RetroSearch Browse

Home - News ( United States | United Kingdom | Italy | Germany ) - Football scores

Showing content from https://patents.google.com/patent/US3414574A/en below:

US3414574A - Certain pyrimido (4, 5-b) indoles and intermediates employed in their preparation

US3414574A - Certain pyrimido (4, 5-b) indoles and intermediates employed in their preparation - Google PatentsCertain pyrimido (4, 5-b) indoles and intermediates employed in their preparation Download PDF Info

Publication number: US3414574A
Authority: US; United States
Prior art keywords: compound; preparation; indoles; parts; pyrimido
Prior art date: 1967-04-21
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

Application number

US632552A

Inventor

Albert J Frey

Goetz E Hardtmann

Ott Hans

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Sandoz AG

Sandoz Inc

Original Assignee

Sandoz AG

Priority date (The priority date 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 date listed.)

1967-04-21

Filing date

1967-04-21

Publication date

1968-12-03

1967-04-21 Application filed by Sandoz AG filed Critical Sandoz AG

1967-04-21 Priority to US632552A priority Critical patent/US3414574A/en

1968-12-03 Application granted granted Critical

1968-12-03 Publication of US3414574A publication Critical patent/US3414574A/en

1985-12-03 Anticipated expiration legal-status Critical

Status Expired - Lifetime legal-status Critical Current

Links

238000002360 preparation method Methods 0.000 title description 7
239000000543 intermediate Substances 0.000 title description 4
IEJAIKPHVAPFSS-UHFFFAOYSA-N 9h-pyrimido[4,5-b]indole Chemical class N1C=NC=C2C3=CC=CC=C3N=C21 IEJAIKPHVAPFSS-UHFFFAOYSA-N 0.000 title description 2
150000001875 compounds Chemical class 0.000 description 21
-1 i.e. Chemical group 0.000 description 10
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 8
125000004435 hydrogen atom Chemical group [H]* 0.000 description 7
238000000034 method Methods 0.000 description 6
150000003839 salts Chemical class 0.000 description 6
239000002253 acid Substances 0.000 description 5
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
238000006243 chemical reaction Methods 0.000 description 4
NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 4
HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
239000000203 mixture Substances 0.000 description 4
238000010992 reflux Methods 0.000 description 4
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 3
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
125000001309 chloro group Chemical group Cl* 0.000 description 3
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 2
OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
241000416162 Astragalus gummifer Species 0.000 description 2
FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
229920002261 Corn starch Polymers 0.000 description 2
GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
241000124008 Mammalia Species 0.000 description 2
229920001615 Tragacanth Polymers 0.000 description 2
239000004480 active ingredient Substances 0.000 description 2
125000000217 alkyl group Chemical group 0.000 description 2
238000009835 boiling Methods 0.000 description 2
125000004432 carbon atom Chemical group C* 0.000 description 2
239000008120 corn starch Substances 0.000 description 2
XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
235000019253 formic acid Nutrition 0.000 description 2
238000010438 heat treatment Methods 0.000 description 2
150000002475 indoles Chemical class 0.000 description 2
239000008101 lactose Substances 0.000 description 2
239000000314 lubricant Substances 0.000 description 2
235000019359 magnesium stearate Nutrition 0.000 description 2
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
239000008213 purified water Substances 0.000 description 2
238000007363 ring formation reaction Methods 0.000 description 2
239000000243 solution Substances 0.000 description 2
239000002904 solvent Substances 0.000 description 2
239000000725 suspension Substances 0.000 description 2
239000000454 talc Substances 0.000 description 2
235000012222 talc Nutrition 0.000 description 2
229910052623 talc Inorganic materials 0.000 description 2
239000000196 tragacanth Substances 0.000 description 2
235000010487 tragacanth Nutrition 0.000 description 2
229940116362 tragacanth Drugs 0.000 description 2
SVYOXGBINYWSDQ-UHFFFAOYSA-N 1,4-dioxane;ethanol Chemical compound CCO.C1COCCO1 SVYOXGBINYWSDQ-UHFFFAOYSA-N 0.000 description 1
QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
229910019142 PO4 Inorganic materials 0.000 description 1
QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
235000011054 acetic acid Nutrition 0.000 description 1
239000002671 adjuvant Substances 0.000 description 1
125000005907 alkyl ester group Chemical group 0.000 description 1
229940030600 antihypertensive agent Drugs 0.000 description 1
239000002220 antihypertensive agent Substances 0.000 description 1
239000002830 appetite depressant Substances 0.000 description 1
125000004429 atom Chemical group 0.000 description 1
239000002585 base Substances 0.000 description 1
SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
229940077388 benzenesulfonate Drugs 0.000 description 1
WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
239000011230 binding agent Substances 0.000 description 1
230000037396 body weight Effects 0.000 description 1
239000002775 capsule Substances 0.000 description 1
239000003795 chemical substances by application Substances 0.000 description 1
UXTMROKLAAOEQO-UHFFFAOYSA-N chloroform;ethanol Chemical compound CCO.ClC(Cl)Cl UXTMROKLAAOEQO-UHFFFAOYSA-N 0.000 description 1
235000014113 dietary fatty acids Nutrition 0.000 description 1
239000002934 diuretic Substances 0.000 description 1
229940030606 diuretics Drugs 0.000 description 1
239000003937 drug carrier Substances 0.000 description 1
230000000694 effects Effects 0.000 description 1
239000000839 emulsion Substances 0.000 description 1
KXEKODJGRSIGAU-UHFFFAOYSA-N ethyl 2-amino-1h-indole-3-carboxylate Chemical compound C1=CC=C2C(C(=O)OCC)=C(N)NC2=C1 KXEKODJGRSIGAU-UHFFFAOYSA-N 0.000 description 1
125000004494 ethyl ester group Chemical group 0.000 description 1
238000001704 evaporation Methods 0.000 description 1
229930195729 fatty acid Natural products 0.000 description 1
239000000194 fatty acid Substances 0.000 description 1
150000004665 fatty acids Chemical class 0.000 description 1
239000000945 filler Substances 0.000 description 1
238000001914 filtration Methods 0.000 description 1
238000009472 formulation Methods 0.000 description 1
239000012458 free base Substances 0.000 description 1
229910052500 inorganic mineral Inorganic materials 0.000 description 1
239000007788 liquid Substances 0.000 description 1
VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
238000002844 melting Methods 0.000 description 1
230000008018 melting Effects 0.000 description 1
239000011707 mineral Substances 0.000 description 1
231100000252 nontoxic Toxicity 0.000 description 1
230000003000 nontoxic effect Effects 0.000 description 1
230000000144 pharmacologic effect Effects 0.000 description 1
NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
239000010452 phosphate Substances 0.000 description 1
239000002244 precipitate Substances 0.000 description 1
235000019260 propionic acid Nutrition 0.000 description 1
IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
239000011541 reaction mixture Substances 0.000 description 1
KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
239000008096 xylene Substances 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
- 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
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

