USRE33907E - Anti-spasmodic agents having a heterocyclic ring - Google Patents

Anti-spasmodic agents having a heterocyclic ring Download PDF

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USRE33907E
USRE33907E US07/394,274 US39427489A USRE33907E US RE33907 E USRE33907 E US RE33907E US 39427489 A US39427489 A US 39427489A US RE33907 E USRE33907 E US RE33907E
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propyl
ethyl
methyl
iso
triazolyl
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William M. Davis
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United Pharmaceuticals Inc
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/54—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/38—One sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D249/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/12—1,4-Thiazines; Hydrogenated 1,4-thiazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems

Definitions

  • the present invention relates to new pharmaceutical compounds having useful anti-spasmodic properties.
  • an anti-spasmodic drug is to relieve spasms of the smooth muscles.
  • Smooth muscles line most of the visceral organs.
  • the peristalsis and muscular activity of the stomach, intestines, gall bladder, urinary bladder, lung, the uterus, and to a degree the heart are all largely controlled by smooth muscles.
  • Smooth muscles are innervated by the autonomic nervous system.
  • the autonomic nervous system consists of two antagonistic branches--the sympathetic branch and the parasympathetic branch.
  • the parasympathetic nerve impulses increase the irritability and tension of the smooth muscles; contrariwise, the sympathetic nerve impulses increase the tension and irritability of the muscles of the heart muscle and relax the smooth muscles of the other visceral organs.
  • a spasm in a smooth muscle may be due to one of two causes. Either the smooth muscle may be receiving exaggerated impulses from the autonomic nervous system which create violent contractions in the muscle, or the muscle may be intrinsically stimulated into a spasm (most likely from chemical changes in the surrounding tissue).
  • a spasm due to exaggerated impulses from the parasympathetic branch of the autonomic nervous system may often be corrected by administering atropine (an active alkaloid of belladonna, which serves to break a connection between the parasympathetic nerve and the smooth muscle. This ability and effect of atropine is called a "neurotropic effect".
  • papaverine a derivative of opium which is classed as a narcotic.
  • Papaverine has an ability to decrease intrinsically the contractility of smooth muscle; it has the ability to relax smooth muscles directly. This ability and effect of papaverine is called a "musculotropic effect.”
  • a musculotropic effect In relieving spasms of smooth muscles generally, a musculotropic effect is acknowledged to be superior to a neurotropic effect.
  • a neurotropic effect cannot relieve spasms intrinsic in the smooth muscle itself, while a musculotropic effect, by relaxing and decreasing the irritability and responsiveness of smooth muscle to stimulation from the autonomic nervous system, can help to relieve a smooth muscle spasm even when it is due to exaggerated impulses from the autonomic nervous system.
  • Atropine produces undesirable side-reactions which presents a clinical difficulty.
  • Atropine when given in effective doses, serves to break or partly break all the parasympathetic nerve-smooth muscle connections throughout the body.
  • a spasm in a specific visceral organ such as a gastric or intestinal spasm (the spasm caused by exaggerated nerve impulses from the parasympathetic nervous system) undesirable side-actions due to the breaking of the parasympathetic nerve-muscle connections elsewhere in the body may occur.
  • the most easily recognized of these undesirable side reactions are dilation of the pupil and dryness of the mouth, caused by the breaking of the parasympathetic connections to the iris and the saliva producing mechanism respectively.
  • Atropine is acknowledged to have also a musculotropic effect, but its neurotropic effect is so strong that atropine must be given in minute doses not exceeding (1/60 to 1/40 grain). A dosage of 1/6 to 1/40 of a grain is too small to permit a significant musculotropic effect and when larger doses are administered undesirable side reactions are encountered.
  • U.S. Pat. No. 2,390,555 discloses a class of compounds comprising di-N-substituted aminoethyl esters of diphenylthioacetic acid of the general formula (C 6 H 5 ) 2 --CH--COS--CH 2 CH 2 --R in which R represents a disubstituted amino radical of either the diethylamino group, the morpholino group or the piperidino group with N as the point of attachment.
  • R represents a disubstituted amino radical of either the diethylamino group, the morpholino group or the piperidino group with N as the point of attachment.
