CA1153387A - Substituted amino acids, their use and production and pharmaceutical products containing same - Google Patents
Substituted amino acids, their use and production and pharmaceutical products containing sameInfo
- Publication number
- CA1153387A CA1153387A CA000329666A CA329666A CA1153387A CA 1153387 A CA1153387 A CA 1153387A CA 000329666 A CA000329666 A CA 000329666A CA 329666 A CA329666 A CA 329666A CA 1153387 A CA1153387 A CA 1153387A
- Authority
- CA
- Canada
- Prior art keywords
- group
- signifies
- general formula
- acid
- hydrogen atom
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
- A01N37/12—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing the group, wherein Cn means a carbon skeleton not containing a ring; Thio analogues thereof
-
- 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
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Agronomy & Crop Science (AREA)
- Wood Science & Technology (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Gastroenterology & Hepatology (AREA)
- Pest Control & Pesticides (AREA)
- Plant Pathology (AREA)
- Dentistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Zoology (AREA)
- Environmental Sciences (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Soy Sauces And Products Related Thereto (AREA)
- Solid-Sorbent Or Filter-Aiding Compositions (AREA)
- Peptides Or Proteins (AREA)
- Saccharide Compounds (AREA)
Abstract
ABSTRACT
Acylbiphenylylaminoalkanoic acids of the general formula I
(I),
Acylbiphenylylaminoalkanoic acids of the general formula I
(I),
Description
~ S33~7 The Invention relates to substituted amino acids, their use and production and pharmaceutlcal products containing them.
The compounds according to the invention are used in the pharmaceutical industry for the preparation of medicaments.
In the investigation of N-benzoyl-anilinoalkanecarboxylic -` acids (D.Evans et al., J.Med.Chem. 12 il969) 1006-10) the corresponding butyric acids showed no action of inhibiting inflammation, whilst in German published unexamined Patent Application DE-OS 19 17 036 N-acyl-anilinoalkanoic acids with a choleretic action are described, to which there are also ascribed further effects (DE-OS 2 450 680). a-Phenyl-benzyl-idene-~-amino-alkanoic acids and their derivatives are said to be used in agents with an anti-epileptic action (DE-OS
The compounds according to the invention are used in the pharmaceutical industry for the preparation of medicaments.
In the investigation of N-benzoyl-anilinoalkanecarboxylic -` acids (D.Evans et al., J.Med.Chem. 12 il969) 1006-10) the corresponding butyric acids showed no action of inhibiting inflammation, whilst in German published unexamined Patent Application DE-OS 19 17 036 N-acyl-anilinoalkanoic acids with a choleretic action are described, to which there are also ascribed further effects (DE-OS 2 450 680). a-Phenyl-benzyl-idene-~-amino-alkanoic acids and their derivatives are said to be used in agents with an anti-epileptic action (DE-OS
2 634 288). In further German published unexamined Patent Applications (DE-OS 2 131 626, 2 131 674, 2 131 675, 2 131 679 and 2 131 680) trialkoxy-benzoyl-aminoalkanecarb-oxylic acids are described which shall be used for the prophylaxis and treatment of the cardiac infarction. Now a new class of acylbiphenylylaminoalkanoic acids has been synthesised which are not mentioned in the publications cited nor are they rendered obvious by them. Furthermore it has been found that these acylbiphenylylaminoalkanoic acids possess interesting and particularly advantageous '~
pharmacological properties.
The Invention relates to acylblphenylylaminoalkanolc aclds of the general formula I
R1 _ CO - ~ - CnH2n - COOH (I), A
! in which R1 signifies an aliphatic or alicyclic hydrocarbon radical or an optionally substituted phenyl group, A signifies an optionally substituted and/or hydrogenated biphenylyl radical, n signifies a positive whole number from 3 to 5, and their salts of inorganic or organic bases.
As aliphatic hydrocarbon radicals which may be saturated or unsaturated, one may use straight or branched alkyl radicals 15 with 1 to 7 carbon atoms. Straight alkyl radicals are the methyl, ethyl, propyl, butyl, pentyl, hexyl or heptyl radical, of which those with 1 to 5, particularly 1 to 3 J carbon atoms are preferred. Branched alkyl radicals with 3 to 7 carbon atoms are, for example, the isopropyl, isobutyl, sec.-butyl or 20 tert~-butyl radical, of which those with 3 to 5, particularly with 3 carbon atoms are preferred. Unsaturated hydrocarbon radicals are alkenyl and alkinyl radicals with 2 to 7 carbon atoms, for example the ethenyl, the ethinyl, the 1-propenyl, 1,3-butadienyl, 2-butlnyl ra~ical, of whlch the ,` .
:
~533t37 .1 1-propenyl radical is preferred. As alicycllc hydrocarbon radicals one may use cycloalkyl radicals with 3 to 10 carbon atoms, for example the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl radical, of which those with 5 to 7 carbon atoms are preferred.
As optionally substituted phenyl groups one may use those of the formula R2 ~ R
in which R2, R3 and R4 are the same or different and signify a hydrogen atom, a halogen atom, an alkyl group, a hydroxy group, an alkoxy group, an acyloxy group, an optionally sub-stituted amino group, a nitro group or a trifluoromethylgroup. As halogen atoms R2, R and R one may use fluorine, chlorine or bromine, preferably fluorine and chlorine, espe-cially chlorine. As alkyl groups or alkoxy groups R2, R3 and R4 one may mention inter alia those with 1 to 4 carbon atoms, of which tho5e with 1 to 3, particuIarly those with 1 carbon atom are preferred. As acyloxy groups one may consider inter alia -O-CO-R1 groups, in which R1 has the meaning given above, of which the alkanoyloxy group with 1 to 7, especially 2 to 5 carbon atoms, particularly the acetoxy group, are preferred.
.~
~15~3~7 Besides the unsubstituted amino group one may use as substi-tuents R2, R3 and R4 preponderantly substituted amlno groups, of which for example one may mention alkylamino and dialkyl-amino groups with 1 to 4, preferably 1 or 2, carbon atoms in the alkyl radical, as well as acylamino groups wlth the usual acyl groups used for protecting amino groups, such as alkanoyl groups with 2 to 5 carbon atoms.
As biphenylyl radicals one may use the 2-, 3- or 4-biphenylyl radical. Partially hydrogenated biphenylyl radi-cals are for example the 4-cyclohexyl-phenyl radical, the 4-phenylcyclohexyl radical, the 2-cyclohexylphenyl radical.
As substituents one may use halogen atoms, for example fluor~ne, chlorine or bromine, preferablychlorine, alkyl or alkoxy groups with 1 to 4, preferably 1, carbon atoms, optionally substituted amino groups,hydroxy or nitro groups.
As salts one may use salts of inorganic and organic bases. Pharmacologically incompatible salts are converted by known methods into pharmacologically, that is to say biolo-gically, compatible salts, which are preferred among the salts according to the Invention As cations for the salt formation one uses mainly the cations of the alkali metals, alkaline earth metals or earth metals, but it is also possible to use the corresponding cations of organic nitrogen bases, such as amines, aminoalkanols, amino sugars or basic amino acids.
~l~1533~37 For example one may mention the salts of lithium, sodium, potassium , magnesium, calcium, aluminium, ethylenediamine, dimethylamine, diethylamine, morpholine, plperidlne, pipera-zine, methylcyclohexylamine, benzylamine, ethanolamine, diethanolamine, triethanolamine, tris-(hydroxymethyl)-amino-methane, 2-amino-2-methyl-propanol, 2-amino-2-methyl-1,3-~` propandiol, glucamine, N-methylglucamine, glucosamine, N-methylglucosamine, lysine, ornithine, arginine, quinoline.
A modification of the Invention consists of acylbi-10 phenylylaminoalkanoic acids of the general formula I*
R - CO - I - Cn*H2n* - COOH (I*), in which R signifies an aliphatic hydrocarbon radical with 1 to 7 ~; 15 carbon atoms, an alicyclic hydrocarbon radical with 3 .- to 10 carbon atoms or a phenyl radical , R2 :~ ~ 4 *
R
A* signifies a group of the formula R5 R6* R5* R6* R R6*
, ~ ~ or ~ \
'' ~ '~
`' ~ ` ` :
., ` ~-1~533t~7 ' n* signifies a positive whole number from 3 to S, R2, R3 and R4 are the same or diferent and signlfy a hydrogen atom, a halogen atom, a hydroxy group, an alkyl group with 1 to 4 carbon atoms, an alkoxy group with 1 to 4 carbon atoms, an alkanoyloxy group with 2 to 5 carbon atoms, a nitro group or a trifluoromethyl group, ~! R5 and R6 are the same or different and signify a hydrogen atom, a haiogen atom, a methyl group, a methoxy group, a . hydroxy group or a nitro group, 10 and their salts of inorganic or organic bases.
