US3904761A - Method of preventing thrombosis - Google Patents

Method of preventing thrombosis Download PDF

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Publication number
US3904761A
US3904761A US436796A US43679674A US3904761A US 3904761 A US3904761 A US 3904761A US 436796 A US436796 A US 436796A US 43679674 A US43679674 A US 43679674A US 3904761 A US3904761 A US 3904761A
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compound
platelet aggregation
carbon atoms
aggregation
mammals
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US436796A
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Jr William J Novick
Howard B Lassman
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CNA Holdings LLC
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Hoechst Celanese Corp
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Priority to US436796A priority Critical patent/US3904761A/en
Priority to IL46485A priority patent/IL46485A0/en
Priority to DE2502156A priority patent/DE2502156C2/en
Priority to AU77603/75A priority patent/AU484103B2/en
Priority to NL7500861A priority patent/NL7500861A/en
Priority to ZA00750519A priority patent/ZA75519B/en
Priority to GB3252/75A priority patent/GB1499720A/en
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    • 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
    • A61K31/403—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 condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin

Definitions

  • This invention relates to a novel method of preventing thrombosis in mammals and to a method of preventing platelet aggregation. More specifically, this invention relates to a method of preventing thrombosis and platelet aggregation in mammals which consists of administering to mammals an effective amount of a 'compound of the formula:
  • Y X is hydrogen or hydroxy
  • Y is hydrogen, hydroxy, halogen, alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, or trifluoromethyl
  • Z is alkylene of three to five carbon atoms, alkylene of three to five carbon atoms substituted by alkyl or alkoxy of one to four carbon atoms, divinylene, divinylene substituted by alkyl of one to four carbon atoms,
  • This invention also relates to a method of inhibiting platelet aggregation in blood plasma which consists of adding an effective amount of a compound of the above formula to the plasma.
  • Control rats five injected and five noninjected, are treated in a similar manner, but are given a vehicle solution 10 ml distilled water plus one drop of Tween
  • the rats are anesthetized with sodium pentobarbital (50 mg/kg intraperitoneally) and blood samples are obtained from the abdominal aorta and mixed with 3.8% sodium citrate to a final concentration of 0.38%.
  • the samples are centrifuged for 10 minutes at 200 g at 4C.
  • the platelet-rich plasma (PRP) so obtained is removed by a siliconized Pasteur pipette and placed on ice in a plastic tube. The remaining sample is further centrifuged at 1,300 g at 4C for 35 minutes.
  • PRP platelet-rich plasma
  • the platelet-poor plasma (PPP) so obtained is removed by a siliconized pipette and placed on ice in a plastic tube. Platelet counts are performed using a Model 281 Coulter Counter (Coulter Electronics, Inc., Hialeah, Fla.) and the final platelet count in the PRP is adjusted to 500,00O/mm by dilution with PPP at room temperature. Platelet aggregation studies are performed using a Payton Dual Channel Aggregation Module and Recorder (Payton Associates, lnc., Buffalo,- NY.) with disposable siliconized 0.312 cuvettes and stir bars. 0.45 ml diluted PRP is placed in a cuvette.
  • The-instrument is allowed to equilibrate at 37C with a stirring speed of 1,100 rpm and is calibrated with the corresponding PPP.
  • 0.05 ml Plain Tyrodes Buffer pH 7.35 is added and aggregation is induced by adding 0.05 ml (20 ug/ml) ADP (adenosine diphosphate).
  • Collageninduced aggregation is evaluated by adding 0.1 ml collagen suspension to 0.45 ml PRP.
  • the course of the reaction is monitored by an XY recorder. The extent of aggregation (max. aggregation) is obtained by determining the difference between the'initial and final optical densities.
  • Rates of aggregation are determined as the slopes of the ascending portion of the tracing. Percent of inhibition produced by compound administration is calculated as the inhibition of the change in aggregation between compound and vehicle treated adjuvant-injected rats normalized by the values obtained for vehicle treated noninjected control rats. The absence of a response to the addition of collagen indicates blockade.
  • Table 1 below by way of illustration demonstrate that the compounds of this invention are useful in the inhibition of ADP induced platelet aggregation. Comparable data for Aspirin, the drug commonly used to inhibit platelet aggregation in mammals, is included in Table 1. These results show that the compounds of this invention are efficacious at a lower dose than the reference drug.
  • test compounds 3-( 3-carboXy-4-hydroxyphenyl)- 4,5rdihydro-2-phenylbenzlelindole and Aspirin are prepared and all dilutions made with Plain Tyrodes Buffer. 0.45 ml PRP and 0.05 ml test compound are incubated 3 minutes at 37C prior to the addition of the aggregating agent.
  • the compounds ' are preferably administered orally in a suitable formulation containing effective dosages, which are in the range of about 0.5 to about ,50 mg/kg of body weight perday.
  • effective dosages which are in the range of about 0.5 to about ,50 mg/kg of body weight perday.
  • the compounds are added to the plasma in effective amounts sufficient to form between about 1 X 10' to 1 X l0 molar concentrations.
  • f X is hydrogen or hydroxy
  • Y is hydrogen, hydroxy, halogen, alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, or trifluoromethyl
  • Z is alkylene of three to five carbon atoms, alkylene of three to five carbon atoms substituted by alkyl or alkoxy of one to four carbon atoms, divinylene, divinylene substituted by alkyl of one to four carbon atoms,
  • X is hydrogen or hydroxy and Z is alkylene of three to five carbon atoms
  • X is hydrogen or hydroxy andZ is alkylene of three UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3 904 7 1 DATED September 9, 1975 lNVENTO I Novick et a1.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material 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)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

