CA1094553A - 1-amino substituted indoline derivatives as vasoconstricting agents - Google Patents
1-amino substituted indoline derivatives as vasoconstricting agentsInfo
- Publication number
- CA1094553A CA1094553A CA306,210A CA306210A CA1094553A CA 1094553 A CA1094553 A CA 1094553A CA 306210 A CA306210 A CA 306210A CA 1094553 A CA1094553 A CA 1094553A
- Authority
- CA
- Canada
- Prior art keywords
- formula
- hydrogen
- carbon atoms
- compound
- alkyl
- 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
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- 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
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Peptides Or Proteins (AREA)
- Indole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Abtract The compounds of formula I, I
wherein R1 to R5 and n have various significances, are usefula as vasoconstricting agents.
wherein R1 to R5 and n have various significances, are usefula as vasoconstricting agents.
Description
10~ ~5~3 - l - 100-4837 l-AMINO SUBSTITUTED INDOLINE
DERIVATIVES AS VASOCONSTRICTING AGENTS
The present invention relates to 1-aminoindoline derivati~es.
In accordance with the invention there are provided compounds of formula I, ~ ~ R
R5 1 l2 ~C~ ~ (CH ) wherein one of R1 and R2 is hydrogen and the other is hydrogen or alkyl of 1 to 4 carbon atoms, R3 is hydrogen or alkyl of l to 4 carbon atoms, in the 2- or 3-position, R4 and R5 independently are hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of l to 4 carbon atoms, alkylthio of l to 4 carbon atoms or halogen of atomic number of from 9 to 35, and j~
109 ~553
DERIVATIVES AS VASOCONSTRICTING AGENTS
The present invention relates to 1-aminoindoline derivati~es.
In accordance with the invention there are provided compounds of formula I, ~ ~ R
R5 1 l2 ~C~ ~ (CH ) wherein one of R1 and R2 is hydrogen and the other is hydrogen or alkyl of 1 to 4 carbon atoms, R3 is hydrogen or alkyl of l to 4 carbon atoms, in the 2- or 3-position, R4 and R5 independently are hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of l to 4 carbon atoms, alkylthio of l to 4 carbon atoms or halogen of atomic number of from 9 to 35, and j~
109 ~553
- 2 - 100-4837 n is 2,3 or 4, and pharmaceutically acceptable acid addition salts thereof.
Alkyl, alkoxy and aLkyl ~ o preferably contain 1 or 2, carbon atoms, and especially l carbon atom.~lalogen is preferably chlorine.
Rl,R2,R3 and R5 are preferably hydrogen. R4 is prefer-ably hydrogen, alkyl or halogen, especially hydrogen.
R3 is preferably in the 3 position of the indoline nucleus.
R4 is preferably in the 4,5 or 6, especially in the 4 or 5, preferably in the 4-position.
n is preferably 2.
In accordance with the invention, a compound of formula I
may be obtained by a process comprising cyclizing a compound of formula II, 4 ~
~ N ~ 12 II
R5 N~ / NH
\N ~ 2 n 5 wherein Rl to R5 and n are as defined above and X is a leaving group.
Where necessary or desired the resulting compound of formula I may be converted into a pharmaceutically acceptable acid addition salt thereof.
The process according to the invention may be effected in a manner analogous to known methods for cyclizing analogous amino derivatives. X is e.g. a group -NHRa/ wherein Ra is alkyl of 1 to 4 carbon atoms~ especially ~09'~5~3
Alkyl, alkoxy and aLkyl ~ o preferably contain 1 or 2, carbon atoms, and especially l carbon atom.~lalogen is preferably chlorine.
Rl,R2,R3 and R5 are preferably hydrogen. R4 is prefer-ably hydrogen, alkyl or halogen, especially hydrogen.
R3 is preferably in the 3 position of the indoline nucleus.
R4 is preferably in the 4,5 or 6, especially in the 4 or 5, preferably in the 4-position.
n is preferably 2.
In accordance with the invention, a compound of formula I
may be obtained by a process comprising cyclizing a compound of formula II, 4 ~
~ N ~ 12 II
R5 N~ / NH
\N ~ 2 n 5 wherein Rl to R5 and n are as defined above and X is a leaving group.