Another modification of the Invention consists of acylbi-phenylylaminoalkanoic acids of the general formula I**
.. R1 - CO - I - Cn**H2n** - COOH (I**), A**
: 15 in which R1 signifies an aliphatic hydrocarbon radical with 1 to 5 carbon atoms, an alicyclic hydrocarbon radical with 5 to 7 carbon atoms or a phenyl radical ~2**
~ R
\~
R
A** signifies a group of the formula 1~5;~3E37 5** R6** R5** R6**
~ or n** signifies a positive whole number from 3 to 5, 2**
R signifies a hydrogen atom, R3 and R4 are the same or different and signify a hydrogen atom, a halogen atom, a hydroxy group, a methoxy group, a methyl group, an alkanoyloxy group with 2 to 5 carbon atoms, a nitro group or a trifluoromethyl group, . one of the substituents R5 or R6 signifies a hydrogen atom and the other signifies a hydrogen atom, a halogen atom, 15 a methyl group, a methoxy group, a hydroxy group or a nitro group, and their salts of inorganic or organic bases.
A further modification of the Invention consists of acylbi-phenylylaminoalkanoic acids of the general formula I***
R1 ~ CO ~ 7 ~ Cn***H2n*** (I***)t A***
in which 1 ***
R signifies an aliphatic hydrocarbon radical with 1 to . - 8 -,' `
:' 1~5;~l37
pharmacological properties.
The Invention relates to acylblphenylylaminoalkanolc aclds of the general formula I
R1 _ CO - ~ - CnH2n - COOH (I), A
! in which R1 signifies an aliphatic or alicyclic hydrocarbon radical or an optionally substituted phenyl group, A signifies an optionally substituted and/or hydrogenated biphenylyl radical, n signifies a positive whole number from 3 to 5, and their salts of inorganic or organic bases.
As aliphatic hydrocarbon radicals which may be saturated or unsaturated, one may use straight or branched alkyl radicals 15 with 1 to 7 carbon atoms. Straight alkyl radicals are the methyl, ethyl, propyl, butyl, pentyl, hexyl or heptyl radical, of which those with 1 to 5, particularly 1 to 3 J carbon atoms are preferred. Branched alkyl radicals with 3 to 7 carbon atoms are, for example, the isopropyl, isobutyl, sec.-butyl or 20 tert~-butyl radical, of which those with 3 to 5, particularly with 3 carbon atoms are preferred. Unsaturated hydrocarbon radicals are alkenyl and alkinyl radicals with 2 to 7 carbon atoms, for example the ethenyl, the ethinyl, the 1-propenyl, 1,3-butadienyl, 2-butlnyl ra~ical, of whlch the ,` .
:
~533t37 .1 1-propenyl radical is preferred. As alicycllc hydrocarbon radicals one may use cycloalkyl radicals with 3 to 10 carbon atoms, for example the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl radical, of which those with 5 to 7 carbon atoms are preferred.
As optionally substituted phenyl groups one may use those of the formula R2 ~ R
in which R2, R3 and R4 are the same or different and signify a hydrogen atom, a halogen atom, an alkyl group, a hydroxy group, an alkoxy group, an acyloxy group, an optionally sub-stituted amino group, a nitro group or a trifluoromethylgroup. As halogen atoms R2, R and R one may use fluorine, chlorine or bromine, preferably fluorine and chlorine, espe-cially chlorine. As alkyl groups or alkoxy groups R2, R3 and R4 one may mention inter alia those with 1 to 4 carbon atoms, of which tho5e with 1 to 3, particuIarly those with 1 carbon atom are preferred. As acyloxy groups one may consider inter alia -O-CO-R1 groups, in which R1 has the meaning given above, of which the alkanoyloxy group with 1 to 7, especially 2 to 5 carbon atoms, particularly the acetoxy group, are preferred.
.~
~15~3~7 Besides the unsubstituted amino group one may use as substi-tuents R2, R3 and R4 preponderantly substituted amlno groups, of which for example one may mention alkylamino and dialkyl-amino groups with 1 to 4, preferably 1 or 2, carbon atoms in the alkyl radical, as well as acylamino groups wlth the usual acyl groups used for protecting amino groups, such as alkanoyl groups with 2 to 5 carbon atoms.
As biphenylyl radicals one may use the 2-, 3- or 4-biphenylyl radical. Partially hydrogenated biphenylyl radi-cals are for example the 4-cyclohexyl-phenyl radical, the 4-phenylcyclohexyl radical, the 2-cyclohexylphenyl radical.
As substituents one may use halogen atoms, for example fluor~ne, chlorine or bromine, preferablychlorine, alkyl or alkoxy groups with 1 to 4, preferably 1, carbon atoms, optionally substituted amino groups,hydroxy or nitro groups.
As salts one may use salts of inorganic and organic bases. Pharmacologically incompatible salts are converted by known methods into pharmacologically, that is to say biolo-gically, compatible salts, which are preferred among the salts according to the Invention As cations for the salt formation one uses mainly the cations of the alkali metals, alkaline earth metals or earth metals, but it is also possible to use the corresponding cations of organic nitrogen bases, such as amines, aminoalkanols, amino sugars or basic amino acids.
~l~1533~37 For example one may mention the salts of lithium, sodium, potassium , magnesium, calcium, aluminium, ethylenediamine, dimethylamine, diethylamine, morpholine, plperidlne, pipera-zine, methylcyclohexylamine, benzylamine, ethanolamine, diethanolamine, triethanolamine, tris-(hydroxymethyl)-amino-methane, 2-amino-2-methyl-propanol, 2-amino-2-methyl-1,3-~` propandiol, glucamine, N-methylglucamine, glucosamine, N-methylglucosamine, lysine, ornithine, arginine, quinoline.
A modification of the Invention consists of acylbi-10 phenylylaminoalkanoic acids of the general formula I*
R - CO - I - Cn*H2n* - COOH (I*), in which R signifies an aliphatic hydrocarbon radical with 1 to 7 ~; 15 carbon atoms, an alicyclic hydrocarbon radical with 3 .- to 10 carbon atoms or a phenyl radical , R2 :~ ~ 4 *
R
A* signifies a group of the formula R5 R6* R5* R6* R R6*
, ~ ~ or ~ \
'' ~ '~
`' ~ ` ` :
., ` ~-1~533t~7 ' n* signifies a positive whole number from 3 to S, R2, R3 and R4 are the same or diferent and signlfy a hydrogen atom, a halogen atom, a hydroxy group, an alkyl group with 1 to 4 carbon atoms, an alkoxy group with 1 to 4 carbon atoms, an alkanoyloxy group with 2 to 5 carbon atoms, a nitro group or a trifluoromethyl group, ~! R5 and R6 are the same or different and signify a hydrogen atom, a haiogen atom, a methyl group, a methoxy group, a . hydroxy group or a nitro group, 10 and their salts of inorganic or organic bases.
Another modification of the Invention consists of acylbi-phenylylaminoalkanoic acids of the general formula I**
.. R1 - CO - I - Cn**H2n** - COOH (I**), A**
: 15 in which R1 signifies an aliphatic hydrocarbon radical with 1 to 5 carbon atoms, an alicyclic hydrocarbon radical with 5 to 7 carbon atoms or a phenyl radical ~2**
~ R
\~
R
A** signifies a group of the formula 1~5;~3E37 5** R6** R5** R6**
~ or n** signifies a positive whole number from 3 to 5, 2**
R signifies a hydrogen atom, R3 and R4 are the same or different and signify a hydrogen atom, a halogen atom, a hydroxy group, a methoxy group, a methyl group, an alkanoyloxy group with 2 to 5 carbon atoms, a nitro group or a trifluoromethyl group, . one of the substituents R5 or R6 signifies a hydrogen atom and the other signifies a hydrogen atom, a halogen atom, 15 a methyl group, a methoxy group, a hydroxy group or a nitro group, and their salts of inorganic or organic bases.
