US3882236A - Pharmaceutical compositions containing substituted 2-oxo-indolines and the use thereof to treat anxiety and tension - Google Patents

Pharmaceutical compositions containing substituted 2-oxo-indolines and the use thereof to treat anxiety and tension Download PDF

Info

Publication number
US3882236A
US3882236A US427947A US42794773A US3882236A US 3882236 A US3882236 A US 3882236A US 427947 A US427947 A US 427947A US 42794773 A US42794773 A US 42794773A US 3882236 A US3882236 A US 3882236A
Authority
US
United States
Prior art keywords
oxo
indoline
tension
composition
indolines
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
Application number
US427947A
Inventor
Bryan B Molloy
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.)
Eli Lilly and Co
Original Assignee
Eli Lilly and Co
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.)
Filing date
Publication date
Application filed by Eli Lilly and Co filed Critical Eli Lilly and Co
Priority to US427947A priority Critical patent/US3882236A/en
Application granted granted Critical
Publication of US3882236A publication Critical patent/US3882236A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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
    • C07D209/30—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
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil

Definitions

  • 2-Oxo-indolines are widely recognized in the art; see, for example, British Pat. No. l,247,ll3 and Belgian Pat. No. 756,447. Nowhere, however, does the art recognize that ring-substituted 2-oxo-indolines having the structure defined herein exhibit a useful therapeutic activity. This discovery forms the basis of this invention.
  • this invention relates to a pharmaceutical composition for relieving a condition associated with anxiety, tension, or like emotional disturbance comprising a therapeutically effective dose of an oxoindoline of the formula in which R is C -C alkyl, C C; alkoxy, halo, or trifluoromethyl, in association with a pharmaceutical carrier.
  • Another embodiment of this invention relates to a method of treating a patient to relieve a condition associated with anxiety, tension, or like emotional disturbance which comprises administering to said patient an oxo-indoline of the foregoing formula.
  • the active compounds of the composition of this invention and useful in the process of this invention have the formula 2-Oxo-4-iodoindoline;
  • Oxo-indolines such as the above can be prepared by any of several recognized methods.
  • Another method which is available comprises reduction of the corresponding isatin to the oxo-indoline. This procedure also is described in the aforementioned publication by P. 1... Julian et al., at pp. I29-l30, thereof.
  • the isatins which are reduced to the corresponding oxo-indolines can be prepared from readily available starting materials in accordance with the following sequence:
  • the source of the isatin is a substituted aniline.
  • the substituted aniline in the form of its acid addition salt, is converted to the corresponding isonitrosoacetanilide by reaction with chloral hydrate in the presence of sodium sulfate followed by treatment of the resulting reaction mixture with hydroxylamine hydrochloride.
  • the reaction typically is carried out in water with the reaction mixture being gently heated for a short period of time.
  • the next step in the synthesis involves the conversion of the isonitrosoacetanilide to its corresponding isatin.
  • This ring-closure reaction can be accomplished by treating the isonitrosoacetanilide with polyphosphoric acid at a moderately elevated temperature. Since ringclosure occurs in the position ortho to the anilide nitrogen, two structures can be formed, depending upon the position of the substituent on the ring of the isonitrosoacetanilide and the direction of the ringclosure. 1n the event two products are formed, separation typically can be accomplished by a successive precipitation technique. The reaction product mixture is first brought into aqueous solution by addition of alkali.
  • Precipitation of the two products typically is pH dependent, and one product is precipitated from the solution by acidifying the mixture to a moderately acidic pH of from about 3 to about 5. This product is then collected by filtration or extraction, and the collected product is further purified by standard techniques such as recrystallization. The filtrate then is further acidified, for example, to about pH 1 to effect isolation of the other product. This product is then separately collected and purified by recrystallization from an appropriate solvent.