Where necessary or desired the resulting compound of formula I may be converted into a pharmaceutically acceptable acid addition salt thereof.
The process according to the invention may be effected in a manner analogous to known methods for cyclizing analogous amino derivatives. X is e.g. a group -NHRa/ wherein Ra is alkyl of 1 to 4 carbon atoms~ especially ~09'~5~3
- 3 100-4~37 methyl, or R is hydrogen. The reaction is preferably e~fected in an inert solvent such as methanol or ethanol, or, when the amine of formula IV (see below) is liquid at the reaction temperature, the reaction is convenient-ly effected in the absence of any additional solvent.The reaction is preferably effected in the presence of a mineral acid such as hydrochloric or hydroiodic acid.
The reaction temperature may be from room temperature to about 150C and is preferably at least 50C, e.g. the boiling temperature of the reaction mixture.
The compounds of formula I may be isolated and purified in accordance with known methods.
The compounds of formula I may be present in free form, or in the form of acid addition salts. Acid addition salt forms, for example, the hydrochloride or hydrogen maleate, may be produced from the free form in known manner, and vice-versa.
The compounds of formula I may also be present intauto-meric form, i.e. with the double bond adjacent to one of the other two nitrogen atoms of the guanidine moiety, insofar this nitrogen atom is not substituted by an alkyl group Rl or R2. It is to be appreciated that such tautomeric forms also fall under the scope of formula I.
The production of the starting materials may be effected in known manner.
A compound of formula II may e.g. be produced by reacting a compound of formula III, tO~.~5'~3
The reaction temperature may be from room temperature to about 150C and is preferably at least 50C, e.g. the boiling temperature of the reaction mixture.
The compounds of formula I may be isolated and purified in accordance with known methods.
The compounds of formula I may be present in free form, or in the form of acid addition salts. Acid addition salt forms, for example, the hydrochloride or hydrogen maleate, may be produced from the free form in known manner, and vice-versa.
The compounds of formula I may also be present intauto-meric form, i.e. with the double bond adjacent to one of the other two nitrogen atoms of the guanidine moiety, insofar this nitrogen atom is not substituted by an alkyl group Rl or R2. It is to be appreciated that such tautomeric forms also fall under the scope of formula I.
The production of the starting materials may be effected in known manner.
A compound of formula II may e.g. be produced by reacting a compound of formula III, tO~.~5'~3
- 4 - 100-4837 R--~ 3 `~`C I I I
\S--Y
wherein R3 to R5 and X are as defined abo~e and the group -S-Y is a leaving group, with a compound of formula IV, Rl-NH-(CH2)n N~ 2 IV
wherein Rl, R2 and n are as defined above.
Y may e.g. be alkyl of 1 to 4 carbon atoms, preferably methyl. The reaction conditions may be chosen such as to be ldentical with the conditions for cyclization according to the invention. The compounds of formula III are then advantageously reacted with the compounds of formula IV to give directly the corresponding compounds of formula I, without intermediate isolation of the com-pounds of formula II.
When in the compounds of formula III Y is alkyl of 1 to 4 carbon atoms and X is a group -NH-R , the reaction conditions for producing compounds of formula I directly from corresponding compounds of formula III are analoqous to known reaction conditions for the production of a l-(indolin-l-yl)-guanidine derivative from a l-~indolin-l-yl)-2-(lower)alkylisothiourea.
~9^~553
\S--Y
wherein R3 to R5 and X are as defined abo~e and the group -S-Y is a leaving group, with a compound of formula IV, Rl-NH-(CH2)n N~ 2 IV
wherein Rl, R2 and n are as defined above.
Y may e.g. be alkyl of 1 to 4 carbon atoms, preferably methyl. The reaction conditions may be chosen such as to be ldentical with the conditions for cyclization according to the invention. The compounds of formula III are then advantageously reacted with the compounds of formula IV to give directly the corresponding compounds of formula I, without intermediate isolation of the com-pounds of formula II.