A further modification of the Invention consists of acylbi-phenylylaminoalkanoic acids of the general formula I***
R1 ~ CO ~ 7 ~ Cn***H2n*** (I***)t A***
in which 1 ***
R signifies an aliphatic hydrocarbon radical with 1 to . - 8 -,' `
:' 1~5;~l37
3 carbon atoms or a phenyl radlcal R2* **
R
R~
A*** signifies a group of the formula R5**~ 6*** 5**~ 6***
~ or ~
n*** signifies a positive whole number from 3 to 5, 2***
R signifies a hydrogen atom, R3 and R4 are the same or different and signify a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxy group, a methoxy group or a trifluoromethyl ; - 15group, 5*** 6***
one of the substituents R or R signifies a hydrogen d atom and the other signifies a hydrogen atom or a ` methoxy group, and their salts of inorganic or organic bases.
A preferred form of embodiment of the Invention con-sists of acylbiphenylylaminoalkanoic acids of the general formula I****
R1**** _ C0 - N - Cn****H2n**** - C00~ (I
A****
in which . ~
,, : .
, , ~
33~
, ~**
R signifies an alkyl group with 1 to 3 carbon atoms, an alkenyl group with 2 or 3 carbon atoms or a phenyl group 2****
R3****
R
R~
A*** signifies a group of the formula R5**~ 6*** 5**~ 6***
~ or ~
n*** signifies a positive whole number from 3 to 5, 2***
R signifies a hydrogen atom, R3 and R4 are the same or different and signify a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxy group, a methoxy group or a trifluoromethyl ; - 15group, 5*** 6***
one of the substituents R or R signifies a hydrogen d atom and the other signifies a hydrogen atom or a ` methoxy group, and their salts of inorganic or organic bases.
A preferred form of embodiment of the Invention con-sists of acylbiphenylylaminoalkanoic acids of the general formula I****
R1**** _ C0 - N - Cn****H2n**** - C00~ (I
A****
in which . ~
,, : .
, , ~
33~
, ~**
R signifies an alkyl group with 1 to 3 carbon atoms, an alkenyl group with 2 or 3 carbon atoms or a phenyl group 2****
R3****
4****
,` A**** signifies a group of the formula
,` A**** signifies a group of the formula
5**** IR6****
/~3 O
n**** signifies a positive whole number from 3 to 5, 2****
~ R signifies a hydrogen atom, - R3 signifies a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxy group, a methoxy group or a trifluoro-methyl group, R4 signifies a hydrogen atom or a chlorine atom, one of the substituents R5 or R6 signifies a hydrogen atom, and the other signifies a hydrogen atom or a methoxy 20 group, and their pharmacologicaily compatible salts of inorganic ~- or organic bases.
Particularly preferxed representatives of the forms of - 3****
embodiment I**** are those in which R signifies a "'' . .
:~' , .', ' J~:15;~ 7 ~ fluorine atom, a chlorine atom, a hydroxy group or a methoxy c **** ~ ****
group, R' and Rv signify hydrogen atoms, A~**, 1 , n****, R2 and R4 have the meaning indica-ted above, and their pharmacologically compatlble salts of :` ~5 inorganic or organic bases.
Further especially preferred representatives of the forms of embodiment I*** or I**** are those in which A*** or A***~
have the meaning of a 2-biphenylyl radical, and their pharma-cological~y compatible salts of inorganic or organic bases.
As compounds compri5ed by the general formula I one may mention by way of example ; 4-~4-methoxy-N-(2'-fluoro-biphenyl-2-yl)-benzamido]-butyric acid, 4-~2,4-dichloro-N-(6-methyl-biphenyl-2-yl)-benzamido]-:~ 15 butyric acid, . 4~[N-(2'-ethyl-biphenyl-2-yl)-n-butyramido]-butyric acid, 4-[3-fluoro~4-methyl-N-(3,2'-dimethyl~biphenyl-2-yl)-benz-: amidoI~butyric acid, 4-~3,5-dimethoxy-N-(4-chloro-biphenyl-3-yl)-benzamido]-: 20 butyric acid, 4~[N~(4,4'-dimethyl-biphenyl~3-yl)-hexanoylamido]-butyric acid, 4-~3-trifluoromethyl-N-(6-ethoxy-biphenyl-3-yl)-benzamido]-~ butyric acid, ":
~ ' ~, . .
. .
.:, . .
-:' , .
.. . . .
~1533~t7 4-[2-bromo-N-(2'-methoxy-biphenyl-4-yl)-benzamido]-butyrlc acid, , 4-[3-methoxy-4-methyl-N-(4'-methoxy-biphenyl-4-yl)-benzamido]-- butyric acid, 5-~4-methyl-3-nitro-N-(biphenyl-2-yl)-benzamido]-valeric acid, 5-[3-chloro-N-(4'-methoxy-biphenyl-4-yl)-ben~amido]-valeric acid, 5-t4-fluoro-N-(6-ethoxy-biphenyl-3-yl)-benzamido]-valeric acid, 5~ r 4-methoxy-N-~2l-fluoro-biphenyl-2-yl)-benzamido]-valeric acid, 5-[N-(4'-chloro-biphenyl-4-yl)-methacryloylamido]-valeric acid,
/~3 O
n**** signifies a positive whole number from 3 to 5, 2****
~ R signifies a hydrogen atom, - R3 signifies a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxy group, a methoxy group or a trifluoro-methyl group, R4 signifies a hydrogen atom or a chlorine atom, one of the substituents R5 or R6 signifies a hydrogen atom, and the other signifies a hydrogen atom or a methoxy 20 group, and their pharmacologicaily compatible salts of inorganic ~- or organic bases.
Particularly preferxed representatives of the forms of - 3****
embodiment I**** are those in which R signifies a "'' . .
:~' , .', ' J~:15;~ 7 ~ fluorine atom, a chlorine atom, a hydroxy group or a methoxy c **** ~ ****
group, R' and Rv signify hydrogen atoms, A~**, 1 , n****, R2 and R4 have the meaning indica-ted above, and their pharmacologically compatlble salts of :` ~5 inorganic or organic bases.
Further especially preferred representatives of the forms of embodiment I*** or I**** are those in which A*** or A***~
have the meaning of a 2-biphenylyl radical, and their pharma-cological~y compatible salts of inorganic or organic bases.
As compounds compri5ed by the general formula I one may mention by way of example ; 4-~4-methoxy-N-(2'-fluoro-biphenyl-2-yl)-benzamido]-butyric acid, 4-~2,4-dichloro-N-(6-methyl-biphenyl-2-yl)-benzamido]-:~ 15 butyric acid, . 4~[N-(2'-ethyl-biphenyl-2-yl)-n-butyramido]-butyric acid, 4-[3-fluoro~4-methyl-N-(3,2'-dimethyl~biphenyl-2-yl)-benz-: amidoI~butyric acid, 4-~3,5-dimethoxy-N-(4-chloro-biphenyl-3-yl)-benzamido]-: 20 butyric acid, 4~[N~(4,4'-dimethyl-biphenyl~3-yl)-hexanoylamido]-butyric acid, 4-~3-trifluoromethyl-N-(6-ethoxy-biphenyl-3-yl)-benzamido]-~ butyric acid, ":
~ ' ~, . .
. .
.:, . .
-:' , .
.. . . .
~1533~t7 4-[2-bromo-N-(2'-methoxy-biphenyl-4-yl)-benzamido]-butyrlc acid, , 4-[3-methoxy-4-methyl-N-(4'-methoxy-biphenyl-4-yl)-benzamido]-- butyric acid, 5-~4-methyl-3-nitro-N-(biphenyl-2-yl)-benzamido]-valeric acid, 5-[3-chloro-N-(4'-methoxy-biphenyl-4-yl)-ben~amido]-valeric acid, 5-t4-fluoro-N-(6-ethoxy-biphenyl-3-yl)-benzamido]-valeric acid, 5~ r 4-methoxy-N-~2l-fluoro-biphenyl-2-yl)-benzamido]-valeric acid, 5-[N-(4'-chloro-biphenyl-4-yl)-methacryloylamido]-valeric acid,
6-~2-methoxy-N-(6-methyl-biphenyl-2-yl)-benzamido]-caproic acid, . 15 6-[3,5-dichloro-N-(4,4'-dimethyl-biphenyl-3-yl)-benzamido]-, caproic acid, 6-~2,4-dimethyl-N-(4'-chloro-biphenyl-4-yl)-benzamido]-caproic acid, 6-[3-methoxy-4-methyl-N-(2'-fluoro-biphenyl-2-yl)-benzamido]-caproic acid, 6-[4-nitro-N-(biphenyl-2-yl)-benzamido]-caproic acid, ~ 6-[N-(4'-ethoxy-biphenyl-4-yl)-isovaleroylamido]-caproic - acid.
