl group, a cyano group, a nitro group, an amino group, groups represented by -OR/""1, -COR30, -COcR'3'-1, -CONR30R31, -N (R30) COR31, -N (R30J CONR31R32, -N (R30J SO2R31, -NR30R31, -SOcR30, -SO2NR30R31, -SO2N=CHNR30R31 and -OCONR30R31 (wherein R30, R31 and R32 may be the same or different, each represents a hydrogen atom; an alkyl group of 1 to 6 carbon atoms which may be substituted with one or more substituents selected from the Y1 substituent group; a cycloalkyl group of 3 to 6 carbon atoms which-may be substituted with one or more substituents selected from the Y2 substituent group; a cycloalkylalkyl group of 4 to 9 carbon atoms which may be substituted with one or more substituents selected from the Y2 substituent group; or a phenyl group which may be substituted with one or more substituents selected from the Y2 substituent group) , an alkyl group of 1 to 6 carbon atoms which may be substituted with one or more substituents selected from the Y1 substituent group, and a phenyl group which may be substituted with one or more substituents selected from the Y2 substituent group .
Preferably, the stabilizing ingredient according to the present invention is at least one stabilizing ingredient selected from the group consisting of mannitol, lactose, xylitol, sorbitol, maltitol, maltose, glucose, lactitol and dextrate .
Although the form of the compositions for solid pharmaceutical preparations of the present invention which contain the cyanopyrrolidine derivative or a pharmaceutically acceptable salt thereof and at least one stabilizing ingredient selected from the group consisting of sugars and sugar alcohols is not particularly limited.
In the composition of the present invention for pharmaceutical preparations, the content of an oral additive other than the stabilizing ingredient, which is contained in the composition, is preferably 70wt% or less .
Preferably, the cyanopyrrolidine derivative according to the present invention or a pharmaceutically acceptable salt thereof is a benzenesulfonic acid salt of ( 2S, 4S) -2-cyano-4-fluoro-l- [ (2-hydroxy-l, 1-dimetyl ) ethylami ■ no] acetylpyrrolidine .
The solid pharmaceutical preparation of the present invention contains the composition of the present invention for solid pharmaceutical preparations .
In the solid pharmaceutical preparation of the present invention, it is preferable that the composition for solid pharmaceutical preparations contains an oral additive in addition to the composition for solid pharmaceutical
preparations, when the composition for solid pharmaceutical preparations is in the form of granulated substance .
The composition of the present invention may be in the form of non-granulated substance .
The tablet of the present invention may be that obtained by directly compressing, into a tablet form, the composition which is in the form of non-granulated substance .
The process of the present invention for producing a solid pharmaceutical preparation, comprising : a step of producing a composition for solid pharmaceutical preparations by mixing a cyanopyrrolidine derivative represented by the following general formula ( 1 ) or a pharmaceutically acceptable salt thereof with at least one stabilizing ingredient selected from the group consisting of sugars and sugar alcohols, the composition essentially consisting of the cyanopyrrolidine derivative or a pharmaceutically acceptable salt thereof, and at least one stabilizing ingredient selected from the group consisting of ,sugars and sugar alcohols, [Formula 5 ]
X represents an oxygen atom or a sulfur atom, Y represents a group represented by -CR5R6- [wherein R5 and R6 may be the same or different, each represents a hydrogen atom; wa halogen atom; an alkyl group of 1 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a hydroxyalkyl group of 1 to 5 carbon atoms, a carboxyl group, a mercapto group, an alkylthio group of 1 to 5 carbon atoms , a guanidyl group, a phenyl group which may be substituted, an imidazolyl group, an indolyl group, a group represented by -NHR11 (wherein R11 represents a hydrogen atom, a phenyl group which may be substituted, a pyridyl group which may be substituted, a tert-butoxycarbonyl group or a benzyloxycarbonyl group) , a
group represented by -CONHR12 (wherein R represents a hydrogen atom or a group represented by - (CH2I m-R13 (wherein m represents an integer of 1 to 5, and R13 represents a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl group) ) and a group represented by -OR14
(wherein R14 represents a chain alkyl group of 1 to 5 carbon atoms or a benzyl group) ; or an alkenyl group of 2 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group and a chain alkoxy group of 1 to 5 carbon atoms ] , or a group represented by -CR7R8-CR9R10- (wherein R7' R8' R9 and R10 may be the same or different, each represents a hydrogen atom; a halogen atom; or an alkyl group of 1 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a hydroxyalkyl group of 1 to 5 carbon atoms, a carboxyl group, a mercapto group, an alkylthio group of 1 to 5 carbon atoms, a guanidyl group, a phenyl group - which may be substituted, an imidazolyl group, an indolyl group, a group represented by -NHR11 (wherein R11 represents a hydrogen atom, a phenyl group which may be substituted, a pyridyl group which may be substituted, a tert-butoxycarbonyl group or a benzyloxycarbonyl group) , a group represented by -CONHR12
(wherein R12 represents a hydrogen atom or a group represented by - (CH2) ra-R13 (wherein m represents an integer of 1 to 5, and R13 represents a hydrogen atom, a methoxycarbonyl group, an
ethoxycarbonyl group or a benzyloxycarbonyl group) ) and a group represented by -OR14 (wherein R14 represents a chain alkyl group of 1 to 5 carbon atoms or a benzyl group) , or R7, R9 and an adj acent carbon atom bond together to form: a cycloalkyl group of 3 to 8 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group, a chain alkyl group of 1 to 5 carbon atoms and a chain alkoxy group of 1 to 5 carbon atoms; a cycloalkenyl group of 4 to 8 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group, a chain alkyl group of 1 to 5 carbon atoms and a chain alkoxy group of 1 to 5 carbon atoms ; a bicycloalkyl group of 5 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group/ a carboxyl group, an amino group, an aminocarbonyl group, a chain alkyl group of 1 to 5 carbon atoms and a chain alkoxy group of 1 to 5 carbon atoms ; or a bicycloalkenyl group of 5 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group, a chain alkyl group of 1 to 5 carbon atoms and a chain alkoxy group of 1 to 5 carbon atoms ) ,
W represents a hydrogen atom, an acyl group derived from naturally occurring amino acids, a group represented by the
following general formula (2 ) : [ Formula 6]
[wherein W1 represents an alkanoyl group of 1 to 5 carbon atoms, an arylcarbonyl group which may be substituted or an alkyl group of 1 to 5 carbon atoms, and W2 represents a hydrogen atom or an alkyl group of 1 to 5 carbon atoms] , or a group represented by the following general formula ( 3 ) : [ Formula 7 ]
[wherein W3 and W4 may be the same or different, each represents a hydrogen atom or an alkyl group of 1 to 5 carbon atoms ] ,
Z represents a hydrogen atom; an alkyl group of 1 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a hydroxyalkyl group of 1 to 5 carbon atoms, a carboxyl group, a mercapto group, an alkylthio group of 1 to 5 carbon atoms, a guanidyl group, a phenyl group which may be substituted,
an imidazolyl group, an indolyl group, a group represented by -NHR11 (wherein R11 represents a hydrogen atom, a phenyl group which may be substituted, a pyridyl group which may be substituted, a tert-butoxycarbonyl group or a benzyloxycarbonyl group) , a group represented by -CONHR1" (wherein R1" represents a hydrogen atom or a group represented by - (CHc) 1n-R13 (wherein m represents an integer of 1 to 5, and R1^ represents a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl group) ) and a group represented by -OR14
(wherein R14 represents a chain alkyl group of 1 to 5 carbon atoms or a benzyl group) ; or a group represented by the following general formula ( 4 ) :
[ Formula 8 ]
[wherein R15 and Rlδ may be the same or different, each represents a hydrogen atom; an alkyl group of 1 to 6 carbon atoms which may be substituted with one or more substituents selected from the following Y1 substituent group; a cycloalkyl group of 3 to 6 carbon atoms which may be substituted with one or more substituents selected from the following Y2 substituent group; a cycloalkylalkyl group of 4 to 9 carbon atoms which may be substituted with one or more substituents selected from the
following Y2 substituent group; an alkenyl group of 2 to 6 carbon atoms which may be substituted with one or more substituents selected from the following Y2 substituent group; a cycloalkenyl group of 3 to 6 carbon atoms which may be substituted with one or more substituents selected from the following Y2 substituent group; cycloalkenylalkyl group of 4 to 9 carbon atoms which may be substituted with one or more substituents selected from the following Y~ substituent group, or R15, R16 and an adj acent carbon atom bond together to form a cycloalkyl group of 3 to 10 carbon atoms which may be substituted with one or more substituents selected from the following Y^ substituent group,
A represents a single bond or an alkylene group of 1 to 3 carbon atoms,
R17 represents a group represented by -N (Rlb) COR19, -N (R18) SO2R19, -NR18R20, -SO2R19, -SO2NR18R19, -OCONR18R19, -CH=CH-R21 or -C≡C-R21 ; or a heteroaryl group selected from heteroaryl groups which have at least one oxygen atom and/or one sulfur atom and may also have a nitrogen atom, 6-membered nitrogen- containing aromatic rings , and 9- to 11-membered condensate rings thereof (here, the heteroaryl groups may be substituted with one or more substituents selected from the following Y" substituent group) ,
(wherein R18 and R20 may be the same or different, each represents : a hydrogen atom; an alkyl group of 1 to 10 carbon atoms which may be substituted with one or more substituents selected from the following Y4 substituent group; a cycloalkyl
group of 3 to 6 carbon atoms which may be substituted with one or more substituents selected from the following Y~ substituent group; a cycloalkylalkyl group of 4 to 9 carbon atoms which may be substituted with one or more substituents selected from the following Y2 substituent group; or an arylalkyl group which may be substituted with one or more substituents selected from the following Y3 substituent group,
Riq represents : an alkyl group of 1 to 10 carbon atoms which may be substituted with one or more substituents selected from the following Y4 substituent group; the following Q; or - (C1-S alkylene) -Q, the Ci-3 alkylene may be substituted with one or more substituents selected from a halogen atom and a hydroxyl group, the Q represents an aliphatic or aromatic hydrocarbon selected from the group consisting of a cycloalkyl group of 3 to 10 carbon atoms which may be substituted with one or more substituents selected from the following Y3 substituent group; a bridged cyclic alkyl group of 4 to 10 carbon atoms which may be substituted with one or more substituents selected from the following Y3 substituent group; an alkenyl group of 2 to 10 carbon atoms which may be substituted with one or more substituents selected from the following Y3 substituent group; a cycloalkenyl group of 3 to 10 carbon atoms which may be substituted with one or more substituents selected from the following Y3 substituent group; a bridged cyclic alkenyl group of 4 to 10 carbon atoms which may be substituted with one or more substituents selected from the following YJ substituent group; and aryl groups which
may be substituted with one or more substituents selected from the following Y3 substituent group; or a heterocyclic ring which may be substituted with one or more substituents selected from the following Y5 substituent group,
In R19 , representing an aryl group or heterocyclic ring may form a 5- to 8-membered ring by combining a substituent adj acent to the atom constituting its ring, and may contain one or more heteroatoms in the ring,
R18, R19 or R2υ may bond to an heteroatom adj acent to R18 and R19, R18 and R2υ, or R19 and R2fl to form a 4- to 10-membered heterocyclic ring which may be substituted with one or more substituents selected from the following Y5 substituent group, and