When in the compounds of formula III Y is alkyl of 1 to 4 carbon atoms and X is a group -NH-R , the reaction conditions for producing compounds of formula I directly from corresponding compounds of formula III are analoqous to known reaction conditions for the production of a l-(indolin-l-yl)-guanidine derivative from a l-~indolin-l-yl)-2-(lower)alkylisothiourea.
~9^~553
- 5 - 100-4837 Insofar as the production of the starting materials is not described, these are known or may be produced and purified in accordance with known processes, or in a manner analogous to the processes described above or analogous to kno~n processes.
In the following non-limitative Examples all temperatures are indicated in degrees Centigrade and are uncorrected.
Exam~le 1: 1-(Imidazolidin-2-ylidenamino)indoline To 10 g 1-(indolin-1-yl)-2-methyliscthiourea hydrochloride dissolved in 40 ml ethanol are added 8 ml ethylene diamine and the reaction mixture is boiled for 6 hours ~ith stirring. The mixture is then evaporated to dryness and the residue is extracted from a 1 N solution of sodium hydroxide with methylene chlorid-e. The organic phase is then dried over magnesium sulphate and evaporated. The title compound is obtained (M.P. o~ the hydrogen maleate 171-172 - from ethanol/ether).
The starting material is obtained as follows:
l-Aminoindoline is reacted with benzoyl isothiocyanate in boiling tetrahydrofurane and, after saponification of the product over 15 minutes with diluted sodium hydroxide under reflux, l-(indolin-l-yl)thiourea (M.P. 225-227 - from methanol) is obtained. This product is converted into l-(indolin-l-yl)-2-meth~l-isothiourea hydroiodide by heating up for 1 hour withmethyl iodide in methanol. The free base is obtained by 109~553 ~ 6 - 100-4837 addition of aqueous sodium hydroxide and is further reacted with a 2N methanolic solution of hydrochloric acid to give l-(indolin-l-yl)-2-methylisothiourea hydro-chloride (M.P. 227-229 - from methanol/ether).
The following compounds of formula I are obtained in a manner analogous to ~xample 1, using the corresponding starting materials of formula III, wherein Y is methyl and X is -NH2 or -NH-CH3, and of formula IV:
Ex.No. Rl R2 R3 4 R5 n ¦ M.P.
, . .. _. . ___ .. . . _ 2 H H H 5-Cl H 2b 182-184 3 H H 2-Me H H 2hcl 226-228 4 ~ H 3-Me H ~ 2b 173-174 H H H 4-Me H 2b 148-149
In the following non-limitative Examples all temperatures are indicated in degrees Centigrade and are uncorrected.
Exam~le 1: 1-(Imidazolidin-2-ylidenamino)indoline To 10 g 1-(indolin-1-yl)-2-methyliscthiourea hydrochloride dissolved in 40 ml ethanol are added 8 ml ethylene diamine and the reaction mixture is boiled for 6 hours ~ith stirring. The mixture is then evaporated to dryness and the residue is extracted from a 1 N solution of sodium hydroxide with methylene chlorid-e. The organic phase is then dried over magnesium sulphate and evaporated. The title compound is obtained (M.P. o~ the hydrogen maleate 171-172 - from ethanol/ether).
The starting material is obtained as follows:
l-Aminoindoline is reacted with benzoyl isothiocyanate in boiling tetrahydrofurane and, after saponification of the product over 15 minutes with diluted sodium hydroxide under reflux, l-(indolin-l-yl)thiourea (M.P. 225-227 - from methanol) is obtained. This product is converted into l-(indolin-l-yl)-2-meth~l-isothiourea hydroiodide by heating up for 1 hour withmethyl iodide in methanol. The free base is obtained by 109~553 ~ 6 - 100-4837 addition of aqueous sodium hydroxide and is further reacted with a 2N methanolic solution of hydrochloric acid to give l-(indolin-l-yl)-2-methylisothiourea hydro-chloride (M.P. 227-229 - from methanol/ether).
