IE46152B1 - Ergot peptide aklaloid derivatives - Google Patents
Ergot peptide aklaloid derivativesInfo
- Publication number
- IE46152B1 IE46152B1 IE1838/77A IE183877A IE46152B1 IE 46152 B1 IE46152 B1 IE 46152B1 IE 1838/77 A IE1838/77 A IE 1838/77A IE 183877 A IE183877 A IE 183877A IE 46152 B1 IE46152 B1 IE 46152B1
- Authority
- IE
- Ireland
- Prior art keywords
- compound
- formula
- desoxo
- hydrogen
- addition salt
- Prior art date
Links
- 108090000765 processed proteins & peptides Proteins 0.000 title 1
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 12
- 239000001257 hydrogen Substances 0.000 claims abstract description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000000217 alkyl group Chemical group 0.000 claims abstract 6
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract 6
- 150000002431 hydrogen Chemical group 0.000 claims abstract 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 60
- 239000002253 acid Substances 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 12
- 239000012458 free base Substances 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 239000008024 pharmaceutical diluent Substances 0.000 claims description 3
- 229950001817 alpha-ergocryptine Drugs 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 229960004290 dihydroergocornine Drugs 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 2
- YDOTUXAWKBPQJW-UHFFFAOYSA-N alpha-Ergocryptinine Natural products C1=CC(C=2C(N(C)CC(C=2)C(=O)NC2(C(=O)N3C(C(N4CCCC4C3(O)O2)=O)CC(C)C)C(C)C)C2)=C3C2=CNC3=C1 YDOTUXAWKBPQJW-UHFFFAOYSA-N 0.000 claims 1
- YDOTUXAWKBPQJW-NSLWYYNWSA-N alpha-ergocryptine Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@]2(C(=O)N3[C@H](C(N4CCC[C@H]4[C@]3(O)O2)=O)CC(C)C)C(C)C)C2)=C3C2=CNC3=C1 YDOTUXAWKBPQJW-NSLWYYNWSA-N 0.000 claims 1
- SEALOBQTUQIVGU-QNIJNHAOSA-N dihydroergocornine Chemical compound C1=CC([C@H]2C[C@H](CN(C)[C@@H]2C2)C(=O)N[C@]3(C(=O)N4[C@H](C(N5CCC[C@H]5[C@]4(O)O3)=O)C(C)C)C(C)C)=C3C2=CNC3=C1 SEALOBQTUQIVGU-QNIJNHAOSA-N 0.000 claims 1
- 229960004318 dihydroergocristine Drugs 0.000 claims 1
- OFKDAAIKGIBASY-VFGNJEKYSA-N ergotamine Chemical compound C([C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@@](C(N21)=O)(C)NC(=O)[C@H]1CN([C@H]2C(C3=CC=CC4=NC=C([C]34)C2)=C1)C)C1=CC=CC=C1 OFKDAAIKGIBASY-VFGNJEKYSA-N 0.000 claims 1
- 229960004943 ergotamine Drugs 0.000 claims 1
- XCGSFFUVFURLIX-UHFFFAOYSA-N ergotaminine Natural products C1=C(C=2C=CC=C3NC=C(C=23)C2)C2N(C)CC1C(=O)NC(C(N12)=O)(C)OC1(O)C1CCCN1C(=O)C2CC1=CC=CC=C1 XCGSFFUVFURLIX-UHFFFAOYSA-N 0.000 claims 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- 206010002383 Angina Pectoris Diseases 0.000 abstract description 2
- 229930015720 peptide alkaloid Natural products 0.000 abstract description 2
- -1 ALKALOID DERIVATIVES Compounds Chemical class 0.000 abstract 1
- 208000020401 Depressive disease Diseases 0.000 abstract 1
- 206010020772 Hypertension Diseases 0.000 abstract 1
- 208000028017 Psychotic disease Diseases 0.000 abstract 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 5
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229910000085 borane Inorganic materials 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N hydrochloric acid Substances Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- HEWDOWUUTBCVJP-UHFFFAOYSA-N naphthalene-1,6-disulfonic acid Chemical class OS(=O)(=O)C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 HEWDOWUUTBCVJP-UHFFFAOYSA-N 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 230000003276 anti-hypertensive effect Effects 0.000 description 2