` `' ~
, ., :`:
.
.J
1:~L5;~3e~7 Preferred representatives of the compounds according to the Invention are 4-~4-chloro-N-(biphenyl-2-yl)-benzamido]-butyric acid, 4-GN-(biphenyl-2-yl)-acetamido]-butyric acid, 4-~4 fluoro-N-(biphenyl-2-yl)-benzamido~-butyric acid, 4-[N-(biphenyl-2-yl)-crotonoylamido]-butyric acid, `. 6-[4-chloro-N-(biphenyl-2-yl)-benzamido]-caproic acid, 6-~2,4-dichloro-N-(biphenyl-2-yl)-benzamido]-caproic acid, . 6-[5-chloro-2-methoxy-N-(biphenyl-2-yl)-benzamido]-caproic acid, 5-[2-hydroxy-N-(biphenyl-2-yl)-benzamido]-valeric acid and.their salts.
; The compounds according to the Invention display valuable pharmacological properties which make them commer-: 15 cially utilisable. In warm-blooded animals they develop a protective action for stomach and liver, and in addition they bring about an increase in the secretion of the pancreas and liver (bile). In addition they bring about an inhibition of the formation of glucose from lactate and pyruvate in the : 20 liver.
Because of their advantageous activity, the acylbiphenyl-ylaminoalkanoic acids are suitable for the treatment and prophy-` laxis of diseases which are attributa~le to disorders of the stomach or intestine or to reduced performances of the pancreas, .'--':
:
.
', .
.
~1~153387 bile and/or liver. For example one treats qastric or intes~lnal ulcers, ~illroth II, pancreatic insufficiency, sprue, lndl-gestions and malabsorptions of different aetiology, acute and chronic pancreatitis, indirect disorders of the pancreatic function (supporting of the production of secretin and pancreozymin), as weIl as gall bladder and bile duct inflam-mations, disorders of the bile flow, motility disorders of the bile ducts, a feeling of repletion, flatulence, consti-pation, upper abdominal complaint, hepato-biliar functional disorders, acute and chronic hepatitis, intoxications of the liver, fatty degeneration of the liver, diabetes (maturity - onset diabetes), insulin deficiency diabetes in the form ~of i'brittle diabetes", late diabetic damage The Invention thus furthermore relates to a process for the treatment of mammals suffering from one or more of the above-mentioned diseases. The process is characterised in ~hat a therapeutically active and pharmacologically tolerated amount of one or more compounds of the yeneral formulae I, I*, I**, I*** and I**** and/or salts thereof is administered to the sick mammal. The Invention also relates to the use of the compounds according to the Inven-tion in combating the illnesses indicated above. The Invention likewise comprises the use of the compounds according to the Invention for the preparation of medicaments which are ``:
., ~
.~., .
1~5;~387 employed for combating the illnesses listed.
The Invention further relates to pharmaceutical pro-ducts which contain one or more of the acylbiphenylylamino-alkanoic acids of the general formula I
R1 _ C0 - N - C H - C00~ (I), l n 2n in which R signifies an aliphatic or alicyclic hydrocarbon radical or an optionally substituted phenyl group, A signifies an optionally substituted and/or hydrogenated biphenylyl radical, n signifies a positive whole number from 3 to 5, and/or their pharmacologically compatible salts of inorganic or organic bases.
Forms of embodiment of the pharmaceutical products are those which contain acylbiphenylylaminoalkanoic acids of the formulae I*, I**, I***, I**** or their preferred re-presentatives and/or their pharmacologically compatible salts of inorganic or organic bases.
The pharmaceutical products are produced according to known processes. As pharmaceutical products the new compounds can be used as such or if desired in combination with suitable pharmaceutical carriers. If the new pharmaceutical ~l~S;33~37 preparations in addition to the active principles contain pharmaceutical carriers, the active principle content of these mixtures is 1 to 9S, preferably 15 to 85 per cent by weight of the total mixture.
In accordance with the Invention it is posslble in the field of human and veterinary medicine to use the active principles in any desired form, for example systemic, pro-vided that the formation or maintenance of adequate blood or tissue levels or local concentrations of active principle is ensured. This can either be carried out by oral, rectal or parenteral administration in suitable doses. More advan-tageously the pharmaceutical preparation of the active principle occurs in the form of unit doses which are designed for the particular form of administration desired. A unit dose can be, for example, a tablet, a pill, a capsule, a suppo-sitory, or a measured volume of a powder, a granulate, a solution, an emulsion, a suspension, a sol or a gel.
" Unit dose" in the sense of the present Invention is to be understood to mean a physically determined unit which contains an individual quantitiy of the active component in combination with a pharmaceutical carrier, the active -~ principle content of which corresponds to a fraction or .. .
:
.
, :
.
~:~LS3387 multiple of the therapeutical individual dose. An individual dose preferably contains the quantity of active princlple which is dispensed in a single applicatlon and which corresponds usually to a whole, a half or a third or a quarter of the daily dose.~ If for an individual therapeu-tical administration only a fraction, such as a half or a quarter of the unit dose is required, the unit dose is advantageously divisible, for example in the form of a tablet with a notch for breaking.
The pharmaceutical preparations according to the Invention, if they occur in unit doses and are intended for application, for example to human beings, may contain 0.5 to 1000 mg, advantageously 1 to 750 mg and especially 5 to 500 mg of active principle.
;
Generally speaking, it has been found advantageous both in human medicine and in veterinary medicine, to administer the active principle or principles in oral administration , in a daily dose of 0.01 to 40, preferably 0.1 to 30, especially - 0.2 to 20 mg/kg body weight, possibly in the form of s~veral, ;-~; 20 preferably 2 to 3 individual administrations, in order to , ;~.
achieve the desired results. An individual administration contains the active principle or principles in quantities of 0.0: to 20, preferably o.l to 15, especially 0.2 to 10 mg/kg ' ~53387 body weight.
In a parenteral treatment, for example intramuscular or intravenous application, it is possible to use similar dosages With this therapy one applies 50 to 1000 mg of active 5 principle.
The therapeutical administration of the pharmaceutical preparation is carried out in the case of long-term medication generally at fixed points of time, such as 1 to 4 times a day, for example before or after meals and/or in the evening.
10 In the case of acute attacks the medication is carried out u at varying points of time. Under certain circumstances it may be necessary to differ from the said dosages, namely accor-ding to the nature, the body weight and the age of the patient to be treated, the nature and severity of the disease, the 15 nature of the preparation and the application of the drug as well as the period of time or interval within which the admini-stration takes place. Thus in some cases it may be sufficient to manage with less than the above-mentioned quantity of active principle, whereas in other cases the quantity of 20 active principle mentioned above must be exceeded. The deter-mination of the optimum dosage and type of application of the acti~e principles necessary in each case can at any times be ;~
carried out by the expert on tbe basis of his technical know--~- ledge.
"
; - 18 -,.~
''' :
-,~
~S~3387 The pharmaceutical preparations conslst as a rule of theactive principles according to the Invention and non-toxic pharmaceutically compatible dru~ excipients which are used as an admixture agent, for example in the form of a capsule, a tablet coating, a bag or another container, for the thera-peutically active component. An excipient can, for example, serve as a vehicle for the uptake of the medicament by the body, as a formulation aid, as a sweetening agent, as a flavour corrector, as a colouring material or as a preserva-tive. The carriers are in each instance adapted by the - specialist to the diseases which are to be treated with the pharmaceutical preparations.
For oral-use it is possible to use, for example, tablets, ; pills, hard and soft capsules, for example of gelatine, disper-sible powders, granulates, aqueous and oily suspensions, emulsions, solutions or syrups.
., Tablets can contain inert diluents, for example calcium carbonate, calcium phospnate, sodium phosphate or lactose;
granulating and distributing agents, for example maize starch or alginates; binders such as for example starch, gelatine or gum acacia; and lubricants, such as for example aluminium or magnesium stearate, talcum or silicone oil. They can also ~- be provided with a coating which can alsG be designed in such a way that it gives a delayed dissolution and resorption ,:' 1~533~37 of the drug in the gastrointestinal tract and therefore ensures, for example, a better compatibility, protraction or retarding. Gelatine capsules can contain the pharmaceu-. tical product mixed with a solid diluent, for example calcium : 5 carbonate or kaolin, or an oily diluent, for example olive oil, groundnut oil or liquid paraffin.