The following compounds of formula I are obtained in a manner analogous to ~xample 1, using the corresponding starting materials of formula III, wherein Y is methyl and X is -NH2 or -NH-CH3, and of formula IV:
Ex.No. Rl R2 R3 4 R5 n ¦ M.P.
, . .. _. . ___ .. . . _ 2 H H H 5-Cl H 2b 182-184 3 H H 2-Me H H 2hcl 226-228 4 ~ H 3-Me H ~ 2b 173-174 H H H 4-Me H 2b 148-149
6 H H H 4-OMe H 2hma 160-162
7 H- H H 7-Me H 2hcl 194-196 b = in free form hcl = hydrochloride hma = hydrogen maleate ~ - .. . . .
The compounds of formula I exhibit pharmacological 0 activity. In particular, the compounds possess vasoconstricting activity, as indicated by standard tests. For example, this activity may be observed ln vlvo in rats treated in accordance with the principles of J.S.
Gillespie and T.C. Muir, Br.J. Pharmac.Chemother. ~1967) ~09~5~3 - 7 - 1~0-4837 30, 78-87): a pressor effect is elicited following i.v. administration of from about 0.02 to about 50 ~g/kg, particularly of from about 0.02 to about 0.5 ~g/kg of the compounds.
The compounds are therefore indicated for use as vasoconstricting agents, e.g. for the prophylaxis and treatment of vascular headaches such as migraine, and of orthostatic disorders such as orthostatic hypotension and its symptoms,such as vertigo.
For this use an indicated daily dose is from about 0.0025 to about 1 mg, conveniently administered in - divided doses 2 to ~ times a day in unit dosage from containing from about O.OOP5to about 0.5 mg, or in sustained release form.
The activit~ of the compound of Example 1 is especially interesting.
The compounds of formula I may be administered in free form or in pharmaceutically acceptable acid addition salt form. Such forms exhibit the same order of activity as the free form. The present invention also provides a pharmaceutical composition comprising a compound of formula I, in free form or in pharmaceutically acceptabie salt form, in association with a pharmaceutical carrier or diluent. Such compositions may be in the form of, for example, a solution or a tablet.
The compounds of formula I exhibit pharmacological 0 activity. In particular, the compounds possess vasoconstricting activity, as indicated by standard tests. For example, this activity may be observed ln vlvo in rats treated in accordance with the principles of J.S.
Gillespie and T.C. Muir, Br.J. Pharmac.Chemother. ~1967) ~09~5~3 - 7 - 1~0-4837 30, 78-87): a pressor effect is elicited following i.v. administration of from about 0.02 to about 50 ~g/kg, particularly of from about 0.02 to about 0.5 ~g/kg of the compounds.
The compounds are therefore indicated for use as vasoconstricting agents, e.g. for the prophylaxis and treatment of vascular headaches such as migraine, and of orthostatic disorders such as orthostatic hypotension and its symptoms,such as vertigo.
For this use an indicated daily dose is from about 0.0025 to about 1 mg, conveniently administered in - divided doses 2 to ~ times a day in unit dosage from containing from about O.OOP5to about 0.5 mg, or in sustained release form.
The activit~ of the compound of Example 1 is especially interesting.
The compounds of formula I may be administered in free form or in pharmaceutically acceptable acid addition salt form. Such forms exhibit the same order of activity as the free form. The present invention also provides a pharmaceutical composition comprising a compound of formula I, in free form or in pharmaceutically acceptabie salt form, in association with a pharmaceutical carrier or diluent. Such compositions may be in the form of, for example, a solution or a tablet.
Claims (5)
1. A process for the production of a compound of Formula I, I
wherein one of R1 and R2 is hydrogen and the other is hydrogen or alkyl of 1 to 4 carbon atoms, R3 is hydrogen or alkyl of 1 to 4 carbon atoms, in the 2- or 3-position, R4 and R5 independently are hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms or halogen of atomic number of from 9 to 35, and n is 2, 3 or 4, or a pharmaceutically acceptable acid addition salt thereof, which comprises cyclizing a compound of formula II, - 9 - 100-4837 Australia Canada II
wherein R1 to R5 and n are as deined above and X is a leaving group, and where necessary or desired, converting the resulting compound of formula I into a pharmaceutically acceptable acid addition salt thereof.
