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Sommaire du brevet 1118419 

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L'apparition de différences dans le texte et l'image des Revendications et de l'Abrégé dépend du moment auquel le document est publié. Les textes des Revendications et de l'Abrégé sont affichés :

  • lorsque la demande peut être examinée par le public;
  • lorsque le brevet est émis (délivrance).
(12) Brevet: (11) CA 1118419
(21) Numéro de la demande: 321292
(54) Titre français: ACIDES HEXAHYDRO-1-MERCEPTOACYL-1H-AZEPINE-2- CARBOXYLIQUES ET LEURS ESTERS
(54) Titre anglais: HEXAHYDRO-1-MERCAPTOACYL-1H-AZEPINE-2- CARBOXYLIC ACIDS AND ESTERS
Statut: Périmé
Données bibliographiques
(52) Classification canadienne des brevets (CCB):
  • 260/241.51
(51) Classification internationale des brevets (CIB):
  • C07D 223/06 (2006.01)
(72) Inventeurs :
  • BERNSTEIN, JACK (Etats-Unis d'Amérique)
  • LOSEE, KATHRYN A. (Etats-Unis d'Amérique)
(73) Titulaires :
  • SQUIBB (E.R.) & SONS, INC. (Afghanistan)
(71) Demandeurs :
(74) Agent: OSLER, HOSKIN & HARCOURT LLP
(74) Co-agent:
(45) Délivré: 1982-02-16
(22) Date de dépôt: 1979-02-12
Licence disponible: S.O.
(25) Langue des documents déposés: Anglais

Traité de coopération en matière de brevets (PCT): Non

(30) Données de priorité de la demande:
Numéro de la demande Pays / territoire Date
882,463 Etats-Unis d'Amérique 1978-03-01

Abrégés

Abrégé anglais


HA163

ABSTRACT

HEXAHYDRO-l-MERCAPTOACYL-lH-AZEPINE-2-CARBOXYLIC
ACIDS AND ESTERS
New hexahydro-l-mercaptoacyl-lH-azepine-2-carboxylic
acids and esters which have the general formula


Image


and the corresponding disulfides are useful as hypo-
tensive agents.

Revendications

Note : Les revendications sont présentées dans la langue officielle dans laquelle elles ont été soumises.




The embodiments of the invention in which an exclusive
property or privilege is claimed are defined as follows:-
1. A process for preparing a compound of the formula

Image


wherein R and R1 each is hydrogen or lower alkyl
R2 is hydrogen or lower alkanoyl; and
n is 0 or 1, and basic salts thereof,
characterized by reacting a hexahydro-lH-azepine-2-
carboxylic acid or lower alkyl ester thereof or basic
salt thereof having the formula

Image

with an acyl halide of the formula

Image

wherein R3 is lower alkanoyl and X is halogen and R1 and
n are as previously defined, to form a product wherein R2
is lower alkanoyl and further subjecting said product to
ammonolysis to form a product wherein R2 is hydrogen.
2. A process according to claim 1 wherein R is hydrogen.
3. A process according to claim 1 wherein R1 is
hydrogen or methyl.
4. A process according to claim 1 wherein R2 is acetyl.
5. A process as in claim 1 wherein n is 1.
6. A process as in claim 1 wherein n is 1, R1 is
hydrogen or methyl and R2 is acetyl.
7. A process as in claim 1 wherein n is 1, R1 is
hydrogen or methyl and R2 is hydrogen.
8. A compound of the formula

Image


HA163

wherein R and R1 each is hydrogen or lower alkyl;
R2 is hydrogen or lower alkanoyl; and
n is 0 or l, and basic salts thereof,
whenever prepared by the process of claim 1.
9. A compound according to claim 8 wherein R is
hydrogen, whenever prepared by the process of claim 2.
10. A compound according to claim 8 wherein R1 is
hydrogen or methyl, whenever prepared by the process of
claim 3.
11. A compound according to claim 8 wherein R2 is
acetyl, whenever prepared by the process of claim 4.
12. A compound as in claim 8 wherein n is 1, whenever
prepared by the process of claim 5.
13. A compound as in claim 8 wherein n is 1, R1 is
hydrogen or methyl and R2 is acetyl, whenever prepared by
the process of claim 6.
14. A compound as in claim 8 wherein n is 1, R1 is
hydrogen or methyl and R2 is hydrogen, whenever prepared
by the process of claim 7.


Description

Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.


- `~
1118419 HAl63
,.

HEXAHYDRO-l-MERCAPTOACYL-lH-AZEPINE-2-CARBOXYLIC
ACIDS AND ESTERS

This invention relates to new hexahydro-l-
mercaptoacyl-lH-azepine-2-carboxylic acids and esters
which have the general formula~
(I) o R

C~ ~ :
OOR ~ ~
wherelll R lS; hydrogen, lower qlkyl or a
salt forming ion;
~ Rl~is~hydrogen or lower alkyl;
;~ ~ 15 R2~is~hydrogen or~ lower alkanoyl;
n is 0 or l;
and to the~corresponding dlsulfides, i.~e. wherein R2 is
. ;i , , ~ : ' R
S CH2 ~(CH)n CO


and R,~Rl, and~n have~the ~same~meanlng as above.
~- The asterisks indicate~asymmetric carbon atoms.
25~ The carbon in the mercaptoacyl~sidechain is asymmetric
-~ when Rl is other than hydrogen~
:
;~ The lower alkyl groups represented by the
` symbols are straight or branched~ chain hydrocarbon
radicals having up to seven carbons like methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, t-butyl and the
like. The Cl-C4 member~, especially Cl-C2 members, are
preferred.

:: :

:




- `~ - . :. : : :
: , ,: ' :', ,~ ,

': :
: , -

~ 419 HA163


The ~ower alkanoyl groups are those having the
acyl radicals of the lower (up to seven carbon) fatty
acids like acetyl, propionyl, butyryl, isobutyryl and
the like. Similarly, those lower alkanoyl groups
having up to four carbons, and especially acetyl, are
preferred.
The salt forming ions represented by R are the
ions derived from inorganic or organic bases, including
such salts as alkali metal salts, especially sodium
and potassium, alkaline earth metal salts, especially
calcium and maqnesium, aluminum, dicyclohexylamine salt,
benzathine salt, N-methylglucamine salt, hydrabamine salt,
salts with naturally ocurring amino acids like arginine,
lysine and the like, lower alkylamine salts like methyl-
amine, ethylamine, dimethylamine, triethylamine salts,
etc.
The compounds of formula I are produced by
reacting hexahydro-lH-azepine-2-carboxylic acid (J.
Med. Chem. 14, 501 (1971)) or lower alkyl ester or
Z0 salt thereof with an acyl halide (preferably chloride)
having the formula
(II) 1l 1l
X-c-(cH)n-cH2-s-R3
wherein X is halogen and R3 is lower alkanoyl,
in an inert organic solvent like dimethylaceta~mide,
dimethylformamide, or the like, in the presence of
an organic base like N-methylmorpholine, triethylamine,
pyridine at a temperature in the range of about 20 -
100 C.
The acyl group can be removed, making R2=H, by

4i9
HA163


ammonolysis, uslng aqueous ammonia.
When hexahydro~ -azepine-2-carboxylic acid is
used as the starting material, the product carboxylic
acid can be converted to the lower alkyl ester by
conventional esterification techniques, e.g. with a
diazoalkane like diazomethane, l-n-butyl-3-p-tolyl-
triazene or the like.
When R ln the starting material is lower alkyl,
the product ester can be converted to the free carboxylic
acid by conventional procedures such as hydrolysis
or, in the c~se of the t-butyl ester with trifluoro-
acetic acid and anisole.
The disulfides, i.e., compounds of formula I
wherein R2 is
R
-S-CH2-(CH)n-CO-N ~


are produced by direct oxidation of a compound of
formula I in which R2 i5 hydrogen, e.g., with iodine,
to obtain the symmetrical bis compound.
The products of this invention have one or
more asymmetric carbon atoms as indicated by the
asterisks above. The compounds accordingly exist in
stereoisomeric forms or in racemic mixtures thereof.
All of these are within the scope of the invention.
In general, the L-isomer with respect to the carbon
of the hexahydroazepine carboxylic acid constitutes
the preferred isomeric form.




,,

~ 9 HAl63


The compounds of this invention form basic
salts with various inorganic and organic bases as
described above. They are also included in the scope
of the invention. The non-toxic, physiologically
acceptable salts are preferred, although other salts
are also useful, e.g., in isolation or purifying
the product. The salts are formed in conventian
manner by reacting the free acid form of the product
with one or more equivalents of the appropriate
base providing the desired salt ion in a solvent or
medium in wh-cn the salt is insolubie, or in water and
removing the water by freeze drying. By neutralizing
the salt by conventional methods the free acid form
can be obtained, and if desired, another salt formed.
Additional experimental details are found
in the examples which are preferred embodiments and
also serve as models for the preparation of other
members of the group.
The compounds of this invention inhibit the
conversion of the decapeptide angiotensin I to
angiotensin II by angiotensin converting enzyme and
therefore are useful in reducing or relieving angio-
tensin related hypertension. By the administration of
a composition containing one or a combination of
compounds of formula I or physiologically acceptable
salt thereof, angiotensin dependent hypertension in the
species of mammal e.g., rats, cats, dogs, etc.,
suffering therefrom is alleviated. A single dose, or
preferably two to four divided daily doses, provided
on a basis of about 0.1 to lO0 mg. per kilogram per
day, preferably about 1 to 50 mg. per kilogram per day
is appropriate to reduce blood pressure as indicated
in the animal model experiments described by S. L.
Engel, T. R. Schaeffer, M. H. Waugh and B . Rubin, Proc.
Soc. Exp. Biol. Med. 143, 483 (1973). The substance

