US2951843A - Tetrahydrosoquinoline biguanides - Google Patents
Tetrahydrosoquinoline biguanides Download PDFInfo
- Publication number
- US2951843A US2951843A US831932A US83193259A US2951843A US 2951843 A US2951843 A US 2951843A US 831932 A US831932 A US 831932A US 83193259 A US83193259 A US 83193259A US 2951843 A US2951843 A US 2951843A
- Authority
- US
- United States
- Prior art keywords
- tetrahydroisoquinoline
- compounds
- biguanide
- tetrahydrosoquinoline
- biguanides
- 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 - Lifetime
Links
- 229940123208 Biguanide Drugs 0.000 title claims description 7
- 150000004283 biguanides Chemical class 0.000 title description 8
- UWYZHKAOTLEWKK-UHFFFAOYSA-N tetrahydro-isoquinoline Natural products C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 claims description 16
- -1 BIGUANIDE COMPOUND Chemical class 0.000 claims description 10
- 238000000034 method Methods 0.000 description 7
- 150000003839 salts Chemical class 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- QGBSISYHAICWAH-UHFFFAOYSA-N dicyandiamide Chemical compound NC(N)=NC#N QGBSISYHAICWAH-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 230000003178 anti-diabetic effect Effects 0.000 description 4
- 239000003472 antidiabetic agent Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
- 229910002651 NO3 Inorganic materials 0.000 description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- 229940125708 antidiabetic agent Drugs 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 150000003526 tetrahydroisoquinolines Chemical class 0.000 description 2
- MGFREDWKELGWML-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinolin-2-ium;chloride Chemical compound [Cl-].C1=CC=C2C[NH2+]CCC2=C1 MGFREDWKELGWML-UHFFFAOYSA-N 0.000 description 1
- XNCOSPRUTUOJCJ-UHFFFAOYSA-N Biguanide Chemical compound NC(N)=NC(N)=N XNCOSPRUTUOJCJ-UHFFFAOYSA-N 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000006477 desulfuration reaction Methods 0.000 description 1
- 230000023556 desulfurization Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 150000004800 hydroisoquinoline derivatives Chemical class 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
Definitions
- the present invention relates to new orally effective antidiabetic agents and more particularly to orally efiective biguanide compounds of the tetrahydroisoquinoline series, and to a process of making the same.
- biguanide compounds have antidiabetic properties (see, for instance, Archiv f. exp. Pathol. PharmacoL, vol. 142 (1929), page 290). However, said compounds are unsuitable in the treatment of diabetes mellitus by oral administration because of their high toxicity. Recently, other biguanide compounds have been found to be orally effective antidiabetic agents (Belgian Patent No. 557,985), but they cause nausea and vomiting in a large number of patients, so that they are also too toxic for administration over a prolonged period of time.
- his one object of the present invention to provide new and orally highly eifective antidiabetic biguanide compounds which have a low toxicity combined with a good therapeutical activity.
- Another object of the present invention is to provide a simple and efiective process of making such compounds.
- the new biguanide compounds according to the present invention are prepared according to various methods.
- guanyl tetrahydroisoquinoline may be added to cyanamide which may be substituted, according to the following equation:
- Z-cyano tetrahydroisoquinoline may be reacted with guanidine which may be substituted, according to the following equation:
- Example 1 34 g. of tetrahydroisoquinoline hydrochloride are inti-- mately mixed with 16.8 g. of dicyandiamide. The mixtureis heated in an oil bath of a temperature of 142 C. for 55 minutes. The resulting reaction product is boiled with. cc. of ethanol. After cooling, the solution is filtered; by suction. 34.8 g. of the biguanide compound of Formula II are obtained. Melting point: 226-228 C.
- reaction according to the present invention may be carried out with other alkyl substituted dicyandiamides such as the ethyl, npropyl, isopropyl, n-butyl, isoamyl dicyandiamide and the like. Otherwise the procedure is the same as described in said examples.
- the new tetrahydroisoquinoline biguanide compounds accordingto the present invention are administered in solid form, preferably in shaped form, such as in the form of tablets, pills, dragees, lozenges, and the like shaped preparations, or in powder form, preferably enclosed in gelatin and the like capsules.
- Administration in liquid form such as in the form of emulsion, suspensions, sirups, cough drops, and the like is also possible.
- These solid and liquid preparations are produced in a manner known to the art of compounding and processing pharmaceutical products, whereby the conventional diluting agents, binding agents, lubricants, expanding agents, and the like may be employed.
- the new compounds are preferably administered in the form of their acid addition salts such as the hydrochloride, sulfate, phosphate, nitrate, or the like. Salts with organic acids may also be used such as the salts with acetic acid, citric acid and succinic acid.