wherein one of R1 and R2 is hydrogen and the other is hydrogen or alkyl of 1 to 4 carbon atoms, R3 is hydrogen or alkyl of 1 to 4 carbon atoms, in the 2- or 3-position, R4 and R5 independently are hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms or halogen of atomic number of from 9 to 35, and n is 2, 3 or 4, or a pharmaceutically acceptable acid addition salt thereof, which comprises cyclizing a compound of formula II, - 9 - 100-4837 Australia Canada II
wherein R1 to R5 and n are as deined above and X is a leaving group, and where necessary or desired, converting the resulting compound of formula I into a pharmaceutically acceptable acid addition salt thereof.
2. A compound of formula I as defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof, whenever produced by a process according to claim 1, or an obvious chemical equivalent thereof.
3. A process according to claim 1 for the production of 1-(Imidazolidin-2-ylidenamino)indoline, which comprises cyclizing a compound of formula II, wherein R1 to R5 are hydrogen, n is 2 and X is a leaving group.
4. A process accordlng to claim 1 for the production of 1-(Imidazolidin-2-ylidenamino)indoline, which comprises cyclizing 1-(indolin-1-yl)-2-methylisothiourea hydrochloride by heating it in a mixture of ethanol and ethylene diamine.
5. 1-(Imidazolidin-2-ylidenamino)indoline whenever produced by a process according to claims 3 or 4, or by an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH791577 | 1977-06-28 | ||
| CH7915/77 | 1977-06-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1094553A true CA1094553A (en) | 1981-01-27 |
Family
ID=4332315
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA306,210A Expired CA1094553A (en) | 1977-06-28 | 1978-06-26 | 1-amino substituted indoline derivatives as vasoconstricting agents |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP0000151B1 (en) |
| JP (1) | JPS5412373A (en) |
| AU (1) | AU3746878A (en) |
| CA (1) | CA1094553A (en) |
| DE (1) | DE2860709D1 (en) |
| DK (1) | DK275278A (en) |
| ES (1) | ES471125A1 (en) |
| FI (1) | FI781947A (en) |
| IL (1) | IL55005A (en) |
| IT (1) | IT7850073A0 (en) |
| NZ (1) | NZ187675A (en) |
| PT (1) | PT68217A (en) |
| ZA (1) | ZA783708B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT7950924A0 (en) * | 1978-12-13 | 1979-11-28 | Sandoz Ag | DERIVATIVES OF 1-AMINOINDOLIN THEIR PREPARATION AND APPLICATION AS MEDICINAL PRODUCTS |
| DE3133302A1 (en) * | 1981-08-22 | 1983-03-03 | Beiersdorf Ag, 2000 Hamburg | ISOINDOLIN-2-YL-AMINO-IMIDAZOLINE AND ISOINDOLIN-2-YL-GUANIDINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A MEDICINAL PRODUCT |
| DE3343801A1 (en) * | 1983-12-03 | 1985-06-13 | Dr. Karl Thomae Gmbh, 7950 Biberach | NEW INDOLDER DERIVATIVES, MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF |
| CA3214757A1 (en) | 2021-04-08 | 2022-10-13 | Andreas Loew | Multifuntional molecules binding to tcr and uses thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH529702A (en) * | 1970-07-06 | 1972-10-31 | Sandoz Ag | Optically active benz(c,d)indole derivs - with vasoconstrictive and cns - smoothing activity |
| GB1408362A (en) * | 1973-05-25 | 1975-10-01 | Lepetit Spa | 2-pyrrol-1-yl amino 4,5-dihydro-1-h-imidazole derivatives |
-
1978
- 1978-06-15 EP EP78100166A patent/EP0000151B1/en not_active Expired
- 1978-06-15 DE DE7878100166T patent/DE2860709D1/en not_active Expired