  • the final step in the synthesis from isatins of the oxoindolines used in this invention involves the conversion of the isatin to its corresponding ring-substituted 2-oxoindoline. This can be accomplished by treating the isatin with anhydrous hydrazine at reflux in an appropriate moderately low boiling solvent such as a lower alkyl alcohol. The resulting unisolated isatin derivative, in the form of a hydrazone, is then reacted reductively with a sodium alkoxide. The overall effect is the replacement of the keto function in the 3-position with a methylene group, thereby achieving formation of the oxo-indoline.
  • Recovery can be accomplished by evaporating the solvent, dissolving the residue in water to achieve solution of the water-soluble by-products, and acidification of the mixture to produce precipitation of the final product.
  • the final product can then be purified by recrystallization from a suitable solvent.
  • the pharmaceutically active oxo-indolines can be administered alone or, preferably, in association with a pharmaceutical carrier.
  • the pharmaceutical carrier is selected on the basis of the chosen route of administration and in accordance with standard pharmaceutical practice.
  • the oxo-indolines can be administered orally, either alone, in capsule form, or in the form of tablets or capsules containing excipients such as starch, milk sugar, certain types of clay, and the like.
  • the oxoindolines can also be administered orally in the form of elixirs or oral suspensions which can contain coloring and/or flavoring agents.
  • the oxo-indolines can also be administered parenterally, and, for use in this route of administration, they can be prepared in the form of sterile solutions containing other solutes such as salt or glucose in sufficient quantity to make the solution isotonic.
  • the oxoindoline compositions can be prepared in an oil base such as a peanut or sesame oil.
  • the oxo-indolines of this invention are administered in pharmaceutically effective amounts. Generally, these will range from about 0.5 to about 500 milligrams per day, and preferably from about 2 to about 200 milligrams per day. However, in general, the dosage will depend upon particular circumstances, and these may differ from case to case. For example, the dosage levels will vary with the age, weight, and general health of the recipient as well as various other factors which may be peculiar to the particular recipient. in general, if the oxo-indoline is administered by a parenteral route, a lower dosage, for example, from about 0.1 milligram to about 250 milligrams of the oxo-indoline can be employed.
  • the oxo-indoline composition is in unit dosage form.
  • This expression as used herein refers to a physically discrete unit containing a predetermined dose of the oxo-indoline either alone or in association with a pharmaceutically acceptable carrier or excipient.
  • the unit dosage form may contain from about 0.5 to about 500 milligrams of the active oxo-indoline ingredient.
  • the individ ual weights of three canaries are determined, and a pre determined amount of the acacia suspension, measured in milligrams of test compound per kilogram of body weight of the canary, is orally injected.
  • the birds are placed in a lighted area and observed for a period of one hour, and the length of time that each bird sleeps is noted.
  • No refers to the number of canaries of the Unless otherwise indicated, a test group comprises three canar ies "Min.” refers to the combined total minutes of sleep which were recorded divided by the number of Canaries in the group.
  • Test group is composed of six canaries.
  • a pharmaceutical composition for relieving a condition associated with anxiety and tension comprising a therapeutically effective dose of an oxoindoline of the formula 7.
  • a method of treating a patient to relieve anxiety and tension which comprises administering to said patient a pharmaceutically effective amount of an exeindoline of the formula in which R is C,C alkyl, C -C alkoxy, halo, or trifluoromethyl.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Indole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A pharmaceutical composition containing as an active ingredient a 2-oxo-indoline substituted on the benzene ring by C1-C3 alkyl, C1-C3 alkoxy, halo, or trifluoromethyl, and a method of using the substituted 2-oxoindoline in relieving a condition associated with anxiety, tension, or a like emotional disturbance.

