US2807566A - Method of potentiating drugs affecting the central nervous system and compositions therefor - Google Patents
Method of potentiating drugs affecting the central nervous system and compositions therefor Download PDFInfo
- Publication number
- US2807566A US2807566A US389499A US38949953A US2807566A US 2807566 A US2807566 A US 2807566A US 389499 A US389499 A US 389499A US 38949953 A US38949953 A US 38949953A US 2807566 A US2807566 A US 2807566A
- Authority
- US
- United States
- Prior art keywords
- diphenylpentanoate
- diphenyl
- pentenoate
- diethylaminoethyl
- hydrochloride
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 229940079593 drug Drugs 0.000 title claims description 18
- 239000003814 drug Substances 0.000 title claims description 18
- 239000000203 mixture Substances 0.000 title description 12
- 230000003389 potentiating effect Effects 0.000 title description 11
- 238000000034 method Methods 0.000 title description 7
- 210000003169 central nervous system Anatomy 0.000 title description 6
- 150000002148 esters Chemical class 0.000 claims description 14
- 229940125717 barbiturate Drugs 0.000 claims description 13
- CMCCHHWTTBEZNM-UHFFFAOYSA-N 2-bromo-N-carbamoyl-3-methylbutanamide Chemical compound CC(C)C(Br)C(=O)NC(N)=O CMCCHHWTTBEZNM-UHFFFAOYSA-N 0.000 claims description 6
- OPNPQXLQERQBBV-UHFFFAOYSA-N carbromal Chemical compound CCC(Br)(CC)C(=O)NC(N)=O OPNPQXLQERQBBV-UHFFFAOYSA-N 0.000 claims description 6
- 229960001658 carbromal Drugs 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- KSUUMAWCGDNLFK-UHFFFAOYSA-N apronal Chemical compound C=CCC(C(C)C)C(=O)NC(N)=O KSUUMAWCGDNLFK-UHFFFAOYSA-N 0.000 claims description 4
- PYHXGXCGESYPCW-UHFFFAOYSA-N diphenylacetic acid Chemical class C=1C=CC=CC=1C(C(=O)O)C1=CC=CC=C1 PYHXGXCGESYPCW-UHFFFAOYSA-N 0.000 claims description 4
- 150000007522 mineralic acids Chemical class 0.000 claims description 3
- 150000007524 organic acids Chemical class 0.000 claims description 3
- -1 alkali metal salts Chemical class 0.000 description 52
- 125000004432 carbon atom Chemical group C* 0.000 description 20
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 9
- 229910052708 sodium Inorganic materials 0.000 description 9
- 239000011734 sodium Substances 0.000 description 9
- 125000000217 alkyl group Chemical group 0.000 description 7
- 239000004615 ingredient Substances 0.000 description 7
- VBDOTMIHYRPGLX-UHFFFAOYSA-N 2,2-diphenylpentanoic acid;hydrochloride Chemical compound Cl.C=1C=CC=CC=1C(C(O)=O)(CCC)C1=CC=CC=C1 VBDOTMIHYRPGLX-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 239000004305 biphenyl Substances 0.000 description 6
- 235000010290 biphenyl Nutrition 0.000 description 6
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 6
- IVYXLCYENQNVHM-UHFFFAOYSA-N 2,2-diphenylpentanoic acid Chemical compound C=1C=CC=CC=1C(C(O)=O)(CCC)C1=CC=CC=C1 IVYXLCYENQNVHM-UHFFFAOYSA-N 0.000 description 5
- 125000006267 biphenyl group Chemical group 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- SQYNKIJPMDEDEG-UHFFFAOYSA-N paraldehyde Chemical compound CC1OC(C)OC(C)O1 SQYNKIJPMDEDEG-UHFFFAOYSA-N 0.000 description 5
- 229960003868 paraldehyde Drugs 0.000 description 5
- BLRSCYRFTSBWIH-UHFFFAOYSA-N 2,2-diphenylpent-4-enoic acid Chemical compound C=1C=CC=CC=1C(CC=C)(C(=O)O)C1=CC=CC=C1 BLRSCYRFTSBWIH-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 4
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 4
- 229960002327 chloral hydrate Drugs 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 125000002947 alkylene group Chemical group 0.000 description 3
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- 238000011287 therapeutic dose Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- 230000001773 anti-convulsant effect Effects 0.000 description 2
- 239000001961 anticonvulsive agent Substances 0.000 description 2
- 125000006310 cycloalkyl amino group Chemical group 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 2
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 230000004799 sedative–hypnotic effect Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- LNRZCHCAPUVAOP-UHFFFAOYSA-N 2,2-diphenylhexanoic acid Chemical compound C=1C=CC=CC=1C(C(O)=O)(CCCC)C1=CC=CC=C1 LNRZCHCAPUVAOP-UHFFFAOYSA-N 0.000 description 1
- WBJWXIQDBDZMAW-UHFFFAOYSA-N 2-hydroxynaphthalene-1-carbonyl chloride Chemical compound C1=CC=CC2=C(C(Cl)=O)C(O)=CC=C21 WBJWXIQDBDZMAW-UHFFFAOYSA-N 0.000 description 1
- ZZNFCXDBEFYYQN-UHFFFAOYSA-N 4-methyl-2,2-diphenylpent-4-enoic acid Chemical compound C=1C=CC=CC=1C(C(O)=O)(CC(=C)C)C1=CC=CC=C1 ZZNFCXDBEFYYQN-UHFFFAOYSA-N 0.000 description 1
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- SHCSFZHSNSGTOP-UHFFFAOYSA-N Methyl 4-pentenoate Chemical compound COC(=O)CCC=C SHCSFZHSNSGTOP-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- VIROVYVQCGLCII-UHFFFAOYSA-N amobarbital Chemical compound CC(C)CCC1(CC)C(=O)NC(=O)NC1=O VIROVYVQCGLCII-UHFFFAOYSA-N 0.000 description 1