R21 represents a hydrogen atom; an alkyl group of 1 to 6 carbon atoms which may be substituted with one or more substituents selected from the following Y1 substituent group; an aryl group which may be substituted with one or more substituents selected from the following Y3 substituent group; - or a heteroaryl group which may be substituted with one or more substituents selected from the following Y3 substituent group) ] , or Y, Z and an adj acent nitrogen atom bond together to form a cyclic amino group of 2 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, a chain alkyl group of 1 to 5 carbon atoms and a group represented by -OR22 (wherein R22 represents a chain alkyl group of 1 to 5
carbon atoms, an aminocarbonylmethyl group or a benzyl group) ] , (Y1 substituent group) : a group consisting of a halogen atom, a hydroxyl group, a carboxyl group, a cyano group, an amino group, an aminocarbonyl group, a cycloalkyloxy group of 3 to 5 carbon atoms and an alkoxy group of 1 to 6 carbon atoms,
(Y~ substituent group) : a group consisting of a halogen atom, a hydroxyl group, a carboxyl group, a cyano group, an amino group, an aminocarbonyl group, a cycloalkyloxy group of 3 to
5 carbon atoms, an alkoxy group of 1 to 6 carbon atoms and an alkyl group of 1 to 6 carbon atoms,
(Y3 substituent group) : a group consisting of a halogen atom, a hydroxyl group, a cyano group, a nitro group, an amino group, groups represented by -OR3υ, -COR30, -CO2R30, -CONR30R31, -N (R30) COR31, -N (R30) CONR31R32, -N (R30) SO2R31, -NR30R31, -SO2R30, -SO2NR30R31, -SO2N=CHNR30R31 and -OCONR30R31 (wherein R30, R31 and R32 may be the same or different, each represents a hydrogen atom; ' an alkyl group of 1 to 6 carbon atoms which may be substituted with one or more substituents selected from the Y1 substituent group; a cycloalkyl group of 3 to 6 carbon atoms which may be substituted with one or more substituents selected from the Y2 substituent group; a cycloalkylalkyl group of 4 to 9 carbon atoms which may be substituted with one or more substituents selected from the Y: substituent group; or a phenyl group which may be substituted with one or more substituents selected from the Y2 substituent group) , an alkyl group of 1 to
6 carbon atoms which may be substituted with one or more
substituents selected from the Y1 substituent group, and a phenyl group which may be substituted with one or more substituents selected from the Y2 substituent group,
(Y4 substituent group) : a group consisting of a halogen atom, a hydroxyl group, a cyano group, a nitro group, an amino group, groups represented by -OR30, -COR30, -COiR30, -CONR30R31, -N (R3n) COR3α, -N (R3'-') CONR31R32, -N (R30) SO:R31, -NR30R31, -SO2R30, -SO;NR30R31, -SO2N=CHNR30R31 and -OCONR3υR31 (wherein R30, R31 and RJ~ may be the same or different, each represents a hydrogen atom; an alkyl group of 1 to 6 carbon atoms which may be substituted with one or more substituents selected from the Y1 substituent group; a cycloalkyl group of 3 to 6 carbon atoms which may be substituted with one or more substituents selected from the Y2 substituent group; a cycloalkylalkyl group of 4 to 9 carbon atoms which may be substituted with one or more substituents selected from the Y2 substituent group; or a phenyl group 'which may be substituted with one or more substituents selected from the Y2 substituent group) and a phenyl group which may be substituted with one or more substituents selected from the Y2 substituent group, and
(Y5 substituent group) : a group consisting of an oxo group, a halogen atom, a hydroxyl group, a cyano group, a nitro group, an amino group, groups represented by -OR30, -COR30, -CO2R30, -CONR30R31, -N (R30) COR31, -N (R30) CONR31R32, -N (R30) SO2R31, -NR30R31, -SO2R30, -SO2NR30R31 , -SO2N=CHNR30R31 and -OCONR30R31 (wherein R30, R31 and R32 may be the same or different, each represents a
hydrogen atom; an alkyl group of 1 to 6 carbon atoms which may be substituted with one or more substituents selected from the Y1 substituent group; a cycloalkyl group of 3 to 6 carbon atoms which may be substituted with one or more substituents selected from the Y2 substituent group; a cycloalkylalkyl group of 4 to 9 carbon atoms which may be substituted with one or more substituents selected from the Y" substituent group; or a phenyl group which may be substituted with one or more substituents selected from the Y" substituent group) , an alkyl group of 1 to 6 carbon atoms which may be substituted with one or more substituents selected from the Y1 substituent group, and a phenyl group which may be substituted with one or more substituents selected from the Y2 substituent group .
Another aspect of the process of the present invention for producing solid pharmaceutical preparations is a process in which the step of producing the composition for solid pharmaceutical preparations further includes a step of mixing the cyanopyrrolidine derivative or a pharmaceutically acceptable salt thereof with at least one stabilizing ingredient selected from the group consisting of sugars and sugar alcohols, and granulating the resultant mixture to produce the composition for solid pharmaceutical preparations .
In the process of the present invention for producing solid preparations , it is preferable that the step of producing the composition for solid pharmaceutical preparations be a step in which the cyanopyrrolidine derivative or a pharmaceutically
acceptable salt thereof is mixed with the stabilizing ingredient and then the resultant mixture is granulated in the presence of water .
Another aspect of the process of the present invention for producing solid pharmaceutical preparations is a process in which the step of producing the composition for solid pharmaceutical preparations further includes a step of mixing the cyanopyrrolidine derivative or a pharmaceutically acceptable salt thereof with at least one stabilizing ingredient selected from the group consisting of sugars and sugar alcohols, and directly compressing the resultant mixture into a tablet form.
According to the present invention, it is possible to provide : a composition for solid pharmaceutical preparations ( although it contains a cyanopyrrolidine derivative) capable of ensuring the stability of the cyanopyrrolidine derivative formulated in pharmaceutical preparations and of reducing the decomposition of the cyanopyrrolidine derivative due to the - addition of other oral additives; a solid pharmaceutical preparation containing the composition; and a process for producing the solid pharmaceutical preparation .
BEST MODE FOR CAElRYING OUT THE INVENTION
Hereinafter, the present invention will be described in detail in line with its preferred embodiments .
First, the composition of the present invention for solid pharmaceutical preparations will be described. That is , the composition of the present invention for solid pharmaceutical preparations is characterized in that it essentially consisted of a cyanopyrrolidine derivative represented by the described above general formula ( 1 ) or a pharmaceutically acceptable salt thereof (hereinafter collectively referred to as "a cyanopyrrolidine derivative or the like" ) and at least one stabilizing ingredient selected from the group consisting of sugars and sugar alcohols .
Such a cyanopyrrolidine derivative or the like is a compound that shows an excellent DPPIV inhibiting activity. Examples of compounds that are suitable for such a cyanopyrrolidine derivative or the like include cyanopyrrolidine derivatives or pharmaceutically acceptable salts thereof, represented by the following general formula (5) : [Formula 9]
[wherein R41 represents a halogen atom, a hydroxyl group, an alkoxy group of 1 to 5 carbon atoms or an alkyl group of 1 to 5 carbon atoms, R42 represents a hydrogen atom, a halogen atom,
a hydroxyl group, an alkoxy group of 1 to 5 carbon atoms or an alkyl group of 1 to 5 carbon atoms, or R41 and R4~ bond together to form an oxo group, a hydroxyimino group, an alkoxyimino group of 1 to 5 carbon atoms or an alkylidene group of 1 to 5 carbon atoms,
R43 and R44 each represents a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxy group of 1 to 5 carbon atoms or an alkyl group of 1 to 5 carbon atoms, or R4J and R44 bond together to form an oxo group, a hydroxyimino group, an alkoxyimino group of 1 to 5 carbon atoms or an alkylidene group of 1 to 5 carbon atoms,
X1 represents an oxygen atom or a sulfur atom, Y1 represents a group represented by -CR45R46- [wherein R45 and R46 may be the same or different, each represents : a hydrogen atom; a halogen atom; an alkyl group of 1 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a hydroxyalkyl group of 1 to 5 carbon atoms, a carboxyl group, a mercapto group, an alkylthio group of 1 to 5 carbon atoms , a guanidyl group, a phenyl group which may be substituted, an imidazolyl group, an indolyl group, a group represented by -NHR51 (wherein R51 represents a hydrogen atom, a phenyl group which may be substituted, a pyridyl group which may be substituted, a tert-butoxycarbonyl group or a benzyloxycarbonyl group) , a group represented by -CONHR5" (wherein R5" represents a hydrogen atom or a group represented by - (CHi) m-R53 (wherein m represents
an integer of 1 to 5, and R5J represents a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl group) ) and a group represented by -OR54
(wherein R54 represents a chain alkyl group of 1 to 5 carbon atoms or a benzyl group) ; or an alkenyl group of 2 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group and a chain alkoxy group of 1 to 5 carbon atoms] , or a group represented by -CR47R48-CR49R5υ- (wherein R47, R48, R49 and R50 may be the same or different, each represents : a hydrogen atom; a halogen atom; or an alkyl group of 1 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a hydroxyalkyl group of 1 to 5 carbon atoms, a carboxyl group, a mercapto group, an alkylthio group of 1 to 5 carbon atoms , a guanidyl group, a phenyl group which may be substituted, an imidazolyl group, an indolyl group, a group represented by -NHR51-
(wherein R51 represents a hydrogen atom, a phenyl group which may be substituted, a pyridyl group which may be substituted, a tert-butoxycarbonyl group or a benzyloxycarbonyl group) , a group represented by -CONHR52 (wherein R52 represents a hydrogen atom or a group represented by - (CH2) m-R53 (wherein m represents an integer of 1 to 5, and R5J represents a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl group) ) and a group represented by -OR54
(wherein R54 represents a chain alkyl group of 1 to 5 carbon atoms or a benzyl group) , or R47, R49 and an adj acent carbon atom bond together to form: a cycloalkyl group of 3 to 8 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group, a chain alkyl group of 1 to 5 carbon atoms and a chain alkoxy group of 1 to 5 carbon atoms ; a cycloalkenyl group of 4 to 8 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group, a chain alkyl group of 1 to 5 carbon atoms and a chain alkoxy group of 1 to 5 carbon atoms ; a bicycloalkyl group of 5 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group, a chain alkyl 'group of 1 to 5 carbon atoms and a chain alkoxy group of 1 to 5 carbon atoms; or a bicycloalkenyl group of 5 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group, a chain alkyl group of 1 to 5 carbon atoms and a chain alkoxy group of 1 to 5 carbon atoms) ,
Z1 represents : a hydrogen atom; or an alkyl group of 1 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl
group, a hydroxyalkyl group of 1 to 5 carbon atoms, a carboxyl group, a mercapto group, an alkylthio group of 1 to 5 carbon atoms, a guanidyl group, a phenyl group which may be substituted, an imidazolyl group, an indolyl group, a group represented by -NHR51 (wherein R51 represents a hydrogen atom, a phenyl group which may be substituted, a pyridyl group which may be substituted, a tert-butoxycarbonyl group or a benzyloxycarbonyl group) , a group represented by -CONHR5" (wherein R5~ represents a hydrogen atom or a group represented by - (CH:) m-R53 (wherein m represents an integer of 1 to 5, and R53 represents a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl group) ) and a group represented by -OR54 (wherein R54 represents a chain alkyl group of 1 to 5 carbon atoms or a benzyl group) , or
Y1, Z1 and an adj acent nitrogen atom bond together to form a cyclic amino group of 2 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, a chain alkyl group of 1 to 5 carbon atoms and a group represented by-OR55 (wherein R55 represents a chain alkyl group of 1 to 5 carbon atoms, an aminocarbonylmethyl group or a benzyl group) ] . Detailed descriptions (e . g. , optimal conditions and production process) of these cyanopyrrolidine derivatives and pharmaceutically acceptable salts thereof are disclosed in
International Patent Publication No .02/38541 pamphlet .