Description

United States Patent Molloy May 6, 1975 [54] PHARMACEUTICAL COMPOSITIONS 3,691,199 9/1972 Kobaysahi et al .t 260/325 R CONT SUBSTITUTED 3,720,771 3/1973 Canas-Rodriguez et al 424/274 3,723,457 3/1973 Hirose et al 424/274 Z-OXO-INDOLINES AND THE USE THEREOF TO TREAT ANXIETY AND TENSION Inventor: Bryan B. Molloy, Indianapolis, Ind.
Eli Lilly and Company, Indianapolis, Ind.
Filed: Dec. 26, 1973 Appl. No.: 427,947
Assignee:
References Cited UNITED STATES PATENTS l/l972 McManus et al. 260/325 R Primary ExaminerStanley J. Friedman Attorney, Agent, or FirmWilliam C. Martens, Jr; Everet F. Smith [57} ABSTRACT A pharmaceutical composition containing as an active ingredient a 2-oxoindoline substituted on the benzene ring by (l -C alkyl, C,-C alkoxy, halo, or trifluoromethyl, and a method of using the substituted 2 oxoindoline in relieving a condition associated with anxiety, tension, or a like emotional disturbance.
16 Claims, No Drawings PHARMACEUTICAL COMPOSITIONS CONTAINING SUBSTITUTED Z-OXO-INDOLINES AND THE USE THEREOF TO TREAT ANXIETY AND TENSION BACKGROUND AND SUMMARY OF THE INVENTION This invention relates to therapeutic compositions, and to a process for achieving therapeutic action.
It has been discovered that certain substituted 2-oxoindolines have a useful effect on the central nervous system. In particular, it has been discovered that these compounds exhibit a sedative-hypnotic effect and can be used in the treatment of conditions associated with anxiety, tension, or other emotional disturbance.
2-Oxo-indolines are widely recognized in the art; see, for example, British Pat. No. l,247,ll3 and Belgian Pat. No. 756,447. Nowhere, however, does the art recognize that ring-substituted 2-oxo-indolines having the structure defined herein exhibit a useful therapeutic activity. This discovery forms the basis of this invention.
Specifically, this invention relates to a pharmaceutical composition for relieving a condition associated with anxiety, tension, or like emotional disturbance comprising a therapeutically effective dose of an oxoindoline of the formula in which R is C -C alkyl, C C; alkoxy, halo, or trifluoromethyl, in association with a pharmaceutical carrier.
Another embodiment of this invention relates to a method of treating a patient to relieve a condition associated with anxiety, tension, or like emotional disturbance which comprises administering to said patient an oxo-indoline of the foregoing formula.
DETAILED DESCRIPTION OF THE INVENTION The active compounds of the composition of this invention and useful in the process of this invention have the formula 2-Oxo-4-iodoindoline;
2 -Oxo-6-bromoindoline;
2-Oxo-5-fluoroindoline;
2-Oxo-6-iodoindoline;
2-Oxo-4-trifluoromethylindoline;
2-Oxo-5-trifluoromethylindoline; and the like.
Oxo-indolines such as the above can be prepared by any of several recognized methods.
One standard chemical procedure which is available is that commonly referred to as the Stolle synthesis. This is developed at some depth in P. L. Julian et al., Heterocyclic Compounds, Vol. 3, John Wiley and Sons, Inc., New York (I952), pp. l42-l46, and involves ring-closure of an a-haloacetanilide to the corresponding oxo-indoline. In applying this method to the preparation of compounds defined herein, the particular a-haloacetanilide which is employed will be ringsubstituted so as to reflect the position and identity of the ring substituent of the final product.
Another method which is available comprises reduction of the corresponding isatin to the oxo-indoline. This procedure also is described in the aforementioned publication by P. 1... Julian et al., at pp. I29-l30, thereof.
The isatins which are reduced to the corresponding oxo-indolines can be prepared from readily available starting materials in accordance with the following sequence:
NaeSOa. HONHB.HCI
NH: Cl aC-CH (OH) 2 R 0 ll NH-CCH=NOH Polyphosphorl c act d NaOH O l H The foregoing sequence is merely representative of the preparation of isatins. Isatins are well known in the art and are available from various routes, see, for example, D. J. Bauer and P. W. Sadler, Brit. J. Pharmacol., 15, (1960) pp. 101-110.
In the foregoing sequence, the source of the isatin is a substituted aniline. Typically, the substituted aniline, in the form of its acid addition salt, is converted to the corresponding isonitrosoacetanilide by reaction with chloral hydrate in the presence of sodium sulfate followed by treatment of the resulting reaction mixture with hydroxylamine hydrochloride. The reaction typically is carried out in water with the reaction mixture being gently heated for a short period of time.