- 229940125681 anticonvulsant agent Drugs 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- STDBAQMTJLUMFW-UHFFFAOYSA-N butobarbital Chemical compound CCCCC1(CC)C(=O)NC(=O)NC1=O STDBAQMTJLUMFW-UHFFFAOYSA-N 0.000 description 1
- 229960003874 butobarbital Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 229940116592 central nervous system diagnostic radiopharmaceuticals Drugs 0.000 description 1
- PTNCEMXXWBEVNF-UHFFFAOYSA-N ethyl 2,2-diphenylpentanoate Chemical compound C=1C=CC=CC=1C(C(=O)OCC)(CCC)C1=CC=CC=C1 PTNCEMXXWBEVNF-UHFFFAOYSA-N 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- ALARQZQTBTVLJV-UHFFFAOYSA-N mephobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)N(C)C1=O ALARQZQTBTVLJV-UHFFFAOYSA-N 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 230000001379 nervous effect Effects 0.000 description 1
- 101150009274 nhr-1 gene Proteins 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229960002695 phenobarbital Drugs 0.000 description 1
- 125000003884 phenylalkyl group Chemical group 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- KQPKPCNLIDLUMF-UHFFFAOYSA-N secobarbital Chemical compound CCCC(C)C1(CC=C)C(=O)NC(=O)NC1=O KQPKPCNLIDLUMF-UHFFFAOYSA-N 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch 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
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
- A61K31/515—Barbituric acids; Derivatives thereof, e.g. sodium pentobarbital
Definitions
- This invention relates to a new composition affecting the central nervous system and method of potentiating drugs affecting the central nervous system.
- composition inaccordance with this invention has been found to-be'of great efi'icacy in treating, for example, conditions requiring sedative, hypnosis and/or anti-convulsant action and which have heretofore been treated with barbiturates which are sedative-hynotics and/or anticonvulsants, paraldehyde, choral hydrate, 2-monobromisovalerylurea, allyisopropylacetyl-carbamide and bromdiethylacetylurea.
- composition according to this invention comprises the combination of a centrally acting drug, that is, a
- the drug used in the composition of this invention and which affects the'central nervous system is a sedative-hypnotic and/or anti-convulsant barbiturate, paraldehyde, chloral hydrate, 2-monobromisovalerylurea, allylisopropylace'tylcarbamide or brorndiethylacetylurea.
- the potentiating compound which is utilized in the composition in accordance with this invention is an aminoalkyl ester of a diphenyl' acetic acid derivative or an acid addition salt thereof, the ester having the following structural formula:
- the ester potentiates the central nervous effect of these drugs as evidenced, for example, by increasing the duration of their eifect.
- composition according to this invention will preferably be intimately admixed and may be included in widely varying proportions. It has been found that maximum potentiation occurs when the potentiating compound acts first. Thus, the composition of this invention is used to excellent advantage in multiple doses and in timed delay tablets, and the like.
- a satisfactory range of the potentiating ester is from 60 mg. to 1200 mg. and a preferred range is from 180 mg. to 600 mg.
- the amount of the selected centrally acting drug to be potentiated will vary widely depending on the physiological effect to be achieved. Generally speaking, it is desir able to have from about the standard effective therapeutic dose (U. S. P.) of the selected drug to about one-fourth of the standard dose. It is preferred to use an amount in the range of from the standard efiective therapeutic dose to one-half of the standard dose.
- the standard effective therapeutic doses for the centrally acting drugs used in the composition of this invention are well known in the art.
- the method in accordance with this invention comprises the administration internally of the essential ingredients of the above composition for concurrent physiological action. It is preferred to administer the potentiating ester first for maximum potentiation.
- the administration may be, for example, oral or by intravenous injection; and, if desired, the essential ingredients may be administered in a diiferent manner, i. e., one orally and one intravenously.
- the ranges given above for the essential ingredients are applicable to the method whether these ingredients are administered together or separately.
- the composition may be made up in various forms, as, for example, in a tablet, in a capsule, a powder, or a liquid, such as water, for oral administration.
- the essential ingredients may be extended with any desired excipient as, forexample, sugar of milk or starch.
- the essential ingredients may be mixed with any suitable vehicle, such as, for example, water, a polyhydric alcohol or a mixture thereof.
- a highly efiicient preparation for oral use in accordance with this invention and based on an average body weight of about lbs. may be made up on any of the following formulae, it being appreciated that numerous other combinations and varying amounts of the individual ingredients can be utilized.