  • This patent discloses that the thio analogs of certain disubstituted acetic acid esters of aminoalcohols have desirable anti-spasmodic properties. These compounds have proven to be very effective and are widely used as anti-spasmodics without encountering the undesirable side reactions due to excessive neurotropic effect.
  • U.S. Pat. No. 4,432,977 disclosed new uses, especially for the dilation of the smooth muscles of the upper urinary tract, of the compounds disclosed in U.S. Pat. No. 2,390,555.
  • a new class of anti-spasmodic compounds is provided wherein a heterocyclic nitrogen ring is connected via carbon linkage to the main chain.
  • the new compounds are those having the general formula I ##STR2## wherein:
  • n is an integer from 0 to 2;
  • R 1 is aryl or cycloalkyl
  • R 2 is hydrogen or hydroxyl
  • R 3 is selected from the group consisting of heterocyclic containing the nitrogen atom of a secondary or tertiary amine to which an alkyl group having from 0 to 3 carbon atoms is bonded and no other hetero atoms are present in the ring structure; heterocyclic containing the nitrogen atom of a secondary or tertiary amine to which an alkyl group having from 0 to 3 carbon atoms is bonded and one or more hetero atoms selected from the group consisting of N, O and S are present in the ring structure; bicycloheterocyclic ring system containing the nitrogen atom of a secondary or tertiary amine to which an alkyl group having from 0 to 3 carbon atoms is bonded and no other hetero atoms are present in the ring system; and bicycloheterocyclic ring system containing the nitrogen atom of a secondary or tertiary amine to which an alkyl group having from 0 to 3 carbon atoms is bonded and one or more hetero
  • the present invention also comprises methods of administering the above-described compounds for, but not limited to, the treatment of patients suffering from spasms in the upper and lower gastrointestinal tract, spasm associated with the gall bladder and common bile duct, as well as diarrhea, the irritable bowel syndrome, ureterospasm, bladder irritation, asthma, emphysema, and ophthalmologic injuries.
  • Representative heterocyclic rings include, but are not limited to, the following: 1-methyl-imidazolinyl, 1-ethyl-imidazolinyl, 1-n-propylimidazolinyl, 1-iso-propyl-imidazolinyl, 1-methyl-imidazolyl, 1-ethyl-imidazolyl, 1-n-propyl-imidazolyl, 1-iso-propylimidazolyl, 1-methyl-morpholinyl, 1-ethyl-morpholinyl, 1-n-propyl-morpholinyl, 1-iso-propyl-morpholinyl, 1-methyl-piperazinyl, 1-ethyl-piperazinyl, 1-n-propyl-piperazinyl, 1-iso-propyl-piperazinyl, 1-methyl-piperidinyl, 1-ethyl-piperidinyl 1-n-propyl-piperidinyl, 1-iso-propyl-piperidin
  • the thiol containing a heterocyclic ring may be reacted with diphenylacetyl chloride in dichloromethane by combining the reactants in a 1:1 molar ratio and gently heating under reflux condensation for approximately 1 -2 hours.
  • acyl chlorides may be prepared from the carboxylic acid analogues by reaction with oxalyl chloride as follows: ##STR5##
  • the reaction may be performed under reflux condensation. Following the reaction, which may be complete within a few hours, the acid chlorides may be vacuum-distilled and reacted with a thiol compound as described above.
  • the anti-spasmodic compounds of the present invention may be effective in a dosage range of from about 1 to about 15 mg/kilogram of body weight per day.
  • a preferred dosage is in the range of from about 1.5 to about 11.5 mg/kilogram of body weight per day.
  • a still more preferred dosage range is from about 3 to about 6 mg/kilogram of body weight per day.
  • the anti-spasmodic compounds of the present invention may be combined with a pharmaceutically acceptable carrier and may be administered orally, typically in tablets of 400 mg active ingredient, total 1155 mg, or by intravenous injection, or by topical application.
  • the anti-spasmodic compounds of the present invention may hydrolyze slowly in water, they are preferably not used as a solution or aqueous suspension unless freshly prepared compounds. It may be possible, however, to suspend the microspheres of these compounds in non-aqueous liquids for administration to patients.
  • the compounds of this invention are anti-muscarinic agents (cholinergic-muscarinic receptor antagonists) which inhibit the actions of acetylcholine on autonomic effectors innervated by postganglionic cholinergic nerves as well as on smooth muscle that lacks cholinergic innervation. Since a major component of parasympathetic control of smooth muscle occurs via muscarinic receptors, these compounds may be effective as modifiers of smooth muscle activity.
  • cholinergic-muscarinic receptor antagonists cholinergic-muscarinic receptor antagonists
  • Thiphenamil hydrochloride has been shown to decrease spasms of the gastrointestinal tract, biliary tract, ureter and uterus without producing characteristic atropinic side effects, on salivary and sweat glands, GI glands, or the cardiovascular system.
  • This invention results in compounds which may be as efficacious as thiphenamil hydrochloride, or more so, in relaxing various smooth muscle systems while at the same time demonstrating thiphenamil hydrochloride's lack of associated side-effects.

Abstract

A new class of anti-spasmodic thioester compounds having a heterocyclic ring containing the nitrogen atom of a secondary or tertiary amine or a bicycloheterocyclic ring system containing the nitrogen atom of a secondary or tertiary amine. These compounds have the general formula I ##STR1## wherein: =n is an integer from 0 to 2;
R1 is aryl or cycloalkyl;
=R2 is hydrogen or hydroxyl; and
R3 is selected from the group consisting of heterocyclic containing the nitrogen atom of a secondary or tertiary amine to which an alkyl group having from 0 to 3 carbon atoms is bonded and no other hetero atoms are present in the ring structure; heterocyclic containing the nitrogen atom of a secondary or tertiary amine to which an alkyl group having from 0 to 3 carbon atoms is bonded and one or more hetero atoms selected from the group consisting of N, O and S are present in the ring structure; bicycloheterocyclic ring system containing the nitrogen atom of a secondary or tertiary amine to which an alkyl group having from 0 to 3 carbon atoms is bonded and no other hetero atoms are present in the ring system; and bicycloheterocyclic ring system containing the nitrogen atom of a secondary or tertiary amine to which an alkyl group having from 0 to 3 carbon atoms is bonded and one or more hetero atoms selected from the group consisting of N, O and S are present in the ring system.

