GB2103603A - Ergoline derivatives - Google Patents
Ergoline derivatives Download PDFInfo
- Publication number
- GB2103603A GB2103603A GB08218762A GB8218762A GB2103603A GB 2103603 A GB2103603 A GB 2103603A GB 08218762 A GB08218762 A GB 08218762A GB 8218762 A GB8218762 A GB 8218762A GB 2103603 A GB2103603 A GB 2103603A
- Authority
- GB
- United Kingdom
- Prior art keywords
- ergoline
- general formula
- allyl
- solvent
- ergoline derivatives
- 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.)
- Granted
Links
- AWFDCTXCTHGORH-HGHGUNKESA-N 6-[4-[(6ar,9r,10ar)-5-bromo-7-methyl-6,6a,8,9,10,10a-hexahydro-4h-indolo[4,3-fg]quinoline-9-carbonyl]piperazin-1-yl]-1-methylpyridin-2-one Chemical class O=C([C@H]1CN([C@H]2[C@@H](C=3C=CC=C4NC(Br)=C(C=34)C2)C1)C)N(CC1)CCN1C1=CC=CC(=O)N1C AWFDCTXCTHGORH-HGHGUNKESA-N 0.000 title claims abstract description 7
- 238000000034 method Methods 0.000 claims abstract description 16
- 239000002904 solvent Substances 0.000 claims abstract description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical group C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- 239000012948 isocyanate Substances 0.000 claims description 2
- 150000002513 isocyanates Chemical class 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 3
- -1 ergoline amide Chemical class 0.000 abstract description 2
- 125000003373 pyrazinyl group Chemical group 0.000 abstract description 2
- 125000002098 pyridazinyl group Chemical group 0.000 abstract description 2
- 125000004076 pyridyl group Chemical group 0.000 abstract description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 abstract description 2
- 125000001113 thiadiazolyl group Chemical group 0.000 abstract description 2
- 125000000335 thiazolyl group Chemical group 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- WUDNUHPRLBTKOJ-UHFFFAOYSA-N ethyl isocyanate Chemical compound CCN=C=O WUDNUHPRLBTKOJ-UHFFFAOYSA-N 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- MAUMSNABMVEOGP-UHFFFAOYSA-N (methyl-$l^{2}-azanyl)methane Chemical group C[N]C MAUMSNABMVEOGP-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- HAMGRBXTJNITHG-UHFFFAOYSA-N methyl isocyanate Chemical compound CN=C=O HAMGRBXTJNITHG-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D457/00—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid
- C07D457/04—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 8
- C07D457/06—Lysergic acid amides
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
A process is provided for preparing ergoline derivatives I <IMAGE> substituted phenyl, unsubstituted phenyl, (CH2)nN(CH3)2 wherein n is an integer, R5 = any of values of R6 or H, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiazolyl or thiadiazolyl. The process comprises condensing an ergoline amide (I; 8-substituent replaced by CONHR5) with R6-N=C=O in a solvent at 70 DEG C to 120 DEG C for 24 to 72 hours.
Description
SPECIFICATION
Ergoline derivatives
Description
The invention relates to a process for the preparation of ergoline derivatives.
The invention provides a process for the preparation of ergoline derivatives of the general formual I
wherein R1 represents a hydrogen atom or a methyl group, R2 represents a hydrogen or halogen atom or a methyl group, R3 represents a hydrogen atom or a methoxy group, R4 represents an hydrocarbon group having from 1 to 4 carbon atoms, R6 represents an alkyl group having from 1 to 4 carbon atoms, a cyclohexyl group or a substituted or unsubstituted phenyl group or a dimethylamino alkyl group (CH2)nN(CH3)2 in which n is an integer, R5 represents any of the groups which B6 may represent or a hydrogen atom or a pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiazolyl or thiadiazolyl residue, the process comprising reacting an ergoline amide of the general formula II with an isocyanate of the general formula Ill
wherein R1, R2, R3, R4, B5 and B6 have the above given meanings. The reaction is suitable carried out at a temperature of from 70 to 1200C in solvents such as dioxan, benzene, toluene, cyclohexane or the like for a period of from 24 to 72 hours. At the end of the reaction the products may be isolated and purified following conventional procedures, for example chromatography and/or crystallization and salt formation.