This disclosure describes a method of preventing thrombosis in mammals and inhibiting platelet aggregation which consists of administering an effective amount of a compound of the formula:

WHEREIN X, Y and Z are as defined in the specification.

Description

United States atent 1 Novick, Jr. et al. Sept. 9, 1975 METHOD OF PREVENTING THROMBOSIS [57] ABSTRACT [75] Invent r I William J- N J yn This disclosure describes a method of preventing Howard Lassman, thrombosis in mammals and inhibiting platelet aggre- Flemington, gation which consists of administering an effective [73] Assignee: American Hoechst Corporation, amount of a compound of the formula:
Bridgewater, NJ.
22 Filed: Jan. 25, 1974 Z [21] App]. No.2 436,796 I Y 52 us. (:1 424/274; 260/302 51 Int. c1. A61K 31/40 [58] Field Of Search 424/274 00 E [56] References Cited UNITED STATES PATENTS X 3,687,971 8/1972 Shen et a1. 260/302 X Primary ExaminerStanley J. Friedman Attorney, Agent, or Firm-Curtis, Morris & Safford wherein X, Y and Z are as defined in the specification.
6 Claims, No Drawings 1 METHOD OF PREVENTING THROMBOSIS This invention relates to a novel method of preventing thrombosis in mammals and to a method of preventing platelet aggregation. More specifically, this invention relates to a method of preventing thrombosis and platelet aggregation in mammals which consists of administering to mammals an effective amount of a 'compound of the formula:
wherein Y X is hydrogen or hydroxy; Y is hydrogen, hydroxy, halogen, alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, or trifluoromethyl; and Z is alkylene of three to five carbon atoms, alkylene of three to five carbon atoms substituted by alkyl or alkoxy of one to four carbon atoms, divinylene, divinylene substituted by alkyl of one to four carbon atoms,
This invention also relates to a method of inhibiting platelet aggregation in blood plasma which consists of adding an effective amount of a compound of the above formula to the plasma.
The compounds utilized in these methods of preventing thrombosis and platelet aggregation and their preparation are disclosed in co-pending application U.S. Ser. No. 336,919 filed Mar. 1, 1973.
The prevention of thrombosis in mammals by the administration of the compounds of this invention is dem onstrated by their ability to inhibit platelet aggregation in mammals lF. Michal and B. G. Firkin, Ann. Rev. Pharmacol. 9, 95 1969) Groups of five female Lewis rats, weighing l5()l75 g. each, are injected subcutaneously into plantar surface (sole) of the left hind paw with 0.1 ml Mimlmcterium lmryric'um in white paraffin oil at a concentration of 5 mg/ml. On the tenth day following injection, test compounds are administered orally as aqueous suspensions ml/kg) at a dose of 50 mg/kg. Control rats, five injected and five noninjected, are treated in a similar manner, but are given a vehicle solution 10 ml distilled water plus one drop of Tween Three hours after compound or vehicle administration, the rats are anesthetized with sodium pentobarbital (50 mg/kg intraperitoneally) and blood samples are obtained from the abdominal aorta and mixed with 3.8% sodium citrate to a final concentration of 0.38%. The samples are centrifuged for 10 minutes at 200 g at 4C. The platelet-rich plasma (PRP) so obtained is removed by a siliconized Pasteur pipette and placed on ice in a plastic tube. The remaining sample is further centrifuged at 1,300 g at 4C for 35 