NZ193099A - N,n"-disubstituted-n1-(oxa(thia)azacycloalkylidene)guanidines - Google Patents
N,n"-disubstituted-n1-(oxa(thia)azacycloalkylidene)guanidinesInfo
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- NZ193099A NZ193099A NZ19309980A NZ19309980A NZ193099A NZ 193099 A NZ193099 A NZ 193099A NZ 19309980 A NZ19309980 A NZ 19309980A NZ 19309980 A NZ19309980 A NZ 19309980A NZ 193099 A NZ193099 A NZ 193099A
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Description
New Zealand Paient Spedficaiion for Paient Number 1 93099
193099
Priority Dat®{s): ...
Complete Specification Fiisd:
COTC2.Vh]C0-T^Zb5,CO-lZ>2S7~y • COIIXLIR ;
Class:
tSbticSion Date: ... . 3.1. A P.O. Journal, No:
iWTI
II
Patents Form No. 5 Number
PATENTS ACT 1953 Dated
COMPLETE SPECIFICATION
Heterocyclic Derivatives of Guanidine
-f/V/e McNEILAB, INC. a corporation of the State of Pennsylvania, United States of America, located at Camp Hill Road, Fort Washington, Pennsylvania, United States of America,
do hereby declare the invention for wliich Afwe pray that a Patent may be granted to me/us, and the method by which it is to be performed, to be particularly described in and by th^Xollowing statement:
u.." * " (followed by page la)
P "W^Siffi i''
MN-334
la
BACKGROUND OF THE INVENTION:
In British Patent No. 1,409,768 there are described several heterocyclic derivatives of guanidine in which the heterocyclic moiety is a 5- or 6-membered saturated 1,3-diazacarbocyclic-2-ylidene. These derivatives are unsubstituted on the imino nitrogen of the guanidine moiety. In contrast, the compounds of the present invention differ by being a heterocyclic derivative of guanidine which carries a bulky substituent on the imino nitjogen of the guanidine moiety. Additional prior art, but further related, may be represented by _ U.S. Patent Nos. 3,993r469; 3,9©3y084;
3,914,306, 3,933,836 and 4,073,636; and British Pat. No. 1,341,245.
DESCRIPTION OF THE PREFERRED EMBODIMENTS:
tives. of guanidine having interesting pharmacological properties and, more particularly, to such derivatives having the formula:
wherein:
A is a member selected from the group consisting of 0 and S
This invention relates to new heterocyclic aeriva
(I)
n is the integer zero ox 1;
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R^ is a member selected from the group consisting of methyl and ethyl;
R2 is a member selected from the group consisting of loweralkyl (preferably methyl and ethyl), cycloalkyl having from 3 to 6 carbons (preferably cyclopentyl and cyclohexyl) and aralkyl (preferably benzyl); or
-N
/*!
\
taken together represents a member selected from the
_ group consisting of: 2
-N | , ^ , and \ , wherein W i is a member selected from the group consisting of 0, S, N-loweralkyl (preferably N-methyl) and N-aryl (preferably N-phenyl); and
R^ is a member selected from the group consisting
alkyl having from 4 to 10 carbons (preferably branched), such as, for example, tert-butyl, neopentyl, 1,1,3,3-tetramethylbutyl (tert-octyl) and the like;
phenyl; methvlenedioxyphenyl; phenyl substituted with from 1 to 3 substituents each selected from the group consisting of halo, loweralkyl and lowe: alkoxy; phenyl substituted with a member selected from the group consisting of hydroxy, benzvlcxy, loweralkanovloxy, nitror trifluoromethvl and methylthio;
naphthyl;
cycloalkyl having from 5 to 8 carbons cyclopentyl and cyclohexyl)7
(preferably
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exo-2-norbornyl; endo-2-norboray1; 1-adamantyl;
arylalkyl in which the aryl function is a member selected from the group consisting of phenyl and naphthyl and the alkyl function has from 1 to 4 carbons, such as, for example, benzyl, dl-, d- or 1-a-phenethyl, dl-, d- or l_-a-methylbenzyl, a, a-dimethylbenzyl, a,a-dimethyl-S-phenethyl, dl-, d-or 1_-(a-naphthyl) ethyl and the like; and diphenylalkyl in which the alkyl function has from 1 to 2 carbons, such as, for example, diphenylmethyl, 1,2-ana 2,2-diphenylethyl and the like.
As used herein, the prefix "lower" indicates that the relevant group has 1 to 4 carbons and the term "halo" represents halogens of atomic weight less than 127, i.e., chloro, bromo, fluoro, and iodo.
Due to the presence of amine-like nitrogen atoms in the compounds of formula (I), acid addition salts thereof are readily obtained and such pharmaceutical^ acceptable salts are included within the scope of this invention. The . subject compounds (I) may be converted to their therapeutically active nontoxic acid addition salt form by treatment with an appropriate acid, such as, for example, an inorganic acid.,
such as a hydrbhalic acid, e.g., hydrochloric, hydrobrorrvic and the like, or an organic acid, such as, for example, acetic, propionic, glycolic, pamoic, pyruvic, malonic, succinic,
maleic, fumaric, malic, tartaric, citric, benzoic, cinnamic, mandelic, methanesulfonic, ethanesulfonic, benzenesulfonic, £-toiuenesulfonic, cyclohexanesulfamic, salicylic, ^-aminosalicylic and the like acids. Conversely, the salt form can be converted by treatment with alkali into the free base form.
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The compounds of formula (I)/ wherein A, n, R^, R2, NR1R2 and R3 (other than hydroxyphenyl and loweralka-noyloxyphenyl) are as previously defined, are prepared by reacting a lactam salt of formula (II),
wherein X is either methoxy or ethoxy and Y ^ is either BF^® or OSO2F with a guanidine derivative for formula (III), with stoichiometric quantities of reactants being preferably employed. The preparation of said guanidine derivatives (III) is described in U.S. Patent No. 4,211,867.
It is advantageous to add four to eight molar equivalents of potassium carbonate to the reaction mixture following addition of the guanidine (III) in order to cause the 15 reaction to proceed toward completion. Suitable anhydrous organic solvents for conducting the reaction include lower alkanols, such as, for example, 2-propanol, tert-butanol and the like; ethers, such as, for example, tetrahydrofuran, dioxane and the like; and lower halogenated hydrocarbons, 20 such as, for example, chloroform, methylene chloride, 1,2-dichloroe~£hane and the like. Generally, tert-butanol is preferred. Ambient to reflux temperatures (about 80°C) may generally be employed. The product (IV), in the form of the corresponding HY salt, is converted to the corresponding 25 base form (I) by conventional means, for example, by treatment with a suitable alkali such as alkali metal or alkaline earth metal hydroxides; carbonates and the like. The reaction may be illustrated as follows:
193
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-N Me
S'xn e
0
NR,
!•
H2N—C—NR1R2
(II) (III)
r%)n f3
>==N—C—NR1R2 • HY alkali^ (I)
Me
(IV)
The fluoborates of formula (II), wherein Y ® is BF^ ^ , may be obtained according to procedures described in the literature, e.g., see U.S. Patent Nos. 3, 876,658" and 3/725,435*. Ber. 89, 2063 (1956);
and Org. Synth. 46_, 113, 120 (1966). The fluorosulfonates of formula (II), wherein Y ® is 0S02F ® , are similarly prepared. In general an oxo compound of formula (V) is reacted with an appropriate trialkyl oxonium fluoborate (VI) or methyl fluorosulfonate (VII) to give the corresponding salt (II). The reaction is preferably carried out from 0°C to ambient temperature under an inert dry atmosphere (e.g., nitrogen, argon) in an inert anhydrous lower halohydrocarbon solvent such as, for example, chloroform, 1,2-dichloroethane, methylene dichloride (most preferred) and the like. Other inert anhydrous organic solvents that may be employed include ethers such as, for example, diethyl ether, dioxane, tetr.ahydrofuran (THF) , 1,2-dimethoxv-ethane and the like.. The foregoing reactions may be illustrated as follows:
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c te?2>n
>0
N Me
(IV)
+ CEt}30 4
(VI)
©
(Il-a)
BF
? 0
Me (IV)
+ Me0S02F
(VII)
k^^QEt Me
(Il'-b)
©
FSO.
©
Another method of preparing those formula (I) compounds wherein A is sulfur and n is zero is from the starting material of formula (VIII) wherein:
•s,
Z,=
c>
X N'
Me
Said 2-imino-3-methylthiazolidine (Z^H) may be 5 reacted with an isbthiocyanate of formula (IX), wherein R^ is as previously described other than hydroxvphenyl and•loweralkanoyloxypnenyl, in a reaction-inert organic solvent, e.g., benzene, CJ^Clj* c^^oro^orm and the like • at temperatures ranging from about ambient to reflux. 10 temperatures, for about 2 to 24 hours, in approximately equimolar amounts. The thio function (=S) in the thus-obtained thioureas (X), is then transformed into an alkylthio function (-SR*) by reacting (X) with an alkylating agent of the formula R'X, wherein R' is ethyl or, 15 preferably, methyl, and X is haliae, preferably iodide, viNstosyiate, methosulfate, mesylate, fluorosulfonate and the like. Tvoical solvents for such alkylations include
1 9-30 9 9
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7
ethers, preferably diethyl ether, tetrahydrofuran, or dioxane, lower ketones, e.g., acetone, 2-butanone and the like? halohydrocarbons and loweralkanols, preferably iodide as the alkylating agent in methanol is particularly suitable. Generally, equimolar to a large stoichiometric excess of the alkylating agent is used, the amount depending on the reactivity of the thiourea (X) or its solubility in the solvent employed. The alkylation reaction may be carried out at temperatures ranging from ambient to reflux or in appropriate sealed vessels at higher temperatures. The alkylthio compounds of formula (XI) in acid addition (HX) salt form are then reacted with an appropriate amine of the formula HNR^R^, wherein R^, R2 and NR^R2 are as previously described, preferably in a lower alkanol solvent such as isopropanol and tert-butanol and generally at reflux temperatures of about 40-100°C, to yield the guanidine derivatives of formula (I), in similar acid addition form, which are readily obtained as the corresponding base form by conventional treatment with suitable alkali. The foregoing reactions may be illustrated as follows:
methylene dichloride and methanol, respectively. Methyl
S
II
2^H + R3-NCS
Zj—C—NHR3
(VIII) (IX)
(X)
SR
R'X
HNR..R. —
(XI)
jp
Z{— C—■NR1R2 -HX
NR
alkali
(I) - salt
(I)
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The isothiocyanates of formula (IX), many of which are known, may be prepared according to the extensive processes reported in the literature for making isothiocyanates For example, they may be obtained from the methodologies reported by M. BSgemann et al. in "Methoden der Organische Chemie Houben-Weyl", Eugen Miiller (Ed.), Georg Thieme Verlag (Publ.) Stuttgart, Germany, Vol. 9, page 8 6 7-884 (1955); J. Org, Chem., 36, 1549 (1971); U.S. Pat. No. 3,304,167; "A Npw Synthesis of Aliphatic Isothiocyanates",
Angew. Chem. intemat. Ed., 6_, 174 (1967); Bull. Chem. Soc. Japan, £8 , 2981 (1975); Tetrahedron, 29_, 691 (1973); 15 Chem. Ber., 101, 1746 (1968); and J. Indian Chem. Soc., 52, 148 (1975).
In the foregoing reaction of (XI) with the amine, HNR^^, it is preferred to use a stoichiometric excess of the latter-* for example, in 1:1.05 to 1:2.0 molar ratios. 20 If only a slight excess of the HNR^R2 amine is used, it may be advantageous to add a stoichiometric equivalent of a tertiary alkyl amine, e.g., Et^N, in order to enhance the rate of reaction. Any by-products which may be formed during the course of the reaction can be separated from 25 the desired formula (I) product by standard techniques known in the art, such as, for example, by fractional solubilization.
In each of the foregoing synthetic procedures for preparing formula (I) compounds, hvdroxyphenyl and lower-30 alkanoyloxyphenyl were excluded from the original definition of R^. The formula (I) compounds wherein R^ is ■ hydroxvphenyl may be prepared by hydrolysis of the corresponding R,=methoxyDhenyl derivatives bv conventional
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procedures, e.g., by treatment with HBr or HI and acetic acid. Acylation of the resultant R^hydroxyphenyl derivatives by glacial acetic acid or propionic acid in the presence of excess dicyclohexylcarboditLitti.de affords the corresponding R3=loweralkanoyloxy derivatives of formula (I)
The subject compounds of formula (I) and the acid addition salts thereof possess valuable pharmacological properties, particularly as hypoglycemic agents.
Their ability to lower blood sugar is demonstrated in the following rat glucose tolerance test, which test is a standard and extremely sensitive procedure used in the diagnosis of diabetes and hypoglycemic disease states.
In this test, male Sprague-Davley rats (Charles River 184-250 grams) are given water ad libitum and fasted 24 hours prior to the experiment. Two to five rats are used for each test and control group. Test compounds, 1-200 mc./kg., are administered (s.c., i.p. or orally) suspended in 0.5 or 1.0 milliliter, but preferably the former, of-tQ.5-1.0% methylcellulose vehicle. Control an'.mals are given an equal amount of vehicle. Serial blood samples (0.1 milliliter) are obtained from the tail without anesthesia prior to and at 30, 60, 90, 120, 150 and 180 minutes after administration of 0.8 to 1.0 gram of glucose per kilogram of body weight in 1 milliliter of water. (The glucose is given orally if the test compound has beer., given parenterally, and subcutaneously if the test compound has been given orally.) Specimens, of blood are immediately deproteinized with aqueous solutions of Ba(OH)^ an^ ZnSO^ and glucose levels are determined using the glucose oxidase assay described by L.P. Cawley et al., "Ultra Micro Chemical Analysis of Blood Glucose with Glucose Oxidase", Amer. J. Clin. Path., 32_, 195 (1959). The blood glucose values at each time point are expressed in terms of milligram percent
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(mg glucose/100 ml of blood). The mean glucose values of the controls are compared statistically by the Student's t-Test to the means of the experimental group at each of the corresponding time points- If the compound lowers the blood glucose significantly at any time at a 95% confidence limit, the compound is considered to have hypoglycemic activity. The blood glucose lowering, expressed as percent lowering, is obtained by dividing the difference between the mean blood glucose values for test and control animals by the mean glucose value for the control animal.
In addition to their hypoglycemic activity,
certain of the subject compounds have been found to possess anti-secretory activity and/or cardiovascular activity as demonstrated in tests described in U.S. Patent No. 4,211,867.
The subject compounds (I), in base or salt form, may be formulated into conventional liquid and solid pharmaceutical dosage forms ana preparations, for example, for oral or patenteral administration, according to standard pharmaceutical techniques in the art.
The following examples are intended to illustrate, but not to limit, the scope of the present invention.
Unless otherwise stated, all parts are by weight.
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EXAMPLE I
N-(3-Methyl-2-thiazolidinylidene)-N'-phenyl-thiourea: A solution of 5.9 g (0.04 3 mole) of 2-im.ino-3-methylthiazolidine in 70 ml of dry benzene is refluxed under nitrogen for 2.5 hrs. Some ether is added to the cooled reaction mixture and solids are filtered off, 9.8 g (90%). Recrystallization from acetonitrile-ether (1:1) gives 8.0 g (75%) of pure N-(3-methyl-2-thiazolidinylidene)-N'-phenylthiourea; m.p. 168.5-170.5°C.
EXAMPLE II
By repeating the procedure of Example I, but substituting an equivalent amount of an appropriate R^NCS for the phenylisothiocyanate used therein, there are obtained the following respective N-[2-(3-methyl)-thiazolidinylidene-N'-R^ thioureas of formula (X):
No.
^3
Mo.
-J.
3-F-Ph
21
2,4-di*e-Ph
2
2,4-dir-Ph
22
2,4,5-triMe-Ph
3
•4-CTj-Ph
23
3-Et-Ph
24
4-IsoPr-Ph
S
4-Cl-Ph
4-t-Su-Ph
6
2,4-diCl-Ph
26
3-HOj-Ph
7
2.4.5-cxiCl-Ph
27
3-5M«-?h
«
-Cl-2-OMe-P£
28
1-naphtiyl
9
3-Cl-4-Me-Pb
29
benzhydryl
4-Br-Ph
d,l-«-Me-Bl
11
4-Br-3-Cl-Ph
31
a, s-disethylphenethyl
12
4-3r-3-Me-Ph
32
2, 2-ii?henyl«^.yl
13
3-I-PIi
33
l-»rt«martyl
14
4-OMe-Pfa
34
cyclop«r.cyl
2-QHe-S-Me-Ph
cyclohexyl
16
3.5—diOMe-Ph
3G
exo-2-norbomyl
17
3,4-net>.yIeneiioxy-Ph
. 37
ende- 2 -norbcmy 1
18
4-OEt-Ph
38
neop«ncyl
19
3-OBi-Pfc
39
ter^-ocryl
3-H«-Ph
-40
3,4,5-triOMe-Ph
Note: Ma—OBTihyi; I*oPr»isopropy1; Bu-tutyl;
Ph«phanyl; Bi«b«nryl.
1 930 9 9
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12
EXAMPLE III
Methyl N-(3-methyl-2-thiazolidinvlidene)-N'-phenylcarbamimidothioate hydroiodide: A suspension of 17.0 g (0.067 mole) of N-(3-methyl-2-thiazolidinyl-idene)-N*-phenylthiourea and 11.1 g (0.078 mole) of iodomethane in 350 ml of acetone is refluxed for one hour. The solution is cooled at room temperature overnight (about 16 hours) and solids are filtered off, 25.1 g (95.2%), m.p. 159.5-161.5°C. Recrystallization from methanol-ether (1:1) gives pure methyl N-(3-methyl-2-thiazolidinylidene)-N*-phenylcarbamimidothioate; m.p. 163.5-165 °C.
EXAMPLE IV
By repeating the S-methylation procedure of Example III with each of the thioureas of Example II, the respective corresponding methyl carbamimido-thiate: hydroiodide salts of formula (XI) are obtained.
EXAMPLE V
N-(3-Methyl-2-thiazolidinylidene)-N'-phenyl-1-pyrrolidinecarboximidamide hydroiodide: a mixture of 11.9 g (0.030 mole) of N-(l-methyl-2-thiazolicinyl-iaene)-N'-phenylcarbamimidothioate hydroiodide and 4.4 g (0.062 mole) of pyrrolidine in 200 ml of t-butanol is refluxed for 24 hrs under a slow stream of nitrogen. Sodium hypochlorite and NaOH traps are used to remove the methyl mercaptan formed during the reaction. The reaction mixture is then cooled, ether added, and the solids formed are filtered off to. give 9.3 g (75%) of product. Recrystallizations from acetone-ethyl acetate (1:1) gives 7.8 g (62%) of pure N-(3-methy1-2-thiazolidinylidene)-N'-phenyl-l-pyrrolidinecarboximid-amide hydroiodide; m.p. 157.5-160°C.
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EXAMPLE VI
N - (3-Methyl-2-thiazolidinylidene)-N'-phenyl-4-morpholinecarboximidamide hydro iodide: The procedure of Example V is repeated except that an equivalent amount of morpholine is substituted for the pyrrolidine used therein to yield the product, N'(3-methyl-2-thia-zolidinylidene)-N'-phenyl-4-morpholi necarboximi damide hydroiodide, m.p. (188°) 190-191.5°C.
EXAMPLE VII
N-(4-Methoxyphenyl)-N'-(3-methyl-2-thiazoli-ainvlidene)-1-piper idir.ecarboximidamide fumarate: The procedure of Example V is repeated except that an equivalent amount of piperidine is substituted for the pyrrolidine and an equivalent amount of the pseudo-thiouronium salt of Example IV (Compound No. 14) are utilized as reactants. Basification of the resultant HI salt with aqueous NaOH followed by treatment of the base with an equivalent amount of fumaric acid yields the product, N-(4-methoxyphenyl)-N'-(3-methyl-2-thiazolidinylidene)-1-piperidinecarbcximidamide fumarate, m.p. 159.5-160°C.
EXAMPLE VIII
By repeating the procedure cf Example V but employing an equivalent amount of an appropriate R^R^NH amine and an equivalent amount of the appropriate pseudothiourea from Example IV as starting materials, the following.respective compounds of formula (I) are obtained as the hydroiodide salt.
, c. NR
NR, R.
12
HI
Me
14
Wo. ^3 -HR^ Wo. *3 •~WR1R7
X 3-r-Ph 21 2,4-di.He-Ph ~fO"'"He
2 2,4-diT-Ph "!03 22 214,5-triMe-Ph -I^N-Ph
3 4-C?3—Ph "0s 23 3_E--ph "CI
24 4-IsoPr-Ph N(He)3z
4-Cl-Ph -NHe2 25 4-t-Bu-Ph
6 2,4-diCl-Ph -N (Me)£t 26 3-NOj-Ph
7 2,4,5-triCl-Ph -N(Me)-^sJ 27 3-SMe-Ph
8 5-Cl-2-OMe-Ph -N(Me)-^^ 28 1-naphthyl N-Stj
9 3-Cl-4-Me-Ph -iT^-Me 29 benzhydryl NMe2
4-Br-Ph 30 d.l-a-Ke-Bz N(Me)£t
11 4-Sr-3-Cl-Ph -f] 31 a Pa-diMe- N(Me) <3
phenethyl
12 4-Sr-3-Me-Ph -N(Me)C3^5*i 32 2,2-diphenyl- N(Me)-(s>
™ ethyl
13 3-1-Ph ^ 33 1-adaaantyl -tT^)j-Ke
14 -4-0«e-?h -I^D 34 cyclopentyl -jT^N-Ph
2-OMe-5-Me-Ph 35 cyclohexyl
16 3,5-diOMe-Ph -NEtj 36 exo-2-norborsy1 _K_j r-\
17 3,4-BBtiiyleEM- -NMe, 37 endo-2-n iihi. wyl dicxy-rti
/—v.
18 4-OEt-Ph N(Me)Zt 38 aeopentyl
19 3-OBz-Ph S(Me)-^j 39 tsrt-octyl ~1CS
3-Me-Ph N(Me)-^^ 40 3,4,5-triOfc-rii N0te)C2-?fc
1 93
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IS
EXAMPLE IX
N- (3-Mefchyl-2-oxazolidinylidene) -N'-phenyl-l-pyrro1i di ne-carboximidamide,fumarate: Triethyloxonium fluoroborate is prepared from 1.85g (0.027 mole) of 5 epichlorohydrin in 7 ml of ether and 3.74g (0.027 mole) of boron trifluoride etherate in 3 ml of ether. The solid triethyloxonium fluoroborate is dissolved 'in 10 ml of dry methylene chloride and treated under nitrogen with 2.02g (0.020 mole) of 3-methyloxazolidin-2-one in 20 ml 10 of methylene chloride. The reaction mixture is stirred under nitrogen at room temperature overnight. A 50 ml methylene chloride solution of 4.51g (0.020 mole) of N-phenyl-l-pyrrolidinecarboximidamide free base (obtained from the corresponding hydrochloride salt with 50% 15 sodium hydroxide and dried over potassium carbonate) is added to the reaction mixture and stirred at room temperature overnight.
The solvent is removed in vacuo and the resulting HBF4 salt is recrystallized from 2-propanol/ether (1:1) 20 to give 4.65g of N-(3-methyl-2-oxazolidinylidene)-N'-
phenyl-l-pyrrolidinecarboximidamide HBF^ as a white solid, m.p. 142-1448C. Conversion to the free base is done by partitioning the salt between 3N sodium hydroxide and methylene chloride.. The combined organic layers are dried 25 over potassium carbonate and the solvent removed in vacuo. The resulting oil 2.9g (0.010 mole) is dissolved in 2-propanol and treated with an equimolar amount of fumaric acid in the same solvent. Recrystallization from 2-propanol/ether gives 4.08g (99%) of pure N-(3-Methyl-2-30 oxazolidinylidene)-N'-phenyl—1-pyrrolidine-carboximidamide tumarate, m.p. T60-162°C.
t 930
16
•EXAMPLE X
- N- (2,3,5, 6->Tetrahydro-4~methyl-l, 4-oxazine-3-ylidene)-N'-phenyl-l-pyrrolidinecarboximidamide fumarate: Triethyloxonium fluoroborate is prepared 2 from 3.70g (0.040 mole) of epichlorohydrin in 14 ml of ether and 7.58g (0.054 mole) of boron trifluoride etherate in 6 ml of ether. The solid triethyloxonium fluoroborate is dissolved in 20 ml of dry methylene chloride and treated under nitrogen with 4.60g 10 (0,040 mole) of 4-methyl-l,4-oxazine-2-one in 20 ml of dry methylene chloride. The reaction mixture is stirred under nitrogen at room temperature overnight. A 50 ml methylene chloride solution of N-phenyl-1-pyrrolidinecarboximidamide free base (obtained from 15 12.7g, 0.040 mole of the corresponding hydroiodide with 50% sodium hydroxide and dried over potassium carbonate) is added to the reaction mixture and stirred at room temperature overnight.
The solvent is removed in vacuo and the resulting 20 H3F4 salt is recrystallized from 2-propanol/ether (1:1) to give 10.3g of white solid. Conversion to the free base is done by partitioning the salt between 3N sodium hydroxide and methylene chloride. The combined organic layers are dried over potassium carbonate and the 25 solvent removed in vacuo. The resulting oil, 9.Og
(0.0315 mole, 73%) is dissolved in 2-propanol and treated with an equimolar amount of fumaric acid in the same solvent. The salt is recrystallized from ethanol-ether to give 8.5g of pure N- (.2,3,5, 6-Tetrahydro-4-methyl-l, 30 4-oxazine-3-ylidene) -^N' -phenyl-l-pyrrolidinecarboximici-amide fumarate, m.p. 191-193°C.
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EXAMPLE XI
By following the procedure of Example IX for products having the ring function, 3-methyl-2-oxazolidinyl-r idene, and the procedure of Example X for products having 5 the ring function, 2,3,5,6-tetrahydro-4-methyl-l,4-oxazine-3-ylidene, except that an equivalent amount of an appropriate guanidine of formula (III) is substituted for the N-phenyl-l-pyrrolidinecarboximidamide of each Example, the following respective products of formula (I) are 10 obtained, converted to the indicated acid addition (HX) salt.
(qH2)n
—N—C—NR1R2 • HX
II
3
1
18
n-zero;
No. R3
1 Ph
2 3,4-OBttrylanatiicxy-R'.
3 4-n-Bu-Ph
4 4-OB2-Ph
4-M«-?h
6 3-Cl-Ptl
7 4-N02-Ph
8 benzhydryl
9 exo-2-norborr.vl
* 3,4-diOMe-Ph
11 o,a-diMe-BZ
12 3.4-diCl-Ph
13 1-naphthyl
14 4-OMe-Ph
Bz
16 cyclopentyl
17 3,4,5-triOMe-Ph n-1
18 Ph
19 endo-2-norborayl
3-CF3-?h
21 4-OMe-Ph
22 4-SMe-Ph
23 4-H02-Ph
24 4-OB2-Ph
d,1—a—Me—Bz
26 cyclohexyl
27 tert-octyl
28 1,2-diphenylethyl
29 - 4 -OMe- 2,5 -diiie-Ph
o,a-diMe-phenethyl
31 l-adamantyl
32 3,4-diCl-Ph
33 1-naphthyl
34 aeopentyl
2,4,5-triCl-Ph
-NRj^RJ
O
-o
-NEtj
-a -€
-o -a -o -a
-HMe2 -N£t2
-•a
-H (Me)<^s|
-a
-o
—H(Me)Bz
-a
-N(Me)^F)
—NEtj -N(Me)^j
-o -o
-a -a
-r\>
—NEtj
-iT\>
\ r
-a
-HMe2
-Ps
-•a
-NEtj
-N(Me)3z
-€
-NEt,
HX .
ax
HBr fmnnrate
HI
BC1
H3PO4
h2so4
a&leate
HI
TsOH £ujnarate h3?°4
HI HI HI
fumarate HI
HI HBr
HN03 HI
fianarate maleate HI HI
succinate
HC1
HN03
HC1
EKO
3
HI HC1
£uinar ate HI
fumarate
V _
I93099
MN-334
19
EXAMPLE XII
N- (3-Methyl-2-oxazolidinylidene) -N1 -phenyl-1-- pyrrolidine-carooximidamide fumarate: To a solution of
3-methyloxazolidin-2-one, 2.02 g (0.02 mole), in dry
methylene chloride under dry nitrogen is added 2.28 g
(0.02 mole) of methyl fluorosulfonate in one protion.
After stirring 3 hrs, 4.51 g (0.02 mole) of N-phenyl-1-
pyrrolidinecarboximidamide free base in dry methylene chloride is added. After stirring at room temperature
overnight, the solution is shaken with excess cold 3N
NaOH. The organic layer is separated and dried over l^CO^/ filtered, and the solvent removed in vacuo to afford the crude base. Addition of an equimolar amount of fumaric acid to a solution of the free base in iso-
propanol, followed by recrystallization from isopropanol/ .
ether affords pure N-(3-methyl-2-oxazolidinylidene)-N1-
phenyl-l-pyrrolidinecarboximidamide fumarate; m.p. 160-
162 °C.
-*■ EXAMPLE XIII
[ (2,3,5, 6-Tetrahvdro)-4-methyl1-1,4-
"3" ■' ' >- •<? % *? /'J*
■ thiazinvlidenel-N'-(4-methoxyphenyl)-1-piperidinecarbox-
imidamide hydroiodide: Triethyloxonium fluoborate (0.07
mole) is prepared from 13.2 g (0.093 mole) of boron trifluoride etherate and 6.4 8 g (0.07 mole) of epichloro-
hydrin in anhydrous ether under dry nitrogen. The resultant oily crystals are washed with fresh dry ether by decantation and dissolved in dry methylene chloride. To this solution is added 4.25 g (0.0324 mole) of 4-methyl-
thiamorpholin-3-one (2,3,5,6-tetrahydro-4-methyl-l,4-
thiazin-3-one) and the mixture is stirred 2 hr at room temperature. Then 0.027 mole of N-(4-methoxyphenyl)-1-
piperidinecarboximicamide in 50 ml of dry CI^Cl^ and 11.2 g
(0.08 mole) of anhydrous potassium carbonate are added. The resulting mixture is stirred overnight at ambient temperatures.
' <<*' , -\ .
193099
MN-334
The reaction mixture is filtered and the filtrate is shaken with cold 20% aqueous NaOH. The organic layer is separated and dried over X2CO;3' f'iltered and the solvent ' removed in vacuo to give an oily residue. Kugelrohr 5 distillation (air bath temperature 120-200°C) removes any unchanged N-(4-methoxyphenyl)-1-piperidinecarbox-imidamide. The residue of desired product in base form is converted to the HI salt and recrystallized to aive , ,
3C -3- - " a '}if pure N-y[ . (2,3,5,6-tetrahydro)-4-methyl]-1,4-thiazinyl- ^ "
A
-N'-(4-methoxyphenyl)-1-piperidinecarboximidamide hydroiodide.
EXAMPLE XIV The procedure of Example XIII is followed except that an equivalent quantity of an appropriate guanidine of formula Mil) .is .substituted for the 5 N-(4-methoxyphenyl)-1-piperidinecarboximidamide used therein to yield the following respective products of formula (I), converted to the indicated acid addition
■st^.
(HX) salt.
S NRl f I 11
kNJ=N-C-NR1R2 • HX Me
\ * "I-„ ■ \>\
'£ i jyji «§;:g
193099
MN-334
21
no.
h.
-nr1r2
HX
1
Ph
-NEt2
HI
2
benzhydryl
-€
-base-
3
3-Cl-Ph
/—^
-N ,0 \ I
fumarate
4
2,4,5-triCl-Ph
-O
HCl
BZ
-NMe2
HCl
6
1-naphthyl
-o
HBr
7
dl-a-Me-Bz
-N(Me)^sj
-base-
8
4-N02-Ph
-N(Me)Bz
El
9
3,4-diOMe-?h
-iT^N-Ph
HCl
cyclohexyl
-N(Me)<JS^
HCl
EXAMPLE XV
N-f[ • (2 , 3 , 5 , 6-Tetrahvdro)-4-methvl]-1, 4- „ ~ p
— 3 — w ^ * ■ C X *
thiazinvlidene f-N' - (4-hydroxvphenyl) -1-piperidinecarbox- /< imidamide hydroiodide: A solution of 5.03 g (0.01 mole)
of the R3=4-methoxyphenyl derivative of Example XIII in 7 g of 50% HI and 7 g of glacial acetic acid is heated under reflux for 6 hr. The solvent and excess HI are removed in vacuo to yield the product, N-{[ (2,3,5,6- . ^ ^ tetrahydro)-4-methyl]-1,4-thiazinvlidene}-N1 -(4-hydroxy- ^ ^ v ' phenyl)-1-piperdinecarboximidamide hydroiodide.
v r
193099
MN-334
22
EXAMPLE XVI
By following the hydrolysis procedure of Example XV, except that an equivalent amount of an appropriate R^^-methoxyphenyl derivative is utilized as the precursor to be hydrolyzed, the following respective R3=hydroxyphenyl derivatives of formula (I) are obtained (converted to free base):
1. Precursor: Product:
Compound No. 14 of Example VIII. N-(4-Hydroxyphenyl)-N'-(3-methvl-2-thiazolidinylidene)-1-morpholinecarbox-imidamide.
2. Precursor: Product:
Compound No. 14 of Example XI. N-(4-Hydroxyphenvl)-N1 -(3-methy1-2• oxazolidinylidene)-1-pyrrolidine-carboximidamide.
3. Precursor: Product:
Compound No. 2 1 of Example XI. N-(4-Hydroxyphenyl)-N1-(2,3,5,6-tetrahydro-4-methyl-l,4-oxazine-3-ylidene)-1-pyrrolidinecarboximidamide.
EXAMPLE XVII N-(4-Hvdroxyphenyl)-N'-(3-methyl-2-thiazoli-dinvlidene)-l-piperidinecarboximidamide hydroiodide: To 2.56 g (7.7 mmoles) of the R^^-methoxyphenyl derivative of Example VII (as the free base) is added 4.92 g (19.2 mmoles) of 50% HI and 4.0 g of glacial acetic acid. The resulting mixture is heated (oil bath) under reflux overnight. The excess HI and acetic acid are removed in vacuo and the residue is washed several times with ether and then scratched to afford crystals which are suspended in t-BuOH,.-filtered, and washed
Claims (4)
1. NHS(-2r5cetyloxyphenyl)-N'-((2,3,5, 6-tetrahydro; -4-methyl] -l,4-thiazine-3-ylidine -1-piperidinecarboximidamide HI. 30 2- N- ( 4-Acetyloxyphenvl)-N'- (3-methyl-2-thiazolidinylidene)-
4-morpholinecarboximidamide HI.
3. n— (4-APetyloxyphenyl) -N'-(2,3,5, 6-tetrahydro-4- rnethy 1-1,
4-oxazine-3-ylidene)-l-p-vrrolidinecarboximiaamice HI. .
/<?3
-24-
WHAT W2 CLAIM IS:
1. A heterocyclic derivative of guanidine selected from the group consisting of a compound having the formula: /A \
(CH,)
| n fl»3 A » *•
Me and the pharmaceutical^ acceptable acid addition salts thereof wherein:
!
A is a member selected from the group consisting of 0 and S; n is the integer zero or 1:
R^ is a member selected from the group consisting of methyl and ethyl;
R2 is a member selected from the group consisting of loweralkyl, cyclopentyl, cyclohexyl and benzyl; or
/Ri taken together represents a member selected from
■N ., .
the group consisting of:
*2
/~\ y \
-N , -N^ y, and -N y, wherein W is a member selected from the group consisting of 0, S, N-loweralkyl and N-aryl; and
/
-25-
193099
17 R^ is a member selected from the group consisting of:
18 alkyl having from 4 to 10 carbons;
19 phenyl, methylenedioxyphenyl , phenyl substituted with from
20 1 to 3 substituents each selected from the group
21 consisting of halo, loweralkyl and loweralkoxy;
22 phenyl substituted with a member selected from
23 the group consisting of hydroxy, benzyloxy,
24 loweralkanoyloxy, nitro , trifluoromethyl and
25 methylthio;
26 naphthyl;
27 cyclopentyl; cyclohexyl;
28 exo-2-norbomyl; endo -2-norbornyl; 1-adamantyl;
29 arylalkyl in which the aryl function is phenyl and the
30 alkyl function has from 1 to 4 carbons; and
31 diphenylalkyl in which the alkyl function has from 1 to 2
32 carbons.
1 2. A compound selected from the group consisting
2 of N-(3-methyl-2-thiazolidinylidene)-N'-phenyl-l-pyrrolidiner
3 carboximidamide and the pharmaceutically acceptable acid
4 addition salts thereof.
1 3. A compound selected from the group consisting
2 of N-(3-methyl-2-thiazolidinylidene)-N'-phenyl-1-morpholine-
3 carboximidamide and the pharaaceutically acceptable acid
4 addition salts thereof.
■]
1
2
3
4
1
2
3
4
1
2
3
4
1
2
3
4
1
2
3
4
193099
-26-
4. A compound selected from the group consisting of N- C4-methoxyphenyl) -N(3^methyl-2-thiazolidinylidene) -
. 1-piperidinecarboximidamide and the pharmaceutically acceptable acid addition salts thereof.
5. A compound selected from the group consisting of N-(3-methyl-2-oxazolidinylidene)-N'-phenyl-l-pyrrolidinecarboximidamide and the pharmaceutically acceptable acid addition salts thereof.
6. A compound selected from the group consisting of N- (2, 3, 5,6-tetrahydro-4-methyl-l,4-oxazine-3-ylidene) -N'-phenyl-l-pyrrolidinecarboximidamide and the pharmaceutically acceptable acid addition salts thereof.
7. A compound selected from the group consisting of N-(4—hydroxyphenyl)—N'-(3-methyl-2-thiazolidinylidene)-1-piperidinecarboximidamide and the pharmaceutically acceptable acid addition salts thereof.
8. A compound selected from the group consisting *^ of N-tr ... (2, 3,5, 6-Tetrahydro)-4-methyl]-1,4-thiazinylidene"?-^ N'-(4-methoxyphenyl)-1-piperidinecarboximidamide and the pharmaceutically acceptable acid addition salts thereof.
-27-
193099
9. A hypoglycemic agent, comprising a compound of formula I
herein and a pharmaceutically acceptable carrier therefor.
10. A process for preparing a compound of claim 1 substantially as hereinbefore described with reference to the accompanying examples V-XIX.
11. A process for preparing N-(3-methyl-2-thiazolidinylidene)-N'-phenyl-l-pyrrolidinecarboximidamide and the pharmaceutically acceptable acid addition salts thereof, substantially as hereinbefore described with reference to the accompanying example V.
12.- A process for preparing N-(3-methyl-2-thiazolidinylidene)-N1-phenyl-l-morpholinecarboximidamide and the pharmaceutically acceptable acid addition salts thereof, substantially as hereinbefore described with reference to the accompanying example VI.
1-3. A process for preparing N-(4-methoxyphenyl)-N'-(3-methyl-
2-thiazolidinylidene)-1-piperidinecarboximidamide and the pharmaceutically acceptable acid addition salts thereof, substantially as hereinbefore described with reference to the accompanying example VII.
14. A process for preparing N-(3-methy1-2-oxazolidinylidene)
r-N' -phenyl- 1-pyrrolidinecarboximidamide and the pharmaceutically
-28-
193099
acceptable acid addition salts thereof, substantially as hereinbefore described with reference to the accompanying examples IX and XII.
15. A process for preparing N-(2,3,5,6-tetrahydro-4-methy1-1,4-oxazine-3-ylidene)-N1-phenyl-l-pyrrolidinecarboximidamide and the pharmaceutically acceptable acid addition salts thereof, substantially as hereinbefore described with reference to the accompanying example X.
16. A process for preparing N-(4-hydroxyphenyl)-N1 -(3-methyl-2-thiazolidinylidene)-1-piperidinecarboximidamide and the pharmaceutically acceptable acid addition salts thereof, substantially as hereinbefore described with reference to the accompanying example XVII.
17. A process for preparing N-<[ (2,3,5,6-Tetrahydro)-4-methyl] -1,4-thiazin-3-ylidene>-N'-(4-methoxyphenyl)-1-piperidinecarboximidamide and the pharmaceutically acceptable acid addition salts thereof, substantially as hereinbefore described with reference to the accompanying example XIII.
18. A compound of claim 1 whenever prepared according to the 'process claimed in claim 10.
19. N-(3-Methyl-2-thiazolidinylidene)-N'-phenyl-l-pyrrolidine-
carboximidamide and the pharmaceutically acceptable acid addition salts thereof, whenever prepared according to the process claimed in claim 11 .
. . ~29" 1 93099
20. N-(3-Methy1-2-thiazolidinylidene)-n'-pheny1-l-morpholine-carboximidamide and the pharmaceutically acceptable acid addition salts thereof, whenever prepared according to the process claimed in claim 12.
2 1. N-(4-Methoxyphenyl)-N'-(3-methy1-2-thiazolidinylidene)-1-piperidinecarboximidamide and the pharmaceutically acceptable acid addition salts thereof, whenever prepared according to the process claimed in claim 13.
2 2. N-(3-Methyl-2-oxazlidinylidene)-N'-pheny1-1-pyrrolidine-carboximidamide and the pharmaceutically acceptable acid addition salts thereof, whenever prepared according to the process claimed in claim 14.
2 3. N-(2,3,5,6-Tetrahydro-4-methyl-l,4-oxazine-3-ylidene) -N'-pheny1-1-pyrrolidinecarboximidamide and the pharmaceutically acceptable acid addition salts thereof, whenever prepared according to the process claimed in claim 15.
2 4. N-(4-Hydroxyphenyl)-N'-(3-methyl-2-thiazolidinylidene)-1-piperidinecarboximidamide and the pharmaceutically acceptable acid addition salts thereof, whenever prepared according to the process claimed in claim 16.
25. N-< [ (2 ,3,5,6-Tetrahydro)-4-methyIf-1, 4-thiazin-3-ylidene> -
N'-(4-methoxyphenyl)-1-piperidinecarboximidamide and the pharm aceutically acceptable acid addition salts thereof, whenever prepared according to the process claimed in claim 17.
. , 1 WEST-WALKER, McCABE
V ' ' per: 0(yo ScjJoJtsLT"
ATTORNEYS FOR THE APPLICANT
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NZ19309980A NZ193099A (en) | 1980-03-11 | 1980-03-11 | N,n"-disubstituted-n1-(oxa(thia)azacycloalkylidene)guanidines |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NZ19309980A NZ193099A (en) | 1980-03-11 | 1980-03-11 | N,n"-disubstituted-n1-(oxa(thia)azacycloalkylidene)guanidines |
Publications (1)
Publication Number | Publication Date |
---|---|
NZ193099A true NZ193099A (en) | 1984-07-31 |
Family
ID=19919092
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NZ19309980A NZ193099A (en) | 1980-03-11 | 1980-03-11 | N,n"-disubstituted-n1-(oxa(thia)azacycloalkylidene)guanidines |
Country Status (1)
Country | Link |
---|---|
NZ (1) | NZ193099A (en) |
-
1980
- 1980-03-11 NZ NZ19309980A patent/NZ193099A/en unknown
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