JPS5943464B2 - Method for producing polymorphic crystalline compound of dibenzopyranone - Google Patents
Method for producing polymorphic crystalline compound of dibenzopyranoneInfo
- Publication number
- JPS5943464B2 JPS5943464B2 JP12792474A JP12792474A JPS5943464B2 JP S5943464 B2 JPS5943464 B2 JP S5943464B2 JP 12792474 A JP12792474 A JP 12792474A JP 12792474 A JP12792474 A JP 12792474A JP S5943464 B2 JPS5943464 B2 JP S5943464B2
- Authority
- JP
- Japan
- Prior art keywords
- dimethyl
- crystalline compound
- hydroxy
- dimethylheptyl
- pyran
- 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
- 150000001875 compounds Chemical class 0.000 title claims description 11
- 238000004519 manufacturing process Methods 0.000 title claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- SEQIMZPSZATKQD-UHFFFAOYSA-N benzo[c]chromen-9-one Chemical compound C1=CC=C2C3=CC(=O)C=CC3=COC2=C1 SEQIMZPSZATKQD-UHFFFAOYSA-N 0.000 claims description 3
- 238000001704 evaporation Methods 0.000 claims description 3
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052804 chromium Inorganic materials 0.000 claims description 2
- 239000011651 chromium Substances 0.000 claims description 2
- 238000004455 differential thermal analysis Methods 0.000 claims description 2
- 230000008020 evaporation Effects 0.000 claims description 2
- 230000000704 physical effect Effects 0.000 claims description 2
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 2
- 230000005855 radiation Effects 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 229920002472 Starch Polymers 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- CYQFCXCEBYINGO-UHFFFAOYSA-N THC Natural products C1=C(C)CCC2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3C21 CYQFCXCEBYINGO-UHFFFAOYSA-N 0.000 description 2
- CYQFCXCEBYINGO-IAGOWNOFSA-N delta1-THC Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 CYQFCXCEBYINGO-IAGOWNOFSA-N 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 206010003591 Ataxia Diseases 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- XXGMIHXASFDFSM-UHFFFAOYSA-N Delta9-tetrahydrocannabinol Natural products CCCCCc1cc2OC(C)(C)C3CCC(=CC3c2c(O)c1O)C XXGMIHXASFDFSM-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000007963 capsule composition Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- HCAWPGARWVBULJ-IAGOWNOFSA-N delta8-THC Chemical compound C1C(C)=CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 HCAWPGARWVBULJ-IAGOWNOFSA-N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Pyrane 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造法
、更に詳しくは１−セドロキシ−３一（１′、１′−ジ
メチルヘプチル）−６、６−ジメチル−６、６ａ、７、
８、１Ｏ、１０ａ−ヘキサヒドロ−９Ｈ−ジペンゾ〔ｂ
、ｄ〕ビラン−９−オンの安定な新規同質多形結晶型化
合物の製造法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a polymorphic crystalline compound of dibenzopyranone, more specifically, 1-cedroxy-3-(1',1'-dimethylheptyl)-6,6-dimethyl-6 ,6a,7,
8,1O,10a-hexahydro-9H-dipenzo[b
, d] relates to a method for producing a stable novel homogeneous polymorphic crystalline compound of bilan-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。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.
従来、１−ヒドロキシ−３−アルキル−６、６−ジメチ
ル−６、６ａ、７、８、１Ｏ、１０ａ−ヘキサヒドロ−
９Ｈ−ジペンゾ〔ｂ、ｄ〕ピラン−９−オン類、そのエ
−テル類およびエステル類はΔ８−またはΔ９−テトラ
ヒドロカンナビノ−ル（以下、Δ８−またはΔ゛−ＴＨ
Ｃと略称する。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-tetrahydrocannabinol (hereinafter referred to as Δ8- or Δ゛-TH
It is abbreviated as C.
）製造のための中間体として、米国特許第３．５０７．
８８５号に開示されている。) as an intermediate for the production of U.S. Pat. No. 3.507.
No. 885.
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ビラン類
は水性媒体に対して著しく不溶性であることが知られて
いる。However, no utility of this compound other than the above-mentioned utility as an intermediate is disclosed. Δ9-THC, which is naturally obtained or made by various synthetic methods
and other dibenzobilanes related to its structure are known to be significantly 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榎雑になつ
ている。本発明は１−ヒドロキシ−３−（１′，１′−
ジメチルヘプチル）−６，６−ジメチル−６，６ａ，７
，８，１０，１０ａ−ヘキサヒトロー９Ｈ−ジベンゾ〔
Ｂ，ｄ〕ピラン一９−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'-
dimethylheptyl)-6,6-dimethyl-6,6a,7
,8,10,10a-hexahythro9H-dibenzo[
B, d] Provides a method for producing a stable new polymorphic substance of pyran-9-one, which substance has the following physical properties.