- Example 1 Grams Chloral hydrate 0.6 p-Diethylaminoethyl 2,2-diphenylpentanoatc 0.5
- Example 2 Paraldehyde 3.0 ,B-Diethylaminoethyl 2,2-diphenylpentanoate 0.5
- Example 3 S-phenyl-S-ethylbarbituric acid 0.15 [3-Diethylaminoethyl 2,2-diphenylpentanoate 0.5
- Example 4 S-isoamyl-S-ethylbarbituric acid 0.2 fl-Diethylaminoethyl 2,2-diphenylpentanoate 0.5
- Example 5 Sodium 5-ethyl-5-( l-methylbutyl) barbiturate 0.1 fl-Diethylaminoethyl 2,2-diphenylpentanoate 0.5
- Example 6 N-methyhS-cyclohexenyhS-
- Example 45 S-phenyl-S-ethylbarbituric acid 0.15 fi-Diethylaminoethyl 2,2-diphenylpentanoate
- Example 46 5-isoamyl-5-ethylbarbituric acid 0.2 fl-Diethylaminoethyl 2,2-diphenylpentanoate hydrobromide 0.5
- Example 54 N-methyl-S-cyclohexenyl--methy1barbituric acid (,5 p-Dimethylaminoethyl 2,2-diphenyl-4-pentenoate sulfate 0.
- Example 56 Chloral hydrate 0.6 fl-Diethylaminoethyl 2,2-diphcnyl-4-pentenoate hydrochloride -5
- Example 57 Paraldehyde 3.0 p-Diethylaminoethyl 2,2-dipheny1-4-pentenoate hydrochloride 0.5
- Example 65 Bromdiethylacetylurea 0.9 B-Aminoethyl 2,2-diphenylhexanoate tartrate 0.4
- Example 66 Allylisopropylacetylcarbamide 0.375 B-Benzy1methylaminoethy1 2,2-diphenylpentanoate benzoate 0.5
- a medicinal preparation comprising a centrally acting drug selected from the group consisting of barbiturates, Z-monobromisovaierylurea, allylisopropylacetyl carbamide and bromdiethylacetylurea and a component to substantially increase the effectiveness of the centrally acting drug, said component being selected from the group consisting of an ester of a diphenylacetic acid derivative and organic and inorganic acid addition salts of said ester, the ester having the following structural formula:
- X is selected from a group consisting of alkyl having not in excess of 4 carbon atoms and 'alkenyl having from 3 to 4 carbon atoms
- R is alkylene having from 2 to 4 carbon atoms
- Y is a nitrogen-linked radical selected from the group consisting of piperidino, primary amino, secondary alkyl amino having not in excess of 4 carbon atoms, di-alkyl amino with each alkyl group having not in excess of 4 carbon atoms, secondary cycloalkyl amino having from 5 to 6 carbon atoms, di-cycloalkyl amino having from 5 to 6 carbon atoms in each cycloalkyl group, secondary benzylamino, dibenzylamino, secondary phenethylamino and diphenethylamino.
- ester 10 which comprises administering internally for concurrent physiological action with said drug a member selected from the group consisting of an ester of a diphenylacetic acid derivative and organic and inorganic acid addition salts of said ester, the ester having the following structural formula:
- X is selected from the group consisting of alkyl having not in excess of 4 carbon atoms and alkenyl having from 3 to 4 carbon atoms
- R is alkylene having from 2 to 4 carbon atoms
- Y is a nitrogen-linked radical selected from the group consisting of piperidino, primary amino, secondary alkyl amino having not in excess of 4 carbon atoms, di-alkyl amino with each alkyl group having not in excess of 4 carbon atoms, secondary cycloalkyl amino having from 5 to 6 carbon atoms, di-cycloalkyl amino having from 5 to 6 carbon atoms in each cycloalkyl group, secondary benzylamino, dibenzylamino, secondary phenethylamino and diphenethylamino.
Landscapes
- 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)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
2,807,566 METHOD OF POTENTIATING DRUGS AFFEfiT-ING THE CENTRALNERVOUS SYSTEM AND COM- POSITIONS THEREFOR Edwin J. Fellows, North Hills, Pa., assignor to Smith,
Kline, & French' Laboratories, Philadelphia, Pa., a corporation of Pennsylvania No Drawing. Application October 30, 1 153, Serial No. 389,499
2 Claims. Cl. 167-52) This invention relates to a new composition affecting the central nervous system and method of potentiating drugs affecting the central nervous system.
The composition inaccordance with this invention has been found to-be'of great efi'icacy in treating, for example, conditions requiring sedative, hypnosis and/or anti-convulsant action and which have heretofore been treated with barbiturates which are sedative-hynotics and/or anticonvulsants, paraldehyde, choral hydrate, 2-monobromisovalerylurea, allyisopropylacetyl-carbamide and bromdiethylacetylurea.
The composition according to this invention comprises the combination of a centrally acting drug, that is, a
drug having an affect on the central nervous system, and a compound which potentiates said drug.