Moreover, examples of other compounds that are suitable
for such a cyanopyrrolidine derivative or the like include cyanopyrrolidine derivatives and pharmaceutically acceptable salts thereof, represented by the following general formula ( 6) : [ Formula 10]
[wherein B represents an acyl group derived from naturally occurring amino acids, a group represented by the following general formula ( 7 ) : [ Formula 11]
(wherein B1 represents an alkanoyl group of 1 to 5 carbon atoms, an arylcarbonyl group which may be substituted or an alkyl group of 1 to 5 carbon atoms, and B2 represents a hydrogen atom or an alkyl group of 1 to 5 carbon atoms ) , or a group represented by the following general formula ( 8 ) : [Formula 12]
(wherein B3 and B4 may be the same or different, each represents a hydrogen atom or an alkyl group of 1 to 5 carbon atoms ) , X" represents an oxygen atom or a sulfur atom, Y" represents a group represented by -CR65R66- [wherein R65 and R66 may be the same or different, each represents : a hydrogen atom; a halogen atom; an alkyl group of 1 to 10 carbon atoms which may be substituted with one or more groups ' selected from the group consisting of a halogen atom, a hydroxyl group, a hydroxyalkyl group of 1 to 5 carbon atoms, a carboxyl group, a mercapto group, an alkylthio group of 1 to 5 carbon atoms , a guanidyl group, a phenyl group which may be substituted, an imidazolyl group, an indolyl group, a group represented by -NHR71
(wherein R71 represents a hydrogen atom, a phenyl group which may be substituted, a pyridyl group which may be substituted, a tert-butoxycarbonyl group or a benzyloxycarbonyl group) , a group represented by -CONHR72 (wherein R72 represents a hydrogen atom or a group represented by - (CH2) m-R73 (wherein m represents an integer of 1 to 5, and R73 represents a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl group) ) and a group represented by -OR74
(wherein R74 represents a chain alkyl group of 1 to 5 carbon atoms
or a benzyl group) ; or alkenyl group of 2 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group and a chain alkoxy group of 1 to 5 carbon atoms ] , or a group represented by -CR67R68-CR69R7n- (wherein R67, R58, R69 and R70 may be the same or different, each represents : a hydrogen atom; a halogen atom; or an alkyl group of 1 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a hydroxyalkyl group of 1 to 5 carbon atoms, a carboxyl group, a mercapto group, an alkylthio group of 1 to 5 carbon atoms, a guanidyl group, a phenyl group which may be substituted, an imidazolyl group, an indolyl group, a group represented by -NHR71
(wherein R71 represents a hydrogen atom, a phenyl group which may be substituted, a pyridyl group which may be substituted, a tert-butoxycarbonyl group or a benzyloxycarbonyl group) , a group represented by -CONHR72 (wherein R7: represents a hydrogen atom or a group represented by - (CH2) m-R73 (wherein m represents an integer of 1 to 5, and R73 represents a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl group) ) and a group represented by -OR74
(wherein R74 represents a chain alkyl group of 1 to 5 carbon atoms or a benzyl group) , or R67 , R69 and an adj acent carbon atom bond together to form: a cycloalkyl group of 3 to 8 carbon atoms which may be substituted with one or more groups selected from the
group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group, a chain alkyl group of 1 to 5 carbon atoms and a chain alkoxy group of 1 to 5 carbon atoms ; a cycloalkenyl group of 4 to 8 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group, a chain alkyl group of 1 to 5 carbon atoms and a chain alkoxy group of 1 to 5 carbon atoms; a bicycloalkyl group of 5 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group, a chain alkyl group of 1 to 5 carbon atoms and a chain alkoxy group of 1 to 5 carbon atoms; or a bicycloalkenyl group of 5 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group, a chain alkyl group of 1 to 5 carbon atoms and a chain alkoxy group of 1 to 5 carbon atoms) ,
Z2 represents : a hydrogen atom; or an alkyl group of 1 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a hydroxyalkyl group of 1 to 5 carbon atoms, a carboxyl group, a mercapto group, an alkylthio group of 1 to 5 carbon atoms, a guanidyl group, a phenyl group which may be substituted, an imidazolyl group, an indolyl group, a group represented by
-NHR71 (wherein R71 represents a hydrogen atom, a phenyl group which may be substituted, a pyridyl group which may be substituted, a tert-butoxycarbonyl group or a benzyloxycarbonyl group) , a group represented by -CONHR7" (wherein R/2 represents a hydrogen atom or a group represented by - (CHJ 111-R73 (wherein m represents an integer of 1 to 5, and R73 represents a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl group) ) and a group represented by -OR74 (wherein R74 represents a chain alkyl group of 1 to 5 carbon atoms or a benzyl group) , or
Y2, Z1 and an adj acent nitrogen atom bond together to form a cyclic amino group of 2 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, a chain alkyl group of 1 to 5 carbon atoms and a group represented by -OR75 (wherein R75 represents a chain alkyl group of 1 to 5 carbon atoms, an aminocarbonylmethy1 group or a benzyl group) ] . Detailed descriptions (e . g. , optimal conditions and production process) of these cyanopyrrolidine derivatives and pharmaceutically acceptable salts thereof are disclosed in International Patent Publication No .03/ 095425 pamphlet .
Furthermore, examples of other compounds that are suitable for such a cyanopyrrolidine derivative or the like include cyanofluoropyrrolidine compounds and pharmaceutically acceptable salts and hydrates thereof, represented by the following general formula ( 9 ) :
[ Formula 13 ]
[wherein V represents a hydrogen atom or a fluorine atom,
R81 and R82 may be the same or different, each represents : a hydrogen atom; an alkyl group of 1 to 6 carbon atoms which may be substituted with one or more substituents selected from the Y11 substituent group; a cycloalkyl group of 3 to 6 carbon atoms which may be substituted with one or more substituents selected from the Y12 substituent group; a cycloalkylalkyl group of 4 to 9 carbon atoms which may be substituted with one or more substituents selected from the Y12 substituent group; an alkenyl group -of 2 to 6 carbon atoms which may be substituted with one or more substituents selected from the Y1" substituent group; a cycloalkenyl group of 3 to 6 carbon atoms which may be substituted with one or more substituents selected from the Y12 substituent group; or a cycloalkenylalkyl group of 4 to 9 carbon atoms which may be substituted with one or more substituents selected from the Y12 substituent group, or R81, R82 and an adj acent carbon atom bond together to form a cycloalkyl group of 3 to 10 carbon atoms which may be substituted with one or more substituents selected from the Y12 substituent group,
X3 represents a single bond or an alkylene group of 1 to 3 carbon atoms,
R83 represents : a group represented by -N (R84) COR85, -N (R84) SO2R85, -NR84R86, -SO2R85, -SO2NR84R85, -OCONR84R85, -CH=CH-R87 or -C≡C-R87 ; or a heteroaryl group selected from heteroaryl groups which have at least one oxygen atom and/or one sulfur atom and may also have a nitrogen atom, and 6-membered nitrogen containing aromatic rings, or 9- to 11-membered condensate rings thereof (here, the heteroaryl groups may be substituted with one or more substituents selected from the Y13 substituent group) ,
(wherein R84 and R86 may be the same or different, each represents : a hydrogen atom; an alkyl group of 1 to 10 carbon atoms which may be substituted with one or more substituents selected from the Y14 substituent group; a cycloalkyl group of 3 to 6 carbon atoms which may be substituted with one or more substituents selected from the Y12 substituent group; a cycloalkylalkyl group of 4 to 9 carbon atoms which may be substituted with one or more - substituents selected from the Y12 substituent group; or an arylalkyl group which may be substituted with one or more substituents selected from the Y13 substituent group,
R85 represents : an alkyl group of 1 to 10 carbon atoms which may be substituted with one or more substituents selected from the Y14 substituent group; - (Ci_3 alkylene) -Q; or Q, the C1-3 alkylene may be substituted with one or more substituents selected from a halogen atom and a hydroxyl group, the Q
represents an aliphatic or aromatic hydrocarbon selected from a group consisting of a cycloalkyl group of 3 to 10 carbon atoms which may be substituted with one or more substituents selected from the Y13 substituent group; a bridged cyclic alkyl group of 4 to 10 carbon atoms which may be substituted with one or more substituents selected from the Y13 substituent group; an alkenyl group of 2 to 10 carbon atoms which may be substituted with one or more substituents selected from the Ylj substituent group; a cycloalkenyl group of 3 to 10 carbon atoms which may be substituted with one or more substituents selected from the Y13 substituent group; a bridged cyclic alkenyl group of 4 to 10 carbon atoms which may be substituted with one or more substituents selected from the Y13 substituent group; and an aryl groups which may be substituted with one or more substituents selected from the Y13 substituent group; or a heterocyclic ring which may be substituted with one or more substituents selected from the Y15 substituent group,
In R85 , an aryl group or heterocyclic ring may form a 5- to 8-membered ring by combining a substituent adj acent to the atom constituting its ring, and may contain one or more heteroatoms in the ring,
R84, R85 or R8S may bond to heteroatoms adj acent to R84 and R85, R84 and R86, or R85 and R86 to form a 4- to 10-membered heterocyclic ring which may be substituted with one or more substituents selected from the Y15 substituent group, and
R represents : a hydrogen atom; an alkyl group of 1 to
6 carbon atoms which may be substituted with one or more substituents selected from the Y11 substituent group; an aryl group which may be substituted with one or more substituents selected from the Y13 substituent group; or a heteroaryl group which may be substituted with one or more substituents selected from the Y13 substituent group) ,
Y11 substituent group represents a group consisting of a halogen atom, a hydroxyl group, a carboxyl group, a cyano group, an amino group, an aminocarbonyl group, a cycloalkyloxy group of 3 to 5 carbon atoms and an alkoxy group of 1 to 6 carbon atoms ,
Y12 substituent group represents a group consisting of a halogen atom, a hydroxyl group, a carboxyl group, a cyano group, an amino group, an aminocarbonyl group, a cycloalkyloxy group of 3 to 5 carbon atoms, an alkoxy group of 1 to 6 carbon atoms and an alkyl group of 1 to 6 carbon atoms,
Y13 substituent group represents a group consisting of a halogen atom, a hydroxyl group, a cyano group, a nitro group, an amino group, groups represented by -OR89, -COR89, -CO2R89, -CONR89R90, -N (R89) COR90, -N (R90) CONR90R91, -N (R89) SO2R90, -NR89R90, -SO2R89, -SO2NR89R90, -SO2N=CHNR89R90 and -OCONR89R90 (wherein R89, R90 and R91 may be the same or different, each represents : a hydrogen atom; an alkyl group of 1 to 6 carbon atoms which may be substituted with one or more substituents selected from the Y11 substituent group; a cycloalkyl group of 3 to 6 carbon atoms which may be substituted with one or more substituents selected from the Y12 substituent group; a cycloalkylalkyl group of 4 to
9 carbon atoms which may be substituted with one or more substituents selected from the Y12 substituent group; or a phenyl group which may be substituted with one or more substituents selected from the Y12 substituent group) , an alkyl group of 1 to 6 carbon atoms which may be substituted with one or more substituents selected from the Y11 substituent group, and a phenyl group which may be substituted with one or more substituents selected from the Y12 substituent group,
Y14 substituent group represents a group consisting of a halogen atom, a hydroxyl group, a cyano group, a nitro group, an amino group, groups represented by -OR89, -CORB9, -CO2R89, -CONR89R90, -N (R89) COR90, -N (R89) CONR90R91, -N (R89) SO;R90, -NR89R90, -SO2R89, -SO2NR89R90, -SO2N=CHNR89R90 and -OCONR89R90 (wherein R89, R90 and R91 may be the same or different, each represents : a hydrogen atom; an alkyl group of 1 to 6 carbon atoms which may be substituted with one or more substituents selected from the Y11 substituent group; a cycloalkyl group of 3 to 6 carbon atoms which may be substituted with one or more substituents selected from the Y12 substituent group; a cycloalkylalkyl group of 4 to 9 carbon atoms which may be substituted with one or more substituents selected from the Y12 substituent group; or a phenyl group which may be substituted with one or more substituents selected from the Y12 substituent group) and a phenyl group which may be substituted with one or more substituents selected from the Y12 substituent group, and
Y15 substituent group represents a group consisting of an
oxo group, a halogen atom, a hydroxyl group, a cyano group, a p q o n nitro group, an ammo group, groups represented by -OR " , -COR , -CO2R89, -CONR89R90, -N (R89) COR90, -N (R89) CONR90R91, -N (R89) SO2R90, -NR89R90, -SO2R89, -SO2NR89R90, -SO2N=CHNR89R90 and -OCONR89R90
(wherein R89, R9υ and R91 may be the same or different, each represents : a hydrogen atom; an alkyl group of 1 to 6 carbon atoms which may be substituted with one or more substituents selected from the Ylα substituent group; a cycloalkyl group of 3 to 6 carbon atoms which may be substituted with one or more substituents selected from the Y1" substituent group; a cycloalkylalkyl group of 4 to 9 carbon atoms which may be substituted with one or more substituents selected from the Y1" substituent group; or a phenyl group which may be substituted with one or more substituents selected from the Y1" substituent group) , an alkyl group of 1 to 6 carbon atoms which may be substituted with one or more substituents selected from the Y11 substituent group, and a phenyl group which may be substituted with one or more substituents selected from the Y12 substituent - group] . Detailed descriptions (e . g . , optimal conditions and production process ) of these cyanofluoropyrrolidine compounds or pharmaceutically acceptable salts and hydrates thereof are disclosed in International Patent Publication No .2004/101514 pamphlet.