- 150000001540 azides Chemical class 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- QDSRGNMYEIBMAN-DKKFBQAASA-N (1S,2S,4R,7S)-4-amino-7-benzyl-2-hydroxy-4-propan-2-yl-3-oxa-6,9-diazatricyclo[7.3.0.02,6]dodecan-5-one Chemical compound C([C@H]1CN2CCC[C@H]2[C@]2(O)O[C@](C(N21)=O)(N)C(C)C)C1=CC=CC=C1 QDSRGNMYEIBMAN-DKKFBQAASA-N 0.000 description 1
- QZBUWPVZSXDWSB-NEPJUHHUSA-N (3r,8as)-3-benzyl-2,3,6,7,8,8a-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione Chemical compound C([C@H]1NC([C@@H]2CCCN2C1=O)=O)C1=CC=CC=C1 QZBUWPVZSXDWSB-NEPJUHHUSA-N 0.000 description 1
- QYAPHLRPFNSDNH-MRFRVZCGSA-N (4s,4as,5as,6s,12ar)-7-chloro-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide;hydrochloride Chemical compound Cl.C1=CC(Cl)=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]4(O)C(=O)C3=C(O)C2=C1O QYAPHLRPFNSDNH-MRFRVZCGSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 108010069514 Cyclic Peptides Proteins 0.000 description 1
- 102000001189 Cyclic Peptides Human genes 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 229960004704 dihydroergotamine Drugs 0.000 description 1
- 230000010339 dilation Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000011369 resultant mixture Substances 0.000 description 1
- 238000007790 scraping Methods 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
- 238000005245 sintering Methods 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07D519/02—Ergot alkaloids of the cyclic peptide type
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Cardiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Heart & Thoracic Surgery (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Peptides Or Proteins (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
ERGOT PEPTIDE ALKALOID DERIVATIVES Compounds of formula I, I wherein R1 is alkyl of 1 to 4 carbon atoms, R2 is hydrogen, alkyl of 1 to 4 carbon atoms or benzyl, R3 and R5 are, independently, hydrogen or methyl, R4 is hydrogen or alkyl of 1 to 4 carbon atoms, and R6 and R7 together form a single bond, or R6 and R7 are each hydrogen, R6 is methoxy, and R7 is hydrogen, are useful in the treatment of hypertension, angina pectoris, depressions, neuroses and psychoses.
Description
The present invention also provides a process for the production of a compound of formula I, which comprises a) reducing the 6' carbonyl group in a compound of wherein R^ to R? are as defined above, or b) condensing an acid addition salt of a compound of formula III, wherein R^ to Rg are as defined above, with a reactive acid derivative of a compound of formula IV, - 2 4 6152 wherein R, to R_ are as defined above. 7 Process a) may be effected in one step if desired, using reactive borane, e.g. diborane. The process may be effected in conventional manner for diborane reductions under mild conditions. Conveniently 5 to 15 moles of reactive borane are used per mole of a compound of formula XI. Tetrahydrofuran, diethyl ether or methylene chloride may be used as solvent. Suitable reaction temperatures may be from -20° to 20°C.
Process b) may be effected in conventional manner for condensations to produce analogous ergot cyclic peptide alkaloids.
A suitable acid addition salt of a compound Of formula III is the 2,5-naphthalene-disulphonic acid salt.
Suitable reactive acid derivatives of a compound of formula IV include the acid chloride, the acid azide, and the mixed anhydride with sulphuric or trifluoroacetic acid. It is preferred to use the reactive acid derivative of a compound of formula IV arising out of the reaction of a connound of formula IV with dimethyl formamide or acetamide - 3 46132 and thionyl chloride, phosgene or oxalyl chloride. Preferably triethylamine or pyridine is present during the reaction. Suitable solvents include chloroform, methylene chloride, dimethyl formamide and acetonitrile.
