CA1055493A - Phenothiazines, phenoxazines, and acridan bis-pyrrolinyl derivatives - Google Patents
Phenothiazines, phenoxazines, and acridan bis-pyrrolinyl derivativesInfo
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- CA1055493A CA1055493A CA242,165A CA242165A CA1055493A CA 1055493 A CA1055493 A CA 1055493A CA 242165 A CA242165 A CA 242165A CA 1055493 A CA1055493 A CA 1055493A
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- Prior art keywords
- pyrrolin
- acid addition
- addition salt
- pharmaceutically acceptable
- methyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/12—Antidiarrhoeals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
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- 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
- C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
- C07D265/38—[b, e]-condensed with two six-membered rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
Novel amidine compounds selected from the group consisting of bis-pyrrolinyl derivatives of phenothiazines, phenoxazines and acridans are obtained by reacting a phenothiazine, phenoxazine or acridan with a pyrrolidinone in the presence of phosphorus oxychloride.
The phenothiazine, phenoxazine, or acridan can also be alkylated with 2-chloro-1-(1-pyrrolin-2-yl)-2-pyrroline to provide compounds of the invention. Typical examples of bis-pyrrolinyl derivatives are 2-methoxy-10-[5-methyl-1-(5-methyl-1-pyrrolin-2-yl)-2-pyrrolin-2-yl]-phenothiazine, 10-[1-pyrrolin-2-yl)-2-yl)-2-pyrrolin-2-yl]phenoxazine, and 9,9-dimethyl-10-[5-methyl-1-(5-methyl-1-pyrrolin-2-yl)-2-pyrrolin-2-yl]acridan. The amidine compounds are useful as diuretics, smooth muscle relaxants and antithrombogenic agents.
Novel amidine compounds selected from the group consisting of bis-pyrrolinyl derivatives of phenothiazines, phenoxazines and acridans are obtained by reacting a phenothiazine, phenoxazine or acridan with a pyrrolidinone in the presence of phosphorus oxychloride.
The phenothiazine, phenoxazine, or acridan can also be alkylated with 2-chloro-1-(1-pyrrolin-2-yl)-2-pyrroline to provide compounds of the invention. Typical examples of bis-pyrrolinyl derivatives are 2-methoxy-10-[5-methyl-1-(5-methyl-1-pyrrolin-2-yl)-2-pyrrolin-2-yl]-phenothiazine, 10-[1-pyrrolin-2-yl)-2-yl)-2-pyrrolin-2-yl]phenoxazine, and 9,9-dimethyl-10-[5-methyl-1-(5-methyl-1-pyrrolin-2-yl)-2-pyrrolin-2-yl]acridan. The amidine compounds are useful as diuretics, smooth muscle relaxants and antithrombogenic agents.
Description
',:. ., ., .
PHENOTHIAZINES, PHENOXAZINES AND ACRIDAN
: :~
BackQround of the Invention This invention pertains to heterocyclic carbon compounds which have drug and bio-affecting properties. The invention ls particularly concerned with amidines of the group con~isting of bis-pyrrolinyl phenothiazines, bis-pyrrolinyl acridan, and bis-pyrrolinyl phenoxazines.
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~L05~4~93 The compounds of the invention are of value as smooth muscle rela~allt, antithrombogenlc and as diuretic agents. Other features of the invention are a therapeutic process for producing smooth muscle relaxant, antithrombogenic and diuretic effects in mammals by administration of the amldlne compounds.
United States Patent 3,719,671 discloses monomeric pyrrolinyl phenothiazines as being of interest for their intestinal relaxant and anti-thrombogenic activity. The phenothiazine compounds of the present application are bis-pyrrolinyl phenothiazines.
.:
Summary of the Invention Thi8 inventlon relates to a group of amidines represented by Formula I and non-toxic pharmaceutlcally acceptable acid addition salts thereof.
~ X~
The substances of Formula I are more particularly characterized as bis-pyrrolinyl derivative9 belonging to the group of amidines consisting of bis-pyrrollnyl phenothiazines, bis-pyrrolinyl acridans and bis-pyrrollnyl phenoxazlnes. Substances of Formula I are useful as 1~554'~13 smooth muscle relaxants, inhibitors of platele~ aggregation, and as diuretic a~ent~ in mammals.
In Formula I, '~ is selected from the group consisting of sulfur, oxygen, or the divalent methylene radical -C(ZlZ~)- wherein S Zl and Z~ represent independently selected hydrogen or lower straight chain alkyl of 1 to 4 carbon atoms inclusive. When X is sulfur, the compounds are 10-bis-pyrrolinyl phenothia~lne derivatives. When X i9 oxygen, the compounds are bis-pyrrolinyl phenoxazine derivati~res.
When X sign~fies the divalent radical -C(Z~Z~)-, the oo~pounds are bis-pyrrolinyl acridan derivatives. In the foregoing formulas, Y
represents hydrogen, trifluoromethyl, halogen, lower alkyl, or lower alkoxy; R represents hydrogen or straight chain lower alkyl of 1 to 4 carbon atoms inclusive such a~ methyl, ethyl, propyl and n-butyl.
I~ is to be understood that by the term "halogen" as used throughout the instant disclosure and claims, it is intended to connote all four halogens; i.e., chlorine, bromine, iodine and fluorine. It i9 :
to be understood that by the terms "lower alkyl" and "lower alkoxy" as used throughou~ the instant disclosure and clalms, it is intended that the carbon chain which comprises these groups include both straight and brsnched chain carbon radicals of 1 to 4 carb~n atoms inclusive. Exemplary of the~e carbon chain radicals are methyl, ethyl, propyl9 isopropyl, l-butyl, l-methylpropyl, 2-methylpropyl, and tert.-butyl.
It wlll be apparent to those skilled in the art tha~ compounds o~ Formula I can exist as stereoisomeric modifications when an asymmetrlc center is present. For example, in the case of a compound of Formula I wherein the "bis-pyrrollnyl molety" contains an R-~ubstituent other than hydrogen, such as 2-methoxy-10-~5 methyl-l-~5~methyl-1-pyrrolln-2-yl)-2-pyrrolin-2-yl~phenothiazine, two -~..C355~S3~
asymmetric centers are present resul~ing in two racemic modifications.
It is possible to separate the racemic modifications into individual (t)-pairs on the basis of pnysico-chemical differences such as solubility.
The (~)-pairs can be resolved according to conventional procedures by using appropriate optically active acids. It i5 to be understood that all stereoisomeric forms of the compou~ds of Formula I are considered to be within the purview of this invention.
The amidine compounds of the present invention characterized by Formula I are obtained by:
Reacting a compound selected from the group consisting of a phsnothiaz~ne, acridan, or phenoxazine of the formula -Y (II) ~ith a pyrrolidinone of the formula :, , l (II~) R ~ ~ - 0 H
wherein R, X and Y have the same meanin8 as previously defined in the presence of phosphorus oxychloride in an inert solvent or reacting ~aid phenothiazine, acridan, or phenoxazine with 2-chloro~ 1-pyrrolin-
PHENOTHIAZINES, PHENOXAZINES AND ACRIDAN
: :~
BackQround of the Invention This invention pertains to heterocyclic carbon compounds which have drug and bio-affecting properties. The invention ls particularly concerned with amidines of the group con~isting of bis-pyrrolinyl phenothiazines, bis-pyrrolinyl acridan, and bis-pyrrolinyl phenoxazines.
''~, :
" .,~
:
~L05~4~93 The compounds of the invention are of value as smooth muscle rela~allt, antithrombogenlc and as diuretic agents. Other features of the invention are a therapeutic process for producing smooth muscle relaxant, antithrombogenic and diuretic effects in mammals by administration of the amldlne compounds.
United States Patent 3,719,671 discloses monomeric pyrrolinyl phenothiazines as being of interest for their intestinal relaxant and anti-thrombogenic activity. The phenothiazine compounds of the present application are bis-pyrrolinyl phenothiazines.
.:
Summary of the Invention Thi8 inventlon relates to a group of amidines represented by Formula I and non-toxic pharmaceutlcally acceptable acid addition salts thereof.
~ X~
The substances of Formula I are more particularly characterized as bis-pyrrolinyl derivative9 belonging to the group of amidines consisting of bis-pyrrollnyl phenothiazines, bis-pyrrolinyl acridans and bis-pyrrollnyl phenoxazlnes. Substances of Formula I are useful as 1~554'~13 smooth muscle relaxants, inhibitors of platele~ aggregation, and as diuretic a~ent~ in mammals.
In Formula I, '~ is selected from the group consisting of sulfur, oxygen, or the divalent methylene radical -C(ZlZ~)- wherein S Zl and Z~ represent independently selected hydrogen or lower straight chain alkyl of 1 to 4 carbon atoms inclusive. When X is sulfur, the compounds are 10-bis-pyrrolinyl phenothia~lne derivatives. When X i9 oxygen, the compounds are bis-pyrrolinyl phenoxazine derivati~res.
When X sign~fies the divalent radical -C(Z~Z~)-, the oo~pounds are bis-pyrrolinyl acridan derivatives. In the foregoing formulas, Y
represents hydrogen, trifluoromethyl, halogen, lower alkyl, or lower alkoxy; R represents hydrogen or straight chain lower alkyl of 1 to 4 carbon atoms inclusive such a~ methyl, ethyl, propyl and n-butyl.
I~ is to be understood that by the term "halogen" as used throughout the instant disclosure and claims, it is intended to connote all four halogens; i.e., chlorine, bromine, iodine and fluorine. It i9 :
to be understood that by the terms "lower alkyl" and "lower alkoxy" as used throughou~ the instant disclosure and clalms, it is intended that the carbon chain which comprises these groups include both straight and brsnched chain carbon radicals of 1 to 4 carb~n atoms inclusive. Exemplary of the~e carbon chain radicals are methyl, ethyl, propyl9 isopropyl, l-butyl, l-methylpropyl, 2-methylpropyl, and tert.-butyl.
It wlll be apparent to those skilled in the art tha~ compounds o~ Formula I can exist as stereoisomeric modifications when an asymmetrlc center is present. For example, in the case of a compound of Formula I wherein the "bis-pyrrollnyl molety" contains an R-~ubstituent other than hydrogen, such as 2-methoxy-10-~5 methyl-l-~5~methyl-1-pyrrolln-2-yl)-2-pyrrolin-2-yl~phenothiazine, two -~..C355~S3~
asymmetric centers are present resul~ing in two racemic modifications.
It is possible to separate the racemic modifications into individual (t)-pairs on the basis of pnysico-chemical differences such as solubility.
The (~)-pairs can be resolved according to conventional procedures by using appropriate optically active acids. It i5 to be understood that all stereoisomeric forms of the compou~ds of Formula I are considered to be within the purview of this invention.
The amidine compounds of the present invention characterized by Formula I are obtained by:
Reacting a compound selected from the group consisting of a phsnothiaz~ne, acridan, or phenoxazine of the formula -Y (II) ~ith a pyrrolidinone of the formula :, , l (II~) R ~ ~ - 0 H
wherein R, X and Y have the same meanin8 as previously defined in the presence of phosphorus oxychloride in an inert solvent or reacting ~aid phenothiazine, acridan, or phenoxazine with 2-chloro~ 1-pyrrolin-
2-yl)-2-pyrroline hydrochlorlde in an inert 601vent and thereafter, lf desired, converting the amidine product~ in free base form into acid addition Aalts by reaction wlth inorganic or organic acids.
Illustratlve of suitable phenothiazine reactants which may be empl~yed are:
.... .... . .
.
. . ; , . ~ ' : :
., . .:
~554'3~
phenothiazlne, 2-chlorophenothiazine, 4-chlorophenothiazine, 2-bromophenothiazine, 2-fluorophenothiazine, 2-lodophenothiazine, 2-trifluoromethylphenothiazine, 4-trifluoromethylpheno~chiQzine 2-me~hoxyphenothiazine, 4-methoxyphenothiazine, 2-ethoxyphenothiazine, 2-~-propoxyphenothiazine, 2-i~opropoxyphenothiazine, 2-n-butoxyphenothiazine, 2-isobutoxyphenothiazine, 2-sec.-butoxyphenothiazine, 4-n-butoxyphenothiazine, 2-methylphenothiazine, 4-methylphenothiazine, 2-lsopropylphenothiazine, 2~ethylphenothiazine, 2-n-butylphenothiazlne, 4-methylphenothlazine, 4-isopropylphenothlazine.
Suitable acridan xeactant~ are:
acridan, 2-methoxyacridan, 4-methoxyacridan, ~'' . ' .
.
11355~93 2-chloroacridan 9 4-chloroacridan, 2-trlfluorometnylacrldan, ::
4-trifluoromethylacridan 9 9,9-dimethyl2crldan, 2-chloro-9,9-dimethylacridan, 2-trifluoromethyl 9,9-dimethylacridan 4-methoxy-9,9-dimethylacr$dan, 2-methylacridan, : :
4-me~hylacridan, 4 n-buty~acridan, 2-trifluoromethyl-9-methylacridan, 9-ethyl-9-methylacridan, 9,9-di-n-butylac~idan~
Sui~able phenoxazines are: .
phenoxazine, 2-methoxyphenoxazine, 4-methoxyphenoxazine, 4-i~opropor.yphenoxazine, :
2-methylphenoxazlne, -4~methylphenoxazine, : -4-n-butylphenoxazine, 2-chlorophenoxazine, . 3-chlorophenoxazlne, . -4chlorophenoxazine, 2-trifluoromethylphenoxazine.
Suitable pyrrol dinones are:
2-pyrrolldinone, ' ' '""'' '''";,', -", ''-' " ',', ,'' ',' , ' ' - '~ . ',, '', : ' ' ,,, " , .. ... . .... . .. . . . ................... . . .... ..
,, . .:. . .: , , , , "
~ ~355~33 S-methyl-2-pyrrolidlnone, 5-ethyl-2-pyrrolidinone, 5-n-propyl-2-pyrrolldinone, S-n-butyl-2-pyrrolidinone.
The compounds of Formula I are basic and generally crystalline compounds which are practically insoluble in water, but are readily soluble in most organic solvents and in aqueous solutions of organic or inorganic acids.
The compounds characterized by Formula I can be converted, if desired, to corresponding non-toxic pharmaceutically acceptable acld addi~ion sal~ by admlxtura of the ree base wi~h a selected acid in an inert organic solvent such as ethanol, benzene, ethyl acetate, ether, halo~enated hydrocarbons, and the like. A preferred method of salt preparation ls to treat the base wtth substantially one chemical equivalent of an acid such as hydrogen chloride in ethanol solution. The salt precipitates from the ethanolic solution upon chilling or the addition of ether. I~ is to be understood that both the free base and salt forms of the product~ of Formula I are ~seful for the purpose of the invention although salts are, in some instances, partlcularly preferred because of their increased water solubility.
It is to be understood that the term "non-tox$c pharmaceutically acceptable acid addition salt'l, as used throughout the instant disclosure ant the claims, i8 construed to mean the salt form of an amidtne base of the present invention and an inor~anic or organic acid ~hich exhlbits no significant toxlcity when administered at ~he effective dose for the purpose intended. Some examples of inorganic or organic acids which may be employèd to pro~lde a non-toxic pharmaceutically acceptable acid additlon salt of the compounds of Formula I are:
.... . . . .
:, :
, .. :, ,,, , ~ ''. :
,...
, , , . . ,:
~, , . ~ , ~55~
.
~ulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, sulfamic, acetic, l~ctic, maleic, succinic, malic, fumaTic, tar~aric, citric, glu^onic, glutaric, ascorbic, benzoic, ci~namic, isethionic, and related acids.