More specifically, the drug used in the composition of this invention and which affects the'central nervous system is a sedative-hypnotic and/or anti-convulsant barbiturate, paraldehyde, chloral hydrate, 2-monobromisovalerylurea, allylisopropylace'tylcarbamide or brorndiethylacetylurea.
The following are exemplary of the barbiturates:
5-phenyl-5-ethylbarbituric acid (Phenobarbital) 5-isoamyl-S-ethylbarbituric acid (Amobar'bital) 5-ethyl-5-( l-methylbutylybarbituric acid (Pentobarbital) N-methyl-S-cyclohexenyLS-methyl barbituric acid (Evip 5-allyl-'5-(l-methylbutyl) barbituric acid (Seconal) N-methyl-5-ethyl-S-phenylbarbituric acid (Mebaral) S-N-butyl-S-ethyl barbituric acid (Butethal) and alkali metal salts of these compounds. Where a salt is used the sodium salt is preferred.
Although the above barbiturates are preferred and are particularly advantageous with this. invention, it will be appreciated that other barbiturates can be used equivalently.
The potentiating compound which is utilized in the composition in accordance with this inventionis an aminoalkyl ester of a diphenyl' acetic acid derivative or an acid addition salt thereof, the ester having the following structural formula:
where X=alkyl having not in excess of 8 carbon atoms or alkenyl having not in .excess of '8 carbon atoms; R: alkylene having from 2 to 8 carbon atoms; Y=a nitrogenlinked radical selected from v the group consisting of piperidino, NH2, NHR1, NR1R2, where R1 and R2 are selected from the group consisting of alkyl not in excess of, 8 carbon atoms, cycloalkylradicals not in excess of 8 carbon atoms, phenyl radicals and phenylalkyl radicals, the alkyl portion of the phenylalkyl not exceeding 8 carbon atoms.
The ester potentiates the central nervous effect of these drugs as evidenced, for example, by increasing the duration of their eifect.
Due to the markedly superior potentiation which re- 2,807,563 Patented Sept. 24, 1957 ice sults through its use, a potentiating compound within the scope of the following formula is preferred:
( uHE)2- -(|3OORY 1-diethylamino-2-ethyl-3-propyl 2,2-diphenylA-pentenoate 1 diethylarnino 2-ethyl-3-propyl 2,2-diphenyl-4-pentenoate hydrochloride 1-diethylamino-6-hexy 2,2-diphenyl-4-pentenoate l-diethylamino-G-hexyl 2,2-diphenyl-4-pentenoate hydrochloride l-diethylamino-S-pentyl 2,2-diphenyl-4-pentenoate hydrochloride I 1-diethylamino-4-butyl 2,2-diphenyl-4-pentenoate hydrobromide l-diethylamino-Spentyl 2,2-diphenyl-4-pentenoate sulfate l-diethylamino-G-hexyl 2,2-dipl'1enyl-4-pentenoate tar-trate B-Dihexylaminoethyl 2,2-dip'henyl pentanoate ,B-Diethylaminoethyl 2,2-diphenyl-4-pentenoate fl-Diethylarninoethyl 2,2-diphenyl-4-pentenoate hydrochloride fi-Diethylaminoethyl' 2,2-diphenyl-4-pentenoate hydrobromide fl-Diethylaminoethyl 2,2-diphenyl-4-pentenoate sulfate fi-Dimethylaminoethyl 2,2-diphenyl-4-pentenoate fl-Dimethylaminoethyl 2,2-diphenyl-4-pentenoate tartrate fl-Diinethylarninoethyl 2,2-diphenyl-4-pentenoate hydrobrornide fl-Dimethylaminoethyl 2,2-diphenyl-4-pentenoate benzoate fl-Dimethylaminoethyl 2,2-diphenyl-4-methyl-4-pentenoate ,B-Dimethyla-minoethyl'2,2-diphenyl-4-methyl-4-pentenoate hydrochloride ,B-Dimethylaminoethyl 2,2-diphenyl-4-methyl-4-pentenoate hydrobromide B-Dimethylaminoethyl 2,2-diphenyl-4-methyl-4-pentenoate citrate .p-Piperidinoethyl 2,2-diphenyl-4-pentenoate p-Piperidinoethyl 2,2-diphenyl-4-pentenoate hydrochloride [3-Piperidinoethyl 2,2-diphenyl-4-pentenoate hydrobromide fl-Piperidinoethyl 2,2-diphenyl-4-pentenoate sulfate p-Piperidinoethyl 2,2-diphenylpentanoate B-Piperidinoethyl 2,2-diphenylpentanoate hydrochloride ,B-Piperidinoethyl 2,2-diphenylpentanoate acetate fl-Piperidinoethyl 2,2-diphenylpentanoate sulfate fl-Diethylaminoethyl 2,2-diphenyl-4-methylpentanoate fi-Diethylaminoethy-l 2,Z-diphenyll-methylpentanoate hydrochloride fl-Diethylaminoethyl 2,2-diphenyl-4-methylpentanoate hydrobromide p-Diethylaminoethyl 2,2 diphenyl 4 methylpentanoate phosphate fi-Dimethylaminoethyl 2,2-diphenylpentanoate fl-Dimethylaminoethyl 