CA1292474C - Anti-spasmodic agents having a ring in the main chain - Google Patents

Abstract

A B S T R A C T

A new class of anti-spasmodic compounds having two branch chains is provided. The compounds have the general formula:
where R is selected from the group consisting of:
, , , , , wherein q is an integer from 1 to 4, , , and .
The total number of carbon atoms in R is equal to or less than 20. Furthermore, m is an integer from 1 to 4, n is an integer from 1 to 4, and p is an integer from 1 to 4. X may be nonexistent or may be O, S, NH or CH2 or salts thereof. However, when X is nonexistent the termi-nal group in both the n-chain and the p-chain is a methyl group.

Description

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ANTI-SPASMODI _AGENTS HAVING
A RING IN THE MAIN CHAIN

Background of -the Inven-tion Field of the Invention The present invention relates to new pharmaceutical compounds having useEul anti-spasmodic properties.

Description of the Prior Ar-t 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, in-testines, 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 para-sympathetic nerve impulses increase the irri-tability and tension of the smooth muscles; contrariwise, the sympa-thetic nerve lmpulses increase -the tension and irrita-bility 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 exaggera-ted impulses from the autonomic nervous system which create violent contractions in the muscle, or -the muscle may be intrinsically stimula-ted 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 oEten be corrected by administering a-tropine (an active alkaloid of belladonna which serves -to break a connection between -the parasympathe-tic nerve and the 9;~

smooth muscle. This ability and effect of atropine is call-ed a "neurotropic effect". A spasm intrinsic in -the smooth muscle itself may often be corrected by papaverine (a deriv-ative of opium which is classed as a narcoti.c)~ Papaverine has an ability to decrease in-trinsically 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 mus-culotropic effect is acknowledged to be superior to a neuro-tropic effect. A neurotropic effect cannot relieve spasms intrinsic in the smooth muscle itself, while a musculotropic effect, by relaxing and decreasing the irritability and re-sponsiveness of smooth muscle to stimulation from the auto-nomic nervous system, can help to relieve a smooth musclespasm even when it is due to exaggerated impulses from the autonomic nervous system.
A clinical difficulty with atropine is that oE un-desirable side-reactions. Atropine when given in effective doses, serves -to break or partly break all the parasympa-thetic 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 im-pulses from the parasympathetic nervous system) undesirab]eside-actions due to the breaking oE the parasympathetic nerve-muscle connections elsewhere in -the body may occur.
The most easily recognized of these undesirable si.de re-actions are dilation of the pupi]. and dryness oE the mouth, caused by the breaking of the parasympathetic connections to -the iris and -the saliva producing mechanism respec-tively.
Atropine is ac]snowledged -to have also a musculotropic effect, but its neurotropic effect is so strong that it cannot be given in greater than minute doses (1/60 to 1/40 grain) without encountering the undesirable side reac-tions.
This dosage is too small to permit a significant musculo-tropic effect.

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U.S. Patent No. 2,390,555 discloses a class of com-pounds comprising di-N-substi-tuted aminoethyl es-ters of diphenylthioacetic acid of the general formula (C6H5)2-CFl-COS-CH2CH2-R in which R represents a disubstituted amino radical of either -the diethylamino group, the morpholino group or the piperidino group. This patent was based upon the discovery 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 with-out encountering the undesirable side reactions due -to excessive neurotropic effect.
U.S. Patent No. 4,432,977 discloses new uses, especial-ly for the dilation of the smooth muscles of the upper urinary tract, of the compounds disclosed in U.S. Patent No.

2,390,555.
In Compte Rendu de la Société de Biologie, 140, pp 477-9, (1946) Dupre, Levy and Tchoubar disclose a series of compounds having -the formula (C6H5)(R)CHC(:O)SCH2CH2N-(CH2CH3)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 were prepared by Tchoubar and Letellier-Dupre in Bulletin de la Société 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 (C6H5)2CHCOSCH2CH2N-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 (C6H5)-CH(C6Hll)CSCH2CH2N-R2' wherein both R's are the same and are selected from methyl, ethyl, propyl and butyl groups.

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C.A. Buehler et al in the Journal of Medicinal Chem-istry, 6, pp 230-3 (1963) disclose physiologicall.y active compounds of the general formula R(R')-C(OH)COS(CH2)2NR"2 wherein R and R' are aryl groups.
R~O. Clinton et al in the Journal of the American Chemical Society, 68, pp 2076-7 (1946) synthesized a num-ber of dialkyl aminoalkyl diarylthiolacetates including fluorene-9-carbothioic acid, S-[2-diethylaminoethyl]
ester.

Summary of the Invention A new class of anti-spasmodic compounds is provided having -the general formula:

/(CH2) R 1l S (C 2)m N\

where R is selected from the group consisting of:

CH -'~3 ' ~' -CH2- ' 3/

~CH2- ~3 CH

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~CH2 ~CH,-. (~O-CH- whereln q C~13~(CH2)q is an integer ~rom 1 to 4, Cl~

~ ' .
~ .
O=C O

CH~

~3 C~ n (~ ~ f H -~,`

2 ~
The total number of carl)on atom~s in R is equal to or less ~ n 20 1 urtllcrn)orc!
m is an integer from 1 to 4;
n is an inte~er frorn 1 to 4;
p is an integer Erom'l to 4; ancl X may be nonexistent or may be 0, S, Nll or CH~ or salts thereof, but when X is noncxistent the terminal group in both the n-chain and the p-chain is a methyl ~roup.
A preferred sub-genus, of the compounds hayin~ the above-described general formula, incluc!es the following:

C S CH2 C~12 ~ ; C113,,C ~ C S CH2 CH2 N ~ ; and ~ (rO~C6115 O C1~3 ~ o f~ l s cll2 C~12_~

CH3-tC~12)r wherein r is an inte~er Erom 1 to 4.
The present invention also comprises rnethods of administering the above-de.scribed compounds Eor, but no~ limited to, the treatment of patients suffering from pylorospasm in the upper and lower ~astrointestinal tract, ~spasm associate~
with the gall bladder and comrnon bile cluc~, as well as liarrhea, the irritable bowel syndrolne, ureterospasm, bladder irritation, asthma and emphysema.
Description of the Preferred l~mbocliments The anti-spasmodic compo~lnds of thc prescnt invention are ef~ectlve ~n n d~s~,e ranp,e oE from about 1 to about 15 mg/kilo~ram of body weip7ht per day. ~ preferred dosap,e is in the '5 ran~,e of from about 1.5 to about 11.5 mg/kilogram of body wei~ht pcr day, ~ .5~ill more prcfcrred dosar,e range is from about 3 to about 6 m~/kilop,r.lln of l~ody weip,ht pcr clay.
The anti-spasmodic compounds oE the present invention may be combined with a pharmaceutically acce~table carrier ~n and can be adminlstered orally, typically in tablets of 400 mg active ingredient, total 1155 mg, or by intravenous injection, or by topical application.

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Because the anti-spasmodic compounds of -the present invention generally hydrolyze slowly in water, -they are preferably not used as a serum or suspension unless used as a freshly prepared solution. It is possible, however, to encapsulate microspheres of these compounds in the form of a liquid suspension for administration -to patients.
As specific examples of the compounds of the present invention, there can be mentioned:

4-t-butyl-benzoyl-thio-S-(2-diethylaminoe-thyl)-ester.HCl 3/ ~ CO-S-CH -CH -N-(CH CH ) HCl as well as compounds of the following formulas:
~3 CH -CO-S-CH -CH -N-(CH CH CH CH ) HCl H2-cH2-N-(cH2cH2cH3)2-~ O-CH -CO-S-CH2-CH2-N-(CH2CH3)2 ~ ~ ~ \ ~ CH _co-s-cH2-cEI2-cH2 N (C 3)2 `~ / ~ 2 2 2 e2 2 \ 2/ 2 3 Z~2~7~

~ CH2CH3 , ~ CH2 CO S CH2 CH2N~

\

~ O-CH-CO-S-CH -N-CH -CH -S

O-CH-CO-S-CH -CH -N-CH -CH . HCl CH -CH

CH3 \ A
CH - C ~ CO-S-CH2-CH2-N-CH3 . HCl ; OH
1_CO S CH -CH ~N-(CH CH ) HCl OH
H2-cH2-N-(cH2cH3)2-~ CO-S-CH2-CH2-N ~ ) O=C O
> <

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~ 1000-85 4 ~2~Z47~
~10-C~l -cll-co-s-cll2-cll2-N-(c1l2c113)2 ~1 ~10 Cl~-co-s-c~l2-cll2-N-(cll2cll3)2 ~ICl . . _ The general reaction use~ in thc ~yn~hcsis of the anti-spasmodic compounds described in the followinF, examples of the present invention involves tlle nucleophilic substitution of certain acyl cllloricles with certain ~l~iol compounds, st~ch - as 2-diethylaminocthanethiol. This reaction is illustra~ed in the following formula, wherein R is as defined above:
0 heat R-C-Cl + IIS (CH2)2N(C2H5)2 ~Cl acyl chloride 2-diethylaminoeth~nethiol hydroctlloricle . .

o R-c-s-(cl~2)2N(c2ll5)2 HCl thiol ester hydrochloride 2-diethylaminoctllanethiol was ~urifiecl by re-distillation in vaccuo an~ nitrogen gas. Sub~equently, thc thiol w~s reacted with various acyl chlorides in ~ichloromethane by combining tht! two reactants in a 1:1 molar ratio and ~,ently heating under reflux condensa~ion ~or ap~roximately 1-2 hours. The reaction mixture was thcn cooled in ice-water until crystalll7.ation occurred or, if nece.qsary, in dry ice-ethanol. The crude crystal~q wcrc llarvest~ y suction iltration and were then recryst~llLzed from an appropriate solvent (e.~,. ethyl acctate, acetone, petroleum ether, or dichloromethane).

The desired acyl chlorides may bc preparetl from the carboxylic acid analogues by reac~ioll with oxalyl chlori~e as follows:

_g ~ heat R-C-OH -~ CL-C-C-Cl ~ R-~-Cl -~ 11Cl ~ C02 ~ C0 carboxylie oxalyl acid acid chloride chloride .
The reaetion was performed under reflux eondensation.
Following the reaetion, which was usually complete within a few hours, the aeid chlorides were vacuum-distilled and reac~ed with a thiol compound as described above.
The eompounds of this lnvention nre anti-muscarinie agents (cholinerp,ic-muscarinic receptor antap,onists) whieh 1~ inhibit the actions of acetylcholine on autonomic effectors innervated 1~y post~,an~lionic choliner~,ic nerves as well as on smooth muscle that lacks eholinerp,ic innervation. Sinee a major component of parasympathetic control of smooth rnuscle occurs via muscarinic receptors, these compounds are effective as mocliiers of smooth m~scle activity.
Thiphenamil hydroehloride has been shown to decrease spasm of the ~astrointestinal tract, biliary tract, ureter and uterus without produein~ eharaeteristic atropinie side effects on salivary and sweat ~lancls, GI ~,lands, the eye or n the cardiovascular system. This invention results in eompouncls which are as efficaeious as thiphenamil hydrochloride,'or more so, in relaxin~, various .smooth muscle .systems while at the same time demonstrating thiphenamil hclyrochloride's lack of assoeiated side-effects. Pharmacolor~ical con~irmation of these'a~ents included in vitro orp~an 1)ath work and development of actual receptor-bindinp, dat~.

F,xample 1 1 ono-~5 ~2~2~74 The ~-t-butyl-benzoyl~thio-S-(dlethylaminoethyl)-ester'HCl was tested uslng a muscar~nic receptor preparation ~ro~
r~b~it l~ng tissue. A mea~sure of the ability o this compound to interact with muscarinic receptors, in this preparation, was determined by ~he dep,ree to which the compound competed w~th 13H] Quinuclidinyl Benzilate (hereinEfter referred to as [3H]QNB~for muscarinic receptors ~nd thereby inhibited the usual tissue upta~e of ~3HlQNB~ Fresh peripheral lung tissue from New Zealand White rabbits was minced with sclssors and homogenized wlth a polytron in 10 volume~ o ice cold SOmM sodium phosphate buffer (p~l 7.4~. The homop,enate w~s centrifur,ed ~1000 x ~, 5 min) and thc supcrnntant collec~cd.
The supernatant was then centrifu~,ed (42,000 x ~, 10'min, 4C) and the pellet res~spende~ ln buffer. Follow~ng a fin~l centrifugat~on ~42,000 x g, 10 min, 4C) the resulting pellet wa~ resuspended in 2 ml of phosph~te buffer f~r u~e in binding assays.
The [3H]QNB blnding assay was performed by incubatinp.
aliquots of the lun~ homogcnates (0.8 mg ~rotein/assay) at 37C for 60 min in 2 ml of sodium phosphate buffer which contained 0.1 nM ~311~QNB in the presence of 1 x 10 5 M
concentration of ~he nnti-spasmodic compound to determine inhibition of 1311]QN~ bindlnp,. Followinr, incubatlon, the assay was termin~ted by thc addit~on of ice-cold buffer and rapid filtration throu~,h Whatman ~F-C~,la~s fiber fllters under suction in n ~r~ndel~cell harvester. The filters were remove~, placed individually in 8 ml of ficintillation cockt~il, and counted for radioactivity in a scintill~tion spectrometer.
t3H]QNB whlch bound ln the pre6ence of 1 M atropine was termed "nonspecific" and w~s .substracted from that which bound in the nbsence of atrol-ine (e.~. "spcciflc" bindlnr,).
~11 poin~s wcre detcrmincd in dupllcate.

A~;

1000-85 . . ~ 7~ ' Compound/ Molecular Melting % inhibition of3H[~NB]
formula ~eight Point bindin~ (at a con-(grams) (C) centrat~on o~' of 1.0 x 10- ~1) -- _ _ 4-e-butyl-benzoyl-tllio-S-(2-diethylaminoethyl)-ester'HCl 329.9 16521%
(C~3)3-C ~ CO-S-(CH2)2-N-(CH2C~3)2 HCl -12- . .

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Example 2 The pharmacological actions of one anti-spasmodic compound was studied in a rabbit urinary bladder strip preparation. In general, longitudinal strips were prepared from the base of freshly isolated rabbit bladders and were then suspended under near-physiological conditions in tissue baths. The strips were attached to force transducers and both contractile and relaxant activity was measured. To measure the relaxant effects on the anti-spasmodic compounds on previously-contracted bladder strips, the strips were initially exposed to the muscarinic receptor agonist beth-anechol and allowed to reach a steady level of contractile activity for 20 minutes. At this point cumulative dose-responses to the compound was recorded. The rabbit abdomens were opened through a vertical midline incision. The bladder and ure-thra were dissected free of all surrounding tissues, removed and placed in aerated (95% 2 5% C2) Kreb's~-bicarbonate buffer (pH:7.4) of the following compo-sition (milliosmoles/liter):KCl 4.6, CaC12 2H2O 2.5, KH2PO4 1.2, MgSO4 7H2O 1.2, NaCl 118.2, NaHCO3 24.8, and glucose 10Ø Longitudinal muscle strips were prepared from the bladder base (approximately 6 mm x 4 mm) and suspended in an organ bath containing Kreb's buffer (37C) which was contin-uously aerated with O2:CO2 (95%:5~). Tissues were allowed to equilibrate to a tension of 2 gm for sixty minutes during which time buffer was replaced at 20 minute in-tervals. The contractile and relaxant responses of the muscle s-trips were measured isometrically with a Sta-tham UC3~ force-displace-ment transducer and recorded on an Electronics for Medicine DR8~ oscillographic recorder. Bethanechol was employed as the representative cholinergic agonis-t and, following equilibration, was added to the baths for a final concen-tration of 250 ~M. The tissues were allowed 20 minu-tes to achieve a maintained level of contraction in response to bethanechol and, at this point, cumulative dose-response B~

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measurements for one anti-spasmodic compound were started at concentrations ranging from 10 M -to 10 M. Solutions were added in volumes up to 100 ~1 and were prepared Eresh each day by dissolving them in distilled:deionized water.
Responses were measured 5 minu-tes following any particular cumulative addition and were expressed as a percen-tage of maximal relaxation (e.g. maximal relaxation is the base-line or prebethanechol level of muscle tone).
Dose responses, measured from the standard bethane-chol-contracted rabbit bladder strips, at various concen-trations of 4-t-butyl-benzoyl--thio-S-(2-diethylaminoethyl)-ester.HCl [(CH3)3-C ~ CO-S-(CH2)2-N-(CH2CH3)2.HCl] are presented in Table I:

Table I
Concentration (moles/liter) lo~8 10-7 1o~6 10-5 10-4 Increase in leng-th of rabbit bladder s-trip (cm) 0.1 0.2 0.4 1.3 3.2 20 Decrease in force o~
contraction of rabbit bladder strip (gm) 0.02 0.04 0.08 0.27 0.67 % of maximum relaxation 1.3 2.6 5.2 16.5 40.5 % background relaxation 0.0 0.0 0.0 9.5 31.8 ..
~:1

Claims (13)

1. A compound of the formula:
whereln R is selected from the group consisting of:
non substituted , , , , , , , , non substituted , wherein q is an integer from 1 to 4, , , and ;

the total number of carbon atoms in R is equal to or less than 20, and wherein a is 0 or 1;
m is an integer from 1 to 4;
n is an integer from 0 to 4; and p is an integer from 0 to 4;
provided that when a is 1, X is selected from the group con-sisting of O, S, NH and CH2 and n and p are integers from 1 to 4; and when a is 0 then X is nonexistent and n and p are integers from 0 to 4 and the terminal group in both the n-chain and the p-chain is a methyl group or a pharmaceuti-cally acceptable salt thereof.

2. The compound as defined in Claim 1, wherein R
is , m=2, n=2, p=2 and X is nonexistent.

3. An anti-spasmodic composition comprising a compound according to Claim 1 in association with a pharma-ceutically acceptable carrier.

4. The composition as defined in Claim 3, wherein the compound is administered in a dosage of from about 1 to about 15 mg/kg of body weight per day.

5. The composition as defined in Claim 3, wherein the compound is administered in a preferred dosage of from about 1.5 to about 11.5 mg/kg of body weight per day.

6. The composition as defined in Claim 3, wherein the compound is administered in a more preferred dosage of from about 3 to about 6 mg/kg of body weight per day.

7. The compound as defined in Claim 1, wherein R
is (C6H5)(HOCH2)-CH-, m=2, n=2, p=2 and X is nonexistent.

8. The compound as defined in Claim 1, wherein R
is (C6H5)(OH)-CH-, m=2, n=2, p=2 and X is nonexistent.

9. The compound as defined in Claim 1, wherein R
is , or a pharmaceutically acceptable salt thereof.

10. The compound as defined in Claim 1, wherein R
is , X is CH2, m=2, n=2 and p=2.

11. The compound as defined in Claim 1, wherein R
is , X is CH2, m=2, n=2, p=2 and g is an integer from 1 to 4.

12. The use of a compound according to Claim 1 as an anti-spasmodic.

13. The use of a compound according to Claim 2, 7, 8, 9, 10 or 11 as an anti-spasmodic.