The free base compounds of Formul~ I can be prepared by neutralization of the acid addition salt in aqueous base. In a convenient procedure, the salt is mixed with excess sodium hydroxide in aqueou~ solution, after ~hich the free base can be separated by extraction with a chlorinated hydrocarbo~ or ether solvent. The solvent can be removed by conventional methods such as evaporation or distillatlon and the free base compound can be purified by methods cuch as recrystallization or "short path" distillation at reduced pressure3.
In carrying out the process of the invention for the preparation of the bis-pyrrolinyl compounds characterized by Formula I, a phenothiaz~ne base, or an acridan base, or a phenoxazine base is reacted w~th the ~-pyrrolidinone and phosphorus oxychloride in an inert aprotic solvent. Generally, ratios of from 1 to 2 moles of the pyrrolidinone reactant to 1 mole of phosphorus oxychloride and 1 mole Z0 of the phenothiazine, acridan or phenoxazine base are employed. A
preferred solvant for carrying out the process is 1,2-dichloroethane although other solvents are suitable such as benzene, chloroform, carbon tetrachloride, l,l-dichloroethanej hexane, xylene, and the llke. The process may be oarried out at a temperature of about 0C.
to 150gC. but we generally prefer room temperature in the range of sbout 25-35C. In some instances, the reaction mixture ls permitted to stand for several days but generally the reaction is essentially complete in about 15 hr.
' . ", .
,: , , , , , . ,. . , :
,,, .' .; ,' , '' ' '. ' ."' ' .. ~ .' ' ' :
~55493 Whenever compounds characterized by Formula I wherein R is limited to hydrogen are prepared, an alternate aspect of the process of the present invention comprises reaction o a phenothiazine, acridan, or phenoxa~ine base with the imidoyl chloride "2-chloro~ pyrrolin-2-yl)-2-pyrro]ine hydrochloride" in an inert solvent such as 1,2-dichloroethane.
Alkylation of the phenothiazine, acridan, or phenoxazine base with 2-chloro-1-(1-pyrrolin-2-yl)pyrroline hydrochloride is preferably carried out in 1,2-dichloroethane at reflux temperature.
According to the foregoing process wherein a phenothiazine, acridan, or phenoxazine base ic reacted with a pyrrolidinone and phosphorus oxychloride, monomeric pyrrolinyl compounds described in United States Patent 3,719,671 are also obtained, in addition to the bis-pyrrolinyl compounds of Formula I. For example, reaction of pheno-thiaæine, 2-pyrrolidinone, and phosphorus oxychlorlde in 1,2-dichloroethane provides the bis-pyrrolinyl phenothiazine compounds of the present invention, 'l10-Cl-(l-pyrrolin-2-yl)-2-pyrrolin-2-yl~phenbthiazine" and the monomeric pyrrolinyl derivative 'ilO-C2-(l-pyrrolinyl)]phenothiazine'' descrlbed in the aforementioned United States Patent 3,719,671). Separation of the bis-pyrrolinyl derivatives of the present invention from the monomeric pyrrolinyl by-products is generally effected by washing with a solvent, preferably acetone, wherein the bis-pyrrolinyl derivatives of the present invention are relatively less soluble than the monomeric pyrrolinyl by-products or by distillation.
The bis-pyrrolinyl compounds of the present invention are new chemical substances which have useful pharmacolGgical properties.
~ore particularly, they exert an intestinal relaxant effect similar to that obtainèd with papaverlne. Aside from the intestinal relaxant ::
_ g_ ,,,, . ,. " '. ' " "
'; ~: ''' ,. ,,, ,:, , : ' '" ' ' ,' ; ' ~ ,:
. .
l~S5~33 activity, the bis~pyrrolinyl compounds of Formula I have antithrombogenic properties as demonstrated by thelr ability to inhibit platelet aggregation caused by the addition of adenosine diphosphate to platelet rich plasma.
S Intestinal relaxant activity of the bis-pyrrolinyl compounds of the present invention can be measured in qtandard and accepted tn vitro and in ~ivo pharmacological tests. One such test is carried out essentially as follows. A segment of rabbit ileum is suspended in oxygenated Ty~ode's solu~ion and affixed ~o a tension transducer for electronic recording of isometric contractions. After control responses to a ~tandard dose of a spasmogen such as barium chloride (0.25 mg./ml.) or acetylcholine chloride (1.0 mc~./ml.) are established, the bis-pyrrolinyl compound ls added and the response to the spasmogen in the presence of the test compound, again determined. Test compound effect is measured as the percentage reduction in the response to the spasmogen in the presence of the test compound, from the mean control response. The data are expressed in log dose response curves obtained from a minimum of three trials at each of 2 ~o S different concentrations o the test compound. Estimates are made therefrom of the EC,o or EC,~ (concentration causlng 50% to 75% reductlon r~spectively in the response of the tissue to the spasmogen).
Papaverine, which i9 a well-lcnown smooth muscle relaxant, has an ECso Of 12.2 mcg./ml. in this test against barlu~ chloride ~pasms. In general, the bis-pyrrolinyl substances o Formula I
are more potent than papaverine. As might be expected, certain of the compounds are more active than others. In thi~ respect, there can be mentioned by way of example 9,9-dimethyl-10-[S-methyl-l-(S-methyl-l-pyrrolin-2-yl)-2-pyrrolin-2-yl]acridan hydrochloride, , ,, ' ~554'~
10-[l-tl-pyrrolin-2-~1)-2-pyrrolin~2-yl~phenoxazine and 2-methoxy-10-[5-methyl~ 5-methyl-1-pyrrolin-2-yl)-2-pyrrolin-2-yl~phenothlazine hydrochloride which are 7.6, 3.1 and 1.7 respectively times as potent as papaverine as partlcularly preferred bis pyrrolinyl compounds of the present in~ention.
Apart from intestinal relaxa~t activity, a bis-pyrrolinyl compound of this invention present in an effective amount in the mammalian circula~ory system has the added benefit of providing a protective antithrombogenic effect. Measurement of the antithrombogenic activity of the bis-pyrrolinyl compounds of Formula I can be carriPd out in a standard phar~scological test whlch essentially has been described by Born, Nature, 194, 927 (~962~ and O'srien, J. Clin.
Path., 15, 446 (1962~. This test is a nephelometric method in which the change in turbidity of a specimen of platelet rich blood plasma (generally human blood plasma) is measured on causation of platelet aggregation by additlon of a thrombogenic inducing agent such as adenosine diphosphate or collagen. The compounds of the present lnvention are effective antithrombogenic agents according to this test at concentrations in the order of about 3 ~o 150 mcg./0.5 ml.
human platele~ rich plasma. The antithrombogenic effect iB measured in the intact animal by applying the foregoing test to blood samples withdrawn prior to and after administration of a bis-pyrrollnyl compound of the present inventlon to the test animal.
While compounds of Formula I generally exhibit slgnificant antithromboge~ic activity, compounds which reduce the thrombogenic capacity of collagen or sdenosine diphosphate induced platelet aggregation by 50% or more at concentrations of le~s than 15 mcg./0.5 ml.
: . . , . , : .............................. .. . .
. ,:: . , . ' ,, ' . . ' ' ' ' . . " ,, ~C~5S4'~3 of platelet rich plasma are preferred and by way of example there can be mentioned:
~,9-dlmethyl-10-Cl-(l-pyrrolin-2-yl~-2-pyrrolin-2-yl]acridan;
9,9-dimethyl-10-~5-methyl-1-(5-methyl-l-pyrrolin-2-yl)-2-pyrrolin-2-yl~acridan;
10-~5-methyl-1-(5-methyl-1-pyrrolin-2-yl)-2-pyrrolin-2-yl]-phenothia~ine;
2-methoxy-10-[5-me~hyl-1-(5-methyl-1-pyrrolin-2-yl)-2-pyrrolin-2-yl]phenothiazine;
10~ (1-pyrrolin-2-yl)-2-pyrrolin-2-yl]phenoxazine.
I~ sdditio~ to having intestinal relaxant and antithrombogenic properties, compounds of Formula I are effective diuretic agents as demonstrated by the meth~d of W. L. Lipschitz9 et al., J. Pharmacol.
Expt. Therap., 79, 97 (1943~. In this method, groups of 8 rats a~e fasted 18 hour~ prior to the experiment. A control group is hydrated orally with 25 ml. per kilogram of body weight of isoto~ic saline ~olution which is also the vehicle used for dosing the test compound. -One control group received a dose of 960 mg./kg. of body weight of urea. Animals of other groups are treated with various doses of the tes~ compound. Immediately after treatment, the animals are placed ln a metabolism cages (two rats of the same group per cage) and malntained without food or water for 5 hrs. The volume of urine excreted by each pair is determ~ned after thls period and the pooled urine is analy~ed for sodium, pota6sium, and chloride ions. The re6ults for the test compounds are expressed as ratios of the volume of urlne or total quantities of electrolytes (i.e., sodium, potassium, and chloride) excreted during the experimental period compared to the ~sline and/or urea control group. The test compounds are orally ,: , , .:' . : , . ' ,, ~
~- " : .
: ':
~55~93 administered in doses -anging from 2.7 to 25 mg./kg. of body weight.
In thls test, EDloo values (dose providlng a 100% increase in volume) for 9,9-dimethyl-10-~5~methyl-1-(5-methyl-1-pyrrolin-2-yl)-2-pyrrolin-2-yl]acridan and 10-[5-methyl-1 (5-methyl-1-pyrrolin-2-yl)-2-pyrrolin-2-yl~-2-(trifluoromethyl)phenothiaz~ne are 3.58 and 6.63 mg./kg. body weight respectively.
Bl~-pyrrolinyl compounds of Formula I and non-toxic pharmaceutically acceptable salts thereof may be administered to mammals by either the parenteral or oral route. Pharmacological activity includlng diuretic, antithrombogenic, and intestinal relaxant effects are obtained at non-toxic effective doses of the compounds of Formula I ranging from about 0.01 to 30 mg./kg. body weight. Wi~h respect to ~otal daily dose, optimum intestinal relaxant and antithrombogenic effects are obtained by oral administration of the bis-pyrrolinyl compounds of Formula I in a non-~oxic effective dose ranging from about 0.05 to 100 mg./kg.
body weight. It i8 to be understood that the term "non-toxic effective dose" as used herein refers to the quantity of active ingredient necessary to produce the desired th~rapeutic effect wi~hout causing any significant harmful or deleterious side effects.
The process of the present invention for exerting a pharmacological effect in a mammal comprises atministering to said mammal a non-toxic effectlve dose of from 0.01 to 30 mg./kg. body weight of a bis~pyrrolinyl compound of Formula I or a pharmaceutically acceptable acid addition salt thereof to produce an effect selected from the group consisting of dluretic, antithrombogenic and smooth muscle relaxant therein.
Oral toxicity values (ALD~o) of the substances of Formula I
i~ mice range from abou~ 125 to greater than 1000 milligrams per ',, ,,'' -~ :' ~. . " ',' .. .
-, ' ' ' . .
3L~55~33 `
kilo~ram of body weight. For ln~tance, the ~LD~ o for 10~
pyrrolin-2-yl)-2-pyrrolln-2-yl~phenoxazine hydrochlorlde ls 250-500 mg./kg.
body weight.
The compounds of the present invention can be formulated accordlng to conventional pharmaceutical practlce to provide pharmaceutlcal compositions of unit dosage form which may inrlude, for example, tablets, pills, capsules, powder3, granules, emulsions, suspensions, and the like.
The solid preparations contain the active ingredient in admixture with pharmaceutically acceptable excipients such as inert diluents, for example calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example mal~e, starch or al6inic acid; binding agents, for example starch, - :
gelatin or acacia; and Iubricating agents, for example magneslum stearate, stearic acid or talc. The tablets may be uncoatcd or they may be coated by known techniques so as to de~y disir.tegration and absorption in the gastrointestinal tract and thereby provide a su6tained action over a longer period. ~-Liquid preparations suitable for parenteral adminlstration include solutions, suspensions, or emulsions of the compounds of Formula I. The aqueous suspensions of the pharmaceutlcal dosage forms of the compounds of Formula I contain the active ingredient in admlxture with one or more pharmaceutically acceptable excipients knawn to be 6uitable in the manufacture of aqueous s~lspensions. Suitable excipients ~ `
are, for example, suspending agents such as sodium carbo~ymethylcellulose, methylcellulose, hydroxypropyl~ethylcellulose, sodlum alginate, polyvinyl-pyrrolidone, gum tragacanth and gum a:acia. Suitable dispersing or wetting agents are naturally occurring phosphatides, for example lecithin, and polyoxyethylene stearate.
; , ' - ":' '', - -; , ' , , , - ' ' ': ' . ' ' ~ ' . , ' : ' ~ :
, : , . . .
,. -, :, , .
, ~i5~L~33 Non-aqueous suspensions may be formulated by ~uspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, ~esame oil or coconut oil, or in a mineral oll, for e~ample liquld paraffin. The suspensions may contain a thickening ag~nt such as bees wax, hard paraffin or cetyl alcohol. Sweetenlng and flavoring agents generally used in pharmaceutical compositions may also be lncluded such as saccharin, sodium cyclamate, sugar and caramel to provlde a palataole oral preparation. The compositions may also contain other additional absorbing agents, s~abilizing agents, weighing agents, and buffers-The following examples further illustrate the present invention a~d will enable others skilled ln the art to understand it more completely.
It is to be understood, however, that the invention is not limited solely to the particular examples given b~low.
In regard to "~IR" data, the following notations are employed: s ~ singlet, d - doublet, dd - doublet of doublets, t -triplet, q - quintet, m = multiplet, nm = narrow multiple~, bs = broad slnglet.
~xample 1.- Phosphorus oxychlorlde (3~.3 g., 0.25 mole) in 50 ml. of 1,2-dichloroethane i8 added ln one portion to a stirred mixture of phenothiazine (49.8 8., 0.25 mole) and 2-pyrrolidinone (42.6 g., 0.5 mole) in 250 ml. of 1,2-dichloroethane. The mixture la s~irred for 4 hr. at room temperature, permitted to stand for a period o~ 15 hr. and then poured into a mixture of 200 ml. of 5N
sodlum hydroxide and 100 g. of crushed ice. The 1,2-dichloroethane layer iJ separated and the aqueous layer extracted wlth 100 ml. of adtitional 1,2-dichloroethane. The combined 1,2-dichloroethane fractions are sequentlally extracted with 300 ml. of 1.5N hydrochloric '' ' ' ' . ; :
, . . .... . . . .
~S5~
acid and 20~ ml. of water. The combined acid-water extracts are washed with ether, made basic with 5N sodium hydrDxide and extracted repeatedly with chloroform. After dryi~g over magnesium sulfate, the chloroform ~olution is concentrated and the residual material thus obtained stirred with 200 ml. of acetone to remove the acetone soluble 10-C2-(1-pyrrolinyl)]-phenothiazine by-product and filtered. The filter c~ke i9 washed with additional acetone and dried providi~g 14.1 g. (17% yield) of 10-[1-(1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]PHE~OTHIA2I~ as the frPe base, m.p.
199-201C. The bis-pyrrolinyl phenothiazine free base suspended in 60 ml. of absolute ethanol, acidified with an equivalent of ethanolic hydrogen chloride, treated with decolorizing charcoal, filtered, and diluted with 200-250 ml. of anhydrous ether provides the hydrochloride salt. Crystallization of the hydrochloride salt from absolu~e ethanol-anhydrous ether affords analytically pure 10-[1-(1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL PHENOTHIAZINE]HYDROC~LORIDE solvated with 1/5 mole of ethanol as an off white solid, m.p. 237-239C. (corr.).
~nalvsis. Calcd. for C20Hl9NgS-HCl l/S C2H,OH (percent): C, 64.63;
H, 5.64; Cl, 9.35; N, 11.08. Found (percent): C, 64.68; H, 5.61;
Cl, 9.41; N, 11.18.
NMR delta (ppm)(D2O, HDO reference): 1.75m, 2.96m, 3.41m, 4~23m, 5.88nm, 7.Om.
Example 2.- A 501u~10n of 4-chlorophenothiazine t32.3 g., 0.134 mole) and 2--p~rrolidinone (23 g., 0.27 mole) in 125 ml. of 1,2~dichloroethane i~ added dropwise to a solutlon of 25 phosphoru6 oxychloride (20.5 g., 0.134 mole) in 50 ml. of 1,2-dichloroethane in about 35 min. Isolation of the product from the reaction mixture according to the procedure of Example 1 provides 7-5 8-~ (17.1% yleld) of 4-CHLORO~10-Cl-(l-PYRROLIN-2-YL)-2-PYRROLIN-Gj ~ ~
', 1~355~9~
2-YL]PHENOTHIA2INE free base, m.p. 195~197C. Analytically pure 4-CHLORO-10-Cl-(l-PYRROLIN-2-YL)-2-PYRROLIN-2-YL~PHENOTHIAZINE
EYDROCHLORIDE obtained by crystalllzation from ethanol-ether has a melting point of 232-234C. (corr.).
Analysis. Calcd. for C~oHl8ClN3S-HCl (percent): C, 59.41;
~, 4.74; N, 10.39; Cl, 17.53. Found (percent): C, 59.20; H, 4.74;
N, 10.59; Cl, 17.46.
~MR del~a (ppm)(D20, HDO reference): 1.77m, 2.9;7m9 3.43m, 4.14m, 5.91nm, 6.9m.
Example 3.- Reaction of 2-methoxyphenothiazine, 2-pyrrolidinone and phosphorus oxychloride in 1,2-dichloroethane accordin~ to the procedure of Example 1 affords 2-METHOXY-10-Cl-(l-PYRROLIN-2-YL)-2-PYRROLIN-2-YL~PHENOTHIAZINE free base, m.p.
151-153C. (corr.), from isopropyl alc~hol.
Analysis. Calcd. for C2lH~,N30S (percent): C, 69.39;
H, 5.83; N, 11.56. Found (percent): C, 69.35; H, 5.87; N, 11.76.
~MR delta (ppm~ (CDCl3, TMS reference): 1.78q ~7.0), 2.77m, 3.56t (7~1), 3.71s, 4.19dd (8.0, 9.8), 5.20t (2.8), 6.5m, ~.9m.
~xample 4.- A mixture of 5-~ethyl-2-pyrrolidinone (6.0 g., 0.06 mole), phosphorus oxychloride (9.2 g., 0.06 mole) in 60 ml. of 1,2-dichloroethane 18 re1uxed for 10 min. A solution of phenothiazine (6.0 g., 0.03 mole) in 20 ml. of 1,2-dichloroethane ls added at the end of the reflux perlod and the reaction mixture stlrred and refluxed ~or 20 hr., and then poured on~o 20 ml. of 5N potassium hydroxide and 20 g. of crushed ice. The 1,2-dichloroethane layer is ~eparated and extracted ~7ith 30 ml. of 1.5N hydrochlori& acid and 30 ml. of water removing water soluble by-product 10-C2-(5-methyl-l-pyrrolinyl)]- ~
':
,.. ,, . .,, ,., . :
~554~3 phenothiazine hydrochloride. After drying the 1,2-dichloroethane solution over magr.esium sulfate9 the 1,2-dichloroethane solution is concentrated and the solid thus obtained stirred with 40 ml. of acetone and filtered. Crystallization of the filte~cake from ethanol-ether provides analytically pure 10-[5-~ETHYL-1-(5-~ETHYL-l-PYRROLIN-2-YL)-2-PYRROLI~-2-YL]PHENOTHIAZINE X~DROCHLORIDE in a yield of 17%, m.p. 257-264~C. (corr.).
Analysis. Calcd. for C~aH29~3S-HCl (percent): C9 66.40;
~, 6.03; N, 10.56; Cl, 8.91. Found (percent): C, 66.51; H, 6.14;
10 N, 10.52; Cl, 8.99. ~ -NMR delta (ppm) (CDCl3, TMS reference): 1.41d (6.4), 1.57d (6.2), 1.7-3.5m, 4.05m, 5.62m, 5.86t (2.9), 7.Om, 11.75bs.
Example 5.- Reaction of 5-methyl-2-pyrrolidinone, 2-~ethoxyphenothiazlne and phosphorus oxychloride in 1,2-dichloroethane 15 according to the procedure of Example 4 affords 2-M~THOXY-10-[5 ~LTHYL-1-(5-~ETHYL-l-PYRROLIN-2~YL)-2-PYRROLIN-2-YL]PH~IOTHIAZINE
~XDROCHLORIDE (8.6% yield), m.p. 236.5-238.5C. (corr.), from ethanol-ether.
Analysis. Calcd. for C~3H~,N30S-HCl (percent): C, 64.54;
20 H, 6.12; N, 9.82; Cl, 8.29. Found tpercent): C, 64.50; H, 6.15;
~, g.88; Cl, 8.33.
- NMR delta ~ppm) (CDCl" T~S reference): 1.38d (6.3), 1.54d (6.4), 1.56d (6.4), 1.6-3.3m, 3.70~, 4.10m, 5.57m, 5.81t ~3.0)~
6.8m, 11.93bs, Example 6.- A mlxture of 5-methyl-2-pyrrolidlnone (2.0 g., 0.02 mole) and phosphorus oxychloride (3.0 g., 0.02 mole) in 15 ml.
of 1,2-dichloroethane after ~tanding 15 hr. at room temperature is combined with 9,9-dimethylacridan (2.1 g., 0.01 mole) after a 48 hr.
' ' ~; ' ' ~CI 55~3 period is added to 30 ml. of 5N potassium hydroxide and 30 g. of cruQhed ice. The 1,2-dichlorGethane fraction i5 separated, extracted wlth 50 ml. of 1.5N hydrochloric acld and 50 ml. of water and dried over magnesium sulfate. Concentration of the 1,2-dichloroethane ~olution provides a residue which iB stirred with 100 ml. of ether ~nd filtered. The filter cake containing crude hydrochloride salt of the product is stirred with sodium hydroxide solution affording the free base. Crystallization from n-heptan~ provides 1.3 g.
(35~ yield) of 9,9-D~THYL-10-[5-METHYL-1-(5-METHYL-l-PYRROLIN-2-YL)-19 2-PYRROLIN-2-YLlACRIDA~, m.p. 135-139C. from which the hydrochloride salt is prepared according to the procedure of Example 1. Analytically pure 9,9-D~ETHYL-10-~5-.~THYL-1-(5-METHYL-l-PYRROLIN 2-YL)-2-PYRROLIN-2-YL~ACRIDAN HYDROCHLORIDE, from acetone-ether, has a melting point of 247.5-248.0C. (corr.).
Analysis. Calcd. for C2~H29N30HCl (percent): C, 73.60;
H, 7.41; Ng ;0.30; Cl, 8.69. Found (percent~: C, 73.98; H, 7.40;
~, 10.22; Cl, 8.67.
~MR delta (ppm) (CDCl3, TMS reference): 1.40d (6.2), 1.45d (6.2), 1.61s, 1.70d (6.2), 1.728, 1.8 3.2m, 4.16m, 5.69m, 20 5.82t (2.9), 6.7m, 7.3~, 11.82bs.
2xample 7.- A mixture of acridan (3.6 g., 0.02 mole) and 2-chloro-1~ pyrrolin-2-yl)-2-pyrroline hydrochloride (5.1 g., 0.025 mole), obtalned according to the method of H. Brederick, et al., Chem. Ber., ~ 2292 (1961), in 50 ml. o~ 1,2-dlchloroethane 1~ refluxed for a period of 15 hr. The mixture i~ sequentially extracted with 50 ml. of 1.5N hydrochlorlc acld and three 50 ml. portions of water. Tha combined acid-water extracts are baslfied wlth 5N potassium hydroxlde, extracted with ether and t'ne ethereal extract concentrated. Crystalll~ation - 19 _ :: , ... :. , , , : . , :" , , . , :
~, . , ,, . , . ,, : :
... . .. . . . . ...
~554~3 of the residue thus obtained from ethanol affords the free base 10-[1-(1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL~ACRIDAN, m.p. 179-181 C. which ~-is converted according to the procedure of Example 1 to 10-[1-(1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]ACRIDAN HYDROCHLORIDE, m.p. 212.5-216.5C.
(dec.)(~orr.)., from ethanol-ether.
Analysis. Calcd. for C21H21N2~HCl (percent): C, 71-68;
H, 6.30; N, 11.94; Cl, 10.08. Found (percent): C9 71.43; H, 6.24;
N, 11.90; Cl, 9.85.
NMR delta (ppm) (D20, HDO reference): 1.60m, 2.33m, 2.80m,
Illustratlve of suitable phenothiazine reactants which may be empl~yed are:
.... .... . .
.
. . ; , . ~ ' : :
., . .:
~554'3~
phenothiazlne, 2-chlorophenothiazine, 4-chlorophenothiazine, 2-bromophenothiazine, 2-fluorophenothiazine, 2-lodophenothiazine, 2-trifluoromethylphenothiazine, 4-trifluoromethylpheno~chiQzine 2-me~hoxyphenothiazine, 4-methoxyphenothiazine, 2-ethoxyphenothiazine, 2-~-propoxyphenothiazine, 2-i~opropoxyphenothiazine, 2-n-butoxyphenothiazine, 2-isobutoxyphenothiazine, 2-sec.-butoxyphenothiazine, 4-n-butoxyphenothiazine, 2-methylphenothiazine, 4-methylphenothiazine, 2-lsopropylphenothiazine, 2~ethylphenothiazine, 2-n-butylphenothiazlne, 4-methylphenothlazine, 4-isopropylphenothlazine.
Suitable acridan xeactant~ are:
acridan, 2-methoxyacridan, 4-methoxyacridan, ~'' . ' .
.
11355~93 2-chloroacridan 9 4-chloroacridan, 2-trlfluorometnylacrldan, ::
4-trifluoromethylacridan 9 9,9-dimethyl2crldan, 2-chloro-9,9-dimethylacridan, 2-trifluoromethyl 9,9-dimethylacridan 4-methoxy-9,9-dimethylacr$dan, 2-methylacridan, : :
4-me~hylacridan, 4 n-buty~acridan, 2-trifluoromethyl-9-methylacridan, 9-ethyl-9-methylacridan, 9,9-di-n-butylac~idan~
Sui~able phenoxazines are: .
phenoxazine, 2-methoxyphenoxazine, 4-methoxyphenoxazine, 4-i~opropor.yphenoxazine, :
2-methylphenoxazlne, -4~methylphenoxazine, : -4-n-butylphenoxazine, 2-chlorophenoxazine, . 3-chlorophenoxazlne, . -4chlorophenoxazine, 2-trifluoromethylphenoxazine.
Suitable pyrrol dinones are:
2-pyrrolldinone, ' ' '""'' '''";,', -", ''-' " ',', ,'' ',' , ' ' - '~ . ',, '', : ' ' ,,, " , .. ... . .... . .. . . . ................... . . .... ..
,, . .:. . .: , , , , "
~ ~355~33 S-methyl-2-pyrrolidlnone, 5-ethyl-2-pyrrolidinone, 5-n-propyl-2-pyrrolldinone, S-n-butyl-2-pyrrolidinone.
The compounds of Formula I are basic and generally crystalline compounds which are practically insoluble in water, but are readily soluble in most organic solvents and in aqueous solutions of organic or inorganic acids.
The compounds characterized by Formula I can be converted, if desired, to corresponding non-toxic pharmaceutically acceptable acld addi~ion sal~ by admlxtura of the ree base wi~h a selected acid in an inert organic solvent such as ethanol, benzene, ethyl acetate, ether, halo~enated hydrocarbons, and the like. A preferred method of salt preparation ls to treat the base wtth substantially one chemical equivalent of an acid such as hydrogen chloride in ethanol solution. The salt precipitates from the ethanolic solution upon chilling or the addition of ether. I~ is to be understood that both the free base and salt forms of the product~ of Formula I are ~seful for the purpose of the invention although salts are, in some instances, partlcularly preferred because of their increased water solubility.
It is to be understood that the term "non-tox$c pharmaceutically acceptable acid addition salt'l, as used throughout the instant disclosure ant the claims, i8 construed to mean the salt form of an amidtne base of the present invention and an inor~anic or organic acid ~hich exhlbits no significant toxlcity when administered at ~he effective dose for the purpose intended. Some examples of inorganic or organic acids which may be employèd to pro~lde a non-toxic pharmaceutically acceptable acid additlon salt of the compounds of Formula I are:
.... . . . .
:, :
, .. :, ,,, , ~ ''. :
,...
, , , . . ,:
~, , . ~ , ~55~
.
~ulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, sulfamic, acetic, l~ctic, maleic, succinic, malic, fumaTic, tar~aric, citric, glu^onic, glutaric, ascorbic, benzoic, ci~namic, isethionic, and related acids.
The free base compounds of Formul~ I can be prepared by neutralization of the acid addition salt in aqueous base. In a convenient procedure, the salt is mixed with excess sodium hydroxide in aqueou~ solution, after ~hich the free base can be separated by extraction with a chlorinated hydrocarbo~ or ether solvent. The solvent can be removed by conventional methods such as evaporation or distillatlon and the free base compound can be purified by methods cuch as recrystallization or "short path" distillation at reduced pressure3.
In carrying out the process of the invention for the preparation of the bis-pyrrolinyl compounds characterized by Formula I, a phenothiaz~ne base, or an acridan base, or a phenoxazine base is reacted w~th the ~-pyrrolidinone and phosphorus oxychloride in an inert aprotic solvent. Generally, ratios of from 1 to 2 moles of the pyrrolidinone reactant to 1 mole of phosphorus oxychloride and 1 mole Z0 of the phenothiazine, acridan or phenoxazine base are employed. A
preferred solvant for carrying out the process is 1,2-dichloroethane although other solvents are suitable such as benzene, chloroform, carbon tetrachloride, l,l-dichloroethanej hexane, xylene, and the llke. The process may be oarried out at a temperature of about 0C.
to 150gC. but we generally prefer room temperature in the range of sbout 25-35C. In some instances, the reaction mixture ls permitted to stand for several days but generally the reaction is essentially complete in about 15 hr.
' . ", .
,: , , , , , . ,. . , :
,,, .' .; ,' , '' ' '. ' ."' ' .. ~ .' ' ' :
~55493 Whenever compounds characterized by Formula I wherein R is limited to hydrogen are prepared, an alternate aspect of the process of the present invention comprises reaction o a phenothiazine, acridan, or phenoxa~ine base with the imidoyl chloride "2-chloro~ pyrrolin-2-yl)-2-pyrro]ine hydrochloride" in an inert solvent such as 1,2-dichloroethane.
Alkylation of the phenothiazine, acridan, or phenoxazine base with 2-chloro-1-(1-pyrrolin-2-yl)pyrroline hydrochloride is preferably carried out in 1,2-dichloroethane at reflux temperature.
According to the foregoing process wherein a phenothiazine, acridan, or phenoxazine base ic reacted with a pyrrolidinone and phosphorus oxychloride, monomeric pyrrolinyl compounds described in United States Patent 3,719,671 are also obtained, in addition to the bis-pyrrolinyl compounds of Formula I. For example, reaction of pheno-thiaæine, 2-pyrrolidinone, and phosphorus oxychlorlde in 1,2-dichloroethane provides the bis-pyrrolinyl phenothiazine compounds of the present invention, 'l10-Cl-(l-pyrrolin-2-yl)-2-pyrrolin-2-yl~phenbthiazine" and the monomeric pyrrolinyl derivative 'ilO-C2-(l-pyrrolinyl)]phenothiazine'' descrlbed in the aforementioned United States Patent 3,719,671). Separation of the bis-pyrrolinyl derivatives of the present invention from the monomeric pyrrolinyl by-products is generally effected by washing with a solvent, preferably acetone, wherein the bis-pyrrolinyl derivatives of the present invention are relatively less soluble than the monomeric pyrrolinyl by-products or by distillation.
The bis-pyrrolinyl compounds of the present invention are new chemical substances which have useful pharmacolGgical properties.
~ore particularly, they exert an intestinal relaxant effect similar to that obtainèd with papaverlne. Aside from the intestinal relaxant ::
_ g_ ,,,, . ,. " '. ' " "
'; ~: ''' ,. ,,, ,:, , : ' '" ' ' ,' ; ' ~ ,:
. .
l~S5~33 activity, the bis~pyrrolinyl compounds of Formula I have antithrombogenic properties as demonstrated by thelr ability to inhibit platelet aggregation caused by the addition of adenosine diphosphate to platelet rich plasma.
S Intestinal relaxant activity of the bis-pyrrolinyl compounds of the present invention can be measured in qtandard and accepted tn vitro and in ~ivo pharmacological tests. One such test is carried out essentially as follows. A segment of rabbit ileum is suspended in oxygenated Ty~ode's solu~ion and affixed ~o a tension transducer for electronic recording of isometric contractions. After control responses to a ~tandard dose of a spasmogen such as barium chloride (0.25 mg./ml.) or acetylcholine chloride (1.0 mc~./ml.) are established, the bis-pyrrolinyl compound ls added and the response to the spasmogen in the presence of the test compound, again determined. Test compound effect is measured as the percentage reduction in the response to the spasmogen in the presence of the test compound, from the mean control response. The data are expressed in log dose response curves obtained from a minimum of three trials at each of 2 ~o S different concentrations o the test compound. Estimates are made therefrom of the EC,o or EC,~ (concentration causlng 50% to 75% reductlon r~spectively in the response of the tissue to the spasmogen).
Papaverine, which i9 a well-lcnown smooth muscle relaxant, has an ECso Of 12.2 mcg./ml. in this test against barlu~ chloride ~pasms. In general, the bis-pyrrolinyl substances o Formula I
are more potent than papaverine. As might be expected, certain of the compounds are more active than others. In thi~ respect, there can be mentioned by way of example 9,9-dimethyl-10-[S-methyl-l-(S-methyl-l-pyrrolin-2-yl)-2-pyrrolin-2-yl]acridan hydrochloride, , ,, ' ~554'~
10-[l-tl-pyrrolin-2-~1)-2-pyrrolin~2-yl~phenoxazine and 2-methoxy-10-[5-methyl~ 5-methyl-1-pyrrolin-2-yl)-2-pyrrolin-2-yl~phenothlazine hydrochloride which are 7.6, 3.1 and 1.7 respectively times as potent as papaverine as partlcularly preferred bis pyrrolinyl compounds of the present in~ention.
Apart from intestinal relaxa~t activity, a bis-pyrrolinyl compound of this invention present in an effective amount in the mammalian circula~ory system has the added benefit of providing a protective antithrombogenic effect. Measurement of the antithrombogenic activity of the bis-pyrrolinyl compounds of Formula I can be carriPd out in a standard phar~scological test whlch essentially has been described by Born, Nature, 194, 927 (~962~ and O'srien, J. Clin.
Path., 15, 446 (1962~. This test is a nephelometric method in which the change in turbidity of a specimen of platelet rich blood plasma (generally human blood plasma) is measured on causation of platelet aggregation by additlon of a thrombogenic inducing agent such as adenosine diphosphate or collagen. The compounds of the present lnvention are effective antithrombogenic agents according to this test at concentrations in the order of about 3 ~o 150 mcg./0.5 ml.
human platele~ rich plasma. The antithrombogenic effect iB measured in the intact animal by applying the foregoing test to blood samples withdrawn prior to and after administration of a bis-pyrrollnyl compound of the present inventlon to the test animal.
While compounds of Formula I generally exhibit slgnificant antithromboge~ic activity, compounds which reduce the thrombogenic capacity of collagen or sdenosine diphosphate induced platelet aggregation by 50% or more at concentrations of le~s than 15 mcg./0.5 ml.
: . . , . , : .............................. .. . .
. ,:: . , . ' ,, ' . . ' ' ' ' . . " ,, ~C~5S4'~3 of platelet rich plasma are preferred and by way of example there can be mentioned:
~,9-dlmethyl-10-Cl-(l-pyrrolin-2-yl~-2-pyrrolin-2-yl]acridan;
9,9-dimethyl-10-~5-methyl-1-(5-methyl-l-pyrrolin-2-yl)-2-pyrrolin-2-yl~acridan;
10-~5-methyl-1-(5-methyl-1-pyrrolin-2-yl)-2-pyrrolin-2-yl]-phenothia~ine;
2-methoxy-10-[5-me~hyl-1-(5-methyl-1-pyrrolin-2-yl)-2-pyrrolin-2-yl]phenothiazine;
10~ (1-pyrrolin-2-yl)-2-pyrrolin-2-yl]phenoxazine.
I~ sdditio~ to having intestinal relaxant and antithrombogenic properties, compounds of Formula I are effective diuretic agents as demonstrated by the meth~d of W. L. Lipschitz9 et al., J. Pharmacol.
Expt. Therap., 79, 97 (1943~. In this method, groups of 8 rats a~e fasted 18 hour~ prior to the experiment. A control group is hydrated orally with 25 ml. per kilogram of body weight of isoto~ic saline ~olution which is also the vehicle used for dosing the test compound. -One control group received a dose of 960 mg./kg. of body weight of urea. Animals of other groups are treated with various doses of the tes~ compound. Immediately after treatment, the animals are placed ln a metabolism cages (two rats of the same group per cage) and malntained without food or water for 5 hrs. The volume of urine excreted by each pair is determ~ned after thls period and the pooled urine is analy~ed for sodium, pota6sium, and chloride ions. The re6ults for the test compounds are expressed as ratios of the volume of urlne or total quantities of electrolytes (i.e., sodium, potassium, and chloride) excreted during the experimental period compared to the ~sline and/or urea control group. The test compounds are orally ,: , , .:' . : , . ' ,, ~
~- " : .
: ':
~55~93 administered in doses -anging from 2.7 to 25 mg./kg. of body weight.
In thls test, EDloo values (dose providlng a 100% increase in volume) for 9,9-dimethyl-10-~5~methyl-1-(5-methyl-1-pyrrolin-2-yl)-2-pyrrolin-2-yl]acridan and 10-[5-methyl-1 (5-methyl-1-pyrrolin-2-yl)-2-pyrrolin-2-yl~-2-(trifluoromethyl)phenothiaz~ne are 3.58 and 6.63 mg./kg. body weight respectively.
Bl~-pyrrolinyl compounds of Formula I and non-toxic pharmaceutically acceptable salts thereof may be administered to mammals by either the parenteral or oral route. Pharmacological activity includlng diuretic, antithrombogenic, and intestinal relaxant effects are obtained at non-toxic effective doses of the compounds of Formula I ranging from about 0.01 to 30 mg./kg. body weight. Wi~h respect to ~otal daily dose, optimum intestinal relaxant and antithrombogenic effects are obtained by oral administration of the bis-pyrrolinyl compounds of Formula I in a non-~oxic effective dose ranging from about 0.05 to 100 mg./kg.
body weight. It i8 to be understood that the term "non-toxic effective dose" as used herein refers to the quantity of active ingredient necessary to produce the desired th~rapeutic effect wi~hout causing any significant harmful or deleterious side effects.
The process of the present invention for exerting a pharmacological effect in a mammal comprises atministering to said mammal a non-toxic effectlve dose of from 0.01 to 30 mg./kg. body weight of a bis~pyrrolinyl compound of Formula I or a pharmaceutically acceptable acid addition salt thereof to produce an effect selected from the group consisting of dluretic, antithrombogenic and smooth muscle relaxant therein.
Oral toxicity values (ALD~o) of the substances of Formula I
i~ mice range from abou~ 125 to greater than 1000 milligrams per ',, ,,'' -~ :' ~. . " ',' .. .
-, ' ' ' . .
3L~55~33 `
kilo~ram of body weight. For ln~tance, the ~LD~ o for 10~
pyrrolin-2-yl)-2-pyrrolln-2-yl~phenoxazine hydrochlorlde ls 250-500 mg./kg.
body weight.
The compounds of the present invention can be formulated accordlng to conventional pharmaceutical practlce to provide pharmaceutlcal compositions of unit dosage form which may inrlude, for example, tablets, pills, capsules, powder3, granules, emulsions, suspensions, and the like.
The solid preparations contain the active ingredient in admixture with pharmaceutically acceptable excipients such as inert diluents, for example calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example mal~e, starch or al6inic acid; binding agents, for example starch, - :
gelatin or acacia; and Iubricating agents, for example magneslum stearate, stearic acid or talc. The tablets may be uncoatcd or they may be coated by known techniques so as to de~y disir.tegration and absorption in the gastrointestinal tract and thereby provide a su6tained action over a longer period. ~-Liquid preparations suitable for parenteral adminlstration include solutions, suspensions, or emulsions of the compounds of Formula I. The aqueous suspensions of the pharmaceutlcal dosage forms of the compounds of Formula I contain the active ingredient in admlxture with one or more pharmaceutically acceptable excipients knawn to be 6uitable in the manufacture of aqueous s~lspensions. Suitable excipients ~ `
are, for example, suspending agents such as sodium carbo~ymethylcellulose, methylcellulose, hydroxypropyl~ethylcellulose, sodlum alginate, polyvinyl-pyrrolidone, gum tragacanth and gum a:acia. Suitable dispersing or wetting agents are naturally occurring phosphatides, for example lecithin, and polyoxyethylene stearate.
; , ' - ":' '', - -; , ' , , , - ' ' ': ' . ' ' ~ ' . , ' : ' ~ :
, : , . . .
,. -, :, , .
, ~i5~L~33 Non-aqueous suspensions may be formulated by ~uspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, ~esame oil or coconut oil, or in a mineral oll, for e~ample liquld paraffin. The suspensions may contain a thickening ag~nt such as bees wax, hard paraffin or cetyl alcohol. Sweetenlng and flavoring agents generally used in pharmaceutical compositions may also be lncluded such as saccharin, sodium cyclamate, sugar and caramel to provlde a palataole oral preparation. The compositions may also contain other additional absorbing agents, s~abilizing agents, weighing agents, and buffers-The following examples further illustrate the present invention a~d will enable others skilled ln the art to understand it more completely.
It is to be understood, however, that the invention is not limited solely to the particular examples given b~low.
In regard to "~IR" data, the following notations are employed: s ~ singlet, d - doublet, dd - doublet of doublets, t -triplet, q - quintet, m = multiplet, nm = narrow multiple~, bs = broad slnglet.
~xample 1.- Phosphorus oxychlorlde (3~.3 g., 0.25 mole) in 50 ml. of 1,2-dichloroethane i8 added ln one portion to a stirred mixture of phenothiazine (49.8 8., 0.25 mole) and 2-pyrrolidinone (42.6 g., 0.5 mole) in 250 ml. of 1,2-dichloroethane. The mixture la s~irred for 4 hr. at room temperature, permitted to stand for a period o~ 15 hr. and then poured into a mixture of 200 ml. of 5N
sodlum hydroxide and 100 g. of crushed ice. The 1,2-dichloroethane layer iJ separated and the aqueous layer extracted wlth 100 ml. of adtitional 1,2-dichloroethane. The combined 1,2-dichloroethane fractions are sequentlally extracted with 300 ml. of 1.5N hydrochloric '' ' ' ' . ; :
, . . .... . . . .
~S5~
acid and 20~ ml. of water. The combined acid-water extracts are washed with ether, made basic with 5N sodium hydrDxide and extracted repeatedly with chloroform. After dryi~g over magnesium sulfate, the chloroform ~olution is concentrated and the residual material thus obtained stirred with 200 ml. of acetone to remove the acetone soluble 10-C2-(1-pyrrolinyl)]-phenothiazine by-product and filtered. The filter c~ke i9 washed with additional acetone and dried providi~g 14.1 g. (17% yield) of 10-[1-(1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]PHE~OTHIA2I~ as the frPe base, m.p.
199-201C. The bis-pyrrolinyl phenothiazine free base suspended in 60 ml. of absolute ethanol, acidified with an equivalent of ethanolic hydrogen chloride, treated with decolorizing charcoal, filtered, and diluted with 200-250 ml. of anhydrous ether provides the hydrochloride salt. Crystallization of the hydrochloride salt from absolu~e ethanol-anhydrous ether affords analytically pure 10-[1-(1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL PHENOTHIAZINE]HYDROC~LORIDE solvated with 1/5 mole of ethanol as an off white solid, m.p. 237-239C. (corr.).
~nalvsis. Calcd. for C20Hl9NgS-HCl l/S C2H,OH (percent): C, 64.63;
H, 5.64; Cl, 9.35; N, 11.08. Found (percent): C, 64.68; H, 5.61;
Cl, 9.41; N, 11.18.
NMR delta (ppm)(D2O, HDO reference): 1.75m, 2.96m, 3.41m, 4~23m, 5.88nm, 7.Om.
Example 2.- A 501u~10n of 4-chlorophenothiazine t32.3 g., 0.134 mole) and 2--p~rrolidinone (23 g., 0.27 mole) in 125 ml. of 1,2~dichloroethane i~ added dropwise to a solutlon of 25 phosphoru6 oxychloride (20.5 g., 0.134 mole) in 50 ml. of 1,2-dichloroethane in about 35 min. Isolation of the product from the reaction mixture according to the procedure of Example 1 provides 7-5 8-~ (17.1% yleld) of 4-CHLORO~10-Cl-(l-PYRROLIN-2-YL)-2-PYRROLIN-Gj ~ ~
', 1~355~9~
2-YL]PHENOTHIA2INE free base, m.p. 195~197C. Analytically pure 4-CHLORO-10-Cl-(l-PYRROLIN-2-YL)-2-PYRROLIN-2-YL~PHENOTHIAZINE
EYDROCHLORIDE obtained by crystalllzation from ethanol-ether has a melting point of 232-234C. (corr.).
Analysis. Calcd. for C~oHl8ClN3S-HCl (percent): C, 59.41;
~, 4.74; N, 10.39; Cl, 17.53. Found (percent): C, 59.20; H, 4.74;
N, 10.59; Cl, 17.46.
~MR del~a (ppm)(D20, HDO reference): 1.77m, 2.9;7m9 3.43m, 4.14m, 5.91nm, 6.9m.
Example 3.- Reaction of 2-methoxyphenothiazine, 2-pyrrolidinone and phosphorus oxychloride in 1,2-dichloroethane accordin~ to the procedure of Example 1 affords 2-METHOXY-10-Cl-(l-PYRROLIN-2-YL)-2-PYRROLIN-2-YL~PHENOTHIAZINE free base, m.p.
151-153C. (corr.), from isopropyl alc~hol.
Analysis. Calcd. for C2lH~,N30S (percent): C, 69.39;
H, 5.83; N, 11.56. Found (percent): C, 69.35; H, 5.87; N, 11.76.
~MR delta (ppm~ (CDCl3, TMS reference): 1.78q ~7.0), 2.77m, 3.56t (7~1), 3.71s, 4.19dd (8.0, 9.8), 5.20t (2.8), 6.5m, ~.9m.
~xample 4.- A mixture of 5-~ethyl-2-pyrrolidinone (6.0 g., 0.06 mole), phosphorus oxychloride (9.2 g., 0.06 mole) in 60 ml. of 1,2-dichloroethane 18 re1uxed for 10 min. A solution of phenothiazine (6.0 g., 0.03 mole) in 20 ml. of 1,2-dichloroethane ls added at the end of the reflux perlod and the reaction mixture stlrred and refluxed ~or 20 hr., and then poured on~o 20 ml. of 5N potassium hydroxide and 20 g. of crushed ice. The 1,2-dichloroethane layer is ~eparated and extracted ~7ith 30 ml. of 1.5N hydrochlori& acid and 30 ml. of water removing water soluble by-product 10-C2-(5-methyl-l-pyrrolinyl)]- ~
':
,.. ,, . .,, ,., . :
~554~3 phenothiazine hydrochloride. After drying the 1,2-dichloroethane solution over magr.esium sulfate9 the 1,2-dichloroethane solution is concentrated and the solid thus obtained stirred with 40 ml. of acetone and filtered. Crystallization of the filte~cake from ethanol-ether provides analytically pure 10-[5-~ETHYL-1-(5-~ETHYL-l-PYRROLIN-2-YL)-2-PYRROLI~-2-YL]PHENOTHIAZINE X~DROCHLORIDE in a yield of 17%, m.p. 257-264~C. (corr.).
Analysis. Calcd. for C~aH29~3S-HCl (percent): C9 66.40;
~, 6.03; N, 10.56; Cl, 8.91. Found (percent): C, 66.51; H, 6.14;
10 N, 10.52; Cl, 8.99. ~ -NMR delta (ppm) (CDCl3, TMS reference): 1.41d (6.4), 1.57d (6.2), 1.7-3.5m, 4.05m, 5.62m, 5.86t (2.9), 7.Om, 11.75bs.
Example 5.- Reaction of 5-methyl-2-pyrrolidinone, 2-~ethoxyphenothiazlne and phosphorus oxychloride in 1,2-dichloroethane 15 according to the procedure of Example 4 affords 2-M~THOXY-10-[5 ~LTHYL-1-(5-~ETHYL-l-PYRROLIN-2~YL)-2-PYRROLIN-2-YL]PH~IOTHIAZINE
~XDROCHLORIDE (8.6% yield), m.p. 236.5-238.5C. (corr.), from ethanol-ether.
Analysis. Calcd. for C~3H~,N30S-HCl (percent): C, 64.54;
20 H, 6.12; N, 9.82; Cl, 8.29. Found tpercent): C, 64.50; H, 6.15;
~, g.88; Cl, 8.33.
- NMR delta ~ppm) (CDCl" T~S reference): 1.38d (6.3), 1.54d (6.4), 1.56d (6.4), 1.6-3.3m, 3.70~, 4.10m, 5.57m, 5.81t ~3.0)~
6.8m, 11.93bs, Example 6.- A mlxture of 5-methyl-2-pyrrolidlnone (2.0 g., 0.02 mole) and phosphorus oxychloride (3.0 g., 0.02 mole) in 15 ml.
of 1,2-dichloroethane after ~tanding 15 hr. at room temperature is combined with 9,9-dimethylacridan (2.1 g., 0.01 mole) after a 48 hr.
' ' ~; ' ' ~CI 55~3 period is added to 30 ml. of 5N potassium hydroxide and 30 g. of cruQhed ice. The 1,2-dichlorGethane fraction i5 separated, extracted wlth 50 ml. of 1.5N hydrochloric acld and 50 ml. of water and dried over magnesium sulfate. Concentration of the 1,2-dichloroethane ~olution provides a residue which iB stirred with 100 ml. of ether ~nd filtered. The filter cake containing crude hydrochloride salt of the product is stirred with sodium hydroxide solution affording the free base. Crystallization from n-heptan~ provides 1.3 g.
(35~ yield) of 9,9-D~THYL-10-[5-METHYL-1-(5-METHYL-l-PYRROLIN-2-YL)-19 2-PYRROLIN-2-YLlACRIDA~, m.p. 135-139C. from which the hydrochloride salt is prepared according to the procedure of Example 1. Analytically pure 9,9-D~ETHYL-10-~5-.~THYL-1-(5-METHYL-l-PYRROLIN 2-YL)-2-PYRROLIN-2-YL~ACRIDAN HYDROCHLORIDE, from acetone-ether, has a melting point of 247.5-248.0C. (corr.).
Analysis. Calcd. for C2~H29N30HCl (percent): C, 73.60;
H, 7.41; Ng ;0.30; Cl, 8.69. Found (percent~: C, 73.98; H, 7.40;
~, 10.22; Cl, 8.67.
~MR delta (ppm) (CDCl3, TMS reference): 1.40d (6.2), 1.45d (6.2), 1.61s, 1.70d (6.2), 1.728, 1.8 3.2m, 4.16m, 5.69m, 20 5.82t (2.9), 6.7m, 7.3~, 11.82bs.
2xample 7.- A mixture of acridan (3.6 g., 0.02 mole) and 2-chloro-1~ pyrrolin-2-yl)-2-pyrroline hydrochloride (5.1 g., 0.025 mole), obtalned according to the method of H. Brederick, et al., Chem. Ber., ~ 2292 (1961), in 50 ml. o~ 1,2-dlchloroethane 1~ refluxed for a period of 15 hr. The mixture i~ sequentially extracted with 50 ml. of 1.5N hydrochlorlc acld and three 50 ml. portions of water. Tha combined acid-water extracts are baslfied wlth 5N potassium hydroxlde, extracted with ether and t'ne ethereal extract concentrated. Crystalll~ation - 19 _ :: , ... :. , , , : . , :" , , . , :
~, . , ,, . , . ,, : :
... . .. . . . . ...
~554~3 of the residue thus obtained from ethanol affords the free base 10-[1-(1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL~ACRIDAN, m.p. 179-181 C. which ~-is converted according to the procedure of Example 1 to 10-[1-(1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]ACRIDAN HYDROCHLORIDE, m.p. 212.5-216.5C.
(dec.)(~orr.)., from ethanol-ether.
Analysis. Calcd. for C21H21N2~HCl (percent): C, 71-68;
H, 6.30; N, 11.94; Cl, 10.08. Found (percent): C9 71.43; H, 6.24;
N, 11.90; Cl, 9.85.
NMR delta (ppm) (D20, HDO reference): 1.60m, 2.33m, 2.80m,
3.36m, 3.69s, 4.11m, 5.49nm, 6.9m.
Example 8.- Reaction of 9,9-dimethylacridan, and 2-chloro-1-(1-pyrrolin-2-yl)-2-pyrroline hydrochloride according to the procedure of Example 7 affords a 21~ yield of the free base, 9,9-DI~ETHYL-10-[1-(1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]ACRIDAN, m.p.
166-168C. Acidification of the free base with ethanolic hydrogen chloride according to the procedure of Example 1 provides 9,9-DIMETHYL-10-[1-(1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL~ACRIDAN HYDROCHLORIDE, m.p. 256.5-258C. (dec.)(corr.), from benzene-ether.
Analysis. Calcd. for C23H25N3-HCl (percent): C, 72-71;
H, 6.90; N, 11.06; Cl, 9.33. Found ~percent): C, 72.46; H, 6.82;
N, 10.88; Cl, 9.04.
NMR delta (ppm) (CDC13, TMS reference): 1.61s, 1.73s, 1.90m, 2.29m, 3.07m, 3.72t (7.0), 4.80dd (8.0, 8.5), 5.88t (3.0), 6.7m, 7.3m.
Example 9.- Reaction of phenoxa~ine with 2-chloro-1-(l-pyrrolin-2-yl)pyrroline hydrochloride according to the procedure of Example 7 affords 10-[1~ PYRROLIN-2-YL)-2-PYRROLIN-2-YL]PHENOXAZINE
HYDROCHLORIDE" m.p. 257.5-263 C. (corr.), from ethanol-ether.
.
~55493 Analysis. Calcd. for C~oH~9N30-HCl (percent): C, 67.88;
H, 5.70; N, 11.88; Cl, 10.02. Found (percent): C, 67.52; H, 5.82;
N, 11.83; Cl, 9.85.
NMR delta (ppm) (CDCl3, TMS reference): 2.08m, 2.95m, 3.72t (7.1), 4.65dd (8.0, 8.5), 5.86t (2.9), 6.4m, 6.8m.
Exam~e 10.- Reaction of 2-chlorophenoxazine with 2-chloro-(l-pyrrol~n-2-yl)pyrroline hydrochloride accordin~ to the procedure of Exa~ple 7 affords 2-CHLORO-10-[1-(1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]-PEENOXA2INE HYDROCHLORIDE, m.p. 262.5-264.5C. (dec.)(corr.), from ethanol-ether.
Analysis. Calcd. for CaoH~ClN30~HCl (percent): C, 61.86;
~, 4.93; N, 10.82; Cl, 18.27. Found (per~ént): C~1~61.65; H, 4.~7;
~, 10.79; Cl, 18.16.
NMR del~a (ppm)(CDCl3, TMS reference): 2.17m, 2.98m, 15 3.74t (7.0), 4.68dd (8.0, 9.0), 5.88t (3.0), 6.4m, 6.8m, 12.0bs.
~ xample ll.- Reaction of 2-trifluoromethylphenoxazine with 2-chloro-1-(1-pyrrolin-2-yl)pyrroline hydrochlorlde according to the procedu.e of Example 7 affords the free base, 2-TRIFLUOROMETHYL-10-~l-(l-PYRROLIN-2-YL~-2-PYRROLIN-2-YL]PHENO~AZINE, m.p. 140-142C., from n-hexane. Conv~rsion of the free ba6e affords 2-TRIFLUOROMETHYL-lO~ PYRROLIN~2-YL)-2-PYRROLIN~2-YL]P~ENOXAZIN~ HYDROCHLORIDE
~YDRATE, m.p. 222.5-229C~ (dec.)(corr~).
Anal~ls. Calcd. for C~aH~oF3N~-HCl-H~0 (percent): C, 57.35;
~, 4.81; N, 9.55; Cl, 8.06. Found (percent): C, 57.42; H, 4.78;
25 ~, 9.43; Cl, 8~32.
~ R delta (ppm)(CDCl3, TMS reference): 2.13m, 2.98m, 3.75t (7.0),
Example 8.- Reaction of 9,9-dimethylacridan, and 2-chloro-1-(1-pyrrolin-2-yl)-2-pyrroline hydrochloride according to the procedure of Example 7 affords a 21~ yield of the free base, 9,9-DI~ETHYL-10-[1-(1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]ACRIDAN, m.p.
166-168C. Acidification of the free base with ethanolic hydrogen chloride according to the procedure of Example 1 provides 9,9-DIMETHYL-10-[1-(1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL~ACRIDAN HYDROCHLORIDE, m.p. 256.5-258C. (dec.)(corr.), from benzene-ether.
Analysis. Calcd. for C23H25N3-HCl (percent): C, 72-71;
H, 6.90; N, 11.06; Cl, 9.33. Found ~percent): C, 72.46; H, 6.82;
N, 10.88; Cl, 9.04.
NMR delta (ppm) (CDC13, TMS reference): 1.61s, 1.73s, 1.90m, 2.29m, 3.07m, 3.72t (7.0), 4.80dd (8.0, 8.5), 5.88t (3.0), 6.7m, 7.3m.
Example 9.- Reaction of phenoxa~ine with 2-chloro-1-(l-pyrrolin-2-yl)pyrroline hydrochloride according to the procedure of Example 7 affords 10-[1~ PYRROLIN-2-YL)-2-PYRROLIN-2-YL]PHENOXAZINE
HYDROCHLORIDE" m.p. 257.5-263 C. (corr.), from ethanol-ether.
.
~55493 Analysis. Calcd. for C~oH~9N30-HCl (percent): C, 67.88;
H, 5.70; N, 11.88; Cl, 10.02. Found (percent): C, 67.52; H, 5.82;
N, 11.83; Cl, 9.85.
NMR delta (ppm) (CDCl3, TMS reference): 2.08m, 2.95m, 3.72t (7.1), 4.65dd (8.0, 8.5), 5.86t (2.9), 6.4m, 6.8m.
Exam~e 10.- Reaction of 2-chlorophenoxazine with 2-chloro-(l-pyrrol~n-2-yl)pyrroline hydrochloride accordin~ to the procedure of Exa~ple 7 affords 2-CHLORO-10-[1-(1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]-PEENOXA2INE HYDROCHLORIDE, m.p. 262.5-264.5C. (dec.)(corr.), from ethanol-ether.
Analysis. Calcd. for CaoH~ClN30~HCl (percent): C, 61.86;
~, 4.93; N, 10.82; Cl, 18.27. Found (per~ént): C~1~61.65; H, 4.~7;
~, 10.79; Cl, 18.16.
NMR del~a (ppm)(CDCl3, TMS reference): 2.17m, 2.98m, 15 3.74t (7.0), 4.68dd (8.0, 9.0), 5.88t (3.0), 6.4m, 6.8m, 12.0bs.
~ xample ll.- Reaction of 2-trifluoromethylphenoxazine with 2-chloro-1-(1-pyrrolin-2-yl)pyrroline hydrochlorlde according to the procedu.e of Example 7 affords the free base, 2-TRIFLUOROMETHYL-10-~l-(l-PYRROLIN-2-YL~-2-PYRROLIN-2-YL]PHENO~AZINE, m.p. 140-142C., from n-hexane. Conv~rsion of the free ba6e affords 2-TRIFLUOROMETHYL-lO~ PYRROLIN~2-YL)-2-PYRROLIN~2-YL]P~ENOXAZIN~ HYDROCHLORIDE
~YDRATE, m.p. 222.5-229C~ (dec.)(corr~).
Anal~ls. Calcd. for C~aH~oF3N~-HCl-H~0 (percent): C, 57.35;
~, 4.81; N, 9.55; Cl, 8.06. Found (percent): C, 57.42; H, 4.78;
25 ~, 9.43; Cl, 8~32.
~ R delta (ppm)(CDCl3, TMS reference): 2.13m, 2.98m, 3.75t (7.0),
4~67dd (9.0, 8.0), 5.90t ~3.0), 6.5m, 6.8m, 11.63bs.
. .
.
1~55493 Example 12.- Reaction of 3-chlorophenoxazine with 2-chloro-~l-pyrrolin-2-yl)pyrroline hydrochloride according to the procedure of Example 7 affords 3-CHlORO-10-Cl-tl~PYRROLI~-2-YL)-2-PYRROLIN-2-YL~-PHENOXAZINE HY~ROCHLORIDE, m.p. 262.5-270C. (dec.)(corr.), from ethanol-ether.
Analysis. Calcd. for G20Ml~ClN3OoHCl tpercent): C, 61.86, ~, 4.93; N, 10.82; Cl, 18.27. Found (percent): C, ~1.82; H, 4.99;
M, 10.74; Cl, 18.03.
NMR delta (ppm)(CDCl3, TMS rererence): 2.12m, 2.37m, 10 3.73t (7.0), 4.67dd t9.0, 8.0), 5.87t (3.0), 6.4m, 6.8m.
Example 13.- Reaction of 4 chloropheno~azine with 2-chloro-(l-pyrrolin-2-yl)pyrroline hydrochloride according to the procedure of Example 7 affords 4-CHLORO-10-Cl-(l-PY~ROLIN-2-YL)-2-PYRROLIN-2-YL]-PHENOXAZINE HYDROCHLORIDE, m.p. 278-282C. (dec.), from ethanol-ether.
Anal~sis. Calcd. for C2OH~aclN3o-Hcl (percent): C, 61.86;
H, 4.93; N, 10.82; Cl, lB.27. Found (percent): C, 61.87; H, 4.99;
N, 10.82; Cl, 18.16.
NMR delta (ppm)(CDCl3, TMS reference): 2.11m, 2.97m, 3.74t t7.0), 4.67dd (9.0, 8.0), 5.87t (3.0~, 6.4m, 6.8m.