Suitable reaction temperatures are from -30° to +20°C.
The starting materials are known or may be produced in conventional manner from known compounds.
Thus a compound of formula III may be prepared in known manner for the preparation of an aminocyclol from a compound of formula V; wherein R^ to R^ are as defined above.
For example the corresponding acid may first be formed and then converted via the acid chloride into the corresponding acid amide, which in turn is converted into the amine.
A compound of formula V may be produced by reacting a compound of formula VI, C2H5OOC __ *.och2.c6h5 VI COCI wherein R^ is as defined above, with a compound of formula VII, VII HN CH. wherein R2 and R^ are as defined above, and hydrogenating the resultant product.
A compound of formula VII may be produced by reducing a compound of formula VIII, ΙΟ wherein R2 and R^ are as defined above, with lithium aluminium hydride.
Free base forms of the compounds of formula I may be converted into acid addition salt forms in conventional manner and vice versa. Suitable acids for salt formation -δ46152 include hydrochloric and methane-sulphonic acids.
In the following Examples all temperatures are in degrees Centigrade and are uncorrected.
The title compound of Example 2 forms no part of the · . present invention. It illustrates, however, the process of the invention and the preparation of the starting materials. 61 s a EXAMPLE 1; e^-desgxo-S^lO-dihydro^P^ergocryotine [process a)] 1.15 g of 9,10-dihydro-p-ergocryptine (2 mmols) are suspended and stirred at 0° in 25 ml of absolute tetra5 hydrofuran and then a freshly prepared solution of 20 mmols reactive borane (e.g. from NaBH^ and boron trifluoride etherate) in 35 nl of absolute tetrahydrofuran is added dropwise. After stirring for 4 hours at 0° the solution is cooled. The reaction mixture is carefully treated with 9 ml of 6N-hydrochloric acid, and then stirred for another 30 minutes at +60°, cooled, made alkaline with 30% sodium hydroxide, and then thoroughly extracted with methylene chloride. The methylene chloride extracts are chromatographed on aluminia (activity ΙΙ-III) to yield the title compound in free base form which is recrystallized from methylene chloride/ether. jn M.Pt. 159-160° ; [a]^ =-4 0 (c =0.5 DMP).
The title compound may also be prepared according to the process of Example 2.
EXAMPLE 2: iTraSthZizSLgdesoxogg^lOgdihydro^rgjccrLstyTe. [process b)] A solution of 1.14 ml (17.14 mmols) of oxalyl chloride in 15 ml of absolute acetonitrile is added dropwise to 150 ml of absolute dimethyl forraamide at -15°. - 7 4.87 g (17.14 mmols) of dry l-methyl-9,10-dihydrolysergic acid are then added, and a grey deposit precipitates from the reaction mixture. After stirring for 30 minutes at 0°, the mixture is cooled and treated with 37.5 ml of absolute pyridine, and then 5.14 g of (2R,5S,10aS,10bS)-2-amino-2isopropyl-3-oxo-5-benzyl-10b-hydroxy-perhydrooxazolo[3,2-a]pyrrolo[2,1-c]pyrazine.2,5-naphthalene-disulphonic acid (about 8.5 mmols) are added, The mixture is stirred vigorously for 2 hours, and then the temperature is allowed to increase slowly from -10° to 0°. The mixture is then cooled again and diluted with 40 ml of citratebuffer (pH = 4), and then made alkaline with 2N soda solution. After extraction with chloroform containing a small amount of ethanol, the extract is dried and evaporated The crude product is chromatographed on silicagel, to give the title compound in free base form on elution with 4% methanol in methylene chloride, which is recrystallised from acetone.
JO M.Pt. 183° - 185°; [cc]^ = -77° (c = 1, pyridine).
The title compound may also be prepared by the process of Example 1.
The 2-amino-2-isopropyl-3-oxo-5benzyl-lOb~hydroxyperhydrooxazolo[3,2-a]pyrrolo[2,1-c]pyrazine.2,5-naphthalene· disulphonic acid is obtained as follows :8 46lsa a) J2Sj,7aS].-22benzyl22erhydro283OXO"nyrrolo_[2xl2c2gyrazine 36.4 g (960 mmols) of lithium aluminium hydride are suspended in 1.3 litres of absolute tetrahydrofuran in a nitrogen atmosphere, and a solution of 117.2 g (480 mmols) of L-Phe-L-Pro-lactam in 1.4 litres of absolute tetrahvdrofuran is added dropwise over 45 minutes. After stirring for 18 hours at -10°, the reaction mixture is diluted carefully at this temperature with 350 ml of ethyl acetate and then 350 ml of water. The resultant mixture is filtered.
Repeated extraction of the filter cake with boiling methylene chloride is effected to obtain more product.
The combined organic phases and filtrate are dried with sodium sulphate and evaporated. The pure title compound in free base form crystallises directly from methylene chloride/ether in bright beige crystals; M.Pt. of 135° - 140°; (α]θ - -3.5° (c = 1 in ethanol). b) 12Βχ5£χ122§χΙ2!ΐ5ΐΣ2Ίί2£^ίι.1ί?ίϊζΣ,2ΣΪ£2ΕΕ2Ε'ΖΐΣ2Σ2ς·2Σ§Σΐ22Ε2Ζ];Σ IQbghYBlSiiy^ESSBYHro-oxazolo D_,2-a2gv rrolo^^l^c^gyr azine b)i) 47.8 g (207 mmols) of (2S,7aS)-2-benzyl-perhydro-8oxo-pyrrolo[2,l~c]pyrazine in 160 ml of absolute dioxane are treated with 74.4 g (249 mmols) of S-(+)-isopropyl-benzyloxy-malonic acid mono-ethyl ester mono-acid chloride and 34.9 g (270 mmols) of - 9 4 615 2 N-ethyldiisopropylamine. The mixture is stirred for • 1 hour at +70°. After dilution with 1 litre of ether, the mixture is shaken twice with saturated sodium bicarbonate solution and dried over sodium sulphate.
After evaporation of the solvent, 138 g of a brownish oil containing (2S,7aS) -(2*S--2-benzyloxy-2'-isopropyl-0 ethylmalononyl)-2-benzyl-perhydro-8-oxo-pyrrolo[2,1-c]pyrazine are obtained. b) ii) This oil is dissolved in 1.5 litres of ethanol and is hydrogenated at 60° after addition of 60 g of palladium-active carbon (10% w/w Pd), wherein, after 14 hours, about 6.5 litres of hydrogen are absorbed. After filtration and evaporation of the filtrate, the title compound is recrystallized from isopropyl ether, as yellowish prisms with a M.Pt. of 99° - 100°; [a]20 = -57.7° (c = 0.65 in CHCl3). c) J^BxSS^lOaS^lObfU-2-carboxy-2;:i5oproDyl-320XO;;5;;benzylISk^hydroxy^perhydro^oxazoloD.^alpyrrolgJ^l^c] pyrazine 39.3 g (97.8 mmols) of (2R,5S,10aS,10bS)-2-carbethoxy-220 isopropyl-3-oxo-5-benzyl-10b-hydroxy~perhydro-oxaZolo[3,2-a]pyrrolo[2,1-c]pyrazine are dissolved in 245 ml of methanol and 245 ml of 2 N sodium hydroxide. The mixture is stirred for 3 hours at room temperature, adjusted at 0° to a pH of 4.5 with 2 N hydrochloric acid, - 10 46152 and then extracted repeatedly with ethyl acetate.