- 1978-06-19 DK DK275278A patent/DK275278A/en unknown
- 1978-06-19 FI FI781947A patent/FI781947A/en not_active Application Discontinuation
- 1978-06-26 AU AU37468/78A patent/AU3746878A/en active Pending
- 1978-06-26 IL IL55005A patent/IL55005A/en unknown
- 1978-06-26 CA CA306,210A patent/CA1094553A/en not_active Expired
- 1978-06-26 PT PT68217A patent/PT68217A/en unknown
- 1978-06-26 NZ NZ187675A patent/NZ187675A/en unknown
- 1978-06-26 ES ES471125A patent/ES471125A1/en not_active Expired
- 1978-06-27 JP JP7708578A patent/JPS5412373A/en active Pending
- 1978-06-28 IT IT7850073A patent/IT7850073A0/en unknown
- 1978-06-28 ZA ZA783708A patent/ZA783708B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IL55005A0 (en) | 1978-08-31 |
| EP0000151B1 (en) | 1981-05-20 |
| ZA783708B (en) | 1980-02-27 |
| ES471125A1 (en) | 1979-09-16 |
| DK275278A (en) | 1978-12-29 |
| PT68217A (en) | 1978-07-01 |
| EP0000151A1 (en) | 1979-01-10 |
| NZ187675A (en) | 1981-02-11 |
| JPS5412373A (en) | 1979-01-30 |
| IL55005A (en) | 1981-12-31 |
| FI781947A (en) | 1978-12-29 |
| AU3746878A (en) | 1980-01-03 |
| IT7850073A0 (en) | 1978-06-28 |
| DE2860709D1 (en) | 1981-08-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US3536712A (en) | 1-(amino-dihalo-phenyl)-2-amino-ethanes and -ethanols and salts thereof | |
| US3920636A (en) | Quinazoline compounds | |
| US4059621A (en) | Substituted benzamido propanolamines | |
| AU648394B2 (en) | 4-aryl-thiazole or imidazole derivatives | |
| US5001134A (en) | Piperidines, processes of preparation and medications containing them | |
| EP0309544B1 (en) | Psychotropic bicyclic imides | |
| US4129565A (en) | Isocarbostyril derivatives | |
| HARADA et al. | Development of potent serotonin-3 (5-HT3) receptor antagonists. II. Structure-activity relationships of N-(1-benzyl-4-methylhexahydro-1H-1, 4-diazepin-6-yl) carboxamides | |
| US3699123A (en) | 4-(3-amino-2-hydroxy-propoxy) indole derivatives | |
| IE47103B1 (en) | Dihydrouracils, process for their preparation and medicament containing them | |
| US3592824A (en) | 3-substituted amino-1,2,3,4-tetrahydrocarbazoles | |
| US6028073A (en) | N-substituted 3-azabicyclo (3.2.0)heptane derivatives useful as neuroleptics | |
| GB1563989A (en) | Sulfonamides | |
| CA1094553A (en) | 1-amino substituted indoline derivatives as vasoconstricting agents | |
| US4086353A (en) | Certain azolinylamino (azolidinylimino) indazoles | |
| US4217356A (en) | 2-Imidazolinylamino-2,1,3-benzothiadiazoles | |
| US3573310A (en) | 1-substituted derivatives of 2-indolinone | |
| US3996228A (en) | Pyrimidinoaminoethyl ergoline derivatives | |
| US4208420A (en) | New benzo [d] thiazole derivatives, process for their preparation and their therapeutic applications | |
| US4057560A (en) | 1,2,2A,3,4,5 Hexahydrobenz[c,d]indol-1-yl-2-guanidines | |
| NZ201642A (en) | 1-phenylindazol-3-one derivatives and pharmaceutical compositions | |
| US3732243A (en) | 2-(p-bromophenyl)-9-dimethyl-amino-propyl-9h-imidazo(1,2-a)benzimidazole | |
| US3957785A (en) | Bβ-Pyrimidino-aminomethyl-10α-ergoline and 10α-methoxyergoline derivatives | |
| CA1090804A (en) | 5,6-dihydro-8,9-dimethoxy-1-methyl-3-(phenylamino) imidazo[5,1-a]isoquinoline compounds | |
| US3278541A (en) | Di-substituted-n-alkyl piperidines |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |