US3852353A - Oral hypoglycemic aminophenylsulfonyl-hydrocarbylbiguanides - Google Patents
Oral hypoglycemic aminophenylsulfonyl-hydrocarbylbiguanides Download PDFInfo
- Publication number
- US3852353A US3852353A US00314545A US31454572A US3852353A US 3852353 A US3852353 A US 3852353A US 00314545 A US00314545 A US 00314545A US 31454572 A US31454572 A US 31454572A US 3852353 A US3852353 A US 3852353A
- Authority
- US
- United States
- Prior art keywords
- compound
- insulin
- diabetes mellitus
- group
- treatment
- 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
- 230000002218 hypoglycaemic effect Effects 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 34
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 abstract description 22
- 206010012601 diabetes mellitus Diseases 0.000 abstract description 17
- 102000004877 Insulin Human genes 0.000 abstract description 11
- 108090001061 Insulin Proteins 0.000 abstract description 11
- 229940125396 insulin Drugs 0.000 abstract description 11
- FZERHIULMFGESH-UHFFFAOYSA-N N-phenylacetamide Chemical compound CC(=O)NC1=CC=CC=C1 FZERHIULMFGESH-UHFFFAOYSA-N 0.000 abstract description 8
- 239000000203 mixture Substances 0.000 abstract description 8
- 239000003472 antidiabetic agent Substances 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 229960001413 acetanilide Drugs 0.000 abstract description 4
- 230000002503 metabolic effect Effects 0.000 abstract description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 3
- 230000007363 regulatory process Effects 0.000 abstract description 3
- 230000004936 stimulating effect Effects 0.000 abstract description 3
- 230000002194 synthesizing effect Effects 0.000 abstract description 3
- -1 aromatic radicals Chemical class 0.000 abstract description 2
- 239000000969 carrier Substances 0.000 abstract description 2
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 abstract description 2
- 125000001931 aliphatic group Chemical group 0.000 abstract 2
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical class [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 abstract 1
- 125000004432 carbon atom Chemical group C* 0.000 abstract 1
- 229910052739 hydrogen Inorganic materials 0.000 abstract 1
- 239000001257 hydrogen Substances 0.000 abstract 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 abstract 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 1
- 150000004283 biguanides Chemical class 0.000 description 7
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 6
- 229940100389 Sulfonylurea Drugs 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 239000008103 glucose Substances 0.000 description 6
- 230000009471 action Effects 0.000 description 5
- 229940123208 Biguanide Drugs 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000003538 oral antidiabetic agent Substances 0.000 description 3
- 229940127209 oral hypoglycaemic agent Drugs 0.000 description 3
- 229940125395 oral insulin Drugs 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical group OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 3
- 206010028813 Nausea Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 206010047700 Vomiting Diseases 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 230000000366 juvenile effect Effects 0.000 description 2
- 230000008693 nausea Effects 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 230000008673 vomiting Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 1
- QMNAQPMXDMLOLD-UHFFFAOYSA-N 6-methyl-4-oxo-5,6-dihydrothieno[2,3-b]thiopyran-2-sulfonamide Chemical compound S1C(C)CC(=O)C2=C1SC(S(N)(=O)=O)=C2 QMNAQPMXDMLOLD-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 description 1
- RKWGIWYCVPQPMF-UHFFFAOYSA-N Chloropropamide Chemical compound CCCNC(=O)NS(=O)(=O)C1=CC=C(Cl)C=C1 RKWGIWYCVPQPMF-UHFFFAOYSA-N 0.000 description 1
- 206010010305 Confusional state Diseases 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 241000577218 Phenes Species 0.000 description 1
- JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 229960001466 acetohexamide Drugs 0.000 description 1
- VGZSUPCWNCWDAN-UHFFFAOYSA-N acetohexamide Chemical compound C1=CC(C(=O)C)=CC=C1S(=O)(=O)NC(=O)NC1CCCCC1 VGZSUPCWNCWDAN-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 1
- 229960001761 chlorpropamide Drugs 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 238000009093 first-line therapy Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000005802 health problem Effects 0.000 description 1
- 229940126904 hypoglycaemic agent Drugs 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 229940096978 oral tablet Drugs 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- ICFJFFQQTFMIBG-UHFFFAOYSA-N phenformin Chemical compound NC(=N)NC(=N)NCCC1=CC=CC=C1 ICFJFFQQTFMIBG-UHFFFAOYSA-N 0.000 description 1
- 229960003243 phenformin Drugs 0.000 description 1
- 229960001753 phenformin hydrochloride Drugs 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229960002277 tolazamide Drugs 0.000 description 1
- OUDSBRTVNLOZBN-UHFFFAOYSA-N tolazamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1CCCCCC1 OUDSBRTVNLOZBN-UHFFFAOYSA-N 0.000 description 1
- 229960005371 tolbutamide Drugs 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C317/34—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring
- C07C317/36—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring with the nitrogen atoms of the amino groups bound to hydrogen atoms or to carbon atoms
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
Definitions
- the compound may be incorporated with acceptable carriers to make compositions adapted to be administered orally in the treatment of diabetes mellitus.
- the compound is intended to aid in the regulation of metabolic disturbance in diabetes mellitus not only by stimulating the production and release of insulin but also by functioning as a substitute for insulin in this regulatory process.
- Insulin is of course used extensively in diabetes therapy. But since insulin itself can not be administered orally and must therefore be injected, oral insulin substitutes have been developed. But such substitutes have not been completely safe and effective. The biggest problem has'been to find a drug that would reduce the blood sugar level quickly, help the body metabolize carbohydrates and not produce permanent damage to the system.
- the first of these groups includes tolbutamide, chlorpropamide, tolazamide, and acetohexamide.
- the mechanism of action of these drugs is generally to increase the release of insulin from the functioning beta cells of the intact pancreas.
- the biguanides, and in particular phenformin hydrochloride are completely unrelated to the sulfonylureas in chemical structure and mode of action. They do not stimulate in sulin production, but appear rather to aid in reducing the generation of fats, in facilitating the release of fatty acids and glycerol" from the adipose tissue.
- glucose must be supplied to the body cells and it is hypothesized that the sulfonylureas stimulate this process by increasing cell permeability while the biguanides bring the glucose into the cells by a different mode of action not yet fully understood.
- the invention accordingly comprises a compound having the general formula:
- the new compound(s) of this invention may be prepared according to known methods by synthesizing pamino benzenesulfonamide through the chlorsulfonation of acetanilide and placing a radical group in the para position of the benzene ring consisting of
- the resulting compound(s) may be represented by the general formula:
- the following specific examples present illustrative data demonstrating the effectiveness of the novel compound as an oral diabetic agent.
- the new compound was evaluated by the oral route in terms of its capacity to lower the blood sugar level, raise the production ofpound in a dosageof Zmg/kilo, comparable by weight to a 3 gm dosage for an-average human, a fasting blood sugar sample was taken at zero hour. Glucose was then injected, and further blood samples were taken at intervals of 15,30,60and 90 minutes.
- Table I, ii and HI The findings are given in the following Table I, ii and HI:
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Emergency Medicine (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)
Abstract
An oral hypoglycemic compound for use in the treatment of diabetes mellitus having the general formula
AND WHICH IS ONE OF THE GROUP CONSISTING OF: A. THE COMPOUND WHEREIN R1 is an aliphatic series containing 2 to 8 carbon atoms; B. THE COMPOUND WHEREIN R2 R3 and is a member of the group consisting of hydrogen, aliphatic, and aromatic radicals; and C. THE COMPOUND WHEREIN X represents an amino or a substituted amino radical. The compound is prepared by synthesizing p-amino benzenesulfonamide through the chlorsulfonation of acetanilide and placing a radical group in the para position of the benzene ring. The compound may be incorporated with therapeutically acceptable carriers to make compositions adapted to be administered orally in the treatment of diabetes mellitus. The compound is intended to aid in the regulation of metabolic disturbance in diabetes mellitus not only by stimulating the production and release of insulin but also by functioning as a substitute for insulin in this regulatory process.