- the tetrahydroisoquinoline biguanide compound of the formula 2 1.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE857576X | 1958-08-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US2951843A true US2951843A (en) | 1960-09-06 |
Family
ID=6789605
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US831932A Expired - Lifetime US2951843A (en) | 1958-08-06 | 1959-08-06 | Tetrahydrosoquinoline biguanides |
Country Status (3)
| Country | Link |
|---|---|
| US (1) | US2951843A (enrdf_load_stackoverflow) |
| GB (1) | GB857576A (enrdf_load_stackoverflow) |
| NL (2) | NL241947A (enrdf_load_stackoverflow) |
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3157573A (en) * | 1962-12-18 | 1964-11-17 | Hoffmann La Roche | Antihypertensive 3, 4-dihydro-2(1h)-isoquinolinecarboxamidine |
| US3252989A (en) * | 1963-02-04 | 1966-05-24 | American Home Prod | Pyrazole-1-carboxamidines |
| US3291799A (en) * | 1964-09-21 | 1966-12-13 | Hoffmann La Roche | Isoquinoline carboxamidine |
| US3299078A (en) * | 1962-10-01 | 1967-01-17 | Smith Kline French Lab | Pyrido [3', 4': 4, 5] pyrrolo [3, 2, 1-hi] indoles and-[3, 2, 1-ij] quinolines |
| US3314963A (en) * | 1962-07-23 | 1967-04-18 | Pfizer & Co C | Azabenzocycloalkane-n-carboxamidines |
| US3505336A (en) * | 1968-05-06 | 1970-04-07 | Sterling Drug Inc | 3,4-dihydro-2-(1h)-isoquinolinecarboxamidoximes and lower-alkanoates |
| US3539576A (en) * | 1967-07-17 | 1970-11-10 | American Home Prod | 1,2,3,7,8,12b-hexahydrobenzo(1,2)cyclohepta(3,4,5 - d,e) isoquinolinomethyleneamidoximes and esters thereof |
| US5612332A (en) * | 1984-03-19 | 1997-03-18 | Alteon Inc. | Di- and triaminoguanidines, and methods of use |
| US5852009A (en) * | 1984-03-19 | 1998-12-22 | The Rockefeller University | Compositions, including pharmaceutical compositions, for inhibiting the advanced glycosylation of proteins, and therapeutic methods based thereon |
| US5850840A (en) * | 1995-11-15 | 1998-12-22 | Alteon Inc. | Methods for measurement and treatment predicated on the presence of advanced glycosylation endproducts in tobacco and its combustion byproducts |
| US5877217A (en) * | 1995-12-26 | 1999-03-02 | Alteon Inc. | N-acylaminoalkyl-hydrazinecarboximidamides |
| US6110968A (en) * | 1995-12-26 | 2000-08-29 | The Picower Institute For Medical Research | Methods for treatment predicated on the presence of advanced glycosylation endproducts in tobacco and its combustion byproducts |
| EP2742020A4 (en) * | 2011-08-08 | 2015-03-11 | Hanall Biopharma Co Ltd | N1-CYCLIC AMIN-N5-SUBSTITUTED BIGUANIDE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL COMPOSITION THEREWITH |
-
0
- NL NL120765D patent/NL120765C/xx active
- NL NL241947D patent/NL241947A/xx unknown
-
1959
- 1959-07-10 GB GB23842/59A patent/GB857576A/en not_active Expired
- 1959-08-06 US US831932A patent/US2951843A/en not_active Expired - Lifetime
Non-Patent Citations (1)
| Title |
|---|
| None * |
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3314963A (en) * | 1962-07-23 | 1967-04-18 | Pfizer & Co C | Azabenzocycloalkane-n-carboxamidines |
| US3299078A (en) * | 1962-10-01 | 1967-01-17 | Smith Kline French Lab | Pyrido [3', 4': 4, 5] pyrrolo [3, 2, 1-hi] indoles and-[3, 2, 1-ij] quinolines |
| US3157573A (en) * | 1962-12-18 | 1964-11-17 | Hoffmann La Roche | Antihypertensive 3, 4-dihydro-2(1h)-isoquinolinecarboxamidine |
| US3252989A (en) * | 1963-02-04 | 1966-05-24 | American Home Prod | Pyrazole-1-carboxamidines |
| US3291799A (en) * | 1964-09-21 | 1966-12-13 | Hoffmann La Roche | Isoquinoline carboxamidine |
| US3539576A (en) * | 1967-07-17 | 1970-11-10 | American Home Prod | 1,2,3,7,8,12b-hexahydrobenzo(1,2)cyclohepta(3,4,5 - d,e) isoquinolinomethyleneamidoximes and esters thereof |
| US3505336A (en) * | 1968-05-06 | 1970-04-07 | Sterling Drug Inc | 3,4-dihydro-2-(1h)-isoquinolinecarboxamidoximes and lower-alkanoates |
| US5612332A (en) * | 1984-03-19 | 1997-03-18 | Alteon Inc. | Di- and triaminoguanidines, and methods of use |
| US5852009A (en) * | 1984-03-19 | 1998-12-22 | The Rockefeller University | Compositions, including pharmaceutical compositions, for inhibiting the advanced glycosylation of proteins, and therapeutic methods based thereon |
| US6114323A (en) * | 1984-03-19 | 2000-09-05 | The Rockefeller University | Methods for inhibiting the advanced glycosylation of proteins |
| US5850840A (en) * | 1995-11-15 | 1998-12-22 | Alteon Inc. | Methods for measurement and treatment predicated on the presence of advanced glycosylation endproducts in tobacco and its combustion byproducts |
| US5877217A (en) * | 1995-12-26 | 1999-03-02 | Alteon Inc. | N-acylaminoalkyl-hydrazinecarboximidamides |
| US6110968A (en) * | 1995-12-26 | 2000-08-29 | The Picower Institute For Medical Research | Methods for treatment predicated on the presence of advanced glycosylation endproducts in tobacco and its combustion byproducts |
| EP2742020A4 (en) * | 2011-08-08 | 2015-03-11 | Hanall Biopharma Co Ltd | N1-CYCLIC AMIN-N5-SUBSTITUTED BIGUANIDE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL COMPOSITION THEREWITH |
| US9321742B2 (en) | 2011-08-08 | 2016-04-26 | Immunomet Therapeutics Inc. | N1-cyclic amine-N5-substituted biguanide derivatives, methods of preparing the same and pharmaceutical composition comprising the same |
Also Published As
| Publication number | Publication date |
|---|---|
| NL241947A (enrdf_load_stackoverflow) | |
| GB857576A (en) | 1960-12-29 |
| NL120765C (enrdf_load_stackoverflow) |
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