The next step in the synthesis involves the conversion of the isonitrosoacetanilide to its corresponding isatin. This ring-closure reaction can be accomplished by treating the isonitrosoacetanilide with polyphosphoric acid at a moderately elevated temperature. Since ringclosure occurs in the position ortho to the anilide nitrogen, two structures can be formed, depending upon the position of the substituent on the ring of the isonitrosoacetanilide and the direction of the ringclosure. 1n the event two products are formed, separation typically can be accomplished by a successive precipitation technique. The reaction product mixture is first brought into aqueous solution by addition of alkali. Precipitation of the two products typically is pH dependent, and one product is precipitated from the solution by acidifying the mixture to a moderately acidic pH of from about 3 to about 5. This product is then collected by filtration or extraction, and the collected product is further purified by standard techniques such as recrystallization. The filtrate then is further acidified, for example, to about pH 1 to effect isolation of the other product. This product is then separately collected and purified by recrystallization from an appropriate solvent.
The final step in the synthesis from isatins of the oxoindolines used in this invention involves the conversion of the isatin to its corresponding ring-substituted 2-oxoindoline. This can be accomplished by treating the isatin with anhydrous hydrazine at reflux in an appropriate moderately low boiling solvent such as a lower alkyl alcohol. The resulting unisolated isatin derivative, in the form of a hydrazone, is then reacted reductively with a sodium alkoxide. The overall effect is the replacement of the keto function in the 3-position with a methylene group, thereby achieving formation of the oxo-indoline. Recovery can be accomplished by evaporating the solvent, dissolving the residue in water to achieve solution of the water-soluble by-products, and acidification of the mixture to produce precipitation of the final product. The final product can then be purified by recrystallization from a suitable solvent.
In accordance with this invention, the pharmaceutically active oxo-indolines can be administered alone or, preferably, in association with a pharmaceutical carrier. The pharmaceutical carrier is selected on the basis of the chosen route of administration and in accordance with standard pharmaceutical practice. For example, the oxo-indolines can be administered orally, either alone, in capsule form, or in the form of tablets or capsules containing excipients such as starch, milk sugar, certain types of clay, and the like. The oxoindolines can also be administered orally in the form of elixirs or oral suspensions which can contain coloring and/or flavoring agents. The oxo-indolines can also be administered parenterally, and, for use in this route of administration, they can be prepared in the form of sterile solutions containing other solutes such as salt or glucose in sufficient quantity to make the solution isotonic. For intramuscular administration, the oxoindoline compositions can be prepared in an oil base such as a peanut or sesame oil.
The oxo-indolines of this invention are administered in pharmaceutically effective amounts. Generally, these will range from about 0.5 to about 500 milligrams per day, and preferably from about 2 to about 200 milligrams per day. However, in general, the dosage will depend upon particular circumstances, and these may differ from case to case. For example, the dosage levels will vary with the age, weight, and general health of the recipient as well as various other factors which may be peculiar to the particular recipient. in general, if the oxo-indoline is administered by a parenteral route, a lower dosage, for example, from about 0.1 milligram to about 250 milligrams of the oxo-indoline can be employed. Preferably the oxo-indoline composition is in unit dosage form. This expression as used herein refers to a physically discrete unit containing a predetermined dose of the oxo-indoline either alone or in association with a pharmaceutically acceptable carrier or excipient. The unit dosage form may contain from about 0.5 to about 500 milligrams of the active oxo-indoline ingredient.
The following examples are provided to further illustrate the teaching of this invention and are by no means intended to be limiting upon the scope thereof.