AND WHICH IS ONE OF THE GROUP CONSISTING OF: A. THE COMPOUND WHEREIN R1 is an aliphatic series containing 2 to 8 carbon atoms; B. THE COMPOUND WHEREIN R2 R3 and is a member of the group consisting of hydrogen, aliphatic, and aromatic radicals; and C. THE COMPOUND WHEREIN X represents an amino or a substituted amino radical. The compound is prepared by synthesizing p-amino benzenesulfonamide through the chlorsulfonation of acetanilide and placing a radical group in the para position of the benzene ring. The compound may be incorporated with therapeutically acceptable carriers to make compositions adapted to be administered orally in the treatment of diabetes mellitus. The compound is intended to aid in the regulation of metabolic disturbance in diabetes mellitus not only by stimulating the production and release of insulin but also by functioning as a substitute for insulin in this regulatory process.
Description
Unit States Patent n91 eaphy ORAL HYPOGLYCEMIC AMKNUPHENYLSULIFONYL- HYDROCARBYLBHGUANIDES [76] Inventor: Clifford John Heaphy, 1635 Harvard NE, Albuquerque, N. Mex. 87106 [22] Filed: Dec. 12, 1972 [21] Appl. No.: 314,545
[52] US. Cl. 260/564 13, 260/565, 424/326 [51] lint. Cl. C07c 133/10 [58] Field 0t Search 260/564 B, 565
[56] References Cited UNITED STATES PATENTS 2,908,7l3 10/1959 Mamalis et al 260/564 B Primary Examiner-Leon Zitver Assistant Examiner-Gerald A. Schwartz Attorney, Agent, or Firm-Robert M. Betz [57] ABSTRACT An oral hypoglycemic compound for use in the treatment of diabetes mellitus having the general formula a therapeutically The compound is prepared by synthesizing p-amino benzenesulfonamide through the chlorsulfonation of acetanilide and placing a radical group in the para position of the benzene ring.
The compound may be incorporated with acceptable carriers to make compositions adapted to be administered orally in the treatment of diabetes mellitus.
The compound is intended to aid in the regulation of metabolic disturbance in diabetes mellitus not only by stimulating the production and release of insulin but also by functioning as a substitute for insulin in this regulatory process.
1 Claim, N0 Drawings ORAL HYPOGLYCEMIC AMINOPHENYLSULFONYL I-IIYDROCARBYLBIGUANIDES BACKGROUND 1. Field of the Invention This invention relates to a composition of matter and to the manner of its utilization. More particularly it is concerned with a composition of matter which containsas its essential constituent a basic sulfonamide, paminobenzenesulfonamide, commonly known as sulfanilimide, which is chemically combined with a biguanide derivative to produce a new compound effective as primary therapy in the treatment of diabetes mellitus.
2. Description of the Prior Art According to a'recent National Health Interview Survey, there are estimated to be about 2.8 million diagnosed diabetics in the United States today, and the total number of persons having the disease in this country is considered to be much larger, simply because many individuals dont know they have the disease and may not have yet developed symptoms. However, despite intensive research into this major health problem, the treatment of diabetes mellitus is still far from complete.
Insulin is of course used extensively in diabetes therapy. But since insulin itself can not be administered orally and must therefore be injected, oral insulin substitutes have been developed. But such substitutes have not been completely safe and effective. The biggest problem has'been to find a drug that would reduce the blood sugar level quickly, help the body metabolize carbohydrates and not produce permanent damage to the system.
Today there are a number of oral hypoglycemic agents available, all of which have been successful to a degree. They fall into two groups the sulfonylureas and the biguanides.