This invention relates to pyrimido[4,5-b]indoles, and more particularly to 3-amido-3,4-dihydro-4-oxo-pyrimido [4,5-b]indoles and salts thereof and a process for the preparation thereof.
the invention also relates to intermediates in the preparation of said compounds and a process for preparation of said intermediates.
the 3- amido-3,4-dihydro-4-oxo-pyrimido[4,5-b1indoles of this invention may be represented structurally as follows:
R is a member selected from the group consisting of a hydrogen atom, chloro and methoxy
R is a member selected from the group consisting of a hydrogen atom, and linear alkyl having from I to 3 atoms, i.e., methyl, ethyl and propyl.
Step a involves the 3,414,574 Patented Dec. 3, 1968 ice preparation of a Compound III, i.e., a hydrazide, from a Compound II, i.e., a Z-aminoindol-3-carboxylic acid lower linear alkyl ester, in a conventional manner. It is preferred to prepare the Compound III by heating a Compound II in a large excess of anhydrous hydrazine, e.g., 5 to 20 fold by weight, under reflux. If desired the reaction may be carried out in a suitable solvent, e.g., toluene, using from 1 to 2 molar equivalents of hydrazine and at to 120.
a suitable solvent e.g., toluene
Step b is a cyclization of the Compound III to the corresponding Compound I, which is effected by heating at from to boiling, preferably by refluxing, a Compound III in a large excess, e.g., 5 to 40 fold by weight, of a Compound IV, which is a lower linear fatty acid having from 1 to4 carbon atoms, i.e., formic acid, acetic acid, propionic acid or butyric acid.
the cyclization can be carried out in a suitable solvent, e.g., xylene, using from 2 to 4 equivalents of the Compound IV at temperatures of from 90 to the boiling point of the Compound IV.
Compounds II may be obtained according to the procedure described by C. A. Grob and O. Weissbach in Helvetica Chimica Acta, volume 44, pages 1748 to 1753 (1961).
Compounds I are useful because they have pharmacological activity. They are useful as antihypertensives and diuretics. They are administered to mammals either orally or parenterally in daily doses of from 5 to 20 mg./kg. of body weight, e.g., for large mammals from 300' to 1200 milligrams per diern, preferably administered in doses of from 75 to 600 milligrams; a single daily oral dose is also acceptable.
the compounds may be combined with a pharmaceutically acceptable carrier, and such other conventional adjuvants, as may be necessary, and administered orally in such forms as tablets, capsules, elixirs, suspensions or solutions, or parenterally in such forms as injectable solutions, suspensions or emulsions.
a pharmaceutically acceptable carrier such other conventional adjuvants, as may be necessary, and administered orally in such forms as tablets, capsules, elixirs, suspensions or solutions, or parenterally in such forms as injectable solutions, suspensions or emulsions.
the compounds may be similarly administered in the form of their non-toxic pharmaceutically ac ceptable acid addition salts.
Such salts possess the same order of activity as the free base are readily prepared in conventional manner by reacting the base with the appropriate acid and accordingly are included within the scope of the invention.
Such salts are the mineral acid salts such as the hydrochloride, hydrobromide, sulfate, phosphate and the like and the organic acid salts such as the succinate, benzoate, acetate, maleate, p-toluenesulfonate, benzenesulfonate and the like.
each of the pharmaceutically active compounds of this invention may be incorporated, for oral administration, in a tablet as the sole active ingredient.
a typical tablet is constituted by from 1 to 3 percent binder, e.g., tragacanth; from 3 to 10 percent disintegrating agent, e.g., corn starch; from 2 to 10 percent lubricant, e.g., talcum; from 0.25 to 1.0 percent lubricant, e.g., magnesium stearate; and average dosage of active ingredient; and q.s. percent of filler, e.g., lactose; all percentages being by weight.
Tablets are prepared according to standard tabletting techniques, which are wellknown in the art, employing the necessary amounts of conventional granulating liquids, e.g., alcohol SD-30 and purified water.
An exemplary tabletting formulation for the instant active compounds is:
Alcohol SD-30 purified water, q.s.
the title compound of the example is also useful as an appetite suppressant.
R is a member selected from the group consisting of a hydrogen atom, chloro and methoxy. 4. The compound according to claim 3 wherein R is a hydrogen atom.
NICHOLAS S. RIZZO Primary Examiner.