Description

.Iadd.This application is a continuation, of application Ser. No. 189,957, filed May 3, 1988, now abandoned. .Iaddend.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to new pharmaceutical compounds having useful anti-spasmodic properties.
2. Description of the Prior Art
The purpose of an anti-spasmodic drug is to relieve spasms of the smooth muscles. Smooth muscles line most of the visceral organs. The peristalsis and muscular activity of the stomach, intestines, gall bladder, urinary bladder, lung, the uterus, and to a degree the heart are all largely controlled by smooth muscles. Smooth muscles are innervated by the autonomic nervous system. The autonomic nervous system consists of two antagonistic branches--the sympathetic branch and the parasympathetic branch. On all visceral organs except the heart the parasympathetic nerve impulses increase the irritability and tension of the smooth muscles; contrariwise, the sympathetic nerve impulses increase the tension and irritability of the muscles of the heart muscle and relax the smooth muscles of the other visceral organs.
A spasm in a smooth muscle may be due to one of two causes. Either the smooth muscle may be receiving exaggerated impulses from the autonomic nervous system which create violent contractions in the muscle, or the muscle may be intrinsically stimulated into a spasm (most likely from chemical changes in the surrounding tissue). A spasm due to exaggerated impulses from the parasympathetic branch of the autonomic nervous system may often be corrected by administering atropine (an active alkaloid of belladonna, which serves to break a connection between the parasympathetic nerve and the smooth muscle. This ability and effect of atropine is called a "neurotropic effect". A spasm intrinsic in the smooth muscle itself may often be corrected by papaverine (a derivative of opium which is classed as a narcotic). Papaverine has an ability to decrease intrinsically the contractility of smooth muscle; it has the ability to relax smooth muscles directly. This ability and effect of papaverine is called a "musculotropic effect."
In relieving spasms of smooth muscles generally, a musculotropic effect is acknowledged to be superior to a neurotropic effect. A neurotropic effect cannot relieve spasms intrinsic in the smooth muscle itself, while a musculotropic effect, by relaxing and decreasing the irritability and responsiveness of smooth muscle to stimulation from the autonomic nervous system, can help to relieve a smooth muscle spasm even when it is due to exaggerated impulses from the autonomic nervous system.
Atropine produces undesirable side-reactions which presents a clinical difficulty. Atropine when given in effective doses, serves to break or partly break all the parasympathetic nerve-smooth muscle connections throughout the body. Thus when atropine is given in sufficient dosage to relieve a spasm in a specific visceral organ, such as a gastric or intestinal spasm (the spasm caused by exaggerated nerve impulses from the parasympathetic nervous system) undesirable side-actions due to the breaking of the parasympathetic nerve-muscle connections elsewhere in the body may occur. The most easily recognized of these undesirable side reactions are dilation of the pupil and dryness of the mouth, caused by the breaking of the parasympathetic connections to the iris and the saliva producing mechanism respectively.
Atropine is acknowledged to have also a musculotropic effect, but its neurotropic effect is so strong that atropine must be given in minute doses not exceeding (1/60 to 1/40 grain). A dosage of 1/6 to 1/40 of a grain is too small to permit a significant musculotropic effect and when larger doses are administered undesirable side reactions are encountered.
U.S. Pat. No. 2,390,555 discloses a class of compounds comprising di-N-substituted aminoethyl esters of diphenylthioacetic acid of the general formula (C6 H5)2 --CH--COS--CH2 CH2 --R in which R represents a disubstituted amino radical of either the diethylamino group, the morpholino group or the piperidino group with N as the point of attachment. This patent discloses that the thio analogs of certain disubstituted acetic acid esters of aminoalcohols have desirable anti-spasmodic properties. These compounds have proven to be very effective and are widely used as anti-spasmodics without encountering the undesirable side reactions due to excessive neurotropic effect.
U.S. Pat. No. 4,432,977 disclosed new uses, especially for the dilation of the smooth muscles of the upper urinary tract, of the compounds disclosed in U.S. Pat. No. 2,390,555.
In Compte Rendu de la Societe de Biologie, 140, pp 477-9, (1946) Dupre, Levy and Tchoubar disclose a series of compounds having the formula C6 H5 (R)CH--C(O)--S--CH2 CH2 N(CH2 CH3)2 where R is either a phenyl group, a propyl group, an isopropyl group, a butyl group or an isoamyl group. These compounds are all disclosed as being spasmolytic agents.
Compounds of the same general formula given above are disclosed by Tchoubar and Letellier-Dupre in Bulletin de la Societe Chimique, pp 792-4 (1947) wherein R was a phenyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isoamyl group or hydrogen.
In Farmakol. i. Toksikol. pp 10-17 (1956), Liberman discloses a class of compounds having the general formula (C6 H5)2 CHCOSCH2 CH2 N--R2, wherein both R's are the same and are selected from methyl, ethyl, propyl and butyl groups; and a class of compounds having the general formula (C6 H5)--CH(C6 H11)COSCH2 CH2 N--R2, wherein both R's are the same and are selected from methyl, ethyl, propyl and butyl groups.
C. A. Buehler et al. in the Journal of Medicinal Chemistry, 6, pp 230-3 (1963) disclose physiologically active compounds of the general formula RR'C(OH)COS(CH2)x NR2 ".HCl wherein R and R' are aryl groups, x is 2 or 3, and R2 " is a methyl or ethyl group.
R. O. Clinton et al. in the Journal of the American Chemical Society, 68, pp 2076-7 (1946) disclose synthesis of a number of dialkyl aminoalkyl diarylthiolacetates including fluorene-9-carbothioic acid, S-[2-diethylaminoethyl]ester.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
A new class of anti-spasmodic compounds is provided wherein a heterocyclic nitrogen ring is connected via carbon linkage to the main chain. The new compounds are those having the general formula I ##STR2## wherein:
n is an integer from 0 to 2;
R1 is aryl or cycloalkyl;
R2 is hydrogen or hydroxyl; and
R3 is selected from the group consisting of heterocyclic containing the nitrogen atom of a secondary or tertiary amine to which an alkyl group having from 0 to 3 carbon atoms is bonded and no other hetero atoms are present in the ring structure; heterocyclic containing the nitrogen atom of a secondary or tertiary amine to which an alkyl group having from 0 to 3 carbon atoms is bonded and one or more hetero atoms selected from the group consisting of N, O and S are present in the ring structure; bicycloheterocyclic ring system containing the nitrogen atom of a secondary or tertiary amine to which an alkyl group having from 0 to 3 carbon atoms is bonded and no other hetero atoms are present in the ring system; and bicycloheterocyclic ring system containing the nitrogen atom of a secondary or tertiary amine to which an alkyl group having from 0 to 3 carbon atoms is bonded and one or more hetero atoms selected from the group consisting of N, O and S are present in the ring system.
The present invention also comprises methods of administering the above-described compounds for, but not limited to, the treatment of patients suffering from spasms in the upper and lower gastrointestinal tract, spasm associated with the gall bladder and common bile duct, as well as diarrhea, the irritable bowel syndrome, ureterospasm, bladder irritation, asthma, emphysema, and ophthalmologic injuries.
Representative heterocyclic rings include, but are not limited to, the following: 1-methyl-imidazolinyl, 1-ethyl-imidazolinyl, 1-n-propylimidazolinyl, 1-iso-propyl-imidazolinyl, 1-methyl-imidazolyl, 1-ethyl-imidazolyl, 1-n-propyl-imidazolyl, 1-iso-propylimidazolyl, 1-methyl-morpholinyl, 1-ethyl-morpholinyl, 1-n-propyl-morpholinyl, 1-iso-propyl-morpholinyl, 1-methyl-piperazinyl, 1-ethyl-piperazinyl, 1-n-propyl-piperazinyl, 1-iso-propyl-piperazinyl, 1-methyl-piperidinyl, 1-ethyl-piperidinyl 1-n-propyl-piperidinyl, 1-iso-propyl-piperidinyl, 1-methyl-pyrazolyl, 1-ethyl-pyrazolyl, 1-n-propyl-pyrazolyl, 1-iso-propyl-pyrazolyl, 1-methyl-pyrrolidinyl, 1-ethylpyrrolidinyl, 1-n-propyl-pyrrolidinyl, 1-iso-propyl-pyrrolidinyl, 1-methyl-3-pyrrolinyl, 1-ethyl-3-pyrrolinyl, 1-n-propyl-3-pyrrolinyl, 1-iso-propyl-3-pyrrolinyl, 1-methyl-thiomorpholinyl, 1-ethyl-thiomorpholinyl, 1-n-propyl-thiomorpholinyl, 1-isopropyl-thiomorpholinyl, 4-methyl-1,2,4-triazolyl, 4-ethyl-1,2,4-triazolyl, 4-n-propyl-1,2,4-triazolyl, 4-iso-propyl-1,2,4-triazolyl.
Representative compounds of this invention which contain bicycloheterocyclic ring systems include, but are not limited to, the following: ##STR3##
The general reaction in the synthesis of the antispasmodic compounds described in the following examples of the present invention involves the nucleophilic substitution of, for instance, diphenylacetyl chloride with certain heterocyclic thiol compounds. This reaction may be illustrated in the following scheme: ##STR4##
The thiol containing a heterocyclic ring may be reacted with diphenylacetyl chloride in dichloromethane by combining the reactants in a 1:1 molar ratio and gently heating under reflux condensation for approximately 1 -2 hours.
The desired acyl chlorides may be prepared from the carboxylic acid analogues by reaction with oxalyl chloride as follows: ##STR5##
The reaction may be performed under reflux condensation. Following the reaction, which may be complete within a few hours, the acid chlorides may be vacuum-distilled and reacted with a thiol compound as described above.
The anti-spasmodic compounds of the present invention may be effective in a dosage range of from about 1 to about 15 mg/kilogram of body weight per day. A preferred dosage is in the range of from about 1.5 to about 11.5 mg/kilogram of body weight per day. A still more preferred dosage range is from about 3 to about 6 mg/kilogram of body weight per day.
The anti-spasmodic compounds of the present invention may be combined with a pharmaceutically acceptable carrier and may be administered orally, typically in tablets of 400 mg active ingredient, total 1155 mg, or by intravenous injection, or by topical application.
Because the anti-spasmodic compounds of the present invention may hydrolyze slowly in water, they are preferably not used as a solution or aqueous suspension unless freshly prepared compounds. It may be possible, however, to suspend the microspheres of these compounds in non-aqueous liquids for administration to patients.
As examples which are illustrative of, but are not limited to, the compounds of the present invention, there may be mentioned the following compounds designated as 1(a--x) through 9(a--x). R1, R2 and n for these compounds are located in Table I .[.on page 12.].: ##STR6##
              TABLE I                                                     
______________________________________                                    
        n         R.sub.1   R.sub.2                                       
______________________________________                                    
1a-9a:    0           H         methyl                                    
1b-9b:    0           H         ethyl                                     
1c-9c:    0           H         n-propyl                                  
1d-9d:    0           H         iso-propyl                                
1e-9e:    1           H         methyl                                    
1f-9f:    1           H         ethyl                                     
1g-9g:    1           H         n-propyl                                  
1h-9h:    1           H         iso-propyl                                
1i-9i:    2           H         methyl                                    
1j-9j:    2           H         ethyl                                     
1k-9k:    2           H         n-propyl                                  
1l-9l:    2           H         iso-propyl                                
1m-9m:    0           OH        methyl                                    
1n-9n:    0           OH        ethyl                                     
1o-9o:    0           OH        n-propyl                                  
1p-9p:    0           OH        iso-propyl                                
1q-9q:    1           OH        methyl                                    
1r-9r:    1           OH        ethyl                                     
1s-9s:    1           OH        n-propyl                                  
1t-9t:    1           OH        iso-propyl                                
1u-9u:    2           OH        methyl                                    
1v-9v:    2           OH        ethyl                                     
1w-9w:    2           OH        n-propyl                                  
1x-9x:    2           OH        iso-propyl                                
______________________________________
The compounds of this invention are anti-muscarinic agents (cholinergic-muscarinic receptor antagonists) which inhibit the actions of acetylcholine on autonomic effectors innervated by postganglionic cholinergic nerves as well as on smooth muscle that lacks cholinergic innervation. Since a major component of parasympathetic control of smooth muscle occurs via muscarinic receptors, these compounds may be effective as modifiers of smooth muscle activity.
Thiphenamil hydrochloride has been shown to decrease spasms of the gastrointestinal tract, biliary tract, ureter and uterus without producing characteristic atropinic side effects, on salivary and sweat glands, GI glands, or the cardiovascular system. This invention results in compounds which may be as efficacious as thiphenamil hydrochloride, or more so, in relaxing various smooth muscle systems while at the same time demonstrating thiphenamil hydrochloride's lack of associated side-effects.

Claims (5)

    I claim: .[.1. An antispasmodic agent having the formula.]. ##STR7## .[.wherein:
  1. 4-n-propyl-1,2,4-triazolyl, 4-iso-propyl-1,2,4-triazolyl..]. .[.2. An antispasmodic agent having a formula selected from the group consisting of .]. ##STR8## .[.where n is an integer from 0-2, R1 is H or OH and R2 is
  2. methyl, ethyl, n-propyl or isopropyl..]. .Iadd.3. An antispasmodic agent having the formula .Iaddend. ##STR9## .Iadd.wherein:
    n is an integer from 0 to 2;
    R1 is aryl or cycloalkyl;
    R3 is a heterocyclic nitrogen ring and is selected from the group consisting of 1-methyl-imidazolinyl, 1-ethyl-imidazolinyl, 1-n-propyl-imidazolinyl, 1-iso-propyl-imidazolinyl, 1-methyl-imidazolyl, 1-ethyl-imidazolyl, 1-n-propyl-imidazolyl, 1-iso-propylimidazolyl, 1-methyl-morpholinyl, 1-ethyl-morpholinyl, 1-n-propyl-morpholinyl, 1-iso-propylmorpholinyl, 1-methylpiperazinyl, 1-ethyl-piperazinyl, 1-n-propyl-piperazinyl, 1-iso-propyl-piperazinyl, 1-methyl-piperidinyl, 1-ethyl-piperidinyl, 1-n-propyl-piperidinyl, 1-iso-propyl-piperidinyl, 1-methylpyrazolyl, 1-ethyl-pyrazolyl, 1-n-propyl-pyrazolyl, 1-iso-propylpyrazolyl, 1-methyl-pyrrolidinyl, 1-ethyl-pyrrolidinyl, 1-n-propyl-pyrrolidinyl, 1-iso-propylpyrrolidinyl, 1-methyl-3-pyrrolinyl, 1-ethyl-3-pyrrolinyl, 1-n-propyl-3-pyrrolinyl, 1-iso-propyl-3-pyrrolinyl, 1-methylthiomorpholinyl, 1-ethylthiomorpholinyl, 1-n-propylthiomorpholinyl, 1-isopropylthiomorpholinyl, 4-methyl-1,2,4-triazolyl, 4-ethyl-1,2,4-triazolyl, 4-n-propyl-1,2,4-triazolyl, 4-iso-propyl-1,2,4-triazolyl..Iaddend.
  3. .Iadd. An antispasmodic agent having the formula .Iaddend. ##STR10## .Iadd.wherein m is an integer from 0 to 2, R1 is aryl or cycloalkyl,
    R2 is hydrogen or hydroxyl, and
    R3 is a heterocyclic or bicycloheterocyclic ring connected via carbon linkage to the main chain and is selected from the group consisting of imidazolinyl, imidazolyl, morpholinyl, thiomorpholinyl, pyrazolyl,
  4. 1,2,4-triazolyl, tropanyl and quinuclidyl..Iaddend. .Iadd.5. An antispasmodic agent having the formula .Iaddend. ##STR11## .Iadd.wherein:
    m is an integer from 0 to 2;
    R1 is aryl or cycloalkyl;
    R2 is hydrogen or hydroxyl; and
    R3 is a heterocyclic or bicycloheterocyclic ring selected from the group consisting of 1-methyl-imidazolinyl, 1-ethyl-imidazolinyl, 1-n-propyl-imidazolinyl, 1-iso-propyl-imidazolinyl, 1-methyl-imidazolyl, 1-ethyl-imidazolyl, 1-n-propyl-imidazolyl, 1-isopropyl-imidazolyl, 1-methyl-morpholinyl, 1-ethyl-morpholinyl, 1-n-propyl-morpholinyl, 1-iso-propyl-morpholinyl, 1-methylpyrazolyl, 1-ethyl-pyrazolyl, 1-n-propyl-pyrazolyl, 1-isopropylpyrazolyl, 1-methyl-3-pyrrolinyl, 1-ethyl-3-pyrrolinyl, 1-n-propyl-3-pyrrolinyl, 1-isopropyl-3-pyrrolinyl, 1-methyl-thiomorpholinyl, 1-ethylthiomorpholinyl, 1-n-propylthiomorpholinyl, 1-iso-propylthiomorpholinyl, 4-methyl-1,2,4-triazolyl, 4-ethyl-1,2,4-triazolyl, 4-n-propyl-1,2,4-triazolyl, 4-iso-propyl-1,2,4-triazolyl, .Iaddend. ##STR12##
  5. .Iadd.6. An antispasmodic agent having a formula selected from the group consisting of .Iaddend. ##STR13## .Iadd.where n is an integer from 0-2, R, is H or OH and R2 is methyl, ethyl, n-propyl or isopropyl..Iaddend.
US07/394,274 1986-01-09 1989-08-15 Anti-spasmodic agents having a heterocyclic ring Expired - Fee Related USRE33907E (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2390555A (en) * 1943-08-03 1945-12-11 Poythress William P & Co Antispasmodic agents
US4432977A (en) * 1982-08-27 1984-02-21 William P. Poythress & Company Method for dilating the smooth muscles of the upper urinary tract