The first of these groups, the sulfonlyureas, includes tolbutamide, chlorpropamide, tolazamide, and acetohexamide. The mechanism of action of these drugs is generally to increase the release of insulin from the functioning beta cells of the intact pancreas. The biguanides, and in particular phenformin hydrochloride, are completely unrelated to the sulfonylureas in chemical structure and mode of action. They do not stimulate in sulin production, but appear rather to aid in reducing the generation of fats, in facilitating the release of fatty acids and glycerol" from the adipose tissue.
' Both of these general types of oral insulin substitutes produce toxic effects to one degree or another, such as nausea, vomiting, and mental confusion, and dosage must be carefully controlled. But perhaps most significantly they are of negligible valuev in the treatment of the juvenile onset diabetic and in the more serious adult cases, where insulin injections must still be used extensively.
SUMMARY OF THE INVENTION Objects It is a general object of this invention to provide an oral hypoglycemic compound which'aids in the regulation of metabolic disturbance in diabetes mellitus not only by stimulating the production and release of insulin-from thepancreas but also by functioning as a sub stitute for insulin in this regulatory process.
It is known that, in certain instances, combined therapy with oral hypoglycemic agents in the sulfonylurea group and phenformin (phene'thylhydrochloride) is employed to obtain improved response in diabetic patients, but it is noted that, to applicants knowledge, no chemical combination of any two compounds falling respectively into the sulfonylurea and biguanide groups has been attempted.
It is recognized that glucose must be supplied to the body cells and it is hypothesized that the sulfonylureas stimulate this process by increasing cell permeability while the biguanides bring the glucose into the cells by a different mode of action not yet fully understood.
It is therefore a specific object of this invention to provide an oral insulin substitute by chemically combining the differing modes of action of existing hypoglycemic agents in the sulfonylurea and biguanide groups.
It is yet another object of this invention to provide a hypoglycemic compound which is free of toxic side effects such as nausea, vomiting, and other gastrointestinal disturbances.
It is a still further object of this invention to provide a hypoglycemic compoundeffective in the treatment of juvenile-onset diabetes mellitus.
The invention accordingly comprises a compound having the general formula:
' sitions to a human.
The characteristics and properties of the compound of this invention and the relationship of its constituents will be exemplified in the composition hereinafter described and the scope of the invention will be understood from the claims.
DETAILED DESCRIPTION The new compound(s) of this invention may be prepared according to known methods by synthesizing pamino benzenesulfonamide through the chlorsulfonation of acetanilide and placing a radical group in the para position of the benzene ring consisting of The resulting compound(s) may be represented by the general formula:
ltu
where X, R,, R and R have the previously given meaning. Any selection of radicals within the specified groups may be made without affecting the activity of the resultant compound.
The following example is illustrative of the compound(s) of this invention and the procedure for its (their) preparation, and will, it is believed, serve to make apparent the compound(s) embraced by the general formula given above and the preparation thereof, respectively, it being noted that the utility indicated for the several compounds flows from the elements of the general structure common to all of them.
Preparation of Compound 100 mg. of l-phenethylbiguanide monohydrochloride in powdered form is mixed with 18.755 gm. (0.155 mol) of dry, finely powdered acetanilide and added in small portions and with good stirring of 107.364 gm. (0.92 mol) of chlorosulfonic acid in a dry flask cooled to 10l5 C in a water bath with ice. When the additive has been substantially dissolved, the mixture is allowed to warm to room temperature and is then heated in a steam bath for 10 minutes to complete the reaction. The reaction mixture. is then cooled to room temperature using an ice bath and poured slowly and with stirring over 600 gm. of cracked ice in 100 ml. of water, forming a precipitate. The product is then collected by suction filtration, washed and dried.