After drying the organic extract and evaporating the solvent at below +30°, the title compound crystallises after dilution with ether. M.Pt. 126° - 128° (decomp).After drying for 5 hours at 30° in a high vacuum, the crystals contain ~ 1/2 mol water per mole of title compound. 4) T^R^SS^lOaS^lObS)-S-amino^^^isogrODvl-S^oxo^S^benzyl; ISfeliiy^roxy-Derh^dro^oxazoloflj^-alpyrroloJ^l^c].di) A solution of 3.84 ml (45 mmols) of oxalyl chloride in 15 ml of absolute acetonitrile is added in drops over 10 minutes to a stirred mixture of 4.33 ml (56.3 mmols) of absolute dimethyl formamide and 30 ml of absolute acetonitrile which is cooled to -15°. The mixture is stirred for a further 10 minutes. After dilution of the mixture with 45 ml of absolute ether, 11,25 g (30 mmols) of (2R,5S,10aS,10bS)-2-carboxy-2-isopropyl" 3~oxo-5"benzyl-10b-hydroxy-perhydro-oxazolo[3,2-a]pyrrolo[2,1-c]pyrazine. 1/2 H20 are quickly added. A clear solution is produced, which is stirred for another 10 minutes at -10° thereby producing the acid chloride. dii) A solution of 20 g of sodium azide in 100 ml of water, diluted with 300 ml of methylene chloride, is added to the acid chloride solution-- 11 46152 and the 2-phase mixture is shaken vigorously for 4 minutes. Then, 150 ml of ice-cold, saturated sodium bicarbonate solution are added. The organic phase is separated and dried well over sodium sulphate. After evaporation of the solvent at below 30°, a solution of 7.78 g (27 mmols) of 2,5-naphthalene disulphonic acid in 200 ml of dimethoxyethane and 20 ml of acetonitrile is added. The mixture is then slowly concentrated in a vacuum. After dilution of the mixture with absolute ether, the acid azide is isolated as the 2,5-naphthalene disulphonate salt. diii) 6.35 g (~9mmols) of the salt are heated for 1 hour to 80° in the presence of 120 ml of dimethoxyethane which contains 0.166 ml of water. The title compound is obtained with constant scraping, as a brownish, semi-crystalline powder, which may be used directly after cooling, filtering and drying at room temperature in a high vacuum.
The following compounds may be obtained in analogous manner to that described in Example or 2. - .12 46152 EXAMPLE 7: 15 EXAMPLE 8: EXAMPLE 9,: EXAMPLE 3: 6lzflesoxo;9210-dihydroergocornine M.Pt. 166° - 167°(decomp); [ EXAMPLE 4: iilztfesoxo-ji.jlO^dihydro^ggergosine M.Pt. 194° - 196° (sintering from 185°) j [a]^ = -18° (c = 0.3 in dimethyl formamide).
EXAMPLE 5: 83S2EG^zi22£E22Ylz81z8esoxo;92102dihYdro2E22i2Si22 M.Pt. 186° - 190°; [a]* = "63° (c = 0.3 in dimethyl formamide).
EXAMPLE 6: i^-desoxo^ergotamine M.Pt. 176° - 180°; [a]20 = +17° (c = 0.35 in dimethyl §Lz2£S2ii2Z£l:222Ei2l:i2£ ®lzS25252Z£z2E222£Z2£i22 δ1ζ3£2222Ζ2Ζ2Ε22Ξ£ϊΕ£ί22 formamide).
The compounds of formula I exhibit pharmacological activity. In particular, the compounds of formula I exhibit coronary therapeutic activity as indicated by a coronary dilation and vasodilation in the open chest cat test at an effective dose of from about 0.03 to about 1 mg/kg i.v.
The compounds are therefore indicated for use as coronary therapeutic agents, e.g. for the treatment of angina pectoris.
The compounds also exhibit anti-hypertensive 10 activity as indicated by a blood pressure lowering in the above-mentioned open chest cat test.
The compounds are therefore indicated for use as anti-hypertensives.
An indicated daily dose is from about 10 to about 15 300 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about 2 mg to about 150 mg or in sustained release form.