Example 14.- Reactlon o~ the phenoxazlnes:
2-~ethoxyphenoxazine, 4-methoxyphenoxazine, 4-isopropoxyphenoxazlne, 2-methylphenoxazine, 4-methylphenoxazine, 4-n-butylphenoxazine wlth 2-chloro~ pyrrolin-2-yl)pyrroline hydrochloride accordin~
to the procedure o~ Example 7 providee the respective bis-pyrrolinyl ~355~9~
phenoxazines:
2-METHOXY-10-Cl (l-PYRROLIN-2-YL)-?-PYRROLIN-2~YL]-PHENOXA2INE HYDROCHLORIDE9 m.p. 201.5-206.5C.
(dec.)(corr.). Analysis. Calcd. for C2,H2lNg02-HC
(percent): C, 65.70; H, 5.78; N, lO.9S; Cl, 9.24.
Found tpercent): C, 64.98; H, 5.71; N, 11.04; Cl, 9~23.
NMR delta (ppm)(CDCl3, TMS reference): 2.10m, 3.01m, 3.72t (7.1), 3.7is, 4.63t (7.5), 5.9-6.9m.
4-METHOXY-lO-Cl-tl-PYRROLIN-2-YL)-2-PYRROLIN-2-YL~-PHENOXAZINE, 4-ISOPROPO~Y-lO-Cl-(l-PYRROLIN-2-YL~-2-PYRROLIN-2-YL~- :
PEENOXAZINE, : ~.
2-~ THYL-10-Cl-(l-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]-PHENOXA2INE, 4-NETHYL-10-C~ PYRROLIN-2-YL)~2-PYRROLIN-2-YL]-PEENOXA2INE, 4-n-BUTYL-10-[l-(l-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]-;.. . ...
P~ENO~AZINE.
Lxample 15.- Reaction of phenoxazine with 5-methyl-2-20 pyrrolidinone or 5-n-butyl-2-pyrrolldinone according to ~he procedure ~`
of Example 4 provides the bis-pyrrolinyl phenoxazine3:
10-C5-M~THYL-1-(5-METHYL-l-PYRROLIN-2-YL)-2-PYRROLIN-2-YL~-PHENOXAZINE, 10-C5 n-BUTYL-1-~5-n-BUTYL-l-PYRROLIN-2-YL)-2-PYRROLIN-2- `
YL]PHENOXAæINE. ~ :
Reactlon of 4-chlorophenoxazine with 5-methyl-2-pyrrolidinone according to the procedure of Example 4 provides '; , '' ' . ' ' ' . . , " .
~554~33 4-CHIORO-10-C5-~ETHYL-1-~5-METHYL-l-PYRROLIN-2-'~L)-2-PYRROLIN-2-YL~PHENOXAZINE.
Example 16 .- Reaction of the phenothiazines:
2-trifluorophenothia ine, 2-chlorophenothiazine, 3-chlorophenothiazine, 4-isopropoxyphenothiazine, 2-~ethylphenothiazine, 2-n-butylphenothiazine, 4-methylphenothiazine, 4-isopropylphenothiaæine with 2-chloro-1-(1-pyrrolin-2-yl)pyrroline hydrochloride according to :
the procedure of Example 7 provides the respective bis-pyrrolinyl phenothiazines: :
2-TRIFLUOROMETHYL-10-Cl~(l-PYRROLIN-2-YE)-2-PYRROLIN-2-YL]-P~IENOTHIAZINE, ~ 2-CHLORO-10-[1-(1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]PH~NOIHIAZINE, 3-C~LORO-10-~1-(1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]PHENOTHIAZINE, 4-ISOPROPOXY-10-Cl-(l-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]-PHENOTHIAZINE, 2-METHYL-10-Cl-(l-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]PHENOTHIAZINE, 2-n-Bum-lo-cl- (l-PYRROLIN-2-YL)-2-PYRROLIN-2-YL~PHENOTHIAZINE, 4-METHYL-10-Cl-(l-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]P~IENOTHIAZINE, 4-lSOPROPYL-10-Cl-~l-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]-PHENOTHIAZINE~
Example 17.- Reaction of phenothia~ine with 5-n-butyl-2-pyrrolldinone according to the procedure of Example 4 provides 10-C5-n-BU m -1-~5-n-3UTYL-l-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]PHENOTHIAZINE.
- 24 ~
' ~ ' .: - . , ~55~3 Example 18.- Reaction of the acridans:
2-chloroacridan, 4-methoxyacridan, 4-lsopropoxyacridan, S 4-trifluoro~ethylacridan 9 2-methylacridan, 4-methylacridan, 4-n-butylacridan, 2-trifluoromethyl-9,9-dimethylacridan, 2-trifluoromethyl-9-methylacridan, 2-chloro-9,9-dimethylacridan, i::
9-ethyl-9-~ethylacridan, 9,9-di-n-butylacridan ~ith 2-chloro-1-(1-pyrrolin-2-yl)pyrroline hydrochloride according to the procedure of Example 7 pro~ides the respective bis-pyrrolinyl .
acridans:
2-CHLOP~9-10-[1-(1-PYRROLIN-2-YL)~2-PYRROLIN-2-YL]ACRIDA~, 4-M13THOXY-10-Cl-(l-PYRROLIN-2-YL)-2-PYRROLIN-2-~]ACRIDAN, 4-ISOPROPOXY-10-[1-~1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL~ACRIDAN, : .
4-TRIFLUOROMETHYL-10~Cl-(l-PYRROLIN-2-YL~-2-PYRROLIN-2-YL]-ACRIDAN, 2-METHYL-10-[1-(1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]ACRIDAW, 4-METHYL-10-Cl-tl-PYRROLIN-2-Y~)-2-PYRROLIN-2-YL]ACRIDAN, 4-n-BUTYL-10-[1-(1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]ACRIDhN, 2-TRIFLUOROMETHYL-9,9-DIMETHYL-10-Cl-(l-PYRROLIN-2-YL)-2-PYRROLIN-2-YL~ACRIDhN, 2-TRIFLUO~OMETHYL-9-~ETHYL-10-Cl-~l-PYRROLIN-2-YL)-2-~ PYRROLIN-2-YL~ACRID~N, ., ' ' .
. :
. - 25 - .
:
. .
' . . ' ' - ' ' , . ' :' ,, ~ ~ ' ', ,' ' , , ~3S5~93 2-CHLORO-9,9-DIMETHYL-10-C~ -PYRROLIN-2-YL)-2-PYRROLIN-2-YLlACRIDAN, 9-ET~YL-9-~THYL-10-~1-(l PYRROLIN-2-YL)-2-PYRROLIN-2-YL]-ACRIDAN, 9~9-DI-n-~UTYL-10-[1-{1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL~ACRIDAN.
Example 19.- Reaction of acridan and 2-chloroacridan with '~
. .
.
1~55493 Example 12.- Reaction of 3-chlorophenoxazine with 2-chloro-~l-pyrrolin-2-yl)pyrroline hydrochloride according to the procedure of Example 7 affords 3-CHlORO-10-Cl-tl~PYRROLI~-2-YL)-2-PYRROLIN-2-YL~-PHENOXAZINE HY~ROCHLORIDE, m.p. 262.5-270C. (dec.)(corr.), from ethanol-ether.
Analysis. Calcd. for G20Ml~ClN3OoHCl tpercent): C, 61.86, ~, 4.93; N, 10.82; Cl, 18.27. Found (percent): C, ~1.82; H, 4.99;
M, 10.74; Cl, 18.03.
NMR delta (ppm)(CDCl3, TMS rererence): 2.12m, 2.37m, 10 3.73t (7.0), 4.67dd t9.0, 8.0), 5.87t (3.0), 6.4m, 6.8m.
Example 13.- Reaction of 4 chloropheno~azine with 2-chloro-(l-pyrrolin-2-yl)pyrroline hydrochloride according to the procedure of Example 7 affords 4-CHLORO-10-Cl-(l-PY~ROLIN-2-YL)-2-PYRROLIN-2-YL]-PHENOXAZINE HYDROCHLORIDE, m.p. 278-282C. (dec.), from ethanol-ether.
Anal~sis. Calcd. for C2OH~aclN3o-Hcl (percent): C, 61.86;
H, 4.93; N, 10.82; Cl, lB.27. Found (percent): C, 61.87; H, 4.99;
N, 10.82; Cl, 18.16.
NMR delta (ppm)(CDCl3, TMS reference): 2.11m, 2.97m, 3.74t t7.0), 4.67dd (9.0, 8.0), 5.87t (3.0~, 6.4m, 6.8m.
Example 14.- Reactlon o~ the phenoxazlnes:
2-~ethoxyphenoxazine, 4-methoxyphenoxazine, 4-isopropoxyphenoxazlne, 2-methylphenoxazine, 4-methylphenoxazine, 4-n-butylphenoxazine wlth 2-chloro~ pyrrolin-2-yl)pyrroline hydrochloride accordin~
to the procedure o~ Example 7 providee the respective bis-pyrrolinyl ~355~9~
phenoxazines:
2-METHOXY-10-Cl (l-PYRROLIN-2-YL)-?-PYRROLIN-2~YL]-PHENOXA2INE HYDROCHLORIDE9 m.p. 201.5-206.5C.
(dec.)(corr.). Analysis. Calcd. for C2,H2lNg02-HC
(percent): C, 65.70; H, 5.78; N, lO.9S; Cl, 9.24.
Found tpercent): C, 64.98; H, 5.71; N, 11.04; Cl, 9~23.
NMR delta (ppm)(CDCl3, TMS reference): 2.10m, 3.01m, 3.72t (7.1), 3.7is, 4.63t (7.5), 5.9-6.9m.
4-METHOXY-lO-Cl-tl-PYRROLIN-2-YL)-2-PYRROLIN-2-YL~-PHENOXAZINE, 4-ISOPROPO~Y-lO-Cl-(l-PYRROLIN-2-YL~-2-PYRROLIN-2-YL~- :
PEENOXAZINE, : ~.
2-~ THYL-10-Cl-(l-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]-PHENOXA2INE, 4-NETHYL-10-C~ PYRROLIN-2-YL)~2-PYRROLIN-2-YL]-PEENOXA2INE, 4-n-BUTYL-10-[l-(l-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]-;.. . ...
P~ENO~AZINE.
Lxample 15.- Reaction of phenoxazine with 5-methyl-2-20 pyrrolidinone or 5-n-butyl-2-pyrrolldinone according to ~he procedure ~`
of Example 4 provides the bis-pyrrolinyl phenoxazine3:
10-C5-M~THYL-1-(5-METHYL-l-PYRROLIN-2-YL)-2-PYRROLIN-2-YL~-PHENOXAZINE, 10-C5 n-BUTYL-1-~5-n-BUTYL-l-PYRROLIN-2-YL)-2-PYRROLIN-2- `
YL]PHENOXAæINE. ~ :
Reactlon of 4-chlorophenoxazine with 5-methyl-2-pyrrolidinone according to the procedure of Example 4 provides '; , '' ' . ' ' ' . . , " .
~554~33 4-CHIORO-10-C5-~ETHYL-1-~5-METHYL-l-PYRROLIN-2-'~L)-2-PYRROLIN-2-YL~PHENOXAZINE.
Example 16 .- Reaction of the phenothiazines:
2-trifluorophenothia ine, 2-chlorophenothiazine, 3-chlorophenothiazine, 4-isopropoxyphenothiazine, 2-~ethylphenothiazine, 2-n-butylphenothiazine, 4-methylphenothiazine, 4-isopropylphenothiaæine with 2-chloro-1-(1-pyrrolin-2-yl)pyrroline hydrochloride according to :
the procedure of Example 7 provides the respective bis-pyrrolinyl phenothiazines: :
2-TRIFLUOROMETHYL-10-Cl~(l-PYRROLIN-2-YE)-2-PYRROLIN-2-YL]-P~IENOTHIAZINE, ~ 2-CHLORO-10-[1-(1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]PH~NOIHIAZINE, 3-C~LORO-10-~1-(1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]PHENOTHIAZINE, 4-ISOPROPOXY-10-Cl-(l-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]-PHENOTHIAZINE, 2-METHYL-10-Cl-(l-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]PHENOTHIAZINE, 2-n-Bum-lo-cl- (l-PYRROLIN-2-YL)-2-PYRROLIN-2-YL~PHENOTHIAZINE, 4-METHYL-10-Cl-(l-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]P~IENOTHIAZINE, 4-lSOPROPYL-10-Cl-~l-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]-PHENOTHIAZINE~
Example 17.- Reaction of phenothia~ine with 5-n-butyl-2-pyrrolldinone according to the procedure of Example 4 provides 10-C5-n-BU m -1-~5-n-3UTYL-l-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]PHENOTHIAZINE.
- 24 ~
' ~ ' .: - . , ~55~3 Example 18.- Reaction of the acridans:
2-chloroacridan, 4-methoxyacridan, 4-lsopropoxyacridan, S 4-trifluoro~ethylacridan 9 2-methylacridan, 4-methylacridan, 4-n-butylacridan, 2-trifluoromethyl-9,9-dimethylacridan, 2-trifluoromethyl-9-methylacridan, 2-chloro-9,9-dimethylacridan, i::
9-ethyl-9-~ethylacridan, 9,9-di-n-butylacridan ~ith 2-chloro-1-(1-pyrrolin-2-yl)pyrroline hydrochloride according to the procedure of Example 7 pro~ides the respective bis-pyrrolinyl .
acridans:
2-CHLOP~9-10-[1-(1-PYRROLIN-2-YL)~2-PYRROLIN-2-YL]ACRIDA~, 4-M13THOXY-10-Cl-(l-PYRROLIN-2-YL)-2-PYRROLIN-2-~]ACRIDAN, 4-ISOPROPOXY-10-[1-~1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL~ACRIDAN, : .
4-TRIFLUOROMETHYL-10~Cl-(l-PYRROLIN-2-YL~-2-PYRROLIN-2-YL]-ACRIDAN, 2-METHYL-10-[1-(1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]ACRIDAW, 4-METHYL-10-Cl-tl-PYRROLIN-2-Y~)-2-PYRROLIN-2-YL]ACRIDAN, 4-n-BUTYL-10-[1-(1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]ACRIDhN, 2-TRIFLUOROMETHYL-9,9-DIMETHYL-10-Cl-(l-PYRROLIN-2-YL)-2-PYRROLIN-2-YL~ACRIDhN, 2-TRIFLUO~OMETHYL-9-~ETHYL-10-Cl-~l-PYRROLIN-2-YL)-2-~ PYRROLIN-2-YL~ACRID~N, ., ' ' .
. :
. - 25 - .
:
. .
' . . ' ' - ' ' , . ' :' ,, ~ ~ ' ', ,' ' , , ~3S5~93 2-CHLORO-9,9-DIMETHYL-10-C~ -PYRROLIN-2-YL)-2-PYRROLIN-2-YLlACRIDAN, 9-ET~YL-9-~THYL-10-~1-(l PYRROLIN-2-YL)-2-PYRROLIN-2-YL]-ACRIDAN, 9~9-DI-n-~UTYL-10-[1-{1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL~ACRIDAN.
Example 19.- Reaction of acridan and 2-chloroacridan with '~
5-methyl-2-pyrrolidinone and 5-n-butyl-2-pyrrolidinone respectively according to the procedure of Example 4 provides:
2-CHLORO-10~5-METHYL-1-(5-METHYL-l-PYRROLIN-2-YL)-2-PYRROLIN-2-YL~ACRIDAN, 10-[5-n-BUTYL-1-(5-n-BUTYL-l-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]-ACRIDAN.