75 ml of concentrated ammonium hydroxide isthen added to the above product and the mixture is heated in a steam bath for 30 minutes, and then cooled to room temperature. The reaction mixture is acidified with sulfuric acid and recooled. The new compound of this invention is formed as a precipitate, collected by suction filtration, washed and dried.
The following specific examples present illustrative data demonstrating the effectiveness of the novel compound as an oral diabetic agent. The new compound was evaluated by the oral route in terms of its capacity to lower the blood sugar level, raise the production ofpound in a dosageof Zmg/kilo, comparable by weight to a 3 gm dosage for an-average human, a fasting blood sugar sample was taken at zero hour. Glucose was then injected, and further blood samples were taken at intervals of 15,30,60and 90 minutes. The findings are given in the following Table I, ii and HI:
Table l BloodGlucose Level (mg. per 100 m. liters) Time (min.) Dog. A Dog 8 Table lContinued Blood Glucose Level (mg. per l00 m. liters) Note: These results were determined at professional laboratories in Albuquerque, New Mexico.
The results of these tests showed that the new compound reduced the glucose level and returned it substantially to normal in about minutes. The insulin level increased significantly and then stabilized to normal, and the triglycerides decreased significantly and then returned to normal. The drug has produced no apparent side effects.
While the exact mode of action of the new compound is not as yet completely understood and must await further research it is apparent from the tests performed thus far that the basic premise is established that the beneficial effects achieved by the sulfonylureas and the biguanides separately can be successfully combined chemically in a single compound and there appears to be reasonable likelihood that the new compound will function without harmful side effects. If this proves to be substantiated the new compound promises to offer hope for therapeutic effectiveness not heretofore achieved. With further understanding of the mechanism of the new compound there may also be reason to hope that it will provide the answer to an effective oral hypoglycemic agent for the juvenile diabetic.
It will be understood that although the new compound described herein promises to be effective in small dosages, the exact amount required will vary with conditions such as severity of diabetic symptoms, body weight, and peculiarities of patient response.
Furthermore, it is to be understood that in interpretation of the claims appended hereto that the phrase treating diabetes mellitus" is intended to comprehend obtaining reduction and control of blood glucose levels and other major insulin functions in a diabetic patient by any mode of action inherent in the new compound.
it is to be additionally understood that these skilled in the pharmaceutical art will have no difficulty in combining the new compound with a therapeutically acceptable excipient or carrier of non-toxic and inert character, in order to facilitate formation of an oral tablet adapted to permit quick solution and dispersion of the active ingredients therein.
It will thus be seen that the primary object set forth above is efficiently attained and since certain changes may be made in the above composition of matter without departing from the scope of the invention, it is intended that all matter contained in the above description shall be interpreted as illustrative and not in a limiting sense.
it is also to be understood that the following claims are intended to cover all of the generic and specific features of the invention which, as a matter of language, might be said to fall therebetween.