EXAMPLE To a suspension of 15 g. of 6-chloroisatin in 180 ml. of ethanol were added 30 ml. of hydrazine (97%), and the resulting solution was refluxed for 6 hours. A sodium ethoxide solution was prepared by dissolving 8.3 g. of sodium in 350 ml. of ethanol. The reaction mixture from the reaction of b-chloroisatin and hydrazine, while hot, was slowly added to the sodium ethoxide solution maintained at 70C. Upon completion of the addition, the resulting mixture was refluxed for about 16 hours. The solvent was then removed in vacuo, and the residue was added to about 800 g. of ice water. The pH of the resulting mixture was adjusted to about pH 1-2 by addition of concentrated hydrochloric acid, and the solids which formed were removed by filtration and washed with water. Recrystallization from a mixture of ethanol and water afforded 7.5 g. of 2-oxo-6- chloroindoline, m.p. 189-192C.
Analysis, calculated for C H CINO C, 57.33; H, 3.61; N, 8.36; O, 9.55; C1, 21.15.
Found: C, 57.37; H, 3.80; N, 8.31;O, 9.29; C1, 20.85.
Using procedures similar to the above, the following compounds are prepared. 2-Oxo-6-methylindoline; m.p. 17 l173C.
Anal. Calcd for C H NO:
C, 73.45; H, 6.16; N, 9.52; O, 10.87.
Found: C, 73.18; H, 6.12; N, 9.80; O, 10.97. 2-Oxo-6-methoxyindoline; m.p. 152-155C.
Anal. Calcd for C H NO C, 66.24; H, 5.56; N, 8.58; O, 19.61.
Found: C, 65.97; H, 5.39; N, 8.85; O, 19.75. 2-Oxo-4-methylindoline; m.p. 204206C.
Anal. Calcd for C H NO:
C, 73.45; H, 6.16; N, 9.52; O, 10.87.
Found: C, 73.29; H, 6.36; N, 9.58; O, 10.80. 2-Oxo-5-chloroindoline; m.p. 197-199C. 2-Oxo-4-chloroindoline; m.p. 21 1-213C.
Anal. Calcd for C H CINO:
C, 57.33; H, 3.61; N, 8.38; O, 9.55; C1, 21.15.
Found: C, 57.54; H, 3.88; N, 8.32; O, 9.69; C1, 21.21. 2-Oxo-6-f1uoroindoline; m.p. l39-141C.
Anal. Calcd for C H FNO:
C, 65.58; H, 4.00; N, 9.23.
Found: C, 65.76; H, 4.12; N, 9.35. 2-Oxo-7-chlorindoline; 2-Oxo-5-methoxyindoline', m.p. 151C.
Anal. Calcd for C H NO C, 66.25; H, 5.56; N, 8.58; O, 19.61.
Found: C, 66.12; H, 5.52; N, 8.30; O, 19.83.
' 2-Oxo6-trifluoromethylindoline; m.p. 176-179C.
Anal. Calcd for C H F NO: C, 53.74; H, 3.00, N, 6.96
milligrams of test compound per milliliter. The individ ual weights of three canaries are determined, and a pre determined amount of the acacia suspension, measured in milligrams of test compound per kilogram of body weight of the canary, is orally injected. The birds are placed in a lighted area and observed for a period of one hour, and the length of time that each bird sleeps is noted.
In the Table following is provided the tranquilizing activity of the oxo-indolines which are used in the method and are present in the composition of this in' vention. This activity is determined by means of the aforedescribed test procedure.
TABLE ACTIVITY OF 2-OXO-INDOLINES Milligrams per kilogram weight of canary 160 so 20 1o 5 2.5
R No. Min. No. Min. No. Min. No. Min. No. Min. No. Min No. Min.
P 6-Methy1 2 23 3 1a 2 3o 1 10 1 2 P 1 3 j G-Methoxy 1 3 3 1s 0 -j y i 3 2a 1 a 6-Ch1oro 3 37 3 3s 0 j 4-Ch1oro 3 1 l2 0 i l 6-Fluoro i 3 42 1 7 3 13 o l 1 iSflethoxy a 11 1 11 1 1o 5 o v-neuh l 3 6 33 2 17 2 a 0 a y 1 i 7 2 5 o l l jS-Fluoro 3 l 28 3 l as 3 20 o 1 2 1 s l 5-Chloro 2 13 Q i i 17-Chloro 3 1 37 o l i IG-Trifluoromethyl 3 4s 1 22 1 12 l 5 ll-Trifluoromethy]. 3 l 22 3 i 18 2 2O 4 l t l 1 Footnotes-- test group in which sleep was induced.
"No." refers to the number of canaries of the Unless otherwise indicated, a test group comprises three canar ies "Min." refers to the combined total minutes of sleep which were recorded divided by the number of Canaries in the group.
Test group is composed of six canaries.
I claim:
1. A pharmaceutical composition for relieving a condition associated with anxiety and tension comprising a therapeutically effective dose of an oxoindoline of the formula 7. Composition of claim 1, in which R is trifluoro methyl.
8. A method of treating a patient to relieve anxiety and tension, which comprises administering to said patient a pharmaceutically effective amount of an exeindoline of the formula in which R is C,C alkyl, C -C alkoxy, halo, or trifluoromethyl.
9. Method of claim 8, in which the indoline is administered at the rate of about 0.5 to about 500 milligrams per day,
10. Method of claim 9, in which the indoline is ad ministered at a rate of about 2 to about 200 milligrams per day.
11. Method of claim 8, in which the indoline is administered orally,
12. Method of claim 8, in which R is methyl.
13. Method of claim 8, in which R is methoxyx 14. Method of claim 8, in which R is halo.
15. Method of claim 14, in which R is chloro or fluoro.
16. Method of claim 8, in which R is trifluoromethyl