The starting materials which are employed in the process according to the invention are known compounds or may be prepared by established procedures starting from known compounds; moreover some compounds of formula II are described in our British Patent Applications Nos 8122356 and 8209544, in our Belgian Patent No 888243, in our German Patent Application No 3112861 and in our Japanese Patent
Application No.81/48491.
The preparation of some compounds of general formula I is described in our British Patent Application No.
2074566A. Although the process there described is capable of producing derivatives of the general formula i in which the groups represented by B5 and B6 are the same in good yields its practical value is reduced when used to prepare compounds of the general formula I wherein the groups represented by B5 and B6 are different. In this case both regioisomers are obtained and the yields of the isolated products are often low as a consequence of the isolation difficulties.The process of the present invention proved most practicable because it is regiospecific and eliminates the above mentioned difficulties and because it allows the preparation of certain biologically active compounds which could not be obtained, owing to the instability of the required carbodiimides, with the process previously described in British Patent Application No.
2074566A.
The following Examples illustrate the invention.
EXAMPLE 1 6-Allyl-8ss-[1-ethyl-3-(3-dimethylaminopropyl)-ureidocarbonyl)-ergoline 1: R1 =R2 =R3 H, R4 = a//yt R5 = (CH3)2N.CH2CH2CH2, R6 =C2H5
A mixture of 20 g of 6-allyl-8P-(3-dimethyl-aminopropyl-carbamoyl)-ergoline (m.p. 198-200 C) and 150 ml of ethyl isocyanate in 1000 ml oftoluene were refluxed for 72 hours. The resultant solution was distilled at 70-8Q C and at 30 mm pressure; the residue was applied to a chromatographic column packed with 60 g of kieselgel (0.05-0.2 mm) and eluted with acetone. Eluatefractions shown to contain the product were combined and the solvent was removed therefrom under reduced pressure to give 20 g of the title compound as foam: m.p. 152-154 C as its disphosphate salt.
EXAMPLE 2 6-Allyl-8ss-(1-ethylureidocarbonyl)-ergoline l: R, =R2 =R3=R5=H, R4 =allyl, R5 =C2H5
Operating as in Example 1, but employing 6-allyl-8ss-carbamoyl-ergoline (m.p. 190-193 C) instead of 6-al lyl-8P-(3-dimethylaminopropyl-carbamoyl )-ergoline, the title compound, m.p. 210-212 C, was obtained in 90% yield.
EXAMPLE 3 6-Allyl-8ss-(1,3-dimethylureidocarbonyl)-ergoline 1: R1=R2=R3=H2R4=allyl, R5=R6=CH3
Operating as in Example 1, but employing 6-allyl-8ss-methylcarbamoyl-rgoline instead of 6-allyl-8ss-(3- dimethylaminopropyl-carbamoyl)-ergoline and methyl isocyanate instead of ethyl isocyanate, the title compound, m.p. 106-108 C, was obtained in 87% yield.
Claims (3)
1. A process for the preparatiort of an ergoline derivative of the general formula I as herein defined, the process compfising reacting an ergoline inside of the general formula It as herein defined with an isocyanate of the general formula III as herein defined in a solvent at from 70 C to 120 C for from 24 to 72 hours.