minutes. The platelet-poor plasma (PPP) so obtained is removed by a siliconized pipette and placed on ice in a plastic tube. Platelet counts are performed using a Model 281 Coulter Counter (Coulter Electronics, Inc., Hialeah, Fla.) and the final platelet count in the PRP is adjusted to 500,00O/mm by dilution with PPP at room temperature. Platelet aggregation studies are performed using a Payton Dual Channel Aggregation Module and Recorder (Payton Associates, lnc., Buffalo,- NY.) with disposable siliconized 0.312 cuvettes and stir bars. 0.45 ml diluted PRP is placed in a cuvette. The-instrument is allowed to equilibrate at 37C with a stirring speed of 1,100 rpm and is calibrated with the corresponding PPP. After establishing the baseline, 0.05 ml Plain Tyrodes Buffer pH 7.35 is added and aggregation is induced by adding 0.05 ml (20 ug/ml) ADP (adenosine diphosphate). Collageninduced aggregation is evaluated by adding 0.1 ml collagen suspension to 0.45 ml PRP. Following the addition of the aggregating agent, the course of the reaction is monitored by an XY recorder. The extent of aggregation (max. aggregation) is obtained by determining the difference between the'initial and final optical densities. Rates of aggregation are determined as the slopes of the ascending portion of the tracing. Percent of inhibition produced by compound administration is calculated as the inhibition of the change in aggregation between compound and vehicle treated adjuvant-injected rats normalized by the values obtained for vehicle treated noninjected control rats. The absence of a response to the addition of collagen indicates blockade. The results in Table 1 below by way of illustration demonstrate that the compounds of this invention are useful in the inhibition of ADP induced platelet aggregation. Comparable data for Aspirin, the drug commonly used to inhibit platelet aggregation in mammals, is included in Table 1. These results show that the compounds of this invention are efficacious at a lower dose than the reference drug.
TABLE I EFFECT ON ADP-INDUCED PLATELET AGGREGATION ON TENTH DAY 1N ADJUVANT-INDUCED ARTHRlTlC RATS TABLE I-Continued EFFECT ON ADP-INDUCED PLATELET AGGREGATION ON TENTH DAY IN ADJUVANTJNDUCED ARTHRITIC RATS phenyl )-2-phenylben7. le lindole The results in Table II below by way of illustration demonstrate that the compounds of this invention are useful in the inhibition of collageninduced platelet aggregation. Comparable data for Aspirin is also included. The results again demonstrate that the compounds of this invention are efficacious at a lower dose than the reference drug.
TABLE II EFFECT ON COLLAGEN INDUCED PLATELET AGGREGATION TENTH DAY IN ADJUVANT-INDUCED ARTHRITIC RATS Dose phcnyl )-2-phenylhenz- [e lindole In vitro studies are performed using human platelets obtained by centrifuging blood samples obtained from the anticubital fossa of a normal human volunteer and processed in the same manner as the rat blood samples to obtain PRP and PPP. Platelet'aggregation studies are performed as .described above using 0.45 ml PRP (500,000 platelets/mm) plus 0.05 ml test compound or Plain Tyrodes Buffer and 0.05 ml of either ADP,