What is claimed is:
11. A compound having the formula:
Claims (1)
1. A COMPOUND OF THE FORMULA:
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US00314545A US3852353A (en) | 1972-12-12 | 1972-12-12 | Oral hypoglycemic aminophenylsulfonyl-hydrocarbylbiguanides |
| US509448A US3929999A (en) | 1972-12-12 | 1974-09-26 | Oral hypoglycemic method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US00314545A US3852353A (en) | 1972-12-12 | 1972-12-12 | Oral hypoglycemic aminophenylsulfonyl-hydrocarbylbiguanides |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3852353A true US3852353A (en) | 1974-12-03 |
Family
ID=23220379
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US00314545A Expired - Lifetime US3852353A (en) | 1972-12-12 | 1972-12-12 | Oral hypoglycemic aminophenylsulfonyl-hydrocarbylbiguanides |
Country Status (1)
| Country | Link |
|---|---|
| US (1) | US3852353A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4208430A (en) * | 1979-03-15 | 1980-06-17 | Smithkline Corporation | Pharmaceutical compositions and method of inhibiting phenylethanolamine N-methyltransferase |
| US20060293219A1 (en) * | 2001-02-15 | 2006-12-28 | Ekwuribe Nnochiri N | Methods of treating diabetes mellitus |
| US7199159B2 (en) | 2000-05-26 | 2007-04-03 | Centre National De La Recherche Scientifique (C.N.R.S.) | Use of biguanide derivatives for making a medicine having a wound healing effect |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2908713A (en) * | 1956-11-15 | 1959-10-13 | Vitamins Ltd | Diguanidine derivatives |
-
1972
- 1972-12-12 US US00314545A patent/US3852353A/en not_active Expired - Lifetime
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2908713A (en) * | 1956-11-15 | 1959-10-13 | Vitamins Ltd | Diguanidine derivatives |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4208430A (en) * | 1979-03-15 | 1980-06-17 | Smithkline Corporation | Pharmaceutical compositions and method of inhibiting phenylethanolamine N-methyltransferase |
| US7199159B2 (en) | 2000-05-26 | 2007-04-03 | Centre National De La Recherche Scientifique (C.N.R.S.) | Use of biguanide derivatives for making a medicine having a wound healing effect |
| US20060293219A1 (en) * | 2001-02-15 | 2006-12-28 | Ekwuribe Nnochiri N | Methods of treating diabetes mellitus |
| US7381702B2 (en) * | 2001-02-15 | 2008-06-03 | Biocon Limited | Methods of treating diabetes mellitus |
| US7423014B2 (en) | 2001-02-15 | 2008-09-09 | Biocon Limited | Insulin conjugates for treating diabetes mellitus |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Elkinton et al. | Transfers of potassium in renal insufficiency | |
| Prosser et al. | Diabetes mellitus following rodenticide ingestion in man | |
| WILDER et al. | Intake of Potassium, an Important Consideration in Addison's Disease: A Metabolic Study | |
| Turtle | Glucose and insulin secretory response patterns following diet and tolazamide therapy in diabetes | |
| GB2184653A (en) | Dementia improving and therapeutic agents | |
| US3852353A (en) | Oral hypoglycemic aminophenylsulfonyl-hydrocarbylbiguanides | |
| Walker et al. | Hyperkalemia after triamterene in diabetic patients | |
| Prout et al. | Imipramine poisoning in childhood and suggested treatment | |
| Miller et al. | Diabetes mellitus and autonomic dysfunction after vacor rodenticide ingestion | |
| US3929999A (en) | Oral hypoglycemic method | |
| Pierach et al. | Hematin therapy in porphyric attacks | |
| Bunim | The clinical effects of cortisone and ACTH on rheumatic diseases | |
| JANES et al. | The penetration of C14-labeled atropine into the eye: a comparison of methods of application | |
| MARKS et al. | Flaccid quadriplegia, hyperkalemia, and Addison's disease | |
| Johnson et al. | Accidental ingestion of Vacor rodenticide: the symptoms and sequelae in a 25-month-old child | |
| Satoyoshi et al. | Periodic paralysis: a study of carbohydrate and thiamine metabolism | |
| LOGSDON et al. | Death, probably due to potassium deficiency, following control of diabetic coma | |
| Krause | Studies in Immunity to Tuberculosis: Hypersensitiveness to tuberculo-protein and its Relation to some Tuberculosis Problems | |
| US3057780A (en) | Method for treatment of mental disease | |
| Mendoza et al. | Clonidine poisoning with marked hypotension in a 2½-year-old child | |
| FREEDMAN | Observations on a case of mixed porphyria with special reference to pathogenesis and treatment | |
| Feuerman et al. | Photodermatitis induced by chlorpropamide: a report of five cases | |
| GB1572146A (en) | Agents for the treatment of metabolic disorders and their use | |
| Baetjer | Effects of dehydration and environmental temperature on antimony toxicity | |
| Wight et al. | Rhabdomyolysis with hyperkalaemia after aminophylline overdose |