2. A process according to claim 1 in which the solvent is dioxan, benzene, toluene or cyclohexane.
3. A process for the preparation of an ergoiine derivative of the general formula as herein defined, the process being substantially as described herein with reference to any of the Examples.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB08218762A GB2103603B (en) | 1981-08-11 | 1982-06-29 | Ergoline derivatives |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8124549 | 1981-08-11 | ||
| GB08218762A GB2103603B (en) | 1981-08-11 | 1982-06-29 | Ergoline derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2103603A true GB2103603A (en) | 1983-02-23 |
| GB2103603B GB2103603B (en) | 1985-04-11 |
Family
ID=26280424
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08218762A Expired GB2103603B (en) | 1981-08-11 | 1982-06-29 | Ergoline derivatives |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2103603B (en) |
Cited By (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0191991A3 (en) * | 1984-12-21 | 1989-08-16 | Plessey Overseas Limited | Control circuit including a memory providing step functions |
| WO1990012796A1 (en) * | 1989-04-21 | 1990-11-01 | Schering Aktiengesellschaft Berlin Und Bergkamen | 8-beta-substituted ergolines, a process for manufacturing them, and their use |
| WO1993018034A1 (en) * | 1992-03-12 | 1993-09-16 | Farmitalia Carlo Erba S.R.L. | Process for the preparation of ergoline derivatives |
| US5705510A (en) * | 1993-08-18 | 1998-01-06 | Alcon Laboratories, Inc. | Use of cabergoline and related ergoline derivatives for controlling intraocular pressure |
| WO2001070740A1 (en) * | 2000-03-24 | 2001-09-27 | Pharmacia Italia Spa | Process for preparing crystalline form i of cabergoline |
| WO2001072747A1 (en) * | 2000-03-24 | 2001-10-04 | Pharmacia Italia S.P.A. | Crystalline form ii of cabergoline |
| WO2001072746A1 (en) * | 2000-03-24 | 2001-10-04 | Pharmacia Italia S.P.A. | Crystalline form vii of cabergoline |
| WO2002085902A1 (en) * | 2001-04-16 | 2002-10-31 | Finetech Laboratories Ltd. | Process and intermediates for production of cabergoline and related compounds |
| US6696568B2 (en) | 2001-04-16 | 2004-02-24 | Finetech Ltd. | Process and intermediates for production of cabergoline and related compounds |
| US7026483B2 (en) | 2003-04-21 | 2006-04-11 | Finetech Laboratories, Ltd. | Forms of cabergoline |
| EP1401863A4 (en) * | 2001-06-08 | 2006-04-26 | Sod Conseils Rech Applic | CHIMERO SOMATOSTATIN DOPAMINE ANALOGUE |
| US7186837B2 (en) | 2004-04-30 | 2007-03-06 | Resolution Chemicals | Preparation of cabergoline |
| US7217822B2 (en) | 2005-03-17 | 2007-05-15 | Synthon Ip Inc. | Process for making cabergoline |
| US7238810B2 (en) | 2005-03-23 | 2007-07-03 | Parveen Bhatarah | Preparation of cabergoline |
| US7339060B2 (en) | 2005-03-23 | 2008-03-04 | Resolution Chemicals, Ltd. | Preparation of cabergoline |
| US7939665B2 (en) | 2007-05-04 | 2011-05-10 | Apotex Pharmachem Inc. | Efficient process for the preparation of cabergoline and its intermediates |
| US8338445B2 (en) | 2007-01-31 | 2012-12-25 | Lek Pharmaceuticals D.D. | Crystal form of cabergoline |
| US8952128B2 (en) | 2012-11-01 | 2015-02-10 | Ipsen Pharma S.A.S. | Somatostatin-dopamine chimeric analogs |
| US9777039B2 (en) | 2012-11-01 | 2017-10-03 | Ipsen Pharma S.A.S. | Somatostatin analogs and dimers thereof |
-
1982
- 1982-06-29 GB GB08218762A patent/GB2103603B/en not_active Expired
Cited By (35)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0191991A3 (en) * | 1984-12-21 | 1989-08-16 | Plessey Overseas Limited | Control circuit including a memory providing step functions |
| WO1990012796A1 (en) * | 1989-04-21 | 1990-11-01 | Schering Aktiengesellschaft Berlin Und Bergkamen | 8-beta-substituted ergolines, a process for manufacturing them, and their use |
| US5219862A (en) * | 1989-04-21 | 1993-06-15 | Schering Aktiengesellschaft | 8 beta-substituted ergolines, process for their production and their use |
| WO1993018034A1 (en) * | 1992-03-12 | 1993-09-16 | Farmitalia Carlo Erba S.R.L. | Process for the preparation of ergoline derivatives |