2,2-diphenylpentanoate hydrochloride ,B-Dimethylaminoethyl 2,2-diphenylpentanoate hydrobromide fl-Dimethylamino'ethyl 2,2-diphenylpentanoate acetate fl-Diethylaminoethyl 2,2-diphenylpentanoate n'de p-Diethylaminoethyl 2,2-diphenylpentanoate hydrobromide fl-Diet-hylaminoethyl 2,2-diphenylpentanoate sulfate ,s- (Phenylethylamino) propyl 2,2 diphenyl 3 methyl-4-pentenoate fl-Diethylaminoethyl 2,2-diphenylpentanoate citrate fl-Diet-hylamonoethyl 2,2-diphenylpentanoate benzoate f3 (Phenylethylamino) propyl 2,2 diphenyl 3 methyl-4-pentenoate hydrochloride B (Phenylethylamino) propyl 2,2 diphenyl 3 methyl-4-pentenoate tartrate t3 (Phenylethylamino) propyl 2,2 diphenyl 3 methyl-4-pentenoate benzoate 'y-Dibenzylaminopropyl 2,2-diphenyl-4-hexenoate -Dibenzylaminopropyl 2,2-diphenyl-4-hexenoate hydrochloride 'y-Dibenzylaminopropyl 2,2-diphenyl-4-hexenoate acetate 'y-Dibenzylaminopropyl 2,2-diphenyl-4-hexenoate sulfate fi-Aminoethyl 2,2'diphenylhexanoate fl-Aminoethyl 2,2-diphenylhexanoate hydrochloride B-Aminoethyl 2,2-diphenylhexanoate hydrobromide fl-Aminoethyl 2,2-diphenylhexanoate sulfate fl-Benzylmethylaminoethyl 2,2-diphenylpentanoate fl-Benzylmethylaminoethyl 2,2-diphenylpentanoate hydrochloride ;8-Benzylmethylaminoethyl 2,2-diphenylpentanoate hydrobromide fl-Benzylmethylaminoethyl 2,2-diphenylpentanoate benzoate fl-Methylaminoethyl 2,2-diphenylpentanoate ,B-Methylaminoethyl 2,2 diphenylpentanoate hydrochlor de ,B-Methylaminoethyl 2,2-diphenylpentanoate hydrobromide B-Methylaminoethyl 2,2-diphenylpentanoate sulfate fl-Diethylaminoethyl 2,2-diphenyl-4-methyl-4-pentenoate fl-Diethylaminoethyl 2,2-diphenyl-4-methyl-4pentenoate hydrochloride ,B-Diethylaminoethyl 2,2-diphenyl-4-methyl-4-pentenoate tartrate p-Diethylaminoethyl sulfate B-(Cyclopentylethylamino)-ethyl 2,2-diphenylpentanoate 2,2-diphenyl-4-methyl-4-pentenoate p-(Cyclopentylethylamino) ethyl 2,2 diphenylpentanoate hydrochloride [3- (Cyclopentylethylamino -ethyl 2,2-dipheny1pentanoate hydrobromide fl(Cyclopentylethylamino)-ethyl 2,2-diphenylpentanoate citrate fi-(Cyclohexylethylamino) -ethyl 2,2-diphenylpentanoate 8-(Cyclohexylethylamino)-ethyl 2,2-diphenylpentanoate hydrochloride p-(Cyclohexylethylamino)-ethyl 2,2-diphenylpentanoate hydrobromide fi-(Cyclohexylethylamino)-ethyl 2,2-diphenylpentanoate sulfate fi-Dibenzylaminoethyl 2,2-diphenylhexanoate fl-Dibenzylaminoethyl 2,2-diphenylhexanoate hydrochloride fl-Dibenzylaminoethyl 2,2 diphenylhexanoate hydrobromide fi-Dibenzylaminoethyl 2,2-dipheuylhexanoate sulfate Aminoalkyl esters of diphenyl acetic acid having the above structural formula and the acid addition salts thereof are well known to the art and several methods suitable for their preparation are known. Thus, for example, reference may be had to the following:
1. Craig, Witt, Ullyot, Abstracts of the 116th Meeting of the American Chemical Society, September 123-23 (1949), page 4L. Smith, Kline & FrenchLaboratories.
2. Craig, Witt, Macko, Dacanay, Fellows and Ullyot, J. A. C. S. 73, 1939 (1951), March-Smith, Kline 85 French Laboratories.
3. Larsen, Ruddy, Elpern, McMullin, I. A. C. S. 71, 532 (1949), Feb1uarySterling Winthrop Research Institute.
The essential ingredients of the composition according to this invention will preferably be intimately admixed and may be included in widely varying proportions. It has been found that maximum potentiation occurs when the potentiating compound acts first. Thus, the composition of this invention is used to excellent advantage in multiple doses and in timed delay tablets, and the like.
Generally speaking, the selected potentiating ester will be used in an amount of from about 7 mgm./kgm. of body weight to about 20 mgmJkgm. of body weight. It is, however, preferred to use the selected potentiating ester in an amount of from about 3 mgm./kgm. of body weight to about 10 mgm./kgm. of body weight. The amount of potentiating ester will, of course, vary widely depending upon the centrally acting drug selected and the amount of potentiation desired.