The compounds may be administered in pharmaceutically acceptable acid addition salt form. Such salt forms have the same order of activity as the free base forms. The present invention provides a pharmaceutical composition comprising a compound of formula I as defined above in association with a pharmaceutical carrier or diluent. Such composition may be formulated in conventional manner so as to be for example a solution or a tablet.
In the following claims we make no claim to the following 5 compounds: 6'-desoxo-9, 10-dihydroergotamine; 6'-desoxO"9,10-dihydro-lmethylergotami ne; 6'-desoxo-9,10-dihvdroergocri sti ne; 6'-desoxo9,10-dihydro-1-methylergocristine; and 6'-desoxo-9, 10-dihydro-aergocryptine, and methods for their production.
Claims (5)
1. A process for the production of a compound of formula I, wherein R^ is alkyl of 1 to 4 carbon atoms, R 2 is hydrogen, alkyl of 1 to 4 carbon atoms or benzyl, R 3 30 R 5 aEe » independently, hydrogen or methyl, R^ is hydrogen or alkyl of 1 to 4 carbon atoms, and Rg and R? together form a single bond, or Rg and R? are each hydrogen or R, is methoxy, and o R? .is hydrogen, which comprises _ 16 ΙΟ a) reducing the 6’ carbonyl group in a compound of II wherein R^ to are as defined above, or b) condensing an acid addition salt of a compound of formula III, III wherein Rg to Rg are as defined above, with a reactive acid derivative of a compound of t formula IV -Π46152 wherein R^ to R? are as defined above.
2. A process for the production of a compound of formula I, as stated in Claim 1, substantially as herein5 before described with reference to any one of the Examples 1 to 10.
3. A compound of formula I, whenever produced by a process according to Claim 1 or 2.
4. A compound of formula I, as defined in Claim 1 as defined in claim 1, 10 5. a compound of formula 1/ wherein R^ is methyl, ethyl or isopropyl, R 2 is H, CH^, C 2 H,., n- or iso-C^H^ or R a and Rg are as defined in claim 1 η-, iso- or sec-butyl,or benzyl,and R^ is H, Clly C 2 Hg, n- or iso-C^H? or η-, iso- or sec-butyl, and either Rg and R? are each hydrogen, or together form a bond. 15 6. A compound of Claim 4, which is 6'-desoxo-9, 10-dihydro-β -ergocryptine. 7. A compound of Claim 4, which is 1-methyl~6'-desoxo-9, 10-dihydroergocristine. 8. -A compound of Claim 4, which is 6'-desoxo-9,10 i n dihydroergocornine. - 18 46152 9. A compound of Claim 4, which is 6' -desoxo-9, 10-dihydro - β -ergosine. 10. A compound of Claim 4, which is e-nor-e-isopropyl -6'-desoxo-9, 10-di hydroergotami ne. 5 11. A compound of Claim 4, which is 6' - desoxo ergotamine. 12. A compound of Claim 4, which is 6'-desoxoergocristine. 13. A compound of Claim 4, which is 6'-desoxo -610 ergocryptine. 14. A compound of Claim 4, which is 6'-desoxo -aergocryptine. 15. A compound of any one of Claims 5 to 12 in free base form. 15 16. A compound of any one of Claims 5 to 12 in acid addition salt form. 17. A pharmaceutical composition comprising a compound of any one of Claims 5 to 12 in free base form or in pharmaceutically acceptable acid addition salt form in association 20 with a pharmaceutical carrier or diluent. -19 46152 18. A compound of any one of claims 3,4,13 and 14 in free base form, 19. A compound of any one of claims 3,4,13 and 14 in acid addition salt form.
5. 20. A pharmaceutical compound comprising a compound of any one of claims 3,4,13 and 14 in free base form or pharmaceutically acceptable acid addition salt form in association with a pharmaceutical carrier or diluent. Dated this 5th day of September 1977. BY:>ffiMKINS & CO.,
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1128676A CH623591A5 (en) | 1976-09-06 | 1976-09-06 | Process for the preparation of ergopeptide alkaloid derivatives |
| CH1128776A CH623592A5 (en) | 1976-09-06 | 1976-09-06 | Process for the preparation of ergopeptide alkaloid derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE46152L IE46152L (en) | 1978-03-06 |
| IE46152B1 true IE46152B1 (en) | 1983-03-09 |
Family
ID=25708069
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE1838/77A IE46152B1 (en) | 1976-09-06 | 1977-09-05 | Ergot peptide aklaloid derivatives |
Country Status (15)
| Country | Link |
|---|---|
| JP (1) | JPS5331698A (en) |
| AU (1) | AU512027B2 (en) |
| CA (1) | CA1105007A (en) |
| DE (1) | DE2738730A1 (en) |
| DK (1) | DK147390C (en) |
| ES (1) | ES462080A1 (en) |
| FI (1) | FI64942C (en) |
| FR (1) | FR2363571A1 (en) |
| GB (2) | GB1590149A (en) |
| IE (1) | IE46152B1 (en) |
| IL (1) | IL52896A (en) |
| NL (1) | NL7709683A (en) |
| NZ (1) | NZ185098A (en) |
| PT (1) | PT67003B (en) |
| SE (1) | SE435839B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BR112013033339A2 (en) * | 2011-06-23 | 2016-08-16 | Map Pharmaceuticals Inc | fluorergoline analogs |
-
1977
- 1977-06-02 ES ES462080A patent/ES462080A1/en not_active Expired
- 1977-08-27 DE DE19772738730 patent/DE2738730A1/en not_active Withdrawn
- 1977-08-29 DK DK382777A patent/DK147390C/en active
- 1977-08-29 FI FI772557A patent/FI64942C/en not_active IP Right Cessation
- 1977-08-29 SE SE7709645A patent/SE435839B/en unknown
- 1977-08-31 GB GB36338/77A patent/GB1590149A/en not_active Expired
- 1977-08-31 GB GB9862/80A patent/GB1590150A/en not_active Expired
- 1977-09-02 CA CA286,056A patent/CA1105007A/en not_active Expired
- 1977-09-02 NL NL7709683A patent/NL7709683A/en not_active Application Discontinuation
- 1977-09-05 JP JP10596277A patent/JPS5331698A/en active Pending
- 1977-09-05 PT PT67003A patent/PT67003B/en unknown
- 1977-09-05 NZ NZ185098A patent/NZ185098A/en unknown
- 1977-09-05 FR FR7726893A patent/FR2363571A1/en active Granted
- 1977-09-05 IE IE1838/77A patent/IE46152B1/en unknown
- 1977-09-05 IL IL52896A patent/IL52896A/en unknown
- 1977-09-06 AU AU28572/77A patent/AU512027B2/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| IE46152L (en) | 1978-03-06 |
| IL52896A0 (en) | 1977-11-30 |
| PT67003B (en) | 1979-05-14 |
| AU512027B2 (en) | 1980-09-18 |
| GB1590149A (en) | 1981-05-28 |
| DK147390B (en) | 1984-07-16 |
| JPS5331698A (en) | 1978-03-25 |
| DK147390C (en) | 1985-02-04 |
| FR2363571B1 (en) | 1980-04-18 |
| PT67003A (en) | 1977-10-01 |
| AU2857277A (en) | 1979-03-15 |
| ES462080A1 (en) | 1978-12-01 |
| CA1105007A (en) | 1981-07-14 |
| FI64942B (en) | 1983-10-31 |
| NL7709683A (en) | 1978-03-08 |
| FI64942C (en) | 1984-02-10 |
| GB1590150A (en) | 1981-05-28 |
| SE7709645L (en) | 1978-03-07 |
| FI772557A (en) | 1978-03-07 |
| DK382777A (en) | 1978-03-07 |
| DE2738730A1 (en) | 1978-03-16 |
| FR2363571A1 (en) | 1978-03-31 |
| IL52896A (en) | 1980-07-31 |
| NZ185098A (en) | 1980-04-28 |
| SE435839B (en) | 1984-10-22 |
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