| US5382669A (en) * | 1992-03-12 | 1995-01-17 | Farmitalia Carlo Erba S.R.L. | Process for the preparation of ergoline derivatives |
| CN1038510C (en) * | 1992-03-12 | 1998-05-27 | 法玛西雅厄普约翰公司 | Process for the preparation of ergoline derivatives |
| RU2118323C1 (en) * | 1992-03-12 | 1998-08-27 | Фармация Энд Апджон С.П.А. | Method for production of derivative of ergoline |
| US5705510A (en) * | 1993-08-18 | 1998-01-06 | Alcon Laboratories, Inc. | Use of cabergoline and related ergoline derivatives for controlling intraocular pressure |
| US6800635B2 (en) | 2000-03-24 | 2004-10-05 | Pharmacia Italia, S.P.A. | Crystalline form II of cabergoline |
| AU780744B2 (en) * | 2000-03-24 | 2005-04-14 | Pharmacia Italia S.P.A. | Crystalline form VII of cabergoline |
| WO2001072746A1 (en) * | 2000-03-24 | 2001-10-04 | Pharmacia Italia S.P.A. | Crystalline form vii of cabergoline |
| WO2001072747A1 (en) * | 2000-03-24 | 2001-10-04 | Pharmacia Italia S.P.A. | Crystalline form ii of cabergoline |
| US6673806B2 (en) | 2000-03-24 | 2004-01-06 | Pharmacia Italia S.P.A. | Crystalline form II cabergoline |
| US6680327B2 (en) | 2000-03-24 | 2004-01-20 | Pharmacia Italia Spa | Crystalline form VII of cabergoline |
| US6953854B2 (en) | 2000-03-24 | 2005-10-11 | Pharmacia | Process for preparing crystalline Form I of cabergoline |
| US6727363B2 (en) | 2000-03-24 | 2004-04-27 | Pharmacia Italia Spa | Process for preparing crystalline form I of cabergoline |
| WO2001070740A1 (en) * | 2000-03-24 | 2001-09-27 | Pharmacia Italia Spa | Process for preparing crystalline form i of cabergoline |
| US6696568B2 (en) | 2001-04-16 | 2004-02-24 | Finetech Ltd. | Process and intermediates for production of cabergoline and related compounds |
| WO2002085902A1 (en) * | 2001-04-16 | 2002-10-31 | Finetech Laboratories Ltd. | Process and intermediates for production of cabergoline and related compounds |
| US7572883B2 (en) | 2001-06-08 | 2009-08-11 | Societe De Conseils De Recherches Et D'applications Scientifiques, S.A.S. | Somatostatin-dopamine chimeric analogs |
| EP1401863A4 (en) * | 2001-06-08 | 2006-04-26 | Sod Conseils Rech Applic | CHIMERO SOMATOSTATIN DOPAMINE ANALOGUE |
| US8324386B2 (en) | 2001-06-08 | 2012-12-04 | Ipsen Pharma S.A.S. | Somatostatin-dopamine chimeric analogs |
| US8178651B2 (en) | 2001-06-08 | 2012-05-15 | Ipsen Pharma, S.A.S. | Somatostatin-dopamine chimeric analogs |
| US7579435B2 (en) | 2001-06-08 | 2009-08-25 | Societe De Conseils De Recherches Et D'applications Scientifiques, S.A.S. | Somatostatin-dopamine chimeric analogs |
| US7026483B2 (en) | 2003-04-21 | 2006-04-11 | Finetech Laboratories, Ltd. | Forms of cabergoline |
| US7186837B2 (en) | 2004-04-30 | 2007-03-06 | Resolution Chemicals | Preparation of cabergoline |
| US7217822B2 (en) | 2005-03-17 | 2007-05-15 | Synthon Ip Inc. | Process for making cabergoline |
| US7339060B2 (en) | 2005-03-23 | 2008-03-04 | Resolution Chemicals, Ltd. | Preparation of cabergoline |
| US7238810B2 (en) | 2005-03-23 | 2007-07-03 | Parveen Bhatarah | Preparation of cabergoline |
| US8338445B2 (en) | 2007-01-31 | 2012-12-25 | Lek Pharmaceuticals D.D. | Crystal form of cabergoline |
| US7939665B2 (en) | 2007-05-04 | 2011-05-10 | Apotex Pharmachem Inc. | Efficient process for the preparation of cabergoline and its intermediates |
| US8952128B2 (en) | 2012-11-01 | 2015-02-10 | Ipsen Pharma S.A.S. | Somatostatin-dopamine chimeric analogs |
| US9603942B2 (en) | 2012-11-01 | 2017-03-28 | Ipsen Pharma S.A.S. | Somatostatin-dopamine chimeric analogs |
| US9731027B2 (en) | 2012-11-01 | 2017-08-15 | Ipsen Pharma S.A.S. | Somatostatin-dopamine chimeric analogs |
| US9777039B2 (en) | 2012-11-01 | 2017-10-03 | Ipsen Pharma S.A.S. | Somatostatin analogs and dimers thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| GB2103603B (en) | 1985-04-11 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 732 | Registration of transactions, instruments or events in the register (sect. 32/1977) | ||
| PE20 | Patent expired after termination of 20 years |
Effective date: 20020628 |