Expressed in absolute amounts a satisfactory range of the potentiating ester is from 60 mg. to 1200 mg. and a preferred range is from 180 mg. to 600 mg.
The amount of the selected centrally acting drug to be potentiated will vary widely depending on the physiological effect to be achieved. Generally speaking, it is desir able to have from about the standard effective therapeutic dose (U. S. P.) of the selected drug to about one-fourth of the standard dose. It is preferred to use an amount in the range of from the standard efiective therapeutic dose to one-half of the standard dose. The standard effective therapeutic doses for the centrally acting drugs used in the composition of this invention are well known in the art.
The method in accordance with this invention comprises the administration internally of the essential ingredients of the above composition for concurrent physiological action. It is preferred to administer the potentiating ester first for maximum potentiation. The administration may be, for example, oral or by intravenous injection; and, if desired, the essential ingredients may be administered in a diiferent manner, i. e., one orally and one intravenously. The ranges given above for the essential ingredients are applicable to the method whether these ingredients are administered together or separately.
For administration the composition may be made up in various forms, as, for example, in a tablet, in a capsule, a powder, or a liquid, such as water, for oral administration. The essential ingredients may be extended with any desired excipient as, forexample, sugar of milk or starch. When prepared for injection, the essential ingredients may be mixed with any suitable vehicle, such as, for example, water, a polyhydric alcohol or a mixture thereof.
A highly efiicient preparation for oral use in accordance with this invention and based on an average body weight of about lbs. may be made up on any of the following formulae, it being appreciated that numerous other combinations and varying amounts of the individual ingredients can be utilized.
Example 1 Grams Chloral hydrate 0.6 p-Diethylaminoethyl 2,2-diphenylpentanoatc 0.5 Example 2 Paraldehyde 3.0 ,B-Diethylaminoethyl 2,2-diphenylpentanoate 0.5 Example 3 S-phenyl-S-ethylbarbituric acid 0.15 [3-Diethylaminoethyl 2,2-diphenylpentanoate 0.5 Example 4 S-isoamyl-S-ethylbarbituric acid 0.2 fl-Diethylaminoethyl 2,2-diphenylpentanoate 0.5 Example 5 Sodium 5-ethyl-5-( l-methylbutyl) barbiturate 0.1 fl-Diethylaminoethyl 2,2-diphenylpentanoate 0.5 Example 6 N-methyhS-cyclohexenyhS-methylbarbituric acid 0.25 ,e-Diethylaminoethyl 2,2-diphenylpentanoate 0.5
Example 43 Grams Chloral hydrate 0.6 fl-Diethylaminoethyl 2,2-diphenylpentanoate hydrochloride 0.5
Example 44 Paraldehyde 3.0 p-Diethylaminoethyl 2,2-diphenylpentanoate hydrochloride 0.5
Example 45 S-phenyl-S-ethylbarbituric acid 0.15 fi-Diethylaminoethyl 2,2-diphenylpentanoate Example 46 5-isoamyl-5-ethylbarbituric acid 0.2 fl-Diethylaminoethyl 2,2-diphenylpentanoate hydrobromide 0.5
Example 47 Sodium 5-ethyl-5'( l-methylbutyl)-barbiturate 0.1
B-Diethylaminoethyl 2,2-dipheny1pentanoate citrate 0.5 Example 48 N-methyl-5-cyclohexenyl-S-methylbarbituric acid 0.25 fi-Diethylaminoethyl 2,2-diphenylpentanoate citrate 0.5 Example 49 Sodium 5-allyl-5-( l-methylbutyl -barbiturate 0.1 fl-Diethylaminoethyl 2,2-diphenylpentanoate acetate 0.5 Example 50 N-methyl-S-ethyl-5phenylbarbituric acid 0.1
p-Diethylaminoethyl 2,2-diphenylpentanoate succinate 0.5
Example 51 2-monobromisovalerylurea 0.75 p-Diethylaminoethyl 2,2-dipheny1pentanoate hydrochloride 0.5
Example 52 Bromdiethylacetylurea 0.9 fl-Diethylaminoethyl 2,2-diphenylpentanoate tartrate 0.5
Example 53 Allylisopropylacetylcarbamide 0.375 fi-Diethylaminoethyl 2,'2-diphenylpentanoate benzeate .5
Example 54 N-methyl-S-cyclohexenyl--methy1barbituric acid (,5 p-Dimethylaminoethyl 2,2-diphenyl-4-pentenoate sulfate 0.