For such a cyanopyrrolidine derivative or the like, a benzenesulfonic acid salt of
(2S, 4S) -2-cyano-4-fluoro-l- [ (2-hydroxy-1 , 1-dimethyl ) ethylam
ino] acetylpyrrolidine is more preferable because it is stable when formulated in pharmaceutical preparations . Detailed descriptions (e . g . , optimal conditions and production process ) for such a benzenesulfonic acid salt are disclosed in International Patent Publication No .2004/ 02407 pamphlet .
Examples of sugars and sugar alcohols that are added as stabilizing ingredients in the present invention include glucose, sucrose, raannitol, lactose, xylitol, sorbitol, maltitol, maltose, lactitol and dextrate . Among these, mannitol, lactose, xylitol, sorbitol, maltitol, maltose, glucose, lactitol and dextrate are preferable because it is possible to ensure the stability of the cyanopyrrolidine derivative or the like when it is formulated in pharmaceutical preparations . These sugars and sugar alcohols may be used singly or in combination of two or more .
Although the form of the compositions for solid pharmaceutical preparations of the present invention is not particularly limited, the composition is preferably in the form of granulated substance . In so doing it is made possible to ensure the stability of a cyanopyrrolidine derivative or the like when it is formulated in solid pharmaceutical preparations in which the composition for solid pharmaceutical preparations and an oral additive other than the stabilizing ingredient are contained.
The composition of the present invention for solid pharmaceutical preparations is a composition essentially
consisting of a cyanopyrrolidine derivative or the like and at least one stabilizing ingredient selected from the group consisting of sugars and sugar alcohols .
The content of the cyanopyrrolidine derivative or the like in such a composition for solid pharmaceutical preparations is 2-99wt%, preferably 5-99wt%, more preferably 10-90wt%, still more preferably 15-90wt% . This is because if the content of the cyanopyrrolidine derivative or the like is below the lower limit, it becomes difficult to ensure the stability of the cyanopyrrolidine derivative or the like even when mixed with the stabilizing ingredient .
The content of the sugars and sugar alcohols in such a composition for solid pharmaceutical preparations is l-95wt%. Although the composition of the present invention for solid pharmaceutical preparations essentially consists of a cyanopyrrolidine derivative or the like and at least one stabilizing ingredient selected from the group consisting of sugars and sugar alcohols , an oral additive other than the sugars and sugar alcohols (or stabilizing ingredients) can be added in a small content unless it influences the stability of the cyanopyrrolidine derivative or the like . The content of such a oral additive is 70wt% or less , preferably 60wt% or less , more preferably 50wt% or less , still more preferably 30wt% or less . Especially when the composition of the present invention is in the form of granulated substance, the content of such a oral additive is 10wt% or less, preferably 5wt% or less, more
preferably 2wt% or less . If the content exceeds the upper limit, the stability of the cyanopyrrolidine derivative or the like in the composition for solid pharmaceutical preparations tends to be significantly reduced.
For oral additives other than sugars and sugar alcohols ( stabilizing ingredients ) which can be added in the composition for solid pharmaceutical preparations , oral additives used for solid pharmaceutical preparations that are generally acceptable as medical drugs can be used appropriately. Examples of additives that are relatively less likely to cause the decomposition of the cyanopyrrolidine derivative or the like include stearic acid, calcium stearate , talc and pullulan .
The process for producing such a composition for solid pharmaceutical preparations is not particularly limited; examples of such a process include methods in which the cyanopyrrolidine derivative or the like and the stabilizing ingredient are granulated ( agitation granulation, fluidized bed granulation, extrusion granulation, tumbling fluidized bed- granulation and dry granulation) . In addition, the process for producing such a composition for solid pharmaceutical preparations is not limited to the foregoing granulation methods, and any publicly known process can be used appropriately, e . g . , a process is used in which a composition for solid pharmaceutical preparations is produced by mixing a cyanopyrrolidine derivative or the like and the stabilizing ingredient , and by directly compressing the resultant mixture into a tablet form.
Next, the solid pharmaceutical preparation of the present invention will be described. Specifically, the solid pharmaceutical preparation of the present invention is characterized by containing the composition for solid pharmaceutical preparations . In the solid pharmaceutical preparation of the present invention, the composition for solid pharmaceutical preparations contains a cyanopyrrolidine derivative or the like . For this reason, the decomposition of the cyanopyrrolidine derivative or the like due to the presence of other oral additives is prevented to occur when it is formulated in solid pharmaceutical preparations .
In such a solid pharmaceutical preparation, the composition for solid pharmaceutical preparations is preferably present in the form of granulated substance, and the solid pharmaceutical preparation preferably contains additional oral additives . If the composition for solid pharmaceutical preparations is present in the form of granulated substance, it is possible to ensure the stability of the cyanopyrrolidine - derivative or the like formulated in solid pharmaceutical preparations even when it is mixed with oral additives other than the stabilizing ingredients .
The oral additives added in the solid pharmaceutical preparation of the present invention are not particularly limited, and those used for solid pharmaceutical preparations that are generally acceptable as medical drugs can be used appropriately. Examples of these oral additives include
diluents, binders , disintegrators , plasticizers and lubricants . Examples of diluents include : sugar- and sugar alcohol-based diluents such as glucose, sucrose, mannitol, lactose, xylitol, sorbitol, maltitol and dextrate; cellulose-based diluents such as microcrystalline cellulose ; starch-based diluents such as cornstarch; and inorganic diluents such as dibasic calcium phosphate anhydrous . Examples of binders include cellulose-based binders such as methylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose . Examples of disintegrators include cellulose-based disintegrators such as carmellose calcium, low substituted hydroxypropylcellulose and cross carmellose sodium, and starch-based disintegrators such as partially pregelatinized starch and carboxymethyl starch sodium. Examples of plasticizers include inorganic-based plasticzers such as light sillic acid anhydride . Examples of lubricants include stearic acid, ' magnesium stearate, calcium stearate, talc and sodium stearyl fumarate . These oral additives may be used singly or in combination of two or more . In addition, the proportion of these oral additives in solid pharmaceutical preparations is not particularly limited . They can be added in an appropriate content .
The composition of the present invention for solid pharmaceutical preparations , and the solid pharmaceutical preparation of the present invention have been described. The process for producing the solid pharmaceutical preparation of
the present invention will be described below.
The process for producing the composition for solid pharmaceutical preparations of the present invention is characterized in that it includes a step ( i) in which a cyanopyrrolidine derivative represented by the foregoing general formula ( 1) or a pharmaceutically acceptable salt thereof is mixed with at least one stabilizing ingredient selected from the group consisting of sugars and sugar alcohols (and the resultant mixture may be granulated) to form a composition for solid pharmaceutical preparations, which essentially consists of the cyanopyrrolidine derivative and at least one stabilizing ingredient selected from the group consisting of sugars and sugar alcohols .
The step ( i) is one in which a cyanopyrrolidine derivative or a pharmaceutically acceptable salt thereof ( i . e . , a cyanopyrrolidine derivative or the like) is mixed with at least one stabilizing ingredient selected from the group consisting of sugars and sugar alcohols ( and the resultant mixture may be granulated) to form a composition for solid pharmaceutical preparations , which essentially consists of the cyanopyrrolidine derivative or the like and at least one stabilizing ingredient selected from the group consisting of sugars and sugar alcohols .
A cyanopyrrolidine derivative or the like used in this step ( i) is similar to the cyanopyrrolidine derivative or a pharmaceutically acceptable salt thereof contained in the
foregoing composition of the present invention for solid pharmaceutical preparations .
Although the step for producing such a composition is not particularly limited, if the composition formed in the step (i ) is mixed with oral additives used for solid pharmaceutical preparations that are generally acceptable as medical drugs to form a solid pharmaceutical preparation, it is preferable to adopt a step in which the cyanopyrrolidine derivative or the like, and the sugars and sugar alcohols ( stabilizing ingredients) are mixed together followed by granulation process ; in particular, a process (a) in which they are granulated under the presence of water is preferable ..