すなわち、偏光顕微鏡下に複屈折をを示し、示差熱分析
により１５６℃および１６２゜Ｃで吸熱現象を示し、ま
たフイルタ一にかけた波長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１−ヒドロキシ−３−（Ｐ，ｌ′ジ
メチルヘプチル）−６，６−ジメチル−６，６ａ７８１
０１０ａ−ヘキサヒトロー゛９９９？
９Ｈ−ジベンゾ〔Ｂ，ｄ〕ピラン一９−オンの新規同質
多形結晶型物質はこの化合物のエタノール浴液を生成せ
しめ、２０〜３０℃の範囲の温度で溶媒を蒸発させるこ
とにより製造することができる。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°C. The following X-ray powder diffraction pattern is shown: 1-hydroxy-3-(P,l'dimethylheptyl)-6,6-dimethyl-6,6a781 in the present invention
010a-Hexahitorow 999? A new homogeneous polymorphic crystalline form of 9H-dibenzo[B,d]pyran-9-one can be prepared by forming an ethanol bath of this compound and evaporating the solvent at a temperature in the range of 20-30°C. I can do it.
この工程において好ましくは回転蒸発器を使用する。蒸
発温度は比較的大容量の水浴を使用することにより容易
にその好ましい温度を保持することができる。上記方法
により製せられた１−ヒドロキシ−３−（１１，１′−
ジメチルヘプチノ（ハ）−６，６−ジメチル−６６ａ７
８１０１０ａヘキサヒ９９９９？
ドロー９Ｈ−ジベンゾ〔Ｂ，ｄ〕ピラン一９−オンの比
較的吸収性良好なる同質多形物質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。A rotary evaporator is preferably used in this step. The desired evaporation temperature can be easily maintained by using a relatively large capacity water bath. 1-hydroxy-3-(11,1'-
Dimethylheptino(ha)-6,6-dimethyl-66a7
81010a Hexahi 9999? A pharmacological product containing 1 part of a relatively well-absorbed homogeneous polymorph of Draw 9H-dibenzo[B,d]pyran-9-one is thoroughly mixed with 9 parts of corn starch, and the mixture is placed in a plug-in gelatin capsule. An absorption test was conducted by administering this 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、震いおよび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′，１′−ジ
メチルヘプチル）−６，６−ジメチル−６６ａ７８１０
１０ａ−ヘキサヒ９ ？ ９９
９
ドロー９Ｈ−ジベンゾ〔Ｂ，ｄ〕ビラン一９−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
ベイラビリテイ一）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 orally administered dosage forms or parenterally injectable 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. Tested after a further 10 weeks with identical results. 1-Hydroxy-3-(1',1'-dimethylheptyl)-6,6-dimethyl-66a7810
10a-hexahi9? 99
9 Other polymorphs of Draw 9H-dibenzo[B,d]bilan-9-one are active in solution or immediately after mixing with starch, but apparently gradually recrystallize or bind to starch. and have an unfavorable effect on 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
１−ヒドロキシ−３−（１１，１′−ジメチルヘプチル
）−６，６−ジメチル−６，６ａ，７，８，１０１０ａ
−ヘキサヒトロー９Ｈ−ジベンゾラ〔Ｂ，ｄ〕ピラン一
９−オン１９のエタノール２５ｍ．１溶液を回転蒸発器
に入れる。Example 1 1-hydroxy-3-(11,1'-dimethylheptyl)-6,6-dimethyl-6,6a,7,8,1010a
-hexahythro9H-dibenzola[B,d]pyran-9-one 19 in ethanol 25m. 1 solution into a rotary evaporator.
Claims (1)
（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−９
Ｈ−ジベンゾ〔ｂ，ｄ〕ピラン−９−オンのエタノ−ル
溶液から溶媒を蒸発させ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 ４．８５ ６０ ４．１０ ０５ ￥ｄ（Å）￥ ￥Ｉ／Ｉ＿０￥ 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造法。[Claims] 1. 1-Hydroxy-3-
(1',1'-dimethylheptyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9
The ethanol solution of H-dibenzo[b,d]pyran-9-one exhibits birefringence under a polarizing microscope as a physical property characterized by evaporation of the solvent, and differential thermal analysis reveals birefringence at 156°C and 162°C. It exhibits an endothermic phenomenon at ℃ and when measured using filtered chromium radiation with a wavelength of 2.2896 Å ¥d(Å)¥ ¥I/I_0¥ 14.5 100 10.5 30 8.4 60 7 .2 40 6.50 20 5.90 30 4.85 60 4.10 05 ¥d(Å)¥ ¥I/I_0¥ 3.90 40 3.35 30 1- showing the X-ray powder diffraction pattern 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.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP12792474A JPS5943464B2 (en) | 1974-11-05 | 1974-11-05 | Method for producing polymorphic crystalline compound of dibenzopyranone |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP12792474A JPS5943464B2 (en) | 1974-11-05 | 1974-11-05 | Method for producing polymorphic crystalline compound of dibenzopyranone |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5156451A JPS5156451A (en) | 1976-05-18 |
| JPS5943464B2 true JPS5943464B2 (en) | 1984-10-22 |
Family
ID=14971991
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP12792474A Expired JPS5943464B2 (en) | 1974-11-05 | 1974-11-05 | Method for producing polymorphic crystalline compound of dibenzopyranone |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5943464B2 (en) |
-
1974
- 1974-11-05 JP JP12792474A patent/JPS5943464B2/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5156451A (en) | 1976-05-18 |
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