Collagen, or epinephrine ("M). Aqueous solutions of test compounds 3-( 3-carboXy-4-hydroxyphenyl)- 4,5rdihydro-2-phenylbenzlelindole and Aspirin are prepared and all dilutions made with Plain Tyrodes Buffer. 0.45 ml PRP and 0.05 ml test compound are incubated 3 minutes at 37C prior to the addition of the aggregating agent. The results in Table III below indicate that on a molar basis 3-( 3-Carboxy-4- hydroxyphenyl)-4,5-dihydro-2-phenylbenzlelindole is more effective than the reference drug (Aspirin) in inhibiting ADP, Collagen, andepinephrine induced platelet aggregation.
TABLE III INHIBITION OF ADP, COLLAGEN AND EPINEPHRINE-INDUCE AGGREGATION OF HUMAN PLATELETS IN VITRO Percent Aggregat- Inhibition Final Molar gating of Maximum Compound Concentration Agent Aggregation 3-( 3-Carboxy-4- 6 X 10 ADP 42.9 hydroxyphenyl 4 5-dihydro-2- 1.2 X 10* Collagen 818 phenylbenz- [elindole 1.2 X 10 Epine- 41.2
phrine Aspirin 1.25, X l0" ADP 45.2 1.25 X 10 Collagen 25.6 2.5 X 10" Epine- 51.5
phrine Clinical studies in human volunteers indicate that single oral doses of or 250 mg of 3-(3-carboxy-4- hydroxyphenyl)-4,5-dihydro-2-phenylbenz[e]indole effectively suppress ADP induced platelet aggregation and block collagen induced platelet aggregation.
For preventing thrombosis and preventing platelet aggregation, the compounds 'are preferably administered orally in a suitable formulation containing effective dosages, which are in the range of about 0.5 to about ,50 mg/kg of body weight perday. To inhibit platelet aggregation in plasma, the compounds are added to the plasma in effective amounts sufficient to form between about 1 X 10' to 1 X l0 molar concentrations.
We claim:
1. A method of preventing thrombosis and inhibiting platelet aggregation in mammals which comprises administering to a mammal an effective amount of a compound of the formula:
wherein f X is hydrogen or hydroxy; Y is hydrogen, hydroxy, halogen, alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, or trifluoromethyl; and Z is alkylene of three to five carbon atoms, alkylene of three to five carbon atoms substituted by alkyl or alkoxy of one to four carbon atoms, divinylene, divinylene substituted by alkyl of one to four carbon atoms,
2. A method of preventing thrombosis and inhibiting platelet aggregation in mammals which comprises administering to a mammal an effective amount of a compound of the formula:
wherein X is hydrogen or hydroxy and Z is alkylene of three to five carbon atoms,
effective amount of a compound of the formula:
. dihydro-2-phenylbenz[ wherein X is hydrogen or hydroxy; Y is hydrogen, hydroxy, halogen, alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, or trifluoromethyl; and Z is alkylene of three to five carbon atoms, alkylene of three to five carbon atoms substituted by alkyl or alkoxy of one to four carbon atoms, divinylene, divinylene substituted by alkyl of one to four carbon atoms,
5. A method of inhibiting platelet aggregation in blood plasma which comprises adding to the plasma an effective amount of a compound of the formula:
wherein to five carbon atoms,
6. The method defined in claim 5, wherein the effective compound is 3-(3-carboxy-4-hydroxyphenyl)-4,5- e]indole.
X is hydrogen or hydroxy andZ is alkylene of three UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3 904 7 1 DATED September 9, 1975 lNVENTO I Novick et a1.
It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:
Column 1, line 35, column 4, line 65 and column 6 line 15,
Column 1, line 45, column 5 line 2 and column 6, line 20,
should read should read Signed and Scaled this Eighth Day of February 1977 [SEAL] Arrest:
RUTH C. MASON Arresting Officer C. MARSHALL DANN Commissioner oj'Parenrs and Trademarks