Examples of granulation methods adopted in the step ( a) for producing such a composition include agitation granulation, kneading granulation, fluidized bed granulation, extrusion granulation and tumbling fluidized bed granulation. Among these," agitation granulation or kneading granulation is preferable . The granulation step of the present invention can adopt a dry granulation method in addition to the granulation methods in the step (a) .
The composition for solid pharmaceutical preparations can be formulated into solid pharmaceutical preparations using methods that are known in the field of solid pharmaceutical preparations, mixing it with oral additives or without mixing it with them.
These oral additives are similar to those described in
the production of the solid pharmaceutical preparation of the present invention . Examples of publicly known methods for formulating the composition for solid pharmaceutical preparations into solid pharmaceutical preparations include : a method in which the composition is directly compressed into tablets to form solid pharmaceutical preparations ; a method in which the composition and oral additives are mixed together before compressed into tablets to form solid pharmaceutical preparations ; a method in which the composition is loaded into a capsule; and a method in which the composition and oral additives are mixed together before loaded into a capsule .
The form of the resultant solid pharmaceutical preparations is not particularly limited. They can be of any form: tablet, powder, granule or capsule .
[Examples ]
"Hereinafter, the present invention will be described in a more detailed manner based on Examples and Comparative Examples . However, the present invention is not limited to Examples described below.
[Examples 1 to 7 ]
In Examples 1 to 7 , ingredients were blended together in contents shown in Table 1 to provide the solid pharmaceutical preparations of the present invention . To be more specific, a benzenesulfonic acid salt of
( 2S, 4S) -2-cyano-4-fluoro-l- [ (2-hydroxy-l , 1-dimetyl) ethylami
no] acetylpyrrolidine (hereinafter referred to as a "compound (a) " ) and sugar alcohols (stabilizing ingredients) were first granulated in an agitation granulator (Vertical Granulator VG5, manufactured by Powrex Corporation) to produce granulated substance . Thereafter, the resultant granulated substance were dried in a fluidized bed drier ( FL-MINI, manufactured by Freund Corporation) to produce compositions for solid pharmaceutical preparations .
The compositions for solid pharmaceutical preparations thus produced after a drying process were mixed with other oral additives to produce mix powers . The mix powder thus produced was compressed into tablets using a tableting machine (VIRG019, manufactured by Kikusui Seisakusho, Ltd) . In this way tablets ( solid pharmaceutical preparations ) with a diameter of 9mm were obtained.
[Table 1]
(Examples 8 to 9 and Comparative Example 1 )
In Examples 8 to 9 and Comparative Example 1, ingredients were blended together in contents shown in Table 2 to provide solid pharmaceutical preparations . To be more specific, after mixing the compound ( a) mixed with oral additives other than calcium stearate, the resultant mixture was granulated in an agitation granulator (Vertical Granulator VG5, manufactured by Powrex Corporation) to produce granulated substance . Thereafter, the resultant granulated substance were dried in a fluidized bed drier (FL-MINI, manufactured by Freund Corporation) to produce dry powders . The dry powders mixed with Calcium stearate to produce mix powders . The mix powders thus produced were processed into solid pharmaceutical preparations .
[Table 2 ]
[Evaluation of the stability of the compounds ( a) in the solid pharmaceutical preparations obtained in Examples 1 to 4 , 8 and 9 and Comparative Example 1 ]
A stability test was performed for the solid pharmaceutical preparations obtained in Examples 1 to 4 , 8 and
9 and Comparative Example 1 at 4O0C and relative humidity of 75% . In this way the stability of the compound (a) in each solid pharmaceutical preparation was evaluated by determining the total content (%) of the decomposition products of the compound (a) (hereinafter collectively referred tς as "related substances " ) after 1 month ( "IM" in Table 3) , 3 month ( "3M" in
Table 3 ) and 6 month ( " 6M" in Table 3 ) . Note that measurement of the contents of related substances was made as follows .
1. Preparation of sample solutions
First, the solid pharmaceutical preparations obtained in Examples 1 to 4 , 8 and 9 and Comparative Example 1 were pounded in a mortar . Subsequently, the solid pharmaceutical preparations obtained in Example 8 and Comparative Example 1 were brought to a concentration of 200μg/ml with methanol and a mobile phase; those obtained in Examples 1, 2 , 5 to 7 and 9 were brought to a concentration of 400μg/ml with methanol and a mobile phase ; and those obtained in Examples 3 and 4 were brought to a concentration of 800μg/ml with methanol and a mobile phase .
2. Preparation of standard solutions
With methanol and a mobile phase, aliquots of a compound (a) solution were diluted to prepare standard solutions with concentrations that are 0.5% of those of the sample solutions . '
3. Determination of the contents of related substances
Liquid chromatography was carried out in accordance with Japanese Pharmacopoeia, whereby the contents of related substances were determined on the basis of the peak areas derived from the sample and standard solutions . The measurement conditions are as follows :
Detector : Ultraviolet absorption photometer (wavelength: 200nm)
Column: ODS column ( 4.6 x 150mm)
Column temperature : 40°C
Mobile phase : water/acetonitrile/sodium
1-octanesulfonate/phosphoric acid mixture ( 820 : 180 : 1 : 1 ) Flow rate : lmL/min
Area measurement range : about 40 minutes after sample loading Measurement results are shown in Table 3. [Table 3]
(unit : %)
[Evaluation of the stability of the compounds ( a) in the solid pharmaceutical preparation obtained in Examples 5 to 7 and 9 and Comparative Example 1]
The contents of related substances were measured after 1 month from the acceleration test in a similar manner as the contents of the related substances described above . In addition,
an acceleration test was performed for the solid pharmaceutical preparations obtained in Examples 5 to 7 and 9 and Comparative
Example 1 at 65°C . Subsequently, the contents of related substances remained after 2 weeks ( "2W" in Table 4 ) , and 4 weeks
( " 4W" in Table 4 ) were measured in a similar manner as the contents of the above-described related substances . Measurement results are shown in Table 4.
Note that standard solutions used for the measurement of the contents of related substances were prepared in a similar manner as those used for the measurement for the solid pharmaceutical preparation prepared in Examples 1 and 2. Further, sample solutions were prepared in a similar manner as the sample solutions described above after grinding the solid pharmaceutical preparations .
[Table 4 ]
(unit : %)
As can be seen from the results shown in Tables 3 and 4 ,
in the solid pharmaceutical preparations of the present invention (Examples 1 to 9) containing the composition of the present invention for solid pharmaceutical preparations there was a low rate of increase of the contents of related substances, establishing that a cyanopyrrolidine derivative or the like has a high stability compared to the comparative solid pharmaceutical preparation (Comparative Example 1 ) which do not contain sugars and sugar alcohols . That is, it has been established that in the solid pharmaceutical preparations of the present invention, the decomposition of the cyanopyrrolidine derivative or the like is prevented. (Example 10 and Comparative Example 2 )
In Example 10 and comparative Example 2 , ingredients were blended together in contents shown in Table 5 to provide solid pharmaceutical preparations . To be more specific, after mixing the compound (a) and oral additives other than calcium stearate, the re'sultant commixture was mixed with calcium stearate . The resultant mixture was compressed into tablet form by the use of a tableting machine to obtain tablets of 5.5mm in diameter .
[ Table 5 ]
[Evaluation of the stability of the compound (a) in the solid pharmaceutical preparation obtained in Example 10 and Comparative Example 2]
The contents of related substances of the compound (a) in the solid pharmaceutical preparation obtained in Example 10 and Comparative Example 2 were measured in the same manner as that for evaluating the stability of the compound (a) in the solid pharmaceutical preparation obtained in Examples 5 to 7 and Comparative Example 1 described above . Measurement results are shown in Table 6.
Note that standard solutions used for the measurement of the contents of related substances were prepared in a similar manner as those used for the measurement for the solid pharmaceutical preparation prepared in Examples 1 and 2. Further, sample solutions were prepared in a similar manner as
the sample solutions described above after grinding the solid pharmaceutical preparations . [Table 6]
(unit : %)
[ Industrial Applicability]
As described above, according to the present invention, it is possible to provide : a composition for solid pharmaceutical preparations ( although it contains a cyanopyrrolidine derivative or the like) capable of ensuring the stability of the cyanopyrrolidine derivative or the like formulated in pharmaceutical preparations and of reducing the decomposition of the cyanopyrrolidine derivative or the like due to the addition of other oral additives; a solid pharmaceutical preparation containing the composition; and a process for producing the solid pharmaceutical preparation .