~184~9 HAl63


is preferably administered orally, but parenteral
routes such as subcutaneously, intramuscularly,
intravenously or intraperitonealy can also be employed.
The compounds of this invention can be utilized
to achieve the reduction of blood pressure by form-
ulatin~g in conventional compositions such as tablets,
capsules or eIixirs for oral administration or in
~sterile solutions or suspensions for parenteral admin-
~ istration. About I0 to 500 mg. of a compound or
mixture of compounds of formula I or physiologically
acceptable sa;~ is compounded with a physiologically
acceptable vehicle, carrier, ~excipient, binder,
preservative, stabilizer,~flavor, etc., in a unit
dosage form as called for by accepted pharmaceutical
practice. The amount of active~substance in these
aompositions or preparations is such that a suitable
dosage in the range indlcated is obtained.
Sterile compositions for injection can be
formulated acaording to conventional pharmaceutical
praatice by dissolving or~suspending the active
substance in a vehicle such as water for ~injection,
a naturally oaaurringvegetable oll Iike sesame oil, oxxnut ;~-
oil, peanut oilj aottonseed oil, etc., or a synthetic
fatty vehicle like ethyl oleate or the like. Buffers,
preservatives, antioxidants and the like can be incor-
porated as required.
The following examples are illustrative of the
invention and constitute especially preferred embodi-
ments. All temperatures are in degrees aelsius.




- -
.. . .
.. . . , ~.
:

1~18419
HA163


Example 1
a) l-t3-Acetylthio-l-oxopropyl)hexahydro-lH-azepine-2-
carboxylic acid
To a suspension of 3.22g of hexahydro-lH-azepine-
2-carboxylic acid and 4.04g of N-methylmorpholine in
100 ml. of dimethylacetamide there is added dropwise,
with vigorous stirring at 25 , 3.32g of 3-acetylthio-
propionyl chloride. There is a slight temperature
rise during this addition. The reaction mixture is
heated on a steam bath (internal temperature 85 - 90 )
for 4 hrs., ~uring which time a clear solution forms.
The reaction mixture is cooled and the precipitated
solid of N-methylmorpholine hydrochloride is removed by
filtration.
The filtrate is concentrated under reduced pressure
to remove the solvent and the residue is triturated with
dilute hydrochloric acid. The mixture is extracted
with ethyl acetate which is then dried with anhydrous
magnesium sulfate and concentrated under reduced
pressure to yield 1-(3-acetylthio-1-oxopropyl)hexahydro-
lH-azepine-2-carboxylic acid as a viscous oil.
b) Hexahydro-1-(3-mercapto-1-oxopropyl)-lH-azepine-2-
carboxylic acid
A solution of 4.9g of 1-~3-acetylthio-1-
oxopropyl)hexahydro-lH-azepine-2-carboxylic acid in
dilute aqueous ammonia (30 ml of H2O and 12 ml. of
concentrated aqueous ammonia) is stirred under nitrogen,
at 10 for 30 mins. and at room temperature for 3 hrs.
The reaction mixture is then extracted with ethyl
acetate and made strongly acidic with 20% hydrochloric
acid. The precipitated oil is extracted into fresh
ethyl acetate and this solution dried over anhydrous
magnesium sulfate. The solvent is removed under

-
~ 419 HA163


reduced pressure, leaving a viscous oily residue. This
is dissolved in benzene and lyophilized to yield the
desired hexahydro~ 3-mercapto-1-oxopropyl)-lH-azepine-
2-carboxylic acid as a hydrated viscous oil. Analysis
S calcd. for CloH17NO3S-H2O: C, 48.17~, H, 7.68~;
N, 5.60~; S, 12.85%.
Found: C, 48.39%; H, 7.~7~
N, 5.40~; S, 13.02%.
Example 2
1-(2-Acetylthio-l-oxoethyl)hexahydro-lH-azepine-2-
carboxylic acid
.