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2390555A (en) * 1943-08-03 1945-12-11 Poythress William P & Co Antispasmodic agents
US4432977A (en) * 1982-08-27 1984-02-21 William P. Poythress & Company Method for dilating the smooth muscles of the upper urinary tract

Non-Patent Citations (15)

* Cited by examiner, † Cited by third party
Title
Buehler et al., Chemical Abstracts, vol. 58 (1963) 12458b. *
Buehler et al., Chemical Abstracts, vol. 63 (1965) 10496g. *
Buehler et al., Journal of Medicinal Chemistry, vol. 6 (1963) pp. 230 233. *
Buehler et al., Journal of Medicinal Chemistry, vol. 6 (1963) pp. 230-233.
Buehler et al., Journal of Medicinal Chemistry, vol. 8 (1965) pp. 643 647. *
Buehler et al., Journal of Medicinal Chemistry, vol. 8 (1965) pp. 643-647.
Clinton et al., Journal of the American Chemical Society, vol. 65 (1946) pp. 2076 2077. *
Clinton et al., Journal of the American Chemical Society, vol. 65 (1946) pp. 2076-2077.
Dupre et al., Compte Rendu de la Societe de Biologie, vol. 140 (1946) pp. 477 479. *
Dupre et al., Compte Rendu de la Societe de Biologie, vol. 140 (1946) pp. 477-479.
Goodman et al., The Pharmacological Basis of Therapeutics, 6th Ed, MacMillan Publishing, New York, p. 132. *
Liberman, Farmakol. i Toksikol, vol. 19, No. 6 (1956) pp. 10 17. *
Liberman, Farmakol. i Toksikol, vol. 19, No. 6 (1956) pp. 10-17.
Tchouban et al., Bulletin de la Societe Chimique (1947) pp. 792 794. *
Tchouban et al., Bulletin de la Societe Chimique (1947) pp. 792-794.

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