Aqueous suspensions can contain suspension agents, for f example sodium carboxymethylcellulose, methylcellulose,hydroxypropylcellulose, sodium alginate, polyvinylpyrrolidone, - 10 gum dragon or gum acacia; dispersants and wetting agents, for example polyoxyethylene stearate, heptadecaethylene oxycetanol, polyoxyethylene sorbitol monooleate, polyoxy-' ethylene sorbitan monooleate or lecithin; preservatives, .j . such as for example methyl or propyl hydroxybenzoates;
~ 15 :flavouring materials; sweetening agents, for example sodium ;~ cyclamate, saccharin.
Oily suspensions cancontain for example groundnut oil, olive oil, sesame oil, coconut oil or liquid paraffin and . thickeners such as for example beeswaxr paraffin wax or cetyl alcohol; also they may contain sweeteners, flavouring materials and anti-oxidants.
. Powders and granulates which are dispersible in water can contain the pharmaceutical products in admixture with ispersants, wetting agents and suspending agents, for example '' ~ - 20 - ~
' : i ~ 1 S33R7 t:hose mentioned above, as well as sweeteners, flavouring materials and colouring materials.
Emulsions can contain, for example, olive oil, ground-nut oil or liquid paraffin as well as emulsifiers, such as for example gum acacia, gum dragon, phosphatides, sorbitan mono~
oleate, polyoxyethylene sorbitan monooleate, and sweeteners and flavouring materials.
For rectal use of the pharmaceutical products one uses suppositories, which are produced with the help of binders which melt at rectal temperature, for example cocoa butter or polyethyleneglycols.
For parenteral use of the pharmaceutical products one uses sterile injectable aqueous suspensions, isotonic saline solutions or other solutions which can contain dispersants or wetting agents and/or pharmacologically compatible diluents, for example propyleneglycol or butyleneglycol.
The active principle or principles can if desired be formulated with one or more of the said carrier materials or additives also in a microencapsulated form.
If the acylbiphenylylaminoalkanoic acids according to the In~ention and/or their salts are to be used for the treatment of diseases which are based on disorders of the stomach or intestine or on reduced performances of the pancreas, bile and/or liver, the pharmaceutical preparations can also contain ~53387 :
one or more other pharmacologlcally actlve components of other groups of pharmaceutical products, such as antacids, for example aluminium hydroxide, magnesium aluminate; tran-` guilizers, such as benzodiazeplnes, for example Diazepam;
`~ 5 spasmolytics, such as for example Bietamiverin, Camylofin;
anticholinergics, such as for example oxyphencyclimine, phencarbamide; despumation agents, for example dimethylpoly-s;iloxane; laxatives, for example Bisacodyl; swelling agents;
~; if desired also ferments, bile acids, antibiotics, vitamins, amino acids or fatty acid mixtures.
If the acylbiphenylylaminoalkanoic acids and/or their salts are formulated as antidiabetic products, the pharma-ceutical preparations can also contain one or more pharma-cologically active components belonging to different groups of pharmaceutical products, such as additional antidiabetics Isulphonamides, sulphonyl ureas), for example carbutamide, i~
t:olbutamide, chlorpropamide, glibenclamide, glibornuride, glis-oxepide, gliquidone, glymidine, or hypolipidaemics, such as benzafibrat or nicotinic acid as well as their derivatives and salts.
A further object of the Invention is a process for the production of acylbiphenylylaminoalkanoic acids of the general formula I
.~
~' ,,.
.
: , 115;~3~37 R1 _ C0 ~ ~ ~ Cn~I2n ~ COOH (I), . :Ln which R signifies an aliphatic or alicyclic hydrocarbon radical or an optionally substituted phenyl group, ~ signifies an optionally substituted and/or hydrogenated biphenylyl radical, n signifies a positive whole number from 3 to 5, .~ and their salts of inorganic and organic bases, which is .' 10 c:haracterised by the fact that a) a biphenylylaminoalkanoic acid of the general formula II
A NH n 2n (II), i.n which A and n habe the meanings given above, if desired with protection of the carboxyl group, is acylated with an acyl ~` 15 clerivative of the general formula III
R1 _ C0 - R (III), i.n which R7 signifies a leaving group or a R1-C0-0- group, and R1 has the meaning given above, and if desired is then con-verted into a salt or else b) a biphenylylaminoalkenoic acid of the general formula IV
R1 _ C0 - Nl ~ CnH2n-2 ~IV), A
:Ln which R1, A and n have the meanings given above, is hydro-genated, if desired with protection of the carboxyl group, :
.~
~ 15,~-~3~37 and if desired is then converted into a salt or c~ a functional acylbiphenylylaminoalkanoic acld derlvatlve o~ the general formula V
1 _ C0 - N - C H2 - G (V), A
in which R1, A and n have the meanings given above and G
; s:ignifies a functional derivative of a carboxyl group, i!; solvolysed and if desired is then converted into a salt.
For the production of the compounds of modifications I~, I**, I*** or I**** corresponding initial materials Il*, II**, II*** or II****; III*, III**, III*** or III****;
IV*, IV**, IV*** or rv**** or V*, V**, V*** or V**** in which the substituents have the corresponding meaning, are reacted.
If the biphenylylaminoalkanoic acids of the formula 15 I r are reacted with the protection of the carboxyl group, those representatives are used the protective groupsof which do not react with the acyl derivatives III. Suitable represen-tatives are for example esters of alkanols, including those with 1 to 5 carbon atoms, or phenalkanols, such as methyl, propyl, butyl, benzyl or phenethyl esters, possibly also solutions with inorganic or organic bases, such as alkali or alkaline earth metal hydroxides, ammonia, tertiary nitro-. .
- ~4 -~S;3~3~7 ! ~en bases (for example triethylamine, pyrldlne).
In the acyl derivatives III a leaving group R is for example a hydroxy group, a halogen atom, preferably a chlorine or bromine atom, an alkylsulphonyloxy or benzenesulphonyl-oxy gro~p, such as a mesyloxy or p-tolylsulphonyloxy group, ; an alkoxy group, preferably a methoxy or ethoxy group, an alkylmercapto group, such as a methylmercapto or ethylmer-apto group.
The reaction of the biphenylylaminoalkanoic acids II
with the acyl derivatives III is carried out by known processes. The reaction is carried out in suitable solvents, ;such as water or hydrocarbons, for example benzene, toluene, xylene, or ethers, for example tetrahydrofuran, dioxan, 1,2-dimethoxyethane, or ketones, for example methylethyl-ketone, or amides, for example dimethylformamide, orsulphoxides, for example dimethylsulphoxide.
Expediently the acylation, if R signifies a leaving group, is carried out in the presence of an acid-binding agent (proton acceptor). Suitable as such one may mention by way of example alkali metal hydroxides such as sodium hydro-xide, potassium hydroxide, or alkali metal carbonates sucn as sodlum carbonate, potassium carbonate, or tertiary amines such as pyridine, triethylamine, ethyldiisopropylamine.
i33R7 :[f the acyl derivatives III are acid anhydrides, that is to say if R signifies the R -C0-0- group, it is also sufficient 1:o heat the compounds II and III in an inert solvent.
',The reaction can be varied within wide limits, for example --20 to ~100C, temperatures around room temperature (10 to :30 C) being preferred. If the compounds II are acylated with 1:he protection of the carboxyl group, then after the acylation the protective group is split off again in the ~usual manner. If salts are used as protective group, the libera-:10 tion of the acids I obtained is effected by reaction with a suitable mineral acid, such as hydrochloric acid, or sul-phuric acid. If esters are used as protective groups, the acylation is followed by the saponification of the reaction product to give compounds of the formula I. The saponification i.s preferably carried out with an alcoholic (for example ethanolic) alkali metal hydroxide (for example potassium hydroxide) solution at room temperature, optionally with the addition of an inert diluent such as dioxan or benzene.
The initial compounds of the formula II are produced by various processes which are in themselves known. Thus, t:hey are obtained by reacting halogenalkanoic acids of the - formula VI, preferably with the protection of the carboxyl ';
~ - 26 -', , :, .
. .
5~33~37 ., group as an ester group, with a biphenylylamlne of the i.ormula VII
R n 2n A - NH2 ~ VI) (VII), :Ln which n and A have the meanings given above and R8 signifies a halogen atom, preferably a chlorine or bromine atom. The reaction is expediently carried out in the presence of an inert solvent, for example benzene, cyclohexane, diethyl ether, with the addition of a proton acceptor. One may use for this purpose, for example, an excess of the amine VII used for the reaction. If desired, however, it is also possible to add a different proton acceptor.
The starting products II are also obtained by reacting an alkenoic acid ester VIII
15CH2 = CH ~Cn-2H2n-4 (VIII), ; i.n which n has the meaning given above and R signifies an alkyl group with 1 to 5 carbon atoms or a benzyl group, ~lith a biphenylylamine VII. The reaction is expediently c:arried out in the presence of an inert solvent, such as hydrocarbons, for example benzene, toluene, xylene or ethers, ,' .
~`l . .
for example tetrahydrofuran, dioxan, 1,2-dimethoxyethane, or ]cetones, for example methylethylketone, or amides, for example dimethylformamide, or sulphoxides, for example dimethylsul-phoxlde, or nitriles, for example acetonitrile. Expediently the reactants are heated in the solvent, for example by boiling under reflux.
The protective group R is expediently split off only after the reaction of the resultant intermediate products II with the acyl derivatives III so as to obtain the end ~ 10 products I.
;~ The initial compounds II are also obtained by the sol-volysis of functional biphenylylaminoalkanoic acid derivatives of the general formula IX
` A - NH - C H - G (IX), - 15 in which A, n and G have the meanings given above, by ; means of processes which are known to the technician.
- E:xpedient forms of execution are described under process - variant c).
~ The starting products II are further obtained by :
reacting biphenylylamines VII with lactones of the general formula X
CnH2n C=O (X), r; ~ O
; - 28 -.
1~S~3~37 in which n has the meaning glven above, ln a known manner.
The reactlon ls carrled out for example by heatlng the reactants VII and X (e.g. to the boiling polnt of the solvent) i.n inert solvents such as ethers, for example diethyl ether, t:etrahydrofuran or nitriles, for example acetonitrile. The acid obtained can then be converted if desired into the corresponding esters, for example by heating in the corres-ponding alcohols in the presence of a mineral acid, such as hydrochloric acid or sulphuric acid.
The intermediate products II are alternatively obtained in a known manner by the hydrogenation of biphenylyliminoal-~:anoic acids XI
A - N = CH - (CH2)n-1 (XI) in which A and n have the meaning given above, optionally with the protection of the carboxyl group in a known manner.
l'he hydrogenation is carried out for example with Raney nickel under hydrogen pressures of 1 to 250 atmospheres at room temperature in absolute ethanol.
The acids XI are accessible by reacting the biphenyl-ylamines VII with oxo-acid esters XII
0 = CH ~ (CH2)n 1 ~ C0 - 0 - R (XII), - in which n and R have the meanings given above.
; - 29 -~ \
;~
533~37 .
The hydrogenation accordlng to process varlant b) ls c:arried out accoxding to methods such as are known to the t:echnician, Thus the biphenylylaminoalkenoic aclds IV are hydrogenated with hydrogen in the presence of a transition ~, 5 metal or noble metal catalyst or ~he corresponding oxides or :, j complexes in inert solvents. Suitable metals, for example, ~-j are platinum, palladium, iridium, rhodium. A summary of the i hydrogenation process is to be found inter alia in Kirk-Othmer 11, 418-462; Ullmann 10, 109-114, 541-555i 14, . , .
630-649. The splitting off of any protective group which may be present is carried out in the usual manner.
The alkenoic acids IV are obtained for example from t:he halogenalkenoic acid esters XIII
R _ C H2n 2 ~ C0 - 0 - R (XIII), in which R and n have the meanings given above and R10 ~;ignifies a halogen atom, preferably a bromine atom, by amination with a biphenylylamine VII, acylation with an acyl ;. clerivative IIIand if desired subsequent saponification.
r' l'he production is carried out by known methods, halogenation ~production of XIII) and amination, for example analogous to J.Heterocycl.Chem. 8 (1971) 21; acylation and saponifi-cation are carried out analogously to the description of ~' . .
~ , . .
... .
:, :
. .
: . .
~lS~ 7 the present Application.
The halogenalkanolc acids VI and blphenylylamlnes VII are known compounds or are produced by analogy processes;
` for example the halogenalkanoic acids VI are accessible by `1 5 solvolysis, such as hydrolysis or alcoholysis, of the corresponding lactones and subsequent halogenation. Thebiphenylyl-~ amines VII are obtained by the reduction of corresponding ; nitro compounds which are accessible by the nitration of corresponding biphenyls.
` 10 The solvolysis according to process variant c) is carried - out by processes known to the technician. A functional acid derivative in this case is understood to mean a derivative whose functional group G can be converted by solvolysis into 1:he free carboxyl group. Typical representatives are for ~xample those in which G signifles a -~N group or a-C y group, in which signifies an ox~gen or a sulphur atom or a substituted nitrogen atom, especially an imino, alkylimino or hydroxy-imino group and Y signifies a hydroxy group or a monovalent eliminable electrophilic radical, especially a free or substituted amino group, preferably a monoalkyl or dialkyl or aryl ' ... ' .
~5;~.3~7 amino group, a hydroxyamino or hydrazino group, a hydra-zobenzene group, a 2-hydroxyethylamino group, a free or substituted mercapto group, preferably an alkylthio group, a substituted hydroxy group, preferably an alkoxy group, an azido, a chloro or bromo radical, a morpholino group or a piperidino group, in which Y is not a hydroxy group if X represents an oxygen atom.
An alkyl radical of an alkylimino, a monoalkylamino, a dialkylamino, an alkylthio and an alkoxy group is to be understood to mean an alkyl radical with up to 5 carbon atoms, whilst an aryl radical of an arylamino group is to be understood to mean an aryl radical with up to 10 carbon atoms.
Preferred representatives of the acid derivative V are those in which G signifies a -CN group or a -C y group, :in which ; ,Y signifies an oxygen atom, a sulphur atom or an imino group and ; Y signifies an amino, monoalkylamino, dialkylamino, phenyl-amino, alkoxy, alkylthio, chloro or bromo radical.
Particularly preferred representatives of the acid derivative V are the corresponding acid amides, alkyl esters t)f the acid and nitriles, that is to say those compounds :`
of the formula V in which G represents a -C0-NH2l -C0-NH-R
-C0-NR 2~ -C0-0-R or -CN group and R has the meaning given above. They constitute valuable intermediate products for the production of the compounds I and their salts.
For the solvolysis of the functional carboxylic acid derivatives V one uses a medium which gives off water, which consists wholly or partly of water or of agents which split off water under hydrolysis conditions. The reaction can be carried out as a homogeneous reaction, in which case one usually operates in the presence of a polar organic sol-; vent or a solutizer. Advantageously one uses as solvent, for example, low-molecular alcohols, dioxan, acetone, low-molecular carboxylic acids, N-methylpyrrolidone, sulpholan or dimethylsulphoxide. However, it is also possible to carry out the hydrolysis as a heterogeneous reaction. The pH of the medium which splits off water depends upon the chemical nature of the acid derivative used, but also on the nature of the compound of the general formula I which is desired and it can therefore be neutral, acid or basic. It is adjusted to the desired value with acids, bases or buffers.
The hydrolysis temperatures are between 0C and the boiling point of the medium which splits off water, generally 1.15~ 7 ¦ between 0 and 150 C, and especially between 20 and 120 C.
The hydrolysis temperatures depend individually also on whether one operates under pressure or without pressure.
The reaction times are between 10 minutes and 20 hours according to the charge, the reaction temperatures and other reaction parameters. After the hydrolysis has ended, the acids :r are isolated by using the usual methods, for example by recrystallisation or by the acidification of their solutions, :Lf desired with the concentration of their solutions.
~ 10 In order to purify it, their alkaline solution can be ; extracted with an organic solvent which is not miscible with the alkaline solution , for example diethyl ether, benzene, chlorobenzene, chloroform or methylene chloride.
The carboxylic acid derivatives V are obtained by methods which are current to the technician. For example they are obtained by the reaction of functional halogenalkanoic acid clerivatives XIV
R ~ (CH2)n ~ G (XIV), i.n which R8, n and G have the meanings giv~en above, with 20 biphenylylamines VII followed by acylation with acyl derivatives ; III.
The conversion of the acids of the general formula I
or of the modifications I*, I**, I***, I*** into their salts J~lS3387 .1 can be carried out by direct alkaline hydrolysls of the acld derivatives of the formula V. As alkaline reactant one uses the particular inorganic or organic base whose salt is c~esired. However, one also obtains the salts if one reacts ; 5 l_he acids of the general formula I with the stoichiometrical equivalent of corresponding base, for example sodium hydroxide or sodium alcoholate, or else readily soluble salts are con-verted by double decomposition into sparingly soluble salts, or else any salts are converted into pharmacologically com-patible salts.
The following Examples illustrate the Invention in greater detail, but without restricting it. The abbreviations ~IP and BP signify melting point and boiling point respectively.
. .
, - 35 -~ ~5;33~7 EXAMPLE
~-~p-chtoro-lV-t~ipha~yI-2-yZJ~cmi~]butyr~o aoid Rl - p-chlorophenyl, A ~ ~iphenyl-2-yl, n ~ 3 a) ~:yt ~-fbiphsny?,-2-yZ)~rn7toou~yrat2 ~ 5 30.0 g of 2-amLnobiphenyl, 23.4 g of ethyl ciisoprooyl-amine and 35.4 g o ethyl 4-bromobutyrate are heated together to 1~0 for 3 hours while s~irr_ng. After cooling, ~he reaction pro~uct is sti-r2d with die~yl - ether, the precipitated salt is filtered ofr, and the residue ~remaining after evaporating of~ the ether) is recrystallized from isopropyl alcohol to obt~in 32.0 g (63.7% of theory) o~ ethyl g-(biphenyl-2-yl)amino-butyrate, ,u~ 60 to 62.
~) 2~:yZ 4-~cn~ro-.~-tbiphenyZ-2-yZ~b~r.z~r~dolDu~yl~crte 9.8 g of p-chlorobenzoyl chloride is added drop by drop at ~oom t~mper~tur_ (while stirring and withi~ 30 minutes) to a solution of 16.0 g of ethyl 4-~biphenyl-2-yl)-; aminobutyrate and 7.3 g of ethyl diisoprooyl~mine in 70 ~1 of benzene. After a further hour, ~he precipitate is ~iltered o'f, the filtrate is evaporated, and the evaporation residue is recrystallized from cyclohexane to obtain 18.0 g (75.6% o theory) o ethyl 4-[(p-chloro-N-(biphenyl-2-yl)benzamido]butyrate, ~P 100 to 102~.
c) ~-~p-ch~oro-~Y-(biph2nyZ-2-ytJbenzomido3b~yric c~id 15.0 g of ethyl 4-[p-chloro-N-~biphenyl-2-yl)benzamido]-butyrate is dissolved in 100 ml of benzene and, after the addi~ion thereto of a solution of 2.8 g of potassium hydroxide in 20 ml of ethanol, is then stirred at room temperature ~or S hours. The solvent is then distilled off *n v~c~o, and the obtained residue is dissolved in water. The resulting aqueous solution is acidi'ied with - dilute hydrochloric acid, and the precipitate, wnic~
; 10 separates out, is taken up in methyle~e chloride. The residue remai.~ing, after drying and distilling o~ he methylene chloride, is recrystallized from an et~anol/
water mixture ~2:1) to obtain 10.1 g ~72.1~ o- tneory) o~ 4-~?-chloro-N-(biphenyl-2-yl)ber.zamido]butyric acid, '~ 135 to 137.
~-[m-triJ7 oromet~y~ -fbipher.yl-2^yZ)ben2c~i~o]butyric ccid Rl = ~,a,~-trifluoro-m-tolyl, A = bipheryl-2-yl, n = 3 a) EthyZ ~-[n~-trif~wrome~.yZ-~Y-~oiDhe7~yZ-2-yZ)benz ~ o]Duty~ct Anal~gously to Example I b, 11.8 g of ethyl 4-(biphenyl-2-yl)aminobutyrate and 5.4 g of ethyldiisopropyl~mine are reacted in 70 ml of benzene with 8.7 g of m-tri-fluoromethylbenzoyl chloride. The reaction product is recrystallized from a mixture of iso?ropyl alcohol and water (1:1) to obtain 16.0 g (8~.4% of theory) of ' "
'. :
:
,:
. .
`:
1~5;33t37 .
ethyl-4-~m-trifluoromethyl-N-~biphenyl-2-yl)benzamido]-butyrate, .~P 65 to 67.
b,l 4- ~m-t2~J~wr~m~thy~-tV-tbiph~ny~-2-ylJb~nzam~o~ty2~:a ~o*d 16.0 g o~ et.iyl-4-~m-~rlfluoromethyl-N-(biphenyl-2-yl)-benzamido]butyrate in 50 ml of benzene are ~ixed with a solution of 3.4 g of potassium hydroxide in 25 ml of ethanol and sti~red at roo~ temperature for 8 hours.
'~hen further processed analogously to Exa~ple 1 c, ; 13.1 g ~91.3% of ~Iheory) of 4-~m-trifluoro~et~yl-~-io (biphenyl-2-yl)benzamidolbutyric acid, .~P 156 to 15~, are obtained.
, ~-~[p-J^Zuoro-~-(Dip~nyt-2-yZ)benz ~i~olsu~yr~c ~ci~
L
R' - p-fluorophenyl, A = biphenyl-2-yl, n = 3 a'l ~ yI 4-~p-f~ ipkenyZ-Z-uI)be?~zc7ndo]butyratz Analogously to Example 1 b 10.0 g of ethyl 4-(biphenyl-2-yl)aminobutyrate and 4.6 g of ethyldiisopro2ylamir.e ~n 50 ml of benzene are reactod with 5. 6 g of p-fluorobenzoyl chloride. The reaction product is recrystallized from cyclohexane to obtain 12.1 g ~84.6% of theory) of ethyl 4-tp-fluoro-N-(bi2he~yl-2-yl) benzamido butyrate, MP 83 to 84.
~ .
.' ' '.,~ ' .
'' ', , i~S~33~37 b) Ç-[p-fZwro-,~ ipheny~-2-ylJ~nzam~o]butyric c~id 11.2 g of ethyl 4-~p-~luoro-N-(biphenyl-2~yl)~enzamido]-butyrate in S0 ml of benzene is m~xed with a solution o~
2.2 g of potassium hydroxide in 20 ml o~ ethanol and S stirred at room temperat~re for 8 hours. When prccessed analogously to Example 1 c, 7.1 g t71.7~ of theory) of 4-~p-fluoro-N-(biphenyl-2-yl)benzamido]butyric acid, ~P 120 to 122, are obtaine~.
4 [ S-cnIoro- 2-metnosy-~- ~b:Dne~y 1, - 2-y ZJ oen~c:~ ] ou~;~ric a~d R-L ~ S-chloro-2-metho~yphenyl, A - biphenyl-2-yl, n = 3 Analosously to Exa~ple 1 , 10.0 5 of ethyl 4-(:biphenyl-2-yl)aminobutyrate and 4.6 g of ethyldiisopropyl-~In;ne in 50 ~1 of benzene are reacted with a solution of .3 g of 5-chloro-2-methoxybenzoyl chloride in 20 ml o benzene to obtain, as reaction ?roduct, 1;.0 g (94.1~ of theory) Oc ethyl 4-[S-chloro-2-methoxy-N-(bi2henyl-2-vl)benz-amido]butyrate as a viscous non-distillable oil. ~e saponification of this ester yields 12.4 g (88~ of theory~
c,f 4-[5-chloro-2-methoxy-N-(biphenyl-2-yl)benzamido]butyric z.cid, MP 160 to 162.
- 3~ -~, ., ~1533R7 , ~- [N- ~b~ph~nyl-2-yt)ccs~o ] ~u~yria aoid -C~3, A ~ biphenyl-2-yl, n ~ 3 Analogously to Exampla 1, 16.0 g of ethyl 4-(biphenyl-2-yl)aminobutyrate and 7.3 g of ethyldiisopropyl- -am~ne in 70 ml of benzene are reacted with 4.4 g o~ acetyl chlo~ide to obtain, as reaction product, 14.0 g ~76.2~ or theory) of ethyl 4-[N-(biphenyl-2-yl)acetamido]butyrate as a viscous non-distillable oil. The saponification of this ~ . 10 ester and recrystallization of the crude product obtained ; f~om isopropyl alcohol yields 10.1 g (79.03 of theory) of 4-[~J-~bipnenyl-2-yl)acet~;do3bu~yric acid, .~P 12~ to 125.
" .
-~i2h2nyI-2-yZJoro~m~y~s~b]~utyr~c ~ d .~
; Analogo~sly to Example 1, 10.0 g of ethyl 4-(biphenyl-2-yl)aminobutyrate and 4.6 g o~ ethyldiisopropyl-amine in 70 ml of benzene are reacted with 3.8 g of crotonyl chloride to obtain, as reaction product, 10.1 g (81.5% of theory) of ethyl 4-tN-tbiphenyl-2-yl)crotonoylamido]butyrate - as a viscous non-distillable oil. The saponification of this ester and recrystallization of the crude prodt~ct . obtained from isopropyl alcohol yields 5.1 g (55~ of theory) of 4~ biphenyl-2-yl)crotonoylamido]butyric acid, ,~P 127 to 128.