Claims (16)

1. A pharmaceutical composition for relieving a condition associated with anxiety and tension comprising a therapeutically effective dose of an oxo-indoline of the formula
2. Composition of claim 1 which comprises from about 0.5 to about 500 milligrams of the indoline in association with a pharmaceutical carrier.
3. Composition of claim 1, in which R is methyl.
4. Composition of claim 1, in which R is methoxy.
5. Composition of claim 1, in which R is halo.
6. Composition of claim 5, in which R is chloro or flUoro.
7. Composition of claim 1, in which R is trifluoromethyl.
8. A METHOD OF TREATING A PATIENT TO RELIEVE ANXIETY AND TENSION, WHICH COMPRISES ADMINISTERING TO SAID PATIENT A PHARMACEUTICALLY EFFECTIVE AMOUNT OF AN OXO-INDOLINE OF THE FORMULA
9. Method of claim 8, in which the indoline is administered at the rate of about 0.5 to about 500 milligrams per day.
10. Method of claim 9, in which the indoline is administered at a rate of about 2 to about 200 milligrams per day.
11. Method of claim 8, in which the indoline is administered orally.
12. Method of claim 8, in which R is methyl.
13. Method of claim 8, in which R is methoxy.
14. Method of claim 8, in which R is halo.
15. Method of claim 14, in which R is chloro or fluoro.
16. Method of claim 8, in which R is trifluoromethyl.
US427947A 1973-12-26 1973-12-26 Pharmaceutical compositions containing substituted 2-oxo-indolines and the use thereof to treat anxiety and tension Expired - Lifetime US3882236A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US427947A US3882236A (en) 1973-12-26 1973-12-26 Pharmaceutical compositions containing substituted 2-oxo-indolines and the use thereof to treat anxiety and tension

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US427947A US3882236A (en) 1973-12-26 1973-12-26 Pharmaceutical compositions containing substituted 2-oxo-indolines and the use thereof to treat anxiety and tension

Publications (1)

Publication Number Publication Date
US3882236A true US3882236A (en) 1975-05-06

Family

ID=23696951

Family Applications (1)

Application Number Title Priority Date Filing Date
US427947A Expired - Lifetime US3882236A (en) 1973-12-26 1973-12-26 Pharmaceutical compositions containing substituted 2-oxo-indolines and the use thereof to treat anxiety and tension

Country Status (1)