Claims
1. A composition for solid pharmaceutical preparations , essentially consisting of a cyanopyrrolidine derivative represented by the following general formula ( 1 ) or a pharmaceutically acceptable salt thereof, and at least one stabilizing ingredient selected from the group consisting of sugars and sugar alcohols , [ Formula 1 ]
[wherein R1 represents a halogen atom, a hydroxyl group, an alkoxy group 'of 1 to 5 carbon atoms or an alkyl group of 1 to 5 carbon atoms , R2 represents a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxy group of 1 to 5 carbon atoms or an alkyl group of 1 to 5 carbon atoms, or R1 and R2 bond together to form an oxo group, a hydroxyimino group, an alkoxyimino group of 1 to 5 carbon atoms or an alkylidene group of 1 to 5 carbon atoms, R3 and R4 may be the same or different, each represents a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxy group of 1 to 5 carbon atoms or an alkyl group of 1 to 5 carbon atoms, or R3 and R4 bond together to form an oxo group, a hydroxyimino group, an alkoxyimino group of 1 to 5 carbon atoms or an alkylidene group of 1 to 5 carbon atoms,
X represents an oxygen atom or a sulfur atom, Y represents a group represented by -CR5R6- [wherein R5 and R6 may be the same or different, each represents a hydrogen atom; a halogen atom; an alkyl group of 1 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a hydroxyalkyl group of 1 to 5 carbon atoms, a carboxyl group, a mercapto group, an alkylthio group of 1 to 5 carbon atoms, a guanidyl group, a phenyl group which may be substituted, an imidazolyl group, an indolyl group, a group represented by -NHR11 (wherein R11 represents a hydrogen atom, a phenyl group which may be substituted, a pyridyl group which may be substituted, a tert-butoxycarbonyl group or a benzyloxycarbonyl group) , a group represented by -CONHR12 (wherein R12 represents a hydrogen atom o'r a group represented by - (CH2) In-R13 (wherein m represents an integer of 1 to 5, and R13 represents a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl group) ) and a group represented by -OR14 (wherein R14 represents a chain alkyl group of 1 to 5 carbon atoms or a benzyl group) ; or an alkenyl group of 2 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group and a chain alkoxy group of 1 to 5 carbon atoms] , or a group represented by -CR7R8-CR9R10- (wherein R7' R8' R9 and R10 may be the same or different, each represents a hydrogen atom; a halogen atom; or an alkyl group of 1 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a hydroxyalkyl group of 1 to 5 carbon atoms, a carboxyl group, a mercapto group, an alkylthio group of 1 to 5 carbon atoms, a guanidyl group, a phenyl group which may be substituted, an imidazolyl group, an indolyl group, a group represented by -NHR11 (wherein R11 represents a hydrogen atom, a phenyl group which may be substituted, a pyridyl group which may be substituted, a tert-butoxycarbonyl group or a benzyloxycarbonyl group) , a group represented by -CONHR12 (wherein R12 represents a hydrogen atom or a group represented by - (CH2) Hi-R3"3 (wherein m represents an integer of 1 to 5, and RlJ represents a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl group) ) and a group represented by -OR14 (wherein R14 represents a chain alkyl group of 1 to 5 carbon atoms or a benzyl group) , or R7, R9 and an adj acent carbon atom bond together to form: a cycloalkyl group of 3 to 8 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group, a chain alkyl group of 1 to 5 carbon atoms and a chain alkoxy group of 1 to 5 carbon atoms; a cycloalkenyl group of 4 to 8 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group, a chain alkyl group of 1 to 5 carbon atoms and a chain alkoxy group of 1 to 5 carbon atoms ; a bicycloalkyl group of 5 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group, a chain alkyl group of 1 to 5 carbon atoms and a chain alkoxy group of 1 to 5 carbon atoms ; or a bicycloalkenyl group of 5 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group, a chain alkyl group of 1 to 5 carbon atoms and a chain alkoxy group of 1 to 5 carbon atoms) ,
W represents a hydrogen atom, an acyl group derived from naturally occurring amino acids, a group represented by the following general formula (2 ) : [ Formula 2]
[wherein W1 represents an alkanoyl group of 1 to 5 carbon atoms, an arylcarbonyl group which may be substituted or an alkyl group of 1 to 5 carbon atoms , and W: represents a hydrogen atom or an alkyl group of 1 to 5 carbon atoms] , or a group represented by the following general formula ( 3) : [ Formula 3 ]
[wherein W^ and W4 may be the same or different, each represents a hydrogen atom or an alkyl group of 1 to 5 carbon atoms ] ,
Z represents a hydrogen atom; an alkyl group of 1 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a hydroxyalkyl group of 1 to 5 carbon atoms, a carboxyl group, a mercapto group, an alkylthio group of 1 to 5 carbon atoms, a guanidyl group, a phenyl group which may be substituted, an imidazolyl group, an indolyl group, a group represented by -NHR11* (wherein R11 represents a hydrogen atom, a phenyl group which may be substituted, a pyridyl group which may be substituted, a tert-butoxycarbonyl group or a benzyloxycarbonyl group) , a group represented by -CONHR12 (wherein R12 represents a hydrogen atom or a group represented by - (CH2) m~R13 (wherein m represents an integer of 1 to 5, and R13 represents a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl group) ) and a group represented by -OR14 (wherein R14 represents a chain alkyl group of 1 to 5 carbon atoms Or a benzyl group) ; or a group represented by the following general formula ( 4 ) : [ Formula 4 ]
[wherein R15 and R16 may be the same or different, each represents a hydrogen atom; an alkyl group of 1 to 6 carbon atoms which may be substituted with one or more substituents selected from the following Y1 substituent group; a cycloalkyl group of 3 to 6 carbon atoms which may be substituted with one or more substituents selected from the following Y2 substituent group; a cycloalkylalkyl group of 4 to 9 carbon atoms which may be substituted with one or more substituents selected from the following Y2 substituent group; an alkenyl group of 2 to 6 carbon atoms ' which may be substituted with one or more substituents selected from the following Y2 substituent group; a cycloalkenyl ■ group of 3 to 6 carbon atoms which may be substituted with one or more substituents selected from the following Y2 substituent group; cycloalkenylalkyl group of 4 to 9 carbon atoms which may be substituted with one or more substituents selected from the following Y~ substituent group, or R15, R16 and an adj acent carbon atom bond together to form a cycloalkyl group of 3 to 10 carbon atoms which may be substituted with one or more substituents selected from the following Y2 substituent group, A represents a single bond or an alkylene group of 1 to 3 carbon atoms,
R17 represents a group represented by -N (R18) COR19, -N (R18) SO2R19, -NR18R-0, -SO2R19, -SO2NR18R19, -OCONR18R19, -CH=CH-R21 or -C≡C-R"1 ; or a heteroaryl group selected from heteroaryl groups which have at least one oxygen atom and/or one sulfur atom and may also have a nitrogen atom, 6-membered nitrogen containing aromatic rings , and 9- to 11-membered condensate rings thereof (here, the heteroaryl groups may be substituted with one or more substituents selected from the following Y3 substituent group) ,
(wherein Rlδ and R20 may be the same or different, each represents : a hydrogen atom; an alkyl group of 1 to 10 carbon atoms which may be substituted with one or more substituents selected from the following Y4 substituent group; a cycloalkyl group of 3 to 6 carbon atoms which may be substituted with one or more substituents selected from the following YJ substituent group; a cycloalkylalkyl group of 4 to 9 carbon atoms which maybe substituted with one or more substituents selected from the following Y2 substituent group; or an arylalkyl group which may be substituted with one or more substituents selected from the following YJ substituent group,
R19 represents : an alkyl group of 1 to 10 carbon atoms which may be substituted with one or more substituents selected from the following Y4 substituent group; the following Q; or - (C1-3 alkylene) -Q, the Ci_3 alkylene may be substituted with one or more substituents selected from a halogen atom and a hydroxyl group, the Q represents an aliphatic or aromatic hydrocarbon selected from the group consisting of a cycloalkyl group of 3 to 10 carbon atoms which may be substituted with one or more substituents selected from the following Y3 substituent group; a bridged cyclic alkyl group of 4 to 10 carbon atoms which may be substituted with one or more substituents selected from the following Yό substituent group; an alkenyl group of 2 to 10 carbon atoms which may be substituted with one or more substituents selected from the following Y3 substituent group; a cycloalkenyl group of 3 to 10 carbon atoms which may be substituted with one or more substituents selected from the following Y3 substituent group; a bridged cyclic alkenyl group of 4 to 10 carbon atoms which may be substituted with one or more substituents selected from the following Y3 substituent group; and aryl groups which may be substituted with one or more substituents selected from the following Y3 substituent group; or a heterocyclic ring which may be substituted with one or more substituents selected from the following Y5 substituent group,
In R19 representing an aryl group or heterocyclic ring may form a 5- to 8-membered ring by combining a substituent adj acent to the atom constituting its ring, and may contain one or more heteroatoms in the ring,
R , R or R may bond to an heteroatom adj acent to R and R19, R18 and R-0, or R19 and R20 to form a 4- to 10-membered heterocyclic ring which may be substituted with one or more substituents selected from the following Y5 substituent group, and
R21 represents a hydrogen atom; an alkyl group of 1 to 6 carbon atoms which may be substituted with one or more substituents selected from the following Y1 substituent group; an aryl group which may be substituted with one or more substituents selected from the following Y3 substituent group; or a heteroaryl group which may be substituted with one or more substituents selected from the following Y3 substituent group) ] , or Y, Z and an adjacent nitrogen atom bond together to form a cyclic amino group of 2 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, a chain alkyl group of 1 to 5 carbon atoms and a group represented by -OR22 (wherein R22 represents a chain alkyl group of 1 to 5 carbon atoms, an aminocarbonylmethyl group or a benzyl group) ] ,
(Y1 substituent group) : a group consisting of a halogen atom, a hydroxyl group, a carboxyl group, a cyano group, an amino - group, an aminocarbonyl group, a cycloalkyloxy group of 3 to 5 carbon atoms and an alkoxy group of 1 to 6 carbon atoms,
(Y2 substituent group) : a group consisting of a halogen atom, a hydroxyl group, a carboxyl group, a cyano group, an amino group, an aminocarbonyl group, a cycloalkyloxy group of 3 to 5 carbon atoms , an alkoxy group of 1 to 6 carbon atoms and an alkyl group of 1 to 6 carbon atoms,
(YJ substituent group) : a group consisting of a halogen atom, a hydroxyl group, a cyano group, a nitro group, an amino group, groups represented by -OR30, -COR30, -CO2R30, -CONR30R31, -N (R30) COR31, -N (R30) CONR31R32, -N (R30) SO2R31, -NR30R31, -SO2R30, -SO2NR30R31, -SO2N=CHNR30R31 and -OCONR30R31 (wherein R30, R31 and R32 may be the same or different, each represents a hydrogen atom; an alkyl group of 1 to 6 carbon atoms which may be substituted with one or more substituents selected from the Y1 substituent group; a cycloalkyl group of 3 to 6 carbon atoms which may be substituted with one or more substituents selected from the Y2 substituent group; a cycloalkylalkyl group of 4 to 9 carbon atoms which may be substituted with one or more substituents selected from the Y2 substituent group; or a phenyl group which may be substituted with one or more substituents selected from the Y2 substituent group) , an alkyl group of 1 to 6 carbon atoms which may be substituted with one or more substituents selected from the Y1 substituent group, and a phenyl group "which may be substituted with one or more substituents selected from the Y^ substituent group,
(Y4 substituent group) : a group consisting of a halogen atom, a hydroxyl group, a cyano group, a nitro group, an amino group, groups represented by -OR30, -COR30, -CO2R30, -CONR30R31, -N (R30J COR31, -N (R30) CONR31R32, -N (R30J SO2R31, -NR30R31, -SO2R30, -SO2NR30R31, -SO2N=CHNR30R31 and -OCONR30R31 (wherein R30, R31 and R32 may be the same or different, each represents a hydrogen atom; an alkyl group of 1 to 6 carbon atoms which may be substituted with one or more substituents selected from the Y1 substituent group; a cycloalkyl group of 3 to 6 carbon atoms which may be substituted with one or more substituents selected from the Y" substituent group; a cycloalkylalkyl group of 4 to 9 carbon atoms which may be substituted with one or more substituents selected from the Y~ substituent group; or a phenyl group which may be substituted with one or more substituents selected from the Y"" substituent group) and a phenyl group which may be substituted with one or more substituents selected from the Y" substituent group, and
(Y5 substituent group) : a group consisting of an oxo group, a halogen atom, a hydroxyl group, a cyano group, a nitro group, an amino group, groups represented by -OR30, -CORj0, -CO2R31', -CONR30R31, -N (R3U) COR31, -N (R30J CONR31R32, -N (R30) SO2R31, -NR30R31, -SO2R30, -SO2NR30R31, -SO2N=CHNR30R31 and -OCONR30R31 (wherein R30, R31 and R32 may be the same or different, each represents a hydrogen atom; an alkyl group of 1 to 6 carbon atoms which may be substituted with one or more substituents selected from the Y1 substituent group; a cycloalkyl group of 3 to 6 carbon atoms - which may be substituted with one or more substituents selected from the Y2 substituent group; a cycloalkylalkyl group of 4 to 9 carbon atoms which may be substituted with one or more substituents selected from the Y2 substituent group; or a phenyl group which may be substituted with one or more substituents selected from the Y2 substituent group) , an alkyl group of 1 to 6 carbon atoms which may be substituted with one or more substituents selected from the Y1 substituent group, and a phenyl group which may be substituted with one or more substituents selected from the Y2 substituent group .
2. The composition for solid pharmaceutical preparations according to claim 1 , wherein the stabilizing ingredient is at least one stabilizing ingredient selected from the group consisting of mannitol, lactose, xylitol , sorbitol , maltitol , maltose, glucose, lactitol and dextrate .
3. The composition for solid pharmaceutical preparations according to claim 1 , wherein the composition is in the form of granulated substance .
4. The composition for solid pharmaceutical preparations according to claim 1 , wherein the content of an oral additive other than the stabilizing ingredient, which is contained in the composition, is 70wt% or less .
5 . The composition for solid pharmaceutical preparations according to claim 1 , wherein the cyanopyrrolidine derivative or a pharmaceutically acceptable salt thereof is a benzenesulfonic acid salt of
( 2S , 4S ) -2-cyano-4-fluoro-l- [ (2-hydroxy- l , 1-dimetyl ) ethylami no ] acetylpyrrolidine .
6 . A solid pharmaceutical preparation, containing the composition for solid pharmaceutical preparations according to any one of claims 1 to 5.
7. The solid pharmaceutical preparation according to claim 6, wherein the composition for solid pharmaceutical preparations is in the form of granulated substance , and further contains an oral additive in addition to the composition for solid pharmaceutical preparations .
8. The composition for solid pharmaceutical preparations according to claim 1 , wherein the composition is in the form of non-granulated substance .
9. A tablet obtained by directly compressing, into a tablet form, the composition for solid pharmaceutical preparations according to claim 8.
10. A process for producing a solid pharmaceutical preparation, comprising : a step of producing a composition for solid pharmaceutical preparations by mixing a cyanopyrrolidine derivative represented by the following general formula ( 1 ) or a • pharmaceutically acceptable salt thereof with at least one stabilizing ingredient selected from the group consisting of sugars and sugar alcohols, the composition essentially consisting of the cyanopyrrolidine derivative or a pharmaceutically acceptable salt thereof, and at least one stabilizing ingredient selected from the group consisting of sugars and sugar alcohols , [Formula 5] 
[wherein R1 represents a halogen atom, a hydroxyl group, an alkoxy group of 1 to 5 carbon atoms or an alkyl group of 1 to 5 carbon atoms , R~ represents a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxy group of 1 to 5 carbon atoms or an alkyl group of 1 to 5 carbon atoms, or R1 and R2 bond together to form an oxo group, a hydroxyimino group, an alkoxyimino group of 1 to 5 carbon atoms or an alkylidene group of 1 to 5 carbon atoms, R3 and R4 may be the same or different, each represents a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxy group "of 1 to 5 carbon atoms or an alkyl group of 1 to 5 carbon atoms , or R3 and R4 bond together to form an oxo group, a hydroxyimino group, an alkoxyimino group of 1 to 5 carbon atoms or an alkylidene .group of 1 to 5 carbon atoms,
X represents an oxygen atom or a sulfur atom, Y represents a group represented by -CR5R6- [wherein R5 and R6 may be the same or different, each represents a hydrogen atom; a halogen atom; an alkyl group of 1 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a hydroxyalkyl group of 1 to 5 carbon atoms, a carboxyl group, a mercapto group, an alkylthio group of 1 to 5 carbon atoms , a guanidyl group, a phenyl group which may be substituted, an imidazolyl group, an indolyl group, a group represented by -NHR11 (wherein R11 represents a hydrogen atom, a phenyl group which may be substituted, a pyridyl group which may be substituted, a tert-butoxycarbonyl group or a benzyloxycarbonyl group) , a group represented by -CONHR12 (wherein R12 represents a hydrogen atom or a group represented by - (CH2) m-R13 (wherein m represents an integer of 1 to 5, and R13 represents a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl group) ) and a group represented by -OR14 (wherein R14 represents a chain alkyl group of 1 to 5 carbon atoms or a benzyl group) ; or an alkenyl group of 2 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group and a chain alkoxy group of 1 to 5 carbon atoms] , or a group represented by -CRV-CR9R10- (wherein R7, R8, R9 and R10 may be the same or different, each represents a hydrogen atom; a halogen atom; or an alkyl group of 1 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a hydroxyalkyl group of 1 to 5 carbon atoms, a carboxyl group, a mercapto group, an alkylthio group of 1 to 5 carbon atoms, a guanidyl group, a phenyl group which may be substituted, an imidazolyl group, an indolyl group, a group represented by -NHR11 (wherein R11 represents a hydrogen atom, a phenyl group which may be substituted, a pyridyl group which may be substituted, a tert-butoxycarbonyl group or a benzyloxycarbonyl group) , a group represented by -CONHR1" (wherein R12 represents a hydrogen atom or a group represented by - (CHi) 1n-R13 (wherein m represents an integer of 1 to 5, and R13 represents a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl group) ) and a group represented by -OR14 (wherein R14 represents a chain alkyl group of 1 to 5 carbon atoms or a benzyl group) , or R7, RQ and an adj acent carbon atom bond together to form: a cycloalkyl group of 3 to 8 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group, a chain alkyl group of 1 to 5 carbon atoms and a chain alkoxy group of 1 to 5 carbon atoms ; a cycloalkenyl group of 4 to 8 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group, a chain alkyl group of 1 to 5 carbon atoms and a chain alkoxy group of 1 to 5 carbon atoms ; a bicycloalkyl group of 5 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group, a chain alkyl group of 1 to 5 carbon atoms and a chain alkoxy group of 1 to 5 carbon atoms ; or a bicycloalkenyl group of 5 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group, a chain alkyl group of 1 to 5 carbon atoms and a chain alkoxy group of 1 to 5 carbon atoms) ,
W represents a hydrogen atom, an acyl group derived from naturally occurring amino acids, a group represented by the following general formula (2 ) : [ Formula 6]
[wherein W1 represents an alkanoyl group of 1 to 5 carbon atoms , an arylcarbonyl group which may be substituted or an alkyl group of 1 to 5 carbon atoms , and W2 represents a hydrogen atom or an alkyl group of 1 to 5 carbon atoms] , or a group represented by the following general formula (3) : [ Formula 7 ]
[wherein W3 and W4 may be the same or different, each represents a hydrogen atom or an alkyl group of 1 to 5 carbon atoms ] ,
Z represents a hydrogen atom; an alkyl group of 1 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a hydroxyalkyl group of 1 to 5 carbon atoms, a carboxyl group, a mercapto group, an alkylthio group of 1 to 5 carbon atoms, a guanidyl group, a phenyl group which may be substituted, an imidazolyl group, an indolyl group, a group represented by -NHR11 (wherein R11 represents a hydrogen atom, a phenyl group which may be substituted, a pyridyl group which may be substituted, a tert-butoxycarbonyl group or a benzyloxycarbonyl group) , a group represented by -CONHR12 (wherein' R1" represents a hydrogen atom or a group represented by - (CH?J m-R3"* (wherein m represents an integer of 1 to 5, and R13 represents a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl group) ) and a group represented by -OR14 (wherein R14 represents a chain alkyl group of 1 to 5 carbon atoms or a benzyl group) ; or a group represented by the following- general formula ( 4 ) : [ Formula 8 ]
[wherein R and R may be the same or different, each represents a hydrogen atom; an alkyl group of 1 to 6 carbon atoms which may be substituted with one or more substituents selected from the following Y1 substituent group; a cycloalkyl group of 3 to 6 carbon atoms which may be substituted with one or more substituents selected from the following Y2 substituent group; a cycloalkylalkyl group of 4 to 9 carbon atoms which may be substituted with one or more substituents selected from the following Y2 substituent group ; an alkenyl group of 2 to 6 carbon atoms which may be substituted with one or more substituents selected from the following Y2 substituent group; a cycloalkenyl group of 3 to 6 carbon atoms which may be substituted with one or more substituents selected from the following Y" substituent group; cycloalkenylalkyl group of 4 to 9 carbon atoms which may be substituted with one or more substituents selected from the following Y" substituent group, or R15, R16 and an adj acent carbon atom bond together to form a cycloalkyl group of 3 to 10 carbon atoms 'which may be substituted with one or more substituents selected from the following Y2 substituent group,
A represents a single bond or an alkylene group of 1 to 3 carbon atoms,
R17 represents a group represented by -N (R18 ) COR19, -N (R18) SO2R19, -NR18R20, -SO2R19, -SO2NR18R19, -OCONR18R19, -CH=CH-R21 or -C≡C-R^1; or a heteroaryl group selected from heteroaryl groups which have at least one oxygen atom and/or one sulfur atom and may also have a nitrogen atom, 6-membered nitrogen containing aromatic rings, and 9- to 11-membered condensate rings thereof (here, the heteroaryl groups may be substituted with one or more substituents selected from the following Y3 substituent group) ,
(wherein R18 and R20 may be the same or different, each represents : a hydrogen atom; an alkyl group of 1 to 10 carbon atoms which may be substituted with one or more substituents selected from the following Y4 substituent group; a cycloalkyl group of 3 to 6 carbon atoms which may be substituted with one or more substituents selected from the following Y~ substituent group; a cycloalkylalkyl group of 4 to 9 carbon atoms which may be substituted with one or more substituents selected from the following Y" substituent group; or an arylalkyl group which may be substituted with one or more substituents selected from the following Y3 substituent group,
R19 represents : an alkyl group of 1 to 10 carbon atoms which may be substituted with one or more substituents selected from the following Y4 substituent group; the following Q; or - (Ci_3 alkylene) -Q, the C1-3 alkylene may be substituted with one or more substituents selected from a halogen atom and a hydroxyl group, the Q represents an aliphatic or aromatic hydrocarbon selected from the group consisting of a cycloalkyl group of 3 to 10 carbon atoms which may be substituted with one or more substituents selected from the following Y3 substituent group; a bridged cyclic alkyl group of 4 to 10 carbon atoms which may be substituted with one or more substituents selected from the following Y3 substituent group; an alkenyl group of 2 to 10 carbon atoms which may be substituted with one or more substituents selected from the following YJ substituent group; a cycloalkenyl group of 3 to 10 carbon atoms which may be substituted with one or more substituents selected from the following Y3 substituent group; a bridged cyclic alkenyl group of 4 to 10 carbon atoms which may be substituted with one or more substituents selected from the following Y3 substituent group; and aryl groups which may be substituted with one or more substituents selected from the following Y3 substituent group; or a heterocyclic ring which may be substituted with one or more substituents selected from the following Y5 substituent group,
In R19 , representing an aryl group or heterocyclic ring may form a 5- to 8-membered ring by combining a substituent adj acent to the atom constituting its ring, and may contain one or more heteroatoms in the ring,