Example 55 5-phenyl-5'ethylharbituric acid 0.15
fl-Dimethylaminoethyl 2,2-diphenyl-4-pentenoate phosphate 0.;
Example 56 Chloral hydrate 0.6 fl-Diethylaminoethyl 2,2-diphcnyl-4-pentenoate hydrochloride -5 Example 57 Paraldehyde 3.0 p-Diethylaminoethyl 2,2-dipheny1-4-pentenoate hydrochloride 0.5
Example 58 S-phenyl-S-ethylbarbituric acid 0.15 fi-Dimethylaminoethyl 2,2-diphenyl-4-methyl-4- pentenoate tartrate 0.5
8 Example 59 Grams 5-isoamyl-S-ethylbarbituric acid 0.2
p-Piperidinoethyl 2,2-diphenyl-4-pentenoate hydrobromide r 0.5 I 0 Example 60 Sodium 5-ethy1-5-( l-methylbutyl) -barbiturate 0.1 fl-Piperidinoethyl 2,2-diphenylpentanoate citrate..- 0.5 Example 61 N-methyl-S-cyclohexenyl-S-methylbarbituric acid 0.25 B-Diethylaminoethyl 2,2-dipl1eny1-4-methy1-pentanoate citrate 0.5
Example 62 Sodium 5-allyl-5-(l-methylbutyl)-barbiturate 0.1 fl-Dimethylaminoethyl 2,2-diphenylpentanoate acetate 0.5
Example 63 N-methyI'S-ethy1-5-phenylbarbituric acid 0.1 fl-(Phenylethylamino)-propyl 2,2-dipheny1-3-methy1-4-pentenoate succinate 0.6
Example 64 2-monobromisovalerylurea -a 0.75 -Dibenzylarninopropyl 2,2-diphenyl-4-hexenoate hydrochloride 0.6
Example 65 Bromdiethylacetylurea 0.9 B-Aminoethyl 2,2-diphenylhexanoate tartrate 0.4 Example 66 Allylisopropylacetylcarbamide 0.375 B-Benzy1methylaminoethy1 2,2-diphenylpentanoate benzoate 0.5
Example 67 Sodium 5-phenyl-5-ethylharbiturate 0.15 p-Diethylaminoethyl 2,2-dipheny1pentanoate hydrochloride 0.5
Example 68 Sodium.5-isoamyl-S-ethylbarbiturate 0.2 B-Diethy1aminoethyl 2,2-diphenylpentanoate hydrochloride 0.5
Example 69 5-ethyl-5-(l-methylbutyD-barbituric acid 0.1 fl-Diethylarninoethyl 2,2-diphenylpentanoate hydrochloride Example 70 Sodium N methyl-5-cyclohexenyl-5-mcthylbarbiturate 0.25 ,BDiethylaminoethyl 2,2-diphenylpentanoate hydrochloride 0.5
Example 71 5-allyl-5-(l-methylbutyD-barbituric acid 0.1 fl-Diethylaminoethyl .2,2-diphenylpentanoate hydrochloride 0.5
Example 72 Sodium N-methyl-S-ethyl-S-phenylbarbiturate- 0.1 B-Diethylaminoethyl 2,2-diphenylpentanoate hydrochloride 0.5
Example 73 S-N-butyl-S-ethylbarbituric acid 0.1. [3-Diethylaminoethyl 2,2-diphenylpentanoate hy drochloride 0.5
It is not desired to be limited except as 'set forth in the following claims, it being understood that the above examples are merely illustrative.
This application is a continuation-in-part of application Serial No. 310,141, filed September 17, 1952, now abandoned.
What is claimed is:
1. A medicinal preparation comprising a centrally acting drug selected from the group consisting of barbiturates, Z-monobromisovaierylurea, allylisopropylacetyl carbamide and bromdiethylacetylurea and a component to substantially increase the effectiveness of the centrally acting drug, said component being selected from the group consisting of an ester of a diphenylacetic acid derivative and organic and inorganic acid addition salts of said ester, the ester having the following structural formula:
wherein X is selected from a group consisting of alkyl having not in excess of 4 carbon atoms and 'alkenyl having from 3 to 4 carbon atoms, R is alkylene having from 2 to 4 carbon atoms and Y is a nitrogen-linked radical selected from the group consisting of piperidino, primary amino, secondary alkyl amino having not in excess of 4 carbon atoms, di-alkyl amino with each alkyl group having not in excess of 4 carbon atoms, secondary cycloalkyl amino having from 5 to 6 carbon atoms, di-cycloalkyl amino having from 5 to 6 carbon atoms in each cycloalkyl group, secondary benzylamino, dibenzylamino, secondary phenethylamino and diphenethylamino.
2. The method of potentiating the sedative-hypnotic effect of a centrally acting drug selected from the group consisting of a barbiturate, 2-monobromisovalerylurea, allylisopropylacetylcarb'amide and bromdiethylacetylurea,
10 which comprises administering internally for concurrent physiological action with said drug a member selected from the group consisting of an ester of a diphenylacetic acid derivative and organic and inorganic acid addition salts of said ester, the ester having the following structural formula:
wherein X is selected from the group consisting of alkyl having not in excess of 4 carbon atoms and alkenyl having from 3 to 4 carbon atoms, R is alkylene having from 2 to 4 carbon atoms and Y is a nitrogen-linked radical selected from the group consisting of piperidino, primary amino, secondary alkyl amino having not in excess of 4 carbon atoms, di-alkyl amino with each alkyl group having not in excess of 4 carbon atoms, secondary cycloalkyl amino having from 5 to 6 carbon atoms, di-cycloalkyl amino having from 5 to 6 carbon atoms in each cycloalkyl group, secondary benzylamino, dibenzylamino, secondary phenethylamino and diphenethylamino.
References Cited in the file of this patent Ludwig: Rep'ertorium Pharmazeutischer Spezialpraparate (2. unveranderte Auflage), p. 957.