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Indole Compounds (AREA)

Description

United States Patent 3,414,574 CERTAIN PYRIMIDO(4,5-b)INDOLES AND INTERMEDIATES EMPLOYED IN THEIR PREPARATION Albert J. Frey, Essex Fells, Goetz E. Hardtrnann, Florham Park, and Hans Ott, Convent Station, N.J., assignors to Sandoz Inc., Hanover, NJ.

No Drawing. Filed Apr. 21, 1967, Ser. No. 632,552 4 Claims. (Cl. 260256.4)

ABSTRACT OF THE DISCLOSURE This invention relates to pyrimido[4,5-b]indoles, and more particularly to 3-amido-3,4-dihydro-4-oxo-pyrimido [4,5-b]indoles and salts thereof and a process for the preparation thereof. The invention also relates to intermediates in the preparation of said compounds and a process for preparation of said intermediates. The 3- amido-3,4-dihydro-4-oxo-pyrimido[4,5-b1indoles of this invention may be represented structurally as follows:

0 5 H H 0 REE J 2 R N N/ 2 I 8 l wherein R is a member selected from the group consisting of a hydrogen atom, chloro and methoxy; and

R is a member selected from the group consisting of a hydrogen atom, and linear alkyl having from I to 3 atoms, i.e., methyl, ethyl and propyl.