Example 20.- A solution of 5-methyl-2-pyrrolidinone tl9.8 g., 0.2 mole) in 25 ml. of xylene is added drop-wise to a lS mixture of 2-trifluoromethylphenothiazine (26.7 g., 0.1 mole) and phosphorus o~Jchloride (15.3 g., 0.1 mole) in 125 ml. of refluxing xylene in a two hour period. When the addi~ion i9 complete, refluxing is continued for an additional 1.5 hr., the reactlon mixture poured into 75 ml. of 5 N sodium hydroxide and 75 g~ of crushed ice, and, af~er mixing well, the xylene fraction ls separated. The xylene fraction is sequentially extracted with 100 ml. of 1.5 HCl followed by 100 ml~ of water and then made basic by stlrrlng with 5 N sodlum hydroxide solutlon. Separation of the basified xylene fraction which ls drlet over magnesium sulfate and concentrated under reduced pressure provides a residue whlch is taken up ln 50 ml. of ~enzene and the solutlon then concentrated. An addltlon~l 100 ml. portion of benzene ls added to the residue thus obtalned and the solutlon partially concentrated until crystals begln -, . . . . .. .
,: . , , . , , ,: ~ : , ,,.,,,,, , - , :, '' . ,' .
, . . . . . .. . . .
, " " ,, ,,, , ,: :
l~5S4~3~
to form. After cooling and standing, the mixture is filtered to remove recove~ed 2-trifluoromethylphenotniazine s;arting material. Concentration of the filtrate ~ffords a re3idual material which is taken up in ether, extracted with 1.5 N hydrochloric acid and then with 50 ml. of water.
The combined acid-aqueous extracts are made basic with sodium hydroxide and the mixture extracted with ether. The ethereal extract is dried over magnesium sulfate, filtered, and concentrated. Dlstillation of the resldual oil thrGugh a 6 cm. column provides 10-[5-methyl~ 5-methyl-l-pyrrolin-2-yl)-2-pyrrolin-2-yl]-2-ttrifluoromethyl)phenothiazine 10 free base, bop. 175-185~C./0.15 mm. Hg. The bis-pyrrolinyl phenothiazine free base is taken up in ethanol and acidified with ethanolic hydrogen chloride. Additlon of ether provides the hydrochloride salt which crystalllzed from ethanol affords analytically pure 10-[5-METHYL-1-(5-METHYL-l~PYRROLIN-2-YL)-2-PYRROLIN-2-YL~-2-(TRlFLUOROMETHYL)PHENOTHL~ZINE
15 ~YDROCHLORIDE, m.p. 250-253C. (dec.)(corr.).
Analysi~. Calcd. for C~3H22F3N3S-HCl: C, 59.28; H, 4~98;
N, 9.~2; Cl, 7.61. Found: C, 59.18; H, 5.14; N, 9.05; Cl, 7.39.
NMR delta (ppm)(CDCl3, TMS reference) 1.49d (6.5), ~ -1.55d (6.5), 2.37m, 3.12m, 4.03mJ 5.50m, 5.94m, 7.05m, 11.8bs.
Example 21.- Pharmaceutical Compositions~- The bi~-pyrrolinyl compounds of the present invention characteri~ed by Formula I are compounded with pharmacologically acceptable carriers to provide compositio~s useful in the present invention. Typical of the pharmaceutical composition3 are the ollowing:
2S A. Tablets.- The bis-pyrrolinyl compounds of Formula I
are compounded into tablets according to the following e~ample:
,, . .. .. ' . .. , " , ' : ' .. .. .
: .. . .
. .
:~3~5~
Materials ~mount 9,9-Dimethyl-10-c5~
methyl-l-(;-methyl-l-pyrrolin-2-yl)-2-pyrrolin-2-yl]ac~idan hydrochlo~ide54.9 g.
Magnesium stearate 1.3 g.
Corn starch12.4 g.
Corn starch,1.3 g.
pregelatinlzed Lactose 181.0 g.
The foregoing materials are blended in a t~in-shell blender and then granulated and pressed into tablets employing Z50 mg. each. Each table~
contains about 50 mg. of active ingredient. The tablet may be scored and quartered so that unit dose of 12.5 ~g. of active ingredient may be convenlently obtained.
B. Capsules.- The bis-pyrrollnyl compounds of Formula I ~ -are compounded into capsulPs according to ~he following example:
Materials , Amount Actlve ingredient 125.0 mg.
Lactos2 146.0 mg.
Msgneslum stearate 4.0 g.
The foregoing materials are blended in a twin-shell blender and then 111ed into No. 1 hard gelatin capsules. Each capsule contalns 125 g.
of active ingredient.
C. Solution for oral or parenteral administration.- A
sterile aqueous solution having a concentration of 40 mg. per ml.
of 9,9-dimethyl-10-~5-methyl-1-(5~methyl~1-pyrrolin-2-yl)-2-pyrrolin-2-yl]acridar. hydrochloride i9 prepared by dissolving 400 g. of the substance in 9 liters of water ~or in~ection, U.S.P., :
- 2~ -. : . . .
. .
,, -, .
.. ,- .
.
.
~554~33 ~:
ad~usting the pH to 5.5 with dilute aqueous sodiu~ hydroxide and dilution to 10 liters. This solutlon is then filtered sparkling ciear and filled into 2 ml. glass ampoules and sealed.
While specific embodiments are dlsclosed in the foregoing specification, it will be appreciated that other modifications may be made without departing from the spirit and scope of the appended claims.
, - ~9 _ : ~ " ~ ' ' ', ' . ~ '
2-CHLORO-10~5-METHYL-1-(5-METHYL-l-PYRROLIN-2-YL)-2-PYRROLIN-2-YL~ACRIDAN, 10-[5-n-BUTYL-1-(5-n-BUTYL-l-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]-ACRIDAN.
Example 20.- A solution of 5-methyl-2-pyrrolidinone tl9.8 g., 0.2 mole) in 25 ml. of xylene is added drop-wise to a lS mixture of 2-trifluoromethylphenothiazine (26.7 g., 0.1 mole) and phosphorus o~Jchloride (15.3 g., 0.1 mole) in 125 ml. of refluxing xylene in a two hour period. When the addi~ion i9 complete, refluxing is continued for an additional 1.5 hr., the reactlon mixture poured into 75 ml. of 5 N sodium hydroxide and 75 g~ of crushed ice, and, af~er mixing well, the xylene fraction ls separated. The xylene fraction is sequentially extracted with 100 ml. of 1.5 HCl followed by 100 ml~ of water and then made basic by stlrrlng with 5 N sodlum hydroxide solutlon. Separation of the basified xylene fraction which ls drlet over magnesium sulfate and concentrated under reduced pressure provides a residue whlch is taken up ln 50 ml. of ~enzene and the solutlon then concentrated. An addltlon~l 100 ml. portion of benzene ls added to the residue thus obtalned and the solutlon partially concentrated until crystals begln -, . . . . .. .
,: . , , . , , ,: ~ : , ,,.,,,,, , - , :, '' . ,' .
, . . . . . .. . . .
, " " ,, ,,, , ,: :
l~5S4~3~
to form. After cooling and standing, the mixture is filtered to remove recove~ed 2-trifluoromethylphenotniazine s;arting material. Concentration of the filtrate ~ffords a re3idual material which is taken up in ether, extracted with 1.5 N hydrochloric acid and then with 50 ml. of water.
The combined acid-aqueous extracts are made basic with sodium hydroxide and the mixture extracted with ether. The ethereal extract is dried over magnesium sulfate, filtered, and concentrated. Dlstillation of the resldual oil thrGugh a 6 cm. column provides 10-[5-methyl~ 5-methyl-l-pyrrolin-2-yl)-2-pyrrolin-2-yl]-2-ttrifluoromethyl)phenothiazine 10 free base, bop. 175-185~C./0.15 mm. Hg. The bis-pyrrolinyl phenothiazine free base is taken up in ethanol and acidified with ethanolic hydrogen chloride. Additlon of ether provides the hydrochloride salt which crystalllzed from ethanol affords analytically pure 10-[5-METHYL-1-(5-METHYL-l~PYRROLIN-2-YL)-2-PYRROLIN-2-YL~-2-(TRlFLUOROMETHYL)PHENOTHL~ZINE
15 ~YDROCHLORIDE, m.p. 250-253C. (dec.)(corr.).
Analysi~. Calcd. for C~3H22F3N3S-HCl: C, 59.28; H, 4~98;
N, 9.~2; Cl, 7.61. Found: C, 59.18; H, 5.14; N, 9.05; Cl, 7.39.
NMR delta (ppm)(CDCl3, TMS reference) 1.49d (6.5), ~ -1.55d (6.5), 2.37m, 3.12m, 4.03mJ 5.50m, 5.94m, 7.05m, 11.8bs.
Example 21.- Pharmaceutical Compositions~- The bi~-pyrrolinyl compounds of the present invention characteri~ed by Formula I are compounded with pharmacologically acceptable carriers to provide compositio~s useful in the present invention. Typical of the pharmaceutical composition3 are the ollowing:
2S A. Tablets.- The bis-pyrrolinyl compounds of Formula I
are compounded into tablets according to the following e~ample:
,, . .. .. ' . .. , " , ' : ' .. .. .
: .. . .
. .
:~3~5~
Materials ~mount 9,9-Dimethyl-10-c5~
methyl-l-(;-methyl-l-pyrrolin-2-yl)-2-pyrrolin-2-yl]ac~idan hydrochlo~ide54.9 g.
Magnesium stearate 1.3 g.
Corn starch12.4 g.
Corn starch,1.3 g.
pregelatinlzed Lactose 181.0 g.
The foregoing materials are blended in a t~in-shell blender and then granulated and pressed into tablets employing Z50 mg. each. Each table~
contains about 50 mg. of active ingredient. The tablet may be scored and quartered so that unit dose of 12.5 ~g. of active ingredient may be convenlently obtained.
B. Capsules.- The bis-pyrrollnyl compounds of Formula I ~ -are compounded into capsulPs according to ~he following example:
Materials , Amount Actlve ingredient 125.0 mg.
Lactos2 146.0 mg.
Msgneslum stearate 4.0 g.
The foregoing materials are blended in a twin-shell blender and then 111ed into No. 1 hard gelatin capsules. Each capsule contalns 125 g.
of active ingredient.
C. Solution for oral or parenteral administration.- A
sterile aqueous solution having a concentration of 40 mg. per ml.
of 9,9-dimethyl-10-~5-methyl-1-(5~methyl~1-pyrrolin-2-yl)-2-pyrrolin-2-yl]acridar. hydrochloride i9 prepared by dissolving 400 g. of the substance in 9 liters of water ~or in~ection, U.S.P., :
- 2~ -. : . . .
. .
,, -, .
.. ,- .
.
.
~554~33 ~:
ad~usting the pH to 5.5 with dilute aqueous sodiu~ hydroxide and dilution to 10 liters. This solutlon is then filtered sparkling ciear and filled into 2 ml. glass ampoules and sealed.
While specific embodiments are dlsclosed in the foregoing specification, it will be appreciated that other modifications may be made without departing from the spirit and scope of the appended claims.
, - ~9 _ : ~ " ~ ' ' ', ' . ~ '
Claims (32)
1. A process for preparing an amidine compound selected from the group consisting of 10-(bis-pyrrolinyl)phenothiazines, 10-(bis-pyrrolinyl)acridans and 10-(bis-pyrrolinyl)phenoxazines repre-sented by Formula I
Formula I
and a non-toxic pharmaceutically acceptable acid addition salt thereof wherein X is selected from the group consisting of sulfur, oxygen, or a divalent methylene radical represented by the formula -C(Z1Z2)-, wherein Z1 and Z2 are indepen-dently selected from hydrogen or straight chain lower alkyl of from 1 to 4 carbon atoms inclusive;
Y represents hydrogen, trifluoromethyl, halogen, lower alkyl of from 1 to 4 carbon atoms inclusive or lower alkoxy of 1 to 4 carbon atoms inclusive; and R represents hydrogen or straight chain lower alkyl of 1 to 4 carbon atoms inclusive which comprises reacting a compound selected from the group consisting of a phenothiazine, acridan, or phenoxazine of the formula (II) with a pyrrolidinone of the formula (III) wherein R, X and Y have the same meaning as defined above in the presence of phosphorus oxychloride in an inert solvent or reacting said phenothiazine, acridan, or phenoxazine of Formula II with 2-chloro-1-(1-pyrrolin-2-yl)-2-pyrroline hydrochloride in an inert solvent and thereafter, if desired, converting the amidine product in free base form into an acid addition salt by reaction with an inorganic or an organic acid.
Formula I
and a non-toxic pharmaceutically acceptable acid addition salt thereof wherein X is selected from the group consisting of sulfur, oxygen, or a divalent methylene radical represented by the formula -C(Z1Z2)-, wherein Z1 and Z2 are indepen-dently selected from hydrogen or straight chain lower alkyl of from 1 to 4 carbon atoms inclusive;
Y represents hydrogen, trifluoromethyl, halogen, lower alkyl of from 1 to 4 carbon atoms inclusive or lower alkoxy of 1 to 4 carbon atoms inclusive; and R represents hydrogen or straight chain lower alkyl of 1 to 4 carbon atoms inclusive which comprises reacting a compound selected from the group consisting of a phenothiazine, acridan, or phenoxazine of the formula (II) with a pyrrolidinone of the formula (III) wherein R, X and Y have the same meaning as defined above in the presence of phosphorus oxychloride in an inert solvent or reacting said phenothiazine, acridan, or phenoxazine of Formula II with 2-chloro-1-(1-pyrrolin-2-yl)-2-pyrroline hydrochloride in an inert solvent and thereafter, if desired, converting the amidine product in free base form into an acid addition salt by reaction with an inorganic or an organic acid.
2. The amidine compound selected from the group consisting of 10-(bis-pyrrolinyl)phenothiaæines, 10-(bis-pyrrolinyl)acridan and 10-(bis-pyrrolinyl)phenoxazines represented by Formula I
Formula I
and a non-toxic pharmaceutically acceptable acid addition salt thereof wherein X is selected from the group consisting of sulfur, oxygen, or a divalent methylene radical represented by the formula -C(Z1Z2)-, wherein Z1 and Z2 are indepen-dently selected from hydrogen or straight chain lower alkyl of from 1 to 4 carbon atoms inclusive;
Y represents hydrogen, trifluoromethyl, halogen, lower alkyl of from 1 to 4 carbon atoms inclusive or lower alkoxy of 1 to 4 carbon atoms inclusive; and R represents hydrogen or straight chain lower alkyl of 1 to 4 carbon atoms inclusive wherever prepared by the process of Claim 1 or an obvious chemical equivalent thereof.
Formula I
and a non-toxic pharmaceutically acceptable acid addition salt thereof wherein X is selected from the group consisting of sulfur, oxygen, or a divalent methylene radical represented by the formula -C(Z1Z2)-, wherein Z1 and Z2 are indepen-dently selected from hydrogen or straight chain lower alkyl of from 1 to 4 carbon atoms inclusive;
Y represents hydrogen, trifluoromethyl, halogen, lower alkyl of from 1 to 4 carbon atoms inclusive or lower alkoxy of 1 to 4 carbon atoms inclusive; and R represents hydrogen or straight chain lower alkyl of 1 to 4 carbon atoms inclusive wherever prepared by the process of Claim 1 or an obvious chemical equivalent thereof.
3. The process of preparing 10-[1-(1-pyrrolin-2-yl)-2-pyrrolin-2-yl]phenothiazine and a pharmaceuticallly acceptable non-toxic acid addition salt thereof in accordance with the process of Claim 1 which comprises reacting phenothiazine with 2-pyrrolidinone.
4. The compound 10-[1-(1-pyrrolin-2-yl)-2-pyrrolin-2-yl]-phenothiazine and a pharmaceutically acceptable non-toxic acid addition salt thereof whenever prepared by the process of Claim 3 or an obvious chemical equivalent thereof.