Claims (6)

1. A METHOD OF PREVENTING THROMBOSIS AND INHIBITING PLATELET AGGREGATION IN MAMMALS WHICH COMPRISES ADMINISTERING TO A MAMMAL AN EFFECTIVE AMOUNT OF A COMPOUND OF THEFORMULA:
2. A method of preventing thrombosis and inhibiting platelet aggregation in mammals which comprises administering to a mammal an effective amount of a compound of the formula:
3. The method defined in claim 2, wherein the effective compound is 3-(3-carboxy-4-hydroxyphenyl)-4,5-dihydro-2-phenylbenz(e)indole.
4. A method of inhibiting platelet aggregation in blood plasma which comprises adding to the plasma an effective amount of a compound of the formula:
5. A method of inhibiting platelet aggregation in blood plasma which comprises adding to the plasma an effective amount of a compound of the formula:
6. The method defined in claim 5, wherein the effective compound is 3-(3-carboxy-4-hydroxyphenyl)-4,5-dihydro-2-phenylbenz(e)indole.
US436796A 1974-01-25 1974-01-25 Method of preventing thrombosis Expired - Lifetime US3904761A (en)

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US436796A US3904761A (en) 1974-01-25 1974-01-25 Method of preventing thrombosis
IL46485A IL46485A0 (en) 1974-01-25 1975-01-21 Pharmaceutical compositions for preventing thrombosis comprising condensed pyrrole derivatives
DE2502156A DE2502156C2 (en) 1974-01-25 1975-01-21 Prevention of thrombosis and inhibition of platelet aggregation
AU77603/75A AU484103B2 (en) 1974-01-25 1975-01-24 Method of preventing thrombosis
NL7500861A NL7500861A (en) 1974-01-25 1975-01-24 MEDICINAL PRODUCT AND METHOD FOR THROMBOSIS.
ZA00750519A ZA75519B (en) 1974-01-25 1975-01-24 Method of preventing thrombosis
GB3252/75A GB1499720A (en) 1974-01-25 1975-01-24 Method of preventing thrombosis

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996028168A1 (en) * 1993-04-22 1996-09-19 The Hope Heart Institute Methods for the treatment of thrombosis
US20080249135A1 (en) * 2004-10-04 2008-10-09 Myriad Genetics, Incorporated Compounds for alzheimer's disease
JP2011251962A (en) * 2010-06-03 2011-12-15 Samsung Mobile Display Co Ltd Organic light-emitting element
US9216966B2 (en) 2004-10-04 2015-12-22 John Manfredi Compounds for Alzheimer's disease

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SU843739A3 (en) * 1978-02-17 1981-06-30 Карл Томэ Гмбх (Фирма) Method of preparing carbostyryl or oxyindole derivatives
US4442111A (en) * 1981-07-25 1984-04-10 Dr. Karl Thomae Gesellschaft Mit Beschrankter Haftung Antithrombotic sulfimino and sulfoximino indolinones-2

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3687971A (en) * 1970-06-22 1972-08-29 Merck & Co Inc 4-(pyrrolyl)-salicylic acid derivatives

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3687971A (en) * 1970-06-22 1972-08-29 Merck & Co Inc 4-(pyrrolyl)-salicylic acid derivatives

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996028168A1 (en) * 1993-04-22 1996-09-19 The Hope Heart Institute Methods for the treatment of thrombosis
US20080249135A1 (en) * 2004-10-04 2008-10-09 Myriad Genetics, Incorporated Compounds for alzheimer's disease
US7678823B2 (en) * 2004-10-04 2010-03-16 Myriad Pharmaceticals, Inc. Compounds for alzheimer's disease
US20120225873A1 (en) * 2004-10-04 2012-09-06 Myrexis, Inc. Compounds for alzheimer's disease
US9034871B2 (en) * 2004-10-04 2015-05-19 John Manfredi Compounds for Alzheimer's disease
US9216966B2 (en) 2004-10-04 2015-12-22 John Manfredi Compounds for Alzheimer's disease
JP2011251962A (en) * 2010-06-03 2011-12-15 Samsung Mobile Display Co Ltd Organic light-emitting element
US9067885B2 (en) 2010-06-03 2015-06-30 Samsung Display Co., Ltd. Organic light-emitting device

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ZA75519B (en) 1976-01-28
IL46485A0 (en) 1976-10-31
DE2502156C2 (en) 1985-05-30
GB1499720A (en) 1978-02-01
AU7760375A (en) 1976-07-29
NL7500861A (en) 1975-07-29
DE2502156A1 (en) 1975-10-30

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