Compounds I are obtained according to the procedure of the folliwing reaction scheme wherein R and R are as defined above and R is lower linear alkyl, e.g., having from 1 to 6 carbon atoms:

According to the reaction scheme, Step a involves the 3,414,574 Patented Dec. 3, 1968 ice preparation of a Compound III, i.e., a hydrazide, from a Compound II, i.e., a Z-aminoindol-3-carboxylic acid lower linear alkyl ester, in a conventional manner. It is preferred to prepare the Compound III by heating a Compound II in a large excess of anhydrous hydrazine, e.g., 5 to 20 fold by weight, under reflux. If desired the reaction may be carried out in a suitable solvent, e.g., toluene, using from 1 to 2 molar equivalents of hydrazine and at to 120.

Step b is a cyclization of the Compound III to the corresponding Compound I, which is effected by heating at from to boiling, preferably by refluxing, a Compound III in a large excess, e.g., 5 to 40 fold by weight, of a Compound IV, which is a lower linear fatty acid having from 1 to4 carbon atoms, i.e., formic acid, acetic acid, propionic acid or butyric acid. If desired, the cyclization can be carried out in a suitable solvent, e.g., xylene, using from 2 to 4 equivalents of the Compound IV at temperatures of from 90 to the boiling point of the Compound IV.

Compounds II may be obtained according to the procedure described by C. A. Grob and O. Weissbach in Helvetica Chimica Acta, volume 44, pages 1748 to 1753 (1961).

Compounds I are useful because they have pharmacological activity. They are useful as antihypertensives and diuretics. They are administered to mammals either orally or parenterally in daily doses of from 5 to 20 mg./kg. of body weight, e.g., for large mammals from 300' to 1200 milligrams per diern, preferably administered in doses of from 75 to 600 milligrams; a single daily oral dose is also acceptable.

For the above uses, the compounds may be combined with a pharmaceutically acceptable carrier, and such other conventional adjuvants, as may be necessary, and administered orally in such forms as tablets, capsules, elixirs, suspensions or solutions, or parenterally in such forms as injectable solutions, suspensions or emulsions. Furthermore, the compounds may be similarly administered in the form of their non-toxic pharmaceutically ac ceptable acid addition salts. Such salts possess the same order of activity as the free base, are readily prepared in conventional manner by reacting the base with the appropriate acid and accordingly are included within the scope of the invention. Representative of such salts are the mineral acid salts such as the hydrochloride, hydrobromide, sulfate, phosphate and the like and the organic acid salts such as the succinate, benzoate, acetate, maleate, p-toluenesulfonate, benzenesulfonate and the like.

For example, each of the pharmaceutically active compounds of this invention may be incorporated, for oral administration, in a tablet as the sole active ingredient. A typical tablet is constituted by from 1 to 3 percent binder, e.g., tragacanth; from 3 to 10 percent disintegrating agent, e.g., corn starch; from 2 to 10 percent lubricant, e.g., talcum; from 0.25 to 1.0 percent lubricant, e.g., magnesium stearate; and average dosage of active ingredient; and q.s. percent of filler, e.g., lactose; all percentages being by weight. Tablets are prepared according to standard tabletting techniques, which are wellknown in the art, employing the necessary amounts of conventional granulating liquids, e.g., alcohol SD-30 and purified water. An exemplary tabletting formulation for the instant active compounds is:

Parts Title compound of the example 75 Tragacanth 2 Lactose 14.5 Corn starch 5 Talcum 3 Magnesium stearate 0.5

Alcohol SD-30, purified water, q.s.

The title compound of the example is also useful as an appetite suppressant.

An example illustrative of this invention follows. Throughout this disclosure all temperatures are centigrade (room temperature is 20) and all percents and parts are by weight, unless specified otherwise. Parts by weight are related to parts by volume as a kilogram is related to a liter.

EXAMPLE 3-formamido-3,4-dihydro-4-oxo-pyrimido [-4,5-b]indole This example illustrates the preparation of a Compound I according to the reaction scheme presented above.

(a) 2-aminoindol-3-carboxylic acid hydrazide Dissolve parts of 2-aminoindo1e-3-carboxy1ic acid ethyl ester in 100 parts by volume of 95% anhydrous hydrazine and reflux the mixture for hours. Cool the mixture and evaporate under vacuum to obtain a resi due. Dissolve the residue in methanol and remove the residual hydrazine by evaporating under vacuum. Crystallize the residue from ethanol to obtain crude Compound a, then recrystallize from ethanol-chloroform (2:1) to obtain purified Compound a, melting point (M.P.) 201 to 205.