5. The process of preparing 4-chloro-10-[1-(1-pyrrolin-2-yl)-2-pyrrolin-2-yl]phenothiazine and a pharmaceutically acceptable non-toxic acid addition salt thereof in accordance with the process of Claim 1 which comprises reacting 4-chlorophenothiazine with 2-pyrrolidinone.
6. The compound 4-chloro-10-[1-(1-pyrrolin-2-yl)-2-pyrrolin-2-yl]phenothiazine and a pharmaceutically acceptable non-toxic acid addition salt thereof whenever prepared by the process of Claim 5 or an obvious chemical equivalent thereof.
7. The process of preparing 2-methoxy-10-[1-(1-pyrrolin-2-yl)-2-pyrrolin-2-]phenothiazine and a pharmaceutically acceptable non-toxic acid addition salt thereof in accordance with the process of Claim 1 which comprises reacting 2-methoxyphenothiazine and 2-pyrrolidinone.
8. The compound 2-methoxy-10-[1-(1-pyrrolin-2-yl)-2-pyrrolin-2-yl]phenothiazine and a pharamceutically acceptable non-toxic acid addition salt thereof whenever prepared by the process of Claim 7 or an obvious chemical equivalent thereof.
9. The process of preparing 10-[5-methyl-1-(5-methyl-1-pyrrolin-2-yl)-2-pyrrolin-2-yl]phenothiazine and a pharmaceutically acceptable non-toxic acid addition salt thereof in accordance with the process of Claim 1 which comprises reacting phenothiazine and 5-methyl-2-pyrrolidinone.
10. The compound 10-[5-methyl-1-(5-methyl-1-pyrrolin-2-yl)-2-pyrrolin-2-yl]phenothiazine and a pharmaceutically acceptable non-toxic acid addition salt thereof whenever prepared by the process of Claim 9 or an obvious chemical equivalent thereof.
11. The process of preparing 2-methoxy-10-[5-methyl-1-(5-methyl-1-pyrrolin-2-yl)-2-pyrrolin-2-yl]phenothiazine and a pharmaceutically acceptable non-toxic acid addition salt thereof in accordance with the process of Claim 1 which comprises reacting 2-methoxyphenothiazine and 5-methyl-2-pyrrolidinone.
12. The compound 2-methoxy-10-[5-methyl-1-(5-methyl-1-pyrrolin-2-yl)-2-pyrrolin-2-yl]phenothiazine and a pharmaceutically acceptable non-toxic acid addition salt thereof whenever prepared by the process of Claim 11 or an obvious chemical equivalent thereof.
13. The process of preparing 10-[1-(1-pyrrolin-2-yl)-2-pyrrolin-2-yl]acridan and a pharmaceutically acceptable non-toxic acid addition salt thereof in accordance with the process of Claim 1 which comprises reacting acridan and 2-chloro-1-(1-pyrrolin-2-yl)-2-pyrroline hydrochloride.
14. The compound 10-[1-(1-pyrrolin-2-yl)-2-pyrrolin-2-yl]acridan and a pharmaceutically acceptable non-toxic acid addition salt thereof whenever prepared by the process of Claim 13 or an obvious chemical equivalent thereof.
15. The process of preparing 9,9-dimethyl-10-[1-(1-pyrrolin-2-yl)-2-pyrrolin-2-yl]acridan and a pharmaceutically acceptable non-toxic acid addition salt thereof in accordance with the process of Claim 1 which comprises reacting 9,9-dimethylacridan and 2-chloro-1(1-pyrrolin-2-yl)-2-pyrroline hydrochloride.
16. Th compound of 9,9-dimethyl-10-[1-(l-pyrrolin-2-yl)-2-pyrrolin-2-yl]acridan and a pharmaceutically acceptable non-toxic acid addition salt thereof whenever prepared by the process of Claim 15 or an obvious chemical equivalent thereof.
17. The process of preparing 9,9-dimethyl-10-[5-methyl-1-(5-methyl-I-pyrrolin-2-yl)-2-pyrrolin-2-yl]acridan and a pharmaceutically acceptable non-toxic acid addition salt thereof in accordance with the process of Claim 1 which comprises reacting 9,9-dimethylacridan and 5-methyl-2-pyrrolidinone.
18. The compound 9,9-dimethyl-10-[5-methyl-1-(5-methyl-l-pyrrolin-2-yl)-2-pyrrolin-2-]acridan and a pharmaceutically acceptable non-toxic acid addition salt thereof whenever prepared by the process of Claim 17 or an obvious chemical equivalent thereof.
19. The process of preparing 10-[1-(1-pyrrolin-2-yl)-2-pyrrolin-2-yl]phenoxazine and a pharmaceutically acceptable non-toxic acid addition salt thereof in accordance with the process of Claim 1 which comprises reacting phenoxazine and 2-chloro-1-(1-pyrrolin-2-yl)pyrroline hydrochloride.
20. The compound 10-[1-(1-pyrrlin-2-yl)-2-pyrrolin-2-yl]-phenoxazine and a pharmaceutically acceptable non-toxic acid addition salt thereof whenever prepared by the process of Claim 19 or an obvious chemical equivalent thereof.
21. The process of preparing 2-chloro-10-[1-(1-pyrrolin-2-yl)-2-pyrrolin-2-yl]phenoxazine and a pharmaceutically acceptable non-toxic acid addition salt thereof in accordance with the process of Claim 1 which comprises reacting 2-chlorophenoxazine and 2-chloro-1-(1-pyrrolin-2-yl)pyrroline hydrochloride.
22. The compound 2-chloro-10-[1-(1-pyrrolin-2-yl)-2-pyrrolin-2-yl]phenoxazine and a pharmaceutically acceptable non-toxic acid addition salt thereof whenever prepared by the process of Claim 21 or an obvious chemical equivalent thereof.
23. The process of preparing 3-chloro-10-[l-(l-pyrrolin-2-yl)-2-pyrrolin-2-yl]phenoxazine and a pharmaceutically acceptable non-toxic acid addition salt thereof in accordance with the process of Claim 1 which comprises reacting 3-chlorophenoxazine and 2-chloro-1-(1-pyrrolin-2-yl)pyrroline hydrochloride.
24. The compound 3-chloro-10-[1-(1-pyrrolin-2-yl)-2-pyrrolin-2-yl]phenoxazine and a pharmaceutically acceptable non-toxic acid addition salt thereof whenever prepared by the process of Claim 23 or an obvious chemical equivalent thereof.
25. The compound 4-chloro-10-[1-(1-pyrrolin-2-yl)-2-pyrrolin-2-yl]phenoxazine and a pharmaceutically acceptable non-toxic acid addition salt thereof in accordance with the process of Claim 1 which comprises reacting 4-chlorophenoxazine and 2-chloro-1-(1-pyrrolin-2-yl)pyrroline hydrochloride.
26. The compound 4-chloro-10-[1-(1-pyrrolin-2-yl)-2-pyrrolin-2-yl]phenoxazine and a pharmaceutically acceptable non-toxic acid addition salt thereof whenever prepared by the process of Claim 25 or an obvious chemical equivalent thereof.
27. The process of preparing 2-trifluoromethyl-10-[1-(1-pyrrolin-2-yl)-2-pyrrolin-2-yl]phenoxazine and a pharmaceutically acceptable non-toxic acid addition salt thereof in accordance with the process of Claim 1 which comprises reacting 2-trifluoromethyl-phenoxazine and 2-chloro-1-(1-pyrrolin-2-yl)pyrroline hydrochloride.
28. The compound 2-trifluoromethyl-10-[1-(1-pyrrolin-2-yl)-2-pyrrolin-2-yl]phenoxazine and a pharmaceutically acceptable non-toxic acid addition salt thereof whenever prepared by the process of Claim 27 or an obvious chemical equivalent thereof.
29. The process of preparing 2-methoxy-10-[1-pyrrolin-2-yl)-2-pyrrolin-2-yl]phenoxazine and a pharmaceutically acceptable non-toxic acid addition salt thereof in accordance with the process of Claim 1 which comprises reacting 2-methoxyphenoxazine and 2-chloro-1-(l-pyrrolin-2-yl)pyrroline hydrochloride.
30. The compound 2-methoxy-10-[1-(1-pyrrolin-2-yl)-2-pyrrolin-2-yl]phenoxazine and a pharmaceutically acceptable non-toxic acid addition salt thereof whenever prepared by the process of Claim 29 or an obvious chemical equivalent thereof.
31. The process of preparing 10-[5-methyl-1-(5-methyl-1-pyrrolin-2-yl)-2-pyrrolin-2-yl]-2-(trifluoromethyl)phenothiazine and a pharmaceutically acceptable non-toxic acid addition salt thereof in accordance with the process of Claim 1 which comprises reacting 2-trifluoromethylphenothiazine and 5-methyl-2-pyrrolidinone.
32. The compound 10-[5-methyl-1-(5-methyl-1-pyrrolin-2-yl)-2-pyrrolin-2-yl]-2-(trifluoromethyl)phenothiazine and a pharmaceutically acceptable non-toxic acid addition salt thereof whenever prepared by the process of Claim 31 or an obvious chemical equivalent thereof.
Priority Applications (10)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA242,165A CA1055493A (en) | 1975-12-19 | 1975-12-19 | Phenothiazines, phenoxazines, and acridan bis-pyrrolinyl derivatives |
| ZA412A ZA76412B (en) | 1975-12-19 | 1976-01-26 | Phenothiazines phenoxazines and acridan bis-pyrrolinyl derivatives |
| SE7600806A SE411756B (en) | 1975-12-19 | 1976-01-27 | PROCEDURE FOR PREPARATION OF PHENOTIAZINES, PHENOXAZINES AND ACRIDAN-BIS-PYRROLINYL DERIVATIVES |
| GB336076A GB1474364A (en) | 1975-12-19 | 1976-01-28 | Amidine compounds |
| DE19762603627 DE2603627A1 (en) | 1975-12-19 | 1976-01-30 | NEW AMIDINE COMPOUNDS, THE METHOD OF MANUFACTURING THEM AND THE MEDICINAL PRODUCTS CONTAINING THEM |
| CH133276A CH629801A5 (en) | 1975-12-19 | 1976-02-03 | Process for the preparation of bispyrrolinyl derivatives of phenothiazines, phenoxazines and acridans |
| FR7602950A FR2340091A1 (en) | 1975-12-19 | 1976-02-03 | NEW AMIDINES, THEIR PREPARATION PROCESS AND THE MEDICINAL PRODUCT CONTAINING THEM |
| BE164074A BE838243A (en) | 1975-12-19 | 1976-02-03 | NEW AMIDINES, THEIR PREPARATION PROCESS AND THE MEDICINAL PRODUCT CONTAINING THEM |
| JP1044976A JPS5295677A (en) | 1975-12-19 | 1976-02-04 | Phenothiazines* phenoxazines and acridane biss pyrrolinyl derivatives |
| NL7601276A NL7601276A (en) | 1975-12-19 | 1976-02-09 | PROCESS FOR THE PREPARATION OF NEW AMIDINE COMPOUNDS AND SUCH COMPOUNDS CONTAINING PHARMACEUTICAL PREPARATIONS. |
Applications Claiming Priority (10)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA242,165A CA1055493A (en) | 1975-12-19 | 1975-12-19 | Phenothiazines, phenoxazines, and acridan bis-pyrrolinyl derivatives |
| ZA412A ZA76412B (en) | 1975-12-19 | 1976-01-26 | Phenothiazines phenoxazines and acridan bis-pyrrolinyl derivatives |
| SE7600806A SE411756B (en) | 1975-12-19 | 1976-01-27 | PROCEDURE FOR PREPARATION OF PHENOTIAZINES, PHENOXAZINES AND ACRIDAN-BIS-PYRROLINYL DERIVATIVES |
| GB336076A GB1474364A (en) | 1975-12-19 | 1976-01-28 | Amidine compounds |
| DE19762603627 DE2603627A1 (en) | 1975-12-19 | 1976-01-30 | NEW AMIDINE COMPOUNDS, THE METHOD OF MANUFACTURING THEM AND THE MEDICINAL PRODUCTS CONTAINING THEM |
| CH133276A CH629801A5 (en) | 1975-12-19 | 1976-02-03 | Process for the preparation of bispyrrolinyl derivatives of phenothiazines, phenoxazines and acridans |
| FR7602950A FR2340091A1 (en) | 1975-12-19 | 1976-02-03 | NEW AMIDINES, THEIR PREPARATION PROCESS AND THE MEDICINAL PRODUCT CONTAINING THEM |
| BE164074A BE838243A (en) | 1975-12-19 | 1976-02-03 | NEW AMIDINES, THEIR PREPARATION PROCESS AND THE MEDICINAL PRODUCT CONTAINING THEM |
| JP1044976A JPS5295677A (en) | 1975-12-19 | 1976-02-04 | Phenothiazines* phenoxazines and acridane biss pyrrolinyl derivatives |
| NL7601276A NL7601276A (en) | 1975-12-19 | 1976-02-09 | PROCESS FOR THE PREPARATION OF NEW AMIDINE COMPOUNDS AND SUCH COMPOUNDS CONTAINING PHARMACEUTICAL PREPARATIONS. |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1055493A true CA1055493A (en) | 1979-05-29 |
Family
ID=27578993
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA242,165A Expired CA1055493A (en) | 1975-12-19 | 1975-12-19 | Phenothiazines, phenoxazines, and acridan bis-pyrrolinyl derivatives |
Country Status (10)
| Country | Link |
|---|---|
| JP (1) | JPS5295677A (en) |
| BE (1) | BE838243A (en) |
| CA (1) | CA1055493A (en) |
| CH (1) | CH629801A5 (en) |
| DE (1) | DE2603627A1 (en) |
| FR (1) | FR2340091A1 (en) |
| GB (1) | GB1474364A (en) |
| NL (1) | NL7601276A (en) |
| SE (1) | SE411756B (en) |
| ZA (1) | ZA76412B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5430973A (en) * | 1977-08-09 | 1979-03-07 | Kaoru Hasegawa | Production of high grade carpets with long tuft by utilizing hand hook or automatic hook machine |
| JPH08657U (en) * | 1992-01-14 | 1996-04-16 | 長沢 巌 | Residual gas prevention device for simple gas stove |
| JPH0731992A (en) * | 1993-06-30 | 1995-02-03 | Takara Kogyo Kk | Filter material |
-
1975
- 1975-12-19 CA CA242,165A patent/CA1055493A/en not_active Expired
-
1976
- 1976-01-26 ZA ZA412A patent/ZA76412B/en unknown
- 1976-01-27 SE SE7600806A patent/SE411756B/en unknown
- 1976-01-28 GB GB336076A patent/GB1474364A/en not_active Expired
- 1976-01-30 DE DE19762603627 patent/DE2603627A1/en not_active Withdrawn
- 1976-02-03 BE BE164074A patent/BE838243A/en unknown
- 1976-02-03 CH CH133276A patent/CH629801A5/en not_active IP Right Cessation
- 1976-02-03 FR FR7602950A patent/FR2340091A1/en active Granted
- 1976-02-04 JP JP1044976A patent/JPS5295677A/en active Pending
- 1976-02-09 NL NL7601276A patent/NL7601276A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| SE411756B (en) | 1980-02-04 |
| FR2340091B1 (en) | 1981-12-24 |
| CH629801A5 (en) | 1982-05-14 |
| BE838243A (en) | 1976-08-03 |
| FR2340091A1 (en) | 1977-09-02 |
| ZA76412B (en) | 1977-01-26 |
| GB1474364A (en) | 1977-05-25 |
| NL7601276A (en) | 1977-08-11 |
| JPS5295677A (en) | 1977-08-11 |
| SE7600806L (en) | 1977-07-28 |
| DE2603627A1 (en) | 1977-08-11 |
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