Following the procedure of Example la but
substituting an equivalent amount of acetylthioacetyl
chloride for the 3-acetylthiopropionyl chloride, there
is obtained the desired 1-(2-acetylthio-1-oxoethyl)
hexahydro-lH-azepine-2-carboxylic acid.
Example 3
Hexahydro-1-(2-mercepto-1-oxoethyl)-lH-azepine-2-
carboxylic acid.
Following the procedure of Example lb but
substituting an equivalent amount of l-(2-acetylthio-
l-oxoethyl)hexahydro-lH-azepine-2-carboxylic acid for
the l-(3-acetylthio-1-oxopropyl)hexahydro-1_-azepine-

2-carboxylic acid, there is obtained the desired
hexahydro-l-(2-mercapto-1-oxoethyl)-lH-azepine-2-
carboxylic acid.
Example 4
1-(3-(Acetylthio)-2-methyl-1-oxopropyl)hexahydro-lH-
azepine-2-carboxylic acid.
Following the procedure of Example la but
substituting an equivalent amount of 3-(acetylthio)-


~ 4i9 HA163


2-methylpropionyl chloride for the 3-acetylthiopropionyl
chloride there is obtained the desired l-(3-acetylthio)-
2-methyl-1-oxopropyl)hexahydro-lH-azepine-2-carboxylic
acid.
Example S
Hexah dro-1-(3-merca to-2-methyl-1-oxoproPyl)-lH-
Y P
azepine-2-carboxylic acid.
Following the procedure of Example lb but
substituting an equivalent amount of l-(3-(acetylthio)-
2-methyl-1-oxopropyl)-hexahydro-lH-azepine-2-carboxylic
acid for the l-(3-acetylthio-1-oxopropyl~-hexahydro-
lH-azepine-2-carboxylic acid there is obtained the
desired hexahydro-l-(3-mercapto-2-methyl-1-oxo-
5 propyl)-lH-azepine-2-carboxylic acid.
Example 6
1,1'-(Dithiobis(l-oxopropane-3,1-diyl))bis(hexahydro-
lH-aze~ine-2-carboxYlic acid).
-

Three grams of hexahydro-1-(3-mercapto-1-
oxopropyl)-lH-azepine-2-carboxylic acid is dissolved in
75 ml. of water by adding sufficient lN-sodium
hydroxide to adjust the pH to 6.5. To this solution
there i8 added dropwise, with vigorous stirring, 26 ml.
of a 0.5M iodine solution (95~ ethanol), while maintain-

ing the pH between 5.5 and 6.5. After 15 mins., the
reaction mixture is treated with an aqueous sodium
thiosulfate solution to remove unreacted iodine. The
reaction mixture lS concentrated under reduced pressure
and is then acidified with 20% hydrochloric acid. The
precipitated product is extracted into ethyl acetate,
the solvent dried over anhydrous magnesium sulphate and
concentrated under reduced pressure to yield the desired
1,1'-(dithiobis(l-oxopropane-3,1-diyl)bis(hexahydro-
lH-azepine-2-carboxylic acid).

Dessin représentatif

Désolé, le dessin représentatatif concernant le document de brevet no 1118419 est introuvable.

États administratifs

Pour une meilleure compréhension de l'état de la demande ou brevet qui figure sur cette page, la rubrique Mise en garde , et les descriptions de Brevet , États administratifs , Taxes périodiques et Historique des paiements devraient être consultées.

États administratifs

Titre Date
Date de délivrance prévu 1982-02-16
(22) Dépôt 1979-02-12
(45) Délivré 1982-02-16
Expiré 1999-02-16

Historique d'abandonnement

Il n'y a pas d'historique d'abandonnement

Historique des paiements

Type de taxes Anniversaire Échéance Montant payé Date payée
Le dépôt d'une demande de brevet 0,00 $ 1979-02-12
Titulaires au dossier

Les titulaires actuels et antérieures au dossier sont affichés en ordre alphabétique.

Titulaires actuels au dossier
SQUIBB (E.R.) & SONS, INC.
Titulaires antérieures au dossier
S.O.
Les propriétaires antérieurs qui ne figurent pas dans la liste des « Propriétaires au dossier » apparaîtront dans d'autres documents au dossier.
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Description du
Document 
Date
(yyyy-mm-dd) 
Nombre de pages   Taille de l'image (Ko) 
Dessins 1994-02-02 1 7
Revendications 1994-02-02 2 55
Abrégé 1994-02-02 1 13
Page couverture 1994-02-02 1 12
Description 1994-02-02 8 323