Country Link
US (1) US3882236A (en)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3983242A (en) * 1975-09-08 1976-09-28 Sandoz, Inc. 3-Alkylsulfinyl-2-indolinones and their pharmaceutical compositions and use
EP0208510A2 (en) 1985-07-09 1987-01-14 Pfizer Inc. 1-Substituted oxindole-3-carboxamines as antiinflammatory and analgesic agents
US4929622A (en) * 1987-09-24 1990-05-29 Hoechst-Roussel Pharmaceuticals, Inc. 2,6-Methanopyrrolo-3-benzazocines
US5145965A (en) * 1987-09-24 1992-09-08 Hoechst-Roussel Pharmaceuticals Incorporated 2,6-methanopyrrolo-3-benzazocines
EP0570817A1 (en) * 1992-05-13 1993-11-24 Lonza A.G. Process for the preparation of 5-chloroxindole
WO1994015918A1 (en) * 1993-01-08 1994-07-21 Smithkline Beecham Plc Process for the preparation of substituted indolone derivatives
FR2807659A1 (en) * 2000-04-13 2001-10-19 Centre Nat Rech Scient Pharmaceutical composition containing 5-hydroxy-oxindole or related material, useful for treating cancer, anxiety, hyperactivity, insomnia, depression or muscular pain
US6469181B1 (en) 1995-01-30 2002-10-22 Catalytica, Inc. Process for preparing 2-oxindoles and N-hydroxy-2-oxindoles
US20030181731A1 (en) * 2000-07-19 2003-09-25 Ube Industries., Ltd Process for producing 5-fluorooxyindole and for producing intermediates therefor
US20030207897A1 (en) * 2002-04-22 2003-11-06 Pfizer Inc. Selective inhibitors of cyclooxygenase-2
CN111587239A (en) * 2018-01-02 2020-08-25 基础科学研究院 Method for producing lactam compound and lactam compound produced by same

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3634453A (en) * 1969-10-15 1972-01-11 Pfizer Oxindole carboxamides
US3691199A (en) * 1969-04-19 1972-09-12 Sankyo Co 2-hydroxy-indole-3-dithiocarboxylates
US3720771A (en) * 1968-12-18 1973-03-13 Pfizer 3-substituted-1-phenyl-indolines and indolinones in composition for alleviating mentol depression
US3723457A (en) * 1969-09-30 1973-03-27 Eisai Co Ltd Indoline-2-one derivatives and preparation thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3720771A (en) * 1968-12-18 1973-03-13 Pfizer 3-substituted-1-phenyl-indolines and indolinones in composition for alleviating mentol depression
US3691199A (en) * 1969-04-19 1972-09-12 Sankyo Co 2-hydroxy-indole-3-dithiocarboxylates
US3723457A (en) * 1969-09-30 1973-03-27 Eisai Co Ltd Indoline-2-one derivatives and preparation thereof
US3634453A (en) * 1969-10-15 1972-01-11 Pfizer Oxindole carboxamides