(b) 3-form amide-3,4-dihydro-4-ox0-pyrimido- [4,5 -b] indole Reflux a mixture of 10.4 parts of purified Compound a and 200 parts by volume of 98 to 100% formic acid for 15 hours. Dilute the reaction mixture with 400 parts by volume of water, to form a precipitate of crude title compound, which then separate by filtration and wash on the filter first with 200 parts by volume of water then 50 parts by volume of ethanol and finally 100 parts by volume of diethyl ether. Recrystallize from 500 parts by volume of ethanol-dioxane (1:1) to obtain the purified title compound, M.P. 312 to 315.

Following the procedure described in Step a of this example but replacing the 2-aminoindole-3-carboxylic acid ethyl ester with an equivalent amount of 4-chloro-2- l H I U A J wherein R is a member selected from the group consisting of a hydrogen atom, chloro and methoxy; and R is a member selected from the group consisting of a hydrogen atom, methyl, ethyl and propyl; and (B) a pharmaceutically acceptable acid addition salt of a compound of said formula.

2. The compound according to claim 1 wherein each of R and R is a hydrogen atom.

3. A compound of the formula:

wherein R is a member selected from the group consisting of a hydrogen atom, chloro and methoxy. 4. The compound according to claim 3 wherein R is a hydrogen atom.

References Cited UNITED STATES PATENTS 3,320,278 5/1967 Ruyle et a1. 260-32614 FOREIGN PATENTS 1,363,855 5/1964 France.

OTHER REFERENCES Magidson et al., Chem. Abstracts, vol. 64 (1966), col. 19634.

NICHOLAS S. RIZZO, Primary Examiner.

R. J. GALLAGHER, Assistant Examiner.

US632552A 1967-04-21 1967-04-21 Certain pyrimido (4, 5-b) indoles and intermediates employed in their preparation Expired - Lifetime US3414574A (en) Priority Applications (1) Application Number Priority Date Filing Date Title US632552A US3414574A (en) 1967-04-21 1967-04-21 Certain pyrimido (4, 5-b) indoles and intermediates employed in their preparation Applications Claiming Priority (1) Application Number Priority Date Filing Date Title US632552A US3414574A (en) 1967-04-21 1967-04-21 Certain pyrimido (4, 5-b) indoles and intermediates employed in their preparation Publications (1) Publication Number Publication Date US3414574A true US3414574A (en) 1968-12-03 Family ID=24535965 Family Applications (1) Application Number Title Priority Date Filing Date US632552A Expired - Lifetime US3414574A (en) 1967-04-21 1967-04-21 Certain pyrimido (4, 5-b) indoles and intermediates employed in their preparation Country Status (1) Cited By (4) * Cited by examiner, â Cited by third party Publication number Priority date Publication date Assignee Title US4011324A (en) * 1976-01-20 1977-03-08 Pfizer Inc. Esters and amides of pyrimido[4,5-b]quinolin-4(3H)-one-2-carboxylic acids as antiulcer agents US4044134A (en) * 1974-07-05 1977-08-23 Pfizer Inc. Fused pyrimidin-4(3H)-ones as antiallergy agents US4072679A (en) * 1976-06-15 1978-02-07 E. R. Squibb & Sons, Inc. 1,4- AND 4,10-DIHYDRO-4-OXO-PYRIMIDO (1,2-A)-benzimidazole-3-carboxylic acids, esters and amides CN104804002A (en) * 2015-04-08 2015-07-29 æ²³åå¸èå¤§å¦ Synthesis method for 9H-pyrimido(4,5-b) indole compounds Citations (2) * Cited by examiner, â Cited by third party Publication number Priority date Publication date Assignee Title FR1363855A (en) * 1960-02-04 1964-06-19 Roussel Uclaf New indole derivatives and their preparation process US3320278A (en) * 1965-06-30 1967-05-16 Merck & Co Inc Alpha-(2-amino)-3-indolyl lower aliphatic acid derivatives

1967
- 1967-04-21 US US632552A patent/US3414574A/en not_active Expired - Lifetime

