JPS5943463B2 - Method for producing polymorphic crystalline compound of dibenzopyranone - Google Patents
Method for producing polymorphic crystalline compound of dibenzopyranoneInfo
- Publication number
- JPS5943463B2 JPS5943463B2 JP49127923A JP12792374A JPS5943463B2 JP S5943463 B2 JPS5943463 B2 JP S5943463B2 JP 49127923 A JP49127923 A JP 49127923A JP 12792374 A JP12792374 A JP 12792374A JP S5943463 B2 JPS5943463 B2 JP S5943463B2
- Authority
- JP
- Japan
- Prior art keywords
- crystalline compound
- dimethyl
- hydroxy
- polymorphic crystalline
- hexahydro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/78—Ring systems having three or more relevant rings
- C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrane Compounds (AREA)
- Medicinal Preparation (AREA)
- Peptides Or Proteins (AREA)
- Saccharide Compounds (AREA)
Description
【発明の詳細な説明】
本発明はジベンゾピラノンの多形結晶型化合物の製法、
更に詳しくは１−ヒドロキシー ３−（１’、１’−ジ
メチノＬ−ーーー７チノレ）−６、６−ジメチルー６、
６ａ、７、８、１Ｏ、１０ａ−ヘキサヒドロ−。DETAILED DESCRIPTION OF THE INVENTION The present invention provides a method for producing a polymorphic crystalline compound of dibenzopyranone,
More specifically, 1-hydroxy-3-(1',1'-dimethino L----7tinole)-6,6-dimethyl-6,
6a,7,8,1O,10a-hexahydro-.
９Ｈ−ジペンゾ〔ｂ、ｄ〕ピランー９−オンの安定な新
規同質多形結晶型化合物の製法に関する。The present invention relates to a method for producing a stable new homogeneous polymorphic crystalline compound of 9H-dipenzo[b,d]pyran-9-one.
本発明目的化合物はこれを哺乳動物に経口的に投与した
とき、長期間に渡つてその血中濃度を有意に保持せしめ
ることができる。従来、１−ヒドロキシー３−アルキル
ー６ ６一ジメチルー６、６ａ、７、８、１Ｏ、１０ａ
−へキサヒドロー９Ｈ−ジペンゾ〔ｂ、ｄ）ピランー９
−オン類、そのエーテル類およびエステル類はΔ８−ま
たはΔ９−テトラヒドロカンビノール（以下、Δ８−ま
たはΔ９ＴＨＣと略称する。When the compound of the present invention is orally administered to a mammal, its blood concentration can be maintained significantly for a long period of time. Conventionally, 1-hydroxy-3-alkyl-6 6-dimethyl-6, 6a, 7, 8, 1O, 10a
-hexahydro 9H-dipenzo [b, d) pyran-9
-ones, their ethers and esters are Δ8- or Δ9-tetrahydrocambinol (hereinafter abbreviated as Δ8- or Δ9THC).
製造のための中間体として、米国特許第３．５０７．８
８５号に開示されている。しかし、この化合物は上記中
間体としての有用性以外の有用性については何ら開示さ
れていない。天然に得られるかまたは種々の合成法によ
り製せられるΔ９−ＴＨＣおよびその構造と関連性を有
する他のジベンゾピラン類は水性媒体に対して著しく不
溶性である。As an intermediate for the manufacture, U.S. Patent No. 3.507.8
It is disclosed in No. 85. However, no utility of this compound other than the above-mentioned utility as an intermediate is disclosed. Δ9-THC and other dibenzopyrans related to its structure, either naturally occurring or prepared by various synthetic methods, are highly insoluble in aqueous media.
かかる不溶性物質の経口投与後における吸収量に関して
著しい不確定性が存在するので、従来、この種の化合物
を経口的に投与した場合の薬理学的活性を見極めること
において問題があつた。これら化合物の吸収度に関する
不確定性はこの化合物が固体状態において数種の同質多
形形態で存在する傾向があることにより更に複雑になつ
ている。本発明は１−ヒドロキシ−３−（１！，１′−
ジメチルヘプチノ（ハ）−６，６−ジメチル−６，６ａ
，７ ８ １０ １０ａ−ヘキサヒドロ−９Ｈ−ジ９
９ ９ベンゾ〔ｂ，ｄ〕ビラン
−９−オンの安定な新規同質多形物質の製法を提供する
ものであつて、この物質は次のごとき物理的特性を有す
る。There has heretofore been a problem in determining the pharmacological activity of orally administered compounds of this type because there is significant uncertainty regarding the amount absorbed after oral administration of such insoluble substances. The uncertainty regarding the absorbance of these compounds is further complicated by the fact that the compounds tend to exist in several polymorphic forms in the solid state. The present invention provides 1-hydroxy-3-(1!,1'-
Dimethylheptino(ha)-6,6-dimethyl-6,6a
,7 8 10 10a-hexahydro-9H-di9
The present invention provides a method for producing a stable new polymorphic substance of 99benzo[b,d]bilan-9-one, which has the following physical properties.
すなわち、偏光顕微鏡下に複屈折性を示し、示差熱分析
により１５６℃および１６２℃で吸熱現象を示し、また
フイルターにかけた波長２．２８９６人のクロム輻射線
を使用して測定したとき、下記のＸ線粉末回折図を示す
：本発明における新規同質多形結晶型化合物は次の方法
により製造することができる：アセトンもしくはヘキサ
ンから再結晶して製せられ、経口的に投与したとき吸収
性がなく、生理学的に使用し得ないものであつてかつ咄
乳動物に経口的に投与後その血中濃度を有意に保持し得
ない１−ヒドロキシ−３−（１′，１′−ジメチルヘプ
チル）−６，６−ジメチル−６ ６ａ ７ ８ １０
１０ａ９ ラ ９ ９
９ヘキサヒドロ−９Ｈ−ジベンゾ〔ｂ，ｄ］ビ
ラン−９−オンの多形結晶型化合物のエタノ一ル溶液を
大量の水に強く攪拌しながら加える。That is, it shows birefringence under a polarizing microscope, shows an endothermic phenomenon at 156°C and 162°C by differential thermal analysis, and when measured using filtered chromium radiation with a wavelength of 2.2896 cm, the following: Shows an X-ray powder diffraction pattern: The novel homogeneous polymorphic crystalline compound of the present invention can be produced by the following method: It is produced by recrystallization from acetone or hexane, and when administered orally, the absorption is 1-Hydroxy-3-(1',1'-dimethylheptyl), which cannot be used physiologically and whose blood concentration cannot be maintained significantly after oral administration to mammals. -6,6-dimethyl-6 6a 7 8 10
10a9 la 9 9
An ethanolic solution of the polymorphic crystalline compound of 9hexahydro-9H-dibenzo[b,d]vilan-9-one is added to a large amount of water with vigorous stirring.
このジベンゾピラノン化合物は実質的に水に不溶であつ
て直ちに沈殿する。この沈殿生成を抑制するため短時間
攪拌を続けると前記の物理的特性を有する所望の同質多
形薬剤が沈殿するからこれを濾集し、乾燥する。新規同
質多形結晶型化合物から、より一般的な通常の結晶型化
合物（アセトンもしくはヘキサンから再結晶して得られ
る化合物）への転移を防止するため、結晶生長遅延剤た
とえばポリビニルピロリドン、メチルセルロース、アル
ギン酸ナトリウム、デキストラン、ゼラチンまたはアラ
ビアゴムを使用することができる。This dibenzopyranone compound is substantially insoluble in water and readily precipitates. When stirring is continued for a short period of time to suppress the formation of this precipitate, the desired homogeneous polymorphic drug having the above-mentioned physical properties precipitates, which is collected by filtration and dried. In order to prevent the transition from the new homogeneous polymorphic crystalline compound to the more common normal crystalline compound (compound obtained by recrystallization from acetone or hexane), crystal growth retarders such as polyvinylpyrrolidone, methylcellulose, and alginic acid are used. Sodium, dextran, gelatin or gum arabic can be used.
かかる遅延剤を使用するのが好ましいのであれば、これ
を前記化合物のエタノ一ル溶液の添加に先立つて水に加
えるのが適当である。上記方法により製せられた１−ヒ
ドロキシ−３−（１′，１！−ジメチルヘプチル）−６
，６−ジメチル−６，６ａ，７，８，１０，１０ａ−ヘ
キサヒドロ−９Ｈ−ジベンゾ〔ｂ，ｄ〕ピラン−９ーオ
ンの比較的吸収性大なる同質多形物質１部を含む薬理学
的生成物をコーンスターチ９部と完全に混合し、混合物
を差込み式ゼラチンカプセル中に封入し、これを２匹の
犬に投与してその吸収性試験を行つた。If such a retarder is desired to be used, it is appropriate to add it to the water prior to addition of the ethanolic solution of the compound. 1-hydroxy-3-(1',1!-dimethylheptyl)-6 produced by the above method
, 6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one, including one part of the relatively highly absorbable homogeneous polymorph. The product was thoroughly mixed with 9 parts of corn starch, the mixture was encapsulated in a plug-in gelatin capsule, and its absorption was tested by administering it to two dogs.
この試験においてカプセル剤型に製剤した目的化合物を
経口的に投与した。吸収性を有する他の経口的投与剤型
または非経口的注射剤型を投与した場合に観察される副
作用、即ち点頭痙れん、震いおよぴ運動失調などが観察
された。スターチを配合したカプセル用組成物を２週間
後に試験した結果、本発明の同質多形物質はスターチの
存在下に安定であつた。更に１０週間後に試．験して同
一の結果を得た。１−ヒドロキシ−３−（１！，１１−
ジメチルヘプチノ（ハ）−６，６−ジメチル−６ ６ａ
７ ８ １０ １０ａ−ヘキサヒ９
９ ９ ９ ９ドロ−
９Ｈ−ジベンゾ〔ｂ，ｄ〕ピラン−９−オンの他の同質
多形物質は溶液中またはスターチと混合した直後におい
ては活性を有するが、明らかに徐々に再結晶するかまた
はスターチと結合して生物学的有用率（バイオアベイラ
ビリテイー）に好ましくない影響を与える。In this test, the target compound formulated in capsule form was orally administered. Side effects observed when administering other absorbable oral dosage forms or parenteral injection dosage forms, such as instillation spasms, tremors, and ataxia, were observed. The capsule composition containing starch was tested after two weeks, and the polymorphic substance of the present invention was stable in the presence of starch. Try again after 10 weeks. I tried it and got the same result. 1-hydroxy-3-(1!,11-
Dimethylheptino(ha)-6,6-dimethyl-6 6a
7 8 10 10a-hexahi 9
9 9 9 9 draw
Other polymorphs of 9H-dibenzo[b,d]pyran-9-one are active in solution or immediately after mixing with starch, but apparently gradually recrystallize or combine with starch. Unfavorably affects biological availability.
次に実施例を挙げて本発明の具体的実施態様を説明する
。Next, specific embodiments of the present invention will be described with reference to Examples.
実施例 １
水１０００ｍｌに１−ヒドロキシ−３−（１７，１′ジ
メチルーヘプチル）−６，６−ジメチルー６ ６ａ ７
８ １０ １０ａ−ヘキサヒドロ−９Ｈ−ジベンゾ〔
ｂ，ｄ〕ピラン−９−オン１９のエタノ一ル２５ｍｌ溶
液を、約２５℃で高速攪拌しながら添加する。Example 1 1-Hydroxy-3-(17,1'dimethyl-heptyl)-6,6-dimethyl-6 6a 7 in 1000 ml of water
8 10 10a-hexahydro-9H-dibenzo [
b, d] A solution of pyran-9-one 19 in 25 ml of ethanol is added at about 25° C. with high speed stirring.
エタノ一ル溶液を添加後、約４時間攪拌を続ける。１−
ヒドロキシ−３−（１′，１′−ジメチルヘプチル）−
６，６−ジメチル一６６ａ７８１０１０ａ−ヘキサヒド
ロー９Ｈ−ジベンゾ〔Ｂ，ｄ〕ピラン一９−オンが沈殿
する。After adding the ethanol solution, continue stirring for about 4 hours. 1-
Hydroxy-3-(1',1'-dimethylheptyl)-
6,6-dimethyl-66a781010a-hexahydro-9H-dibenzo[B,d]pyran-9-one precipitates.
Claims (1)
メチルヘプチル）−６′、６′−ジメチル−６，６ａ，
７，８，１０，１０ａ−ヘキサヒドロ９Ｈ−ジベンゾ〔
ｂ，ｄ〕ピラン−９−オンのエタノール溶液を急速攪拌
しながら添加することを特徴とする物理的特性として偏
光顕微鏡下に複屈折性を示し、示差熱分析により１５６
℃および１６２℃で吸熱現象を示し、またフィルターに
かけた波長２．２８９６Åのクロム輻射線を使用して測
定したとき￥ｄ（Å）￥ ￥Ｉ／Ｉ＿０￥ １４．５ １００ １０．５ ３０ ８．４ ６０ ７．２ ４０ ６．５０ ２０ ５．９０ ３０ ￥ｄ（Å）￥ ￥Ｉ／Ｉ＿０￥ ４．８５ ６０ ４．１０ ０５ ３．９０ ４０ ３．３５ ３０ で表わされるＸ線粉末回折図を示す１−ヒドロキシ−３
−（１′，１′−ジメチルヘプチル）−６，６−ジメチ
ル−６，６ａ，７，８，１０，１０ａ−ヘキサヒドロ−
９Ｈ−ジベンゾ〔ｂ，ｄ〕ピラン−９−オンの安定な新
規多形結晶型化合物の製法。[Claims] 1. In a large amount of water, 1-hydroxy-3-(1',1'-dimethylheptyl)-6',6'-dimethyl-6,6a,
7,8,10,10a-hexahydro 9H-dibenzo [
b, d] The ethanol solution of pyran-9-one is added with rapid stirring.As a physical characteristic, it shows birefringence under a polarizing microscope, and 156 by differential thermal analysis.
It exhibits an endothermic phenomenon at 162°C and 162°C, and when measured using filtered chromium radiation with a wavelength of 2.2896 Å. 4 60 7.2 40 6.50 20 5.90 30 ¥d(Å)¥ ¥I/I_0¥ 4.85 60 4.10 05 3.90 40 3.35 30 1-hydroxy-3
-(1',1'-dimethylheptyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-
A method for producing a new stable polymorphic crystalline compound of 9H-dibenzo[b,d]pyran-9-one.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US41301173A | 1973-11-05 | 1973-11-05 | |
| US413011 | 1973-11-05 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5082222A JPS5082222A (en) | 1975-07-03 |
| JPS5943463B2 true JPS5943463B2 (en) | 1984-10-22 |
Family
ID=23635422
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP49127923A Expired JPS5943463B2 (en) | 1973-11-05 | 1974-11-05 | Method for producing polymorphic crystalline compound of dibenzopyranone |
Country Status (24)
| Country | Link |
|---|---|
| JP (1) | JPS5943463B2 (en) |
| AR (1) | AR202670A1 (en) |
| AT (1) | AT335453B (en) |
| BE (1) | BE821720A (en) |
| BG (1) | BG27088A3 (en) |
| CA (1) | CA1028715A (en) |
| CS (1) | CS174793B2 (en) |
| DD (1) | DD115660A5 (en) |
| DE (1) | DE2449927C2 (en) |
| DK (1) | DK136720B (en) |
| ES (1) | ES431672A1 (en) |
| FR (1) | FR2249665B1 (en) |
| GB (1) | GB1487635A (en) |
| HU (1) | HU167751B (en) |
| IE (1) | IE39678B1 (en) |
| IL (1) | IL45742A (en) |
| NL (1) | NL7412682A (en) |
| PH (1) | PH11719A (en) |
| PL (1) | PL94119B1 (en) |
| RO (1) | RO71769A (en) |
| SE (1) | SE407062B (en) |
| SU (1) | SU611591A3 (en) |
| YU (1) | YU287874A (en) |
| ZA (1) | ZA746029B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4278603A (en) * | 1973-11-05 | 1981-07-14 | Eli Lilly And Company | Novel polymorphic crystalline form of dibenzopyranone |
| US4195078A (en) * | 1979-03-09 | 1980-03-25 | Eli Lilly And Company | Nabilone granulation |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3507885A (en) * | 1966-03-25 | 1970-04-21 | Hoffmann La Roche | 3-alkyl-6h-dibenzo(b,d)pyrans |
-
1974
- 1974-09-20 IE IE1949/74A patent/IE39678B1/en unknown
- 1974-09-23 ZA ZA00746029A patent/ZA746029B/en unknown
- 1974-09-25 NL NL7412682A patent/NL7412682A/en not_active Application Discontinuation
- 1974-09-27 PH PH16343A patent/PH11719A/en unknown
- 1974-09-27 IL IL45742A patent/IL45742A/en unknown
- 1974-10-01 CA CA210,510A patent/CA1028715A/en not_active Expired
- 1974-10-05 ES ES431672A patent/ES431672A1/en not_active Expired
- 1974-10-14 SE SE7412921A patent/SE407062B/en unknown
- 1974-10-17 SU SU742069769A patent/SU611591A3/en active
- 1974-10-21 DE DE2449927A patent/DE2449927C2/en not_active Expired
- 1974-10-24 AT AT856674A patent/AT335453B/en not_active IP Right Cessation
- 1974-10-28 YU YU02878/74A patent/YU287874A/en unknown
- 1974-10-31 BE BE150088A patent/BE821720A/en not_active IP Right Cessation
- 1974-10-31 FR FR7436368A patent/FR2249665B1/fr not_active Expired
- 1974-10-31 PL PL1974175276A patent/PL94119B1/pl unknown
- 1974-11-04 HU HUEI574A patent/HU167751B/hu unknown
- 1974-11-04 DK DK573374AA patent/DK136720B/en not_active IP Right Cessation
- 1974-11-04 DD DD182141A patent/DD115660A5/xx unknown
- 1974-11-04 GB GB47516/74A patent/GB1487635A/en not_active Expired
- 1974-11-04 CS CS7516A patent/CS174793B2/cs unknown
- 1974-11-05 RO RO7480429A patent/RO71769A/en unknown
- 1974-11-05 BG BG028123A patent/BG27088A3/en unknown
- 1974-11-05 AR AR256414A patent/AR202670A1/en active
- 1974-11-05 JP JP49127923A patent/JPS5943463B2/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| SE7412921L (en) | 1975-05-06 |
| SE407062B (en) | 1979-03-12 |
| AR202670A1 (en) | 1975-06-30 |
| NL7412682A (en) | 1975-05-07 |
| PL94119B1 (en) | 1977-07-30 |
| SU611591A3 (en) | 1978-06-15 |
| AU7362674A (en) | 1976-04-01 |
| BG27088A3 (en) | 1979-08-15 |
| DE2449927C2 (en) | 1985-07-04 |
| ATA856674A (en) | 1976-07-15 |
| CA1028715A (en) | 1978-03-28 |
| AT335453B (en) | 1977-03-10 |
| IE39678B1 (en) | 1978-12-06 |
| DE2449927A1 (en) | 1975-05-07 |
| DK136720C (en) | 1978-04-24 |
| HU167751B (en) | 1975-12-25 |
| IL45742A (en) | 1978-06-15 |
| DK136720B (en) | 1977-11-14 |
| IL45742A0 (en) | 1974-11-29 |
| BE821720A (en) | 1975-04-30 |
| PH11719A (en) | 1978-05-30 |
| ES431672A1 (en) | 1977-04-16 |
| ZA746029B (en) | 1976-04-28 |
| CS174793B2 (en) | 1977-04-29 |
| FR2249665A1 (en) | 1975-05-30 |
| GB1487635A (en) | 1977-10-05 |
| JPS5082222A (en) | 1975-07-03 |
| RO71769A (en) | 1981-09-24 |
| DD115660A5 (en) | 1975-10-12 |
| IE39678L (en) | 1975-05-05 |
| DK573374A (en) | 1975-07-07 |
| YU287874A (en) | 1984-04-30 |
| FR2249665B1 (en) | 1978-07-21 |
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