Larsen: 1. of the Am. Chem. Soc., vol. 71 (1949), pp. 532, 533.
Craig: I. of the Am. Chem. Soc., vol. 73 (1951), pp. 1339-1441.
Tobolowsky: J. Lab. Clin. Med., vol. 28 (Oct. 1942.), pp. 3138.
Gilman: J. PharmacoL, vol. 74' (Mar. 1942), pp. 290*- 308.
Claims (1)
1. A MEDICINAL PREPARATION COMPRISING A CENTRALLY ACTING DRUG SELECTED FROM THE GROUP CONSISTING OF BARBITURATES, 2-MONOBROMISOVALERYLUREA, ALLYLISOPROPYLACETYLCARBAMIDE AND BROMDIETHYLACETYLUREA AND A COMPONENT TO SUBSTANTIALLY INCREASE THE EFFECTIVENESS OF THE CENTRALLY ACTING DRUG, SAID COMPONENT BEING SELECTED FROM THE GROUP CONSISTING OF AN ESTER OF A DIPHENYLACETIC ACID DERIVATIVE AND ORGANIC AND INORGANIC ACID ADDITION SALT OF SAID ESTER, THE ESTER HAVING THE FOLLOWING STRUCTURAL FORMULA:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US389499A US2807566A (en) | 1953-10-30 | 1953-10-30 | Method of potentiating drugs affecting the central nervous system and compositions therefor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US389499A US2807566A (en) | 1953-10-30 | 1953-10-30 | Method of potentiating drugs affecting the central nervous system and compositions therefor |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US2807566A true US2807566A (en) | 1957-09-24 |
Family
ID=23538502
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US389499A Expired - Lifetime US2807566A (en) | 1953-10-30 | 1953-10-30 | Method of potentiating drugs affecting the central nervous system and compositions therefor |
Country Status (1)
| Country | Link |
|---|---|
| US (1) | US2807566A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3074850A (en) * | 1960-04-18 | 1963-01-22 | Thomae Gmbh Dr K | Analgesic, antipyretic n-methyl-n'-halophenyl-urea |
| US3174994A (en) * | 1962-01-30 | 1965-03-23 | Smith Kline French Lab | Hypocholesterolemic n-oxide compositions |
-
1953
- 1953-10-30 US US389499A patent/US2807566A/en not_active Expired - Lifetime
Non-Patent Citations (1)
| Title |
|---|
| None * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3074850A (en) * | 1960-04-18 | 1963-01-22 | Thomae Gmbh Dr K | Analgesic, antipyretic n-methyl-n'-halophenyl-urea |
| US3174994A (en) * | 1962-01-30 | 1965-03-23 | Smith Kline French Lab | Hypocholesterolemic n-oxide compositions |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DE68924456T2 (en) | Agents for improving drug effects for anti-tumor agents. | |
| CA1161362A (en) | Pharmaceutical compositions containing a corticosteroid substance | |
| JPS60214733A (en) | Pharmaceutical product rendering improved analgesia | |
| US20090312290A1 (en) | Combination of a nitrogen mustard analogue and imatinib for treatment of chronic lymphocytic leukemia | |
| US2807566A (en) | Method of potentiating drugs affecting the central nervous system and compositions therefor | |
| EP0217794A1 (en) | Method for treating the effects of alcohol | |
| US4053617A (en) | 2,1,3-benzothiadiazoles as myolonolytics | |
| US3852450A (en) | Antibacterial compositions containing rifampicin and a pyrimidine derivative | |
| US7846939B2 (en) | Salts and mixture of 9-oxoacridine-10-acetic acid with 1-alkylamino-1-desoxy-polyols, pharmaceutical compositions containing said agents and treatment methods | |
| US3470297A (en) | Coronary dilating compositions and their administration | |
| DE2123318C2 (en) | 4-Butylamino-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-carboxylic acid ethyl ester, process for its preparation and pharmaceutical compositions containing it | |
| US4340609A (en) | Amidinourea derivative veterinary compositions for suppression of parasitemia | |
| JPS63258415A (en) | Immunostimulatory agents containing N-substituted 2-cyanoaziridines | |
| EP0137514B1 (en) | Compounds and compositions for use in preventing and treating obesity | |
| US2647893A (en) | Penicillin salts of methylpentylamine | |
| US3067242A (en) | Di-(n, n-dimethyloctadecylamine) pamoate | |
| US3110650A (en) | Synergistic analgesic compositions | |
| US3462534A (en) | Production of an antidepressant effect with esters of gallic acid | |
| US3129137A (en) | Method of inhibiting gastro-intestinal irritation | |
| GB1458636A (en) | Methods and compositions for killing parasites of warm blooded animals | |
| CA2264101A1 (en) | Preventives/remedies for muscle tissue degenerations | |
| US3034958A (en) | Soporific compositions | |
| JPH03502802A (en) | Antiemetic ergoline derivative | |
| US4035491A (en) | Pharmaceutical composition having synergistic analgesic activity and containing azidomorphine or azidocodeine | |
| DE3874982T2 (en) | ANTIPSYCHOTIC COMPOSITIONS WITH DIOXOPIPERIDINE DERIVATIVES. |