Patent Citations (2) * Cited by examiner, â Cited by third party Publication number Priority date Publication date Assignee Title FR1363855A (en) * 1960-02-04 1964-06-19 Roussel Uclaf New indole derivatives and their preparation process US3320278A (en) * 1965-06-30 1967-05-16 Merck & Co Inc Alpha-(2-amino)-3-indolyl lower aliphatic acid derivatives Cited By (5) * Cited by examiner, â Cited by third party Publication number Priority date Publication date Assignee Title US4044134A (en) * 1974-07-05 1977-08-23 Pfizer Inc. Fused pyrimidin-4(3H)-ones as antiallergy agents US4011324A (en) * 1976-01-20 1977-03-08 Pfizer Inc. Esters and amides of pyrimido[4,5-b]quinolin-4(3H)-one-2-carboxylic acids as antiulcer agents US4072679A (en) * 1976-06-15 1978-02-07 E. R. Squibb & Sons, Inc. 1,4- AND 4,10-DIHYDRO-4-OXO-PYRIMIDO (1,2-A)-benzimidazole-3-carboxylic acids, esters and amides US4109091A (en) * 1976-06-15 1978-08-22 E. R. Squibb & Sons, Inc. Derivatives of 1,4- and 4,10-dihydro-4-oxo-pyrimido[1,2-a]benzimidazole-3-carboxylic acid amides CN104804002A (en) * 2015-04-08 2015-07-29 æ²³åå¸èå¤§å¦ Synthesis method for 9H-pyrimido(4,5-b) indole compounds Similar Documents Publication Publication Date Title EP0289227B1 (en) 1992-04-08 Substituted imidazolyl-alkyl-piperazine and -diazepine derivatives US4148897A (en) 1979-04-10 1,2-Dihydronaphthalene derivatives and pharmaceutical composition US4690924A (en) 1987-09-01 1,7-Naphthyridine derivatives and medicinal preparations containing same AU692563B2 (en) 1998-06-11 Novel pyrrolocarbazoles US3335134A (en) 1967-08-08 Certain 3, 4-dihydrofluoreno[1, 9a, 9-e, f]1, 4-diazepin-3(2h)-ones US3542782A (en) 1970-11-24 5,6-dihydro-8h-isoquino(1,2-b)quinazolines EP0028381B1 (en) 1985-04-10 Azepinoindoles, process for their production and pharmaceutical compositions containing them US3414574A (en) 1968-12-03 Certain pyrimido (4, 5-b) indoles and intermediates employed in their preparation US3652569A (en) 1972-03-28 Ergonine ergoptine and the 1-methyl and 9 10-dihydro derivatives thereof US4622320A (en) 1986-11-11 Oxadiazolylimidazobenzodiazepine, compositions, and method US3666762A (en) 1972-05-30 2{40 {62 -ISOPROPYL-5{40 {60 -n-PROPYL-9,10-DIHYDRO-ERGOPEPTINES CS199610B2 (en) 1980-07-31 Process for preparing 8-8-disubstituted 6-methylergolines and derivatives thereof JPS6245864B2 (en) 1987-09-29 US3818096A (en) 1974-06-18 Compositions of 1,2-dilower alkyl arylpyrazolium quaternary salts and method of lowering blood sugar levels with same US3579517A (en) 1971-05-18 Secondaryamino pyridazines US3496165A (en) 1970-02-17 Octahydro-3-benzazecines US4377689A (en) 1983-03-22 Process for preparing spiro derivatives US3655648A (en) 1972-04-11 2 5-benzodiazonin-3-ones US3459750A (en) 1969-08-05 Asymmetrical triazines US3647877A (en) 1972-03-07 Aminopropionanilides US3497499A (en) 1970-02-24 Dibenzo(b,h)(1,5)diazecines US3530129A (en) 1970-09-22 8h-isoquino(1,2-b)quinazolin-8-ones US3551411A (en) 1970-12-29 2,5-benzodiazonine compounds US4745112A (en) 1988-05-17 Oxadiazolylimidazobenzodiazepine, compositions, and method III US3542783A (en) 1970-11-24 Isoquino(1,2-b)quinazolines

RetroSearch is an open source project built by @garambo | Open a GitHub Issue

Search and Browse the WWW like it's 1997 | Search results from DuckDuckGo

HTML: 3.2 | Encoding: UTF-8 | Version: 0.7.4