R18, R19 or R20 may bond to an heteroatom adj acent to R18 and R1-9, R18 and R20, or R19 and R20 to form a 4- to 10-membered heterocyclic ring which may be substituted with one or more substituents selected from the following Y5 substituent group, and
R21 represents a hydrogen atom; an alkyl group of 1 to 6 carbon atoms which may be substituted with one or more substituents selected from the following Y1 substituent group; an aryl group which may be substituted with one or more substituents selected from the following YJ substituent group; or a heteroaryl group which may be substituted with one or more substituents selected from the following YJ substituent group) ] , or Y, Z and an adj acent nitrogen atom bond together to form a cyclic amino group of 2 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, a chain alkyl group of 1 to 5 carbon atoms and a group represented by -OR"2 (wherein R22 represents a chain alkyl group of 1 to 5 carbon atoms, an aminocarbonylmethyl group or a benzyl group) ] ,
(Y1 substituent group) : a group consisting of a halogen atom, a hydroxyl group, a carboxyl group, a cyano group, an amino group, an aminocarbonyl group, a cycloalkyloxy group of 3 to 5 carbon atoms and an alkoxy group of 1 to 6 carbon atoms,
(Y2 substituent group) : a group consisting of a halogen atom, a hydroxyl group, a carboxyl group, a cyano group, an amino group, an aminocarbonyl group, a cycloalkyloxy group of 3 to 5 carbon atoms, an alkoxy group of 1 to 6 carbon atoms and an alkyl "group of 1 to 6 carbon atoms,
(Y3 substituent group) : a group consisting of a halogen atom, a hydroxyl group, a cyano group, a nitro group, an amino group, groups represented by -OR30, -COR30, -CO2R30, -CONR30R31, -N (R30) COR31, -N (R30) CONR31R32, -N (R30) SO2R31, -NR30R31, -SO2R30, -SO2NR30R31, -SO2N=CHNR30R31 and -OCONR30R31 (wherein R30, R31 and R32 may be the same or different, each represents a hydrogen atom; an alkyl group of 1 to 6 carbon atoms which may be substituted with one or more substituents selected from the Y1 substituent group; a cycloalkyl group of 3 to 6 carbon atoms which may be substituted with one or more substituents selected from the Y2 substituent group; a cycloalkylalkyl group of 4 to 9 carbon atoms which may be substituted with one or more substituents selected from the Y2 substituent group; or a phenyl group which may be substituted with one or more substituents selected from the Y" substituent group) , an alkyl group of 1 to 6 carbon atoms which may be substituted with one or more substituents selected from the Y1 substituent group, and a phenyl group which may be substituted with one or more substituents selected from the Y2 substituent group,
(Y4 substituent group) : a group consisting of a halogen atom, a hydroxyl group, a cyano group, a nitro group, an amino group, groups represented by -OR30, -COR30, -CO2R30, -CONR30R31, -N (R30) COR31, -N (R30) CONR31R32, -N (R30) SO2R31, -NR30R31, -SO2R30, -SO2NR30R31, -SO2N=CHNR30R31 and -OCONR30R31 (wherein R30, R31 and R32 may be the same or different, each represents a hydrogen atom; " an alkyl group of 1 to 6 carbon atoms which may be substituted with one or more substituents selected from the Y1 - substituent group; a cycloalkyl group of 3 to 6 carbon atoms which may be substituted with one or more substituents selected from the Y2 substituent group; a cycloalkylalkyl group of 4 to 9 carbon atoms which may be substituted with one or more substituents selected from the Y2 substituent group; or a phenyl group which may be substituted with one or more substituents selected from the Y" substituent group) and a phenyl group which may be substituted with one or more substituents selected from the Y~ substituent group, and
(Y5 substituent group) : a group consisting of an oxo group, a halogen atom, a hydroxyl group, a cyano group, a nitro group, an amino group, groups represented by -OR30, -COR30, -CO2R30, -CONR30R31 , -N (R30) COR31, -N (R30) CONR31R3S -N (R3υ) SO;R31, -NR30R31, -SO2R30, -SO2NR30R31, -SO2N=CHNR30R31 and -OCONR30R31 (wherein R3υ, R31 and R32 may be the same or different, each represents a hydrogen atom; an alkyl group of 1 to 6 carbon atoms which may be substituted with one or more substituents selected from the Y1 substituent group; a cycloalkyl group of 3 to 6 carbon atoms which may be substituted with one or more substituents selected from the Y2 substituent group; a cycloalkylalkyl group of 4 to 9 carbon atoms which may be substituted with one or more substituents selected from the Y2 substituent group; or a phenyl group which may be substituted with one or more substituents selected from the Y2 substituent group) , an alkyl group of 1 to 6 carbon atoms which may be substituted with one or more substituents selected from the Y1 substituent group, and a phenyl group which may be substituted with one or more substituents selected from the Y2 substituent group .
11. The process according to claim 10, wherein the step of producing the composition for solid pharmaceutical preparations further comprises a step of producing the composition for solid pharmaceutical preparations by mixing the cyanopyrrolidine derivative or a pharmaceutically acceptable salt thereof with at least one stabilizing ingredient selected from the group consisting of sugars and sugar alcohols, and by granulating the resultant mixture .
12. The process according to claim 11 , wherein the step of producing the composition for solid pharmaceutical preparations is a step in which the cyanopyrrolidine derivative or a pharmaceutically acceptable salt thereof is mixed with the stabilizing ingredient and then the resultant mixture is granulated in the presence of water .
13. The process according to claim 10, wherein the step of producing the composition for solid pharmaceutical preparations is a step in which the cyanopyrrolidine derivative or a pharmaceutically acceptable salt thereof is mixed with at least one stabilizing ingredient selected from the group consisting of sugars and sugar alcohols, and then the resultant mixture is directly compressed into a tablet form.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2005-022193 | 2005-01-28 | ||
| JP2005022193A JP2008024592A (en) | 2005-01-28 | 2005-01-28 | Cyanopyrrolidine derivative-containing composition for solid preparation, solid preparation containing the composition and process for producing the solid preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2006080412A2 true WO2006080412A2 (en) | 2006-08-03 |
| WO2006080412A3 WO2006080412A3 (en) | 2006-09-21 |
Family
ID=36570928
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/JP2006/301258 WO2006080412A2 (en) | 2005-01-28 | 2006-01-20 | Cyanopyrrolidine derivative-containing composition for solid pharmaceutical preparations, solid pharmaceutical preparation containing the composition, and process for producing the solid pharmaceutical preparation |
Country Status (6)
| Country | Link |
|---|---|
| JP (1) | JP2008024592A (en) |
| AR (1) | AR052197A1 (en) |
| DO (1) | DOP2006000019A (en) |
| PE (1) | PE20061199A1 (en) |
| TW (1) | TW200637815A (en) |
| WO (1) | WO2006080412A2 (en) |
Citations (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0280999A2 (en) * | 1987-02-24 | 1988-09-07 | Warner-Lambert Company | Stabilized pharmaceutical compositions containing angiotensin-converting enzyme inhibitors |
| WO2000034241A1 (en) * | 1998-12-10 | 2000-06-15 | Novartis Ag | N-substituted 2-cyanopyrrolidines |
| WO2001068603A2 (en) * | 2000-03-10 | 2001-09-20 | Bristol-Myers Squibb Co. | Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl iv, processes for their preparation, and their use |
| WO2001096295A2 (en) * | 2000-06-13 | 2001-12-20 | Novartis Ag | 2-cyanopyrrolidine derivatives and their use as medicaments |
| WO2003057144A2 (en) * | 2001-12-26 | 2003-07-17 | Guilford Pharmaceuticals | Change inhibitors of dipeptidyl peptidase iv |
| EP1333025A1 (en) * | 2000-11-10 | 2003-08-06 | Taisho Pharmaceutical Co., Ltd | Cyanopyrrolidine derivatives |
| WO2003074500A2 (en) * | 2002-03-06 | 2003-09-12 | Sanofi-Aventis | N-aminoacetyl-pyrrolidine-2-carbonitriles and their use as ddp-iv inhibitors |
| WO2004009544A1 (en) * | 2002-07-23 | 2004-01-29 | Yamanouchi Pharmaceutical Co., Ltd. | 2-cyano-4-fluoropyrrolidine derivative or its salt |
| WO2004020407A1 (en) * | 2002-08-29 | 2004-03-11 | Taisho Pharmaceutical Co.,Ltd. | Benzenesulfonate of 4-fluoro-2-cyanopyrrolidine derivative |
| US20040235752A1 (en) * | 2001-06-25 | 2004-11-25 | Pitt Gary Robert William | 3-fluoro-pyrrolidines as antidiabetic agents |
| WO2005021536A2 (en) * | 2003-08-29 | 2005-03-10 | Sanofi-Aventis | Adamantane and azabicyclo-octane and nonane derivatives, process of their preparation and their use as dpp-iv inhibitors |
| WO2005067976A2 (en) * | 2004-01-20 | 2005-07-28 | Novartis Ag | Direct compression formulation and process |
-
2005
- 2005-01-28 JP JP2005022193A patent/JP2008024592A/en active Pending
-
2006
- 2006-01-20 WO PCT/JP2006/301258 patent/WO2006080412A2/en not_active Application Discontinuation
- 2006-01-24 PE PE2006000103A patent/PE20061199A1/en not_active Application Discontinuation
- 2006-01-24 DO DO2006000019A patent/DOP2006000019A/en unknown
- 2006-01-24 AR ARP060100263A patent/AR052197A1/en not_active Application Discontinuation
- 2006-01-25 TW TW095102875A patent/TW200637815A/en unknown
Patent Citations (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0280999A2 (en) * | 1987-02-24 | 1988-09-07 | Warner-Lambert Company | Stabilized pharmaceutical compositions containing angiotensin-converting enzyme inhibitors |
| WO2000034241A1 (en) * | 1998-12-10 | 2000-06-15 | Novartis Ag | N-substituted 2-cyanopyrrolidines |
| WO2001068603A2 (en) * | 2000-03-10 | 2001-09-20 | Bristol-Myers Squibb Co. | Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl iv, processes for their preparation, and their use |
| WO2001096295A2 (en) * | 2000-06-13 | 2001-12-20 | Novartis Ag | 2-cyanopyrrolidine derivatives and their use as medicaments |
| EP1333025A1 (en) * | 2000-11-10 | 2003-08-06 | Taisho Pharmaceutical Co., Ltd | Cyanopyrrolidine derivatives |
| US20040235752A1 (en) * | 2001-06-25 | 2004-11-25 | Pitt Gary Robert William | 3-fluoro-pyrrolidines as antidiabetic agents |
| WO2003057144A2 (en) * | 2001-12-26 | 2003-07-17 | Guilford Pharmaceuticals | Change inhibitors of dipeptidyl peptidase iv |
| WO2003074500A2 (en) * | 2002-03-06 | 2003-09-12 | Sanofi-Aventis | N-aminoacetyl-pyrrolidine-2-carbonitriles and their use as ddp-iv inhibitors |
| WO2004009544A1 (en) * | 2002-07-23 | 2004-01-29 | Yamanouchi Pharmaceutical Co., Ltd. | 2-cyano-4-fluoropyrrolidine derivative or its salt |
| WO2004020407A1 (en) * | 2002-08-29 | 2004-03-11 | Taisho Pharmaceutical Co.,Ltd. | Benzenesulfonate of 4-fluoro-2-cyanopyrrolidine derivative |
| WO2005021536A2 (en) * | 2003-08-29 | 2005-03-10 | Sanofi-Aventis | Adamantane and azabicyclo-octane and nonane derivatives, process of their preparation and their use as dpp-iv inhibitors |
| WO2005067976A2 (en) * | 2004-01-20 | 2005-07-28 | Novartis Ag | Direct compression formulation and process |
Also Published As
| Publication number | Publication date |
|---|---|
| AR052197A1 (en) | 2007-03-07 |
| PE20061199A1 (en) | 2006-11-18 |
| DOP2006000019A (en) | 2006-07-15 |
| JP2008024592A (en) | 2008-02-07 |
| TW200637815A (en) | 2006-11-01 |
| WO2006080412A3 (en) | 2006-09-21 |
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