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3983242A (en) * 1975-09-08 1976-09-28 Sandoz, Inc. 3-Alkylsulfinyl-2-indolinones and their pharmaceutical compositions and use
EP0208510A2 (en) 1985-07-09 1987-01-14 Pfizer Inc. 1-Substituted oxindole-3-carboxamines as antiinflammatory and analgesic agents
US4929622A (en) * 1987-09-24 1990-05-29 Hoechst-Roussel Pharmaceuticals, Inc. 2,6-Methanopyrrolo-3-benzazocines
US5145965A (en) * 1987-09-24 1992-09-08 Hoechst-Roussel Pharmaceuticals Incorporated 2,6-methanopyrrolo-3-benzazocines
EP0570817A1 (en) * 1992-05-13 1993-11-24 Lonza A.G. Process for the preparation of 5-chloroxindole
US5284960A (en) * 1992-05-13 1994-02-08 Lonza Ltd. Process for the production of 5-chloroxindole
US5395963A (en) * 1992-05-13 1995-03-07 Lonza Ltd. Process for chloronitroacetic acid esters
WO1994015918A1 (en) * 1993-01-08 1994-07-21 Smithkline Beecham Plc Process for the preparation of substituted indolone derivatives
US6469181B1 (en) 1995-01-30 2002-10-22 Catalytica, Inc. Process for preparing 2-oxindoles and N-hydroxy-2-oxindoles
FR2807659A1 (en) * 2000-04-13 2001-10-19 Centre Nat Rech Scient Pharmaceutical composition containing 5-hydroxy-oxindole or related material, useful for treating cancer, anxiety, hyperactivity, insomnia, depression or muscular pain
WO2001078722A1 (en) * 2000-04-13 2001-10-25 Centre National De La Recherche Scientifique Pharmaceutical compositions containing 5-hydroxyoxindole and use thereof
US20030181731A1 (en) * 2000-07-19 2003-09-25 Ube Industries., Ltd Process for producing 5-fluorooxyindole and for producing intermediates therefor
US6900335B2 (en) * 2000-07-19 2005-05-31 Ube Industries, Ltd. Process for producing 5-fluorooxindole and for producing intermediates therefor
US20030207897A1 (en) * 2002-04-22 2003-11-06 Pfizer Inc. Selective inhibitors of cyclooxygenase-2
US6846818B2 (en) 2002-04-22 2005-01-25 Pfizer Inc. Selective inhibitors of cyclooxygenase-2
CN111587239A (en) * 2018-01-02 2020-08-25 基础科学研究院 Method for producing lactam compound and lactam compound produced by same
JP2021509116A (en) * 2018-01-02 2021-03-18 インスティテュート フォー ベーシック サイエンスＩｎｓｔｉｔｕｔｅ Ｆｏｒ Ｂａｓｉｃ Ｓｃｉｅｎｃｅ Method for producing lactam compound and lactam compound produced from it
CN111587239B (en) * 2018-01-02 2024-04-02 基础科学研究院 Method for producing lactam compound and lactam compound produced by the method

Similar Documents

Publication Publication Date Title
JP2624901B2 (en) Novel derivative having naphthalene structure, method for producing the same and pharmaceutical composition containing the same
SU820659A3 (en) Method of preparing 4-amino-5-alkylsulfonyl-o-anisamide derivatives,their salts,oxides,left-and right-rotational isomers (their variations)
EP0100200B1 (en) 2-substituted 4-amino-6,7-dimethoxyquinolines
US3562278A (en) 1-(2-(2-substituted-3-indolyl)ethyl)-4-substituted-piperazines
JPS6350354B2 (en)
JPS5989625A (en) Aromatic substituted cyclic amidine obstipantia
US3399201A (en) Aminoalkyl-ethano-anthracenes
JPH0597805A (en) Novel cyclohexylbenzamide derivative, preparation thereof, and application thereof to medicine
US3091568A (en) Therapeutic phthalimidines for relieving cough and producing anesthesia
NZ197582A (en) Dextrorotatory trans-4a,9b-5phenyl-2,3,4,4a,5,9b-hexahydro-1h-pyrido(4,3-b) indoles
CA1082699A (en) Fused pyrimidine derivatives and process for the preparation thereof
US3941883A (en) Aromatic dicarboxamides as anticonvulsants
US3621027A (en) 1-aminoalkyl-2,6-diaryl 4,5,6,7 tetrahydro-4-oxindales
JPH02167279A (en) Apovincamic acid derivative
GB1600969A (en) Heterocyclic compounds
SU927111A3 (en) Process for producing oxime-esters or their salts
US4006161A (en) Thio-substituted 2-oxo-indolines
US3949081A (en) 4-Carbamoyl-1-benzazepines as antiinflammatory agents
US3935214A (en) 2-or 3 keto-3-or-2-phenyl-1,4-disubstituted piperazines
US3647802A (en) 2-amino-4-aryl-3 4-dihydroquinolines
US4598093A (en) 4-amino-tetrahydro-2-naphthoic acid derivatives
US3467755A (en) Compositions and methods for producing sedation and tranquilization with substituted 4,5,6,7- tetrahydro-4-oxindoles
SU810080A3 (en) Method of preparing (d,g)(1,3,6)dioxazocin derivatives or their acid-additive salts
US4622336A (en) 3,3-dialkyl-and 3,3-alkylene-indoline derivatives, processes for their production and pharmaceutical compositions comprising them
US3706765A (en) Hydroxyethano-anthracenes