....
~ 40 -,. .
.~ . , ., .
~S''.3~7 E~AMPLE 7 5-~(p-ahZoro-lY-fbiphen~Z-2-yZ)be*~m~do~va1eric oc%d p-chlorophenyl, A - biphenyl-2-yl, n - 4 50.0 g of 2-am~nobiphenyl, 33.2 g of ethyldiiqopro-: S pylamlne and 61.9 g of ethyl 5-bromovalerate ars reacted : analo~ously to Example 1 a to obtain 80.0 g of ethyl S-~biphenyl-2-yl)aminovalerate a~ a non-crystallizin~ oil.
30.0 g o~ this est~r is reacted, analogously to Example 1 b , with 13.1 g of ethyldiisopropylamine and 17.1 g o~ lor~2~yl chloride in 10 ml of benzene; the ethyl S-[p-c~loro--~-tbiphenyl~2-yl)benz~mldo]valerate obtained as an oily ntermediate product is then saponifi~d analo-gously to ~xample 1 c to obtain 22.1 g ;53.7~ of theory) .` of 5[p-c~loro-~-(biphenyl-2-yl)benz ido]~aleric acid, .~ 15 ~P 170 to 173.
5-[o-hyd~o2y-~V-(b%phenyZ-2-u?,)berl2~dD]vol,eric ccid o-hydroxyohenyl, A = biohenyl-2-yl, n = 4 ~ 15.0 g or ethyl 5-~biphenyl-2-yl)aminovaleratP is : 20 reacted, analogously to Example 1 b, with 6.6 g of ethyl-r' diisopropylamine and 10.0 g of o-acetoxybenzoylchloride in 70 ml of benzene to obtain, as reaction product, 17.0 S
(73O4~ of theory) of ethyl 5-[o-ac~toxy-N-(biphenyl-2-yl)-benzamidolvalerate as a viscous non-dist-llable oil. The . 25 saponification of this ester yields 9.1 g (63.2% of theory) ~: of 5-[o-hydIoxy-N-(biphenyl-2-yl)bænzamldo]valeric acid, 138 to 139.
,,: , .; - 41 -:
.
.
. .
."'' ~
S;~31 37 6-~p~htoro-1V-tbiphenyt-2-yt)benz~o]c~pro*o aci,~l Rl p-chlorophenyl, A 8 biphenyl-2-yl, n - S
20.0 g of 2-aminobiphenyl, 15.3 g of ethyldiiso-propylamine and 26.3 g of ~thyl 6-bromocaproate are reacted, analosously to Example 1 a , to obtain 36.0 g of ethyl 5-~biphenyl-2~yl)aminocaproate as a non-crystallizing oil.
18.0 g of this ester are reacted, analogously to Ex~mple 1 b , with 7.5 g of ethyldiisopropylamine and ~0.1 g of p-chlorobenzoyl chloride in ~0 ml of b~nzene. The resulting reaction product is purified chromatographically o~er a silica gel column (eluent: methylene chloride) to obtain 11.5 g (44.2~ of theory) of ethyl 6-~p-chloro-~-(biphenyl-2-yl)benzamido]caproate as a viscous non-distillable oil.
Sap~nification of this ester yields 8.1 g (75.1~ of theory) of 6-[p-chloro-N-(biphenyl-2-yl)benzamido]caproic acid, ~P 93 to 95~.
6-[5-c;~toro-2-me~h.o~J-iY-tbiphsnyt-2-yt)benz~n~o]caproic ac~d 8.0 g of ethyl 6-tbiphenyl-2-yl)aminocaproate and 3.3 g of ethyldiisopropylamine in S0 ml of benzene a~e ,.
re~cted with a solution of 5.3 g of 5-chloro-2-.~et~oxy-benzoyl chloride in 20 ml of benzene, analogously to Example 1 a, to obtain, as _eaction product, 11.1 g . ~ . .
., .
: ' /
5,~33~7 I ~90~ of theory) of ethyl 6-~S-cbloro-2-methoxy-N-(~iphenyl-2-yl)benzamudolcaproate as a visco~s non-distillable oil.
The saponi~ication of this ester yields 7.0 g ~67~ o~
theory) of 6-tS-chloro-2-methoxy-N-~biphenyl-2-yl)bcnzamido]-caproic acid, r~ 164 to 165.
, 6-[D-~biphenyt^2-yl)isobutyrcmidb]c3~roic c^i~
Rl ~ -C~(Ca3)2, A - biphenyl-2-yl, n s ;
~ Analogously to Example 10 10.0 5 of ethyl `: 10 6-(biphenyl-2-yl)a~inocaproate, 4.2 g of ethyldiisooropyl-a~ine a~d 3.4 isobutyryl chloride n 70 .~1 of benzene yields 8.~ g (72.6~ of ~heory) or ethyl 6^~N-(biphenyl-2-yl)iso-buty.~ido]caproate as a ~iscous non distillable oil. The saponification of this ester yields 6.1 g ~74~ of t~eory) l; of 6-~N-(biphenyl-2-yl)isobutyr~mido]caproic ac d, MP 120 to 121.
:' .
s-~p-~htoro~ bipnenyt-~-yZ)benzcm*~o]ou~yr~c c~ d .. Rl ~ p-chlorophenyl, A = biphenyl-4-yl, n = 3 a) Ethyl 4-(biphenyI-4-ylJc~ nob%~ityr2te : 24.0 g (57.3~ of theory) of ethyl 4-(biphenyl-4-yl)-- aminobutyrate, ~ 82 to 84, are obtained analogously ,, .,` ` ' ..' . i .~., ..
31.~ 3~7 to Example 1 b , from 25.0 g o. 4-aminobiphenyl, 19.2 g of ethyldiisopropylamine and 28.9 g of ethyl 4-bro -butyrate.
b) 4^~p-cn~ tY-(biphenyI-~-y?,~benz~rr~do]bu~yrw cci~l S ~nalogously to Example 1 b, 10.0 g of ethyl 4-(bi?henyl-4-yl)aminobutyrate and 4.6 g of ethyldiisopropylamine Ln ~0 ml o~ ber.zene are reactad with 6.2 g of p-chloro-benzoyl chloride to obtain 9.4 g (62.9% of theory1 Of ethyl 4-tp-chloro-~-~biphenyl-4-yl)benza~ido]butyrate as a viscous non-distillable oil. Saponification of this ester, analogously to Example 1 a- , vields 7.0 g (79.7% of theory) of 4-[p-chloro-N-~biphenyl-4-vl)-benzamido]butyric acid, ~P 192 to 194.
~_{p-c~loro-~-(6-metho~y-oip~enyZ-3-yl)oe~zomi~o]o~tyq-~c aci~
'.
Rl , p-chlorophenyl, A - 6-methoxybiphenyl-3-yl, n = 3 a) 2ti~yI 4-~6-metno~ ipner~yZ-3-yt)~rwtoo~yrat~
; 29.; g of 5-amino-2-methoxybiphenyl, 19.2 g of ethyl-diisopropylamine and 28.9 g of ethyl 4-bromobutyrate are heated together (while stirring) for 4 hours at 125. After cooling, the resulting reaction ?roauc~
~ is stirred with diethyl ether and filtered from the ;; precipitated salt. The residue (remaining after evapora--~ ting off the ether) is recrystallized from isopropyl .' . . .
~.15;~3~37 alcohol to obtain 22.5 g t48.5~ of theory) of ethyl 4-~6-methoxybiphenyl-3-yl)aminobutyrate, .~P ~1 to 72.
b) 4- [p~hloro-.V-~6~ho~ybip~enyZ-3-yI)b~ do]~utyr~ ¢oid 8.0 g of ethyl 4-(6-methoxybiphenyl-3-yl)a~lnobutyrate and, 3.3 g of ethyldiisopropylamine in S0 ml of benzene are reacted, analogously to Example 1 b , with 4.6 g of p-chlorobenzoyl chloride. The reaction product is dissolved in 50 ml of benzene a~d, after the acdi~ion thereto of a solution of 2.3 g of potassium hydroxide ~10 in 20 ml o~ ethanol, is t~en stirred for 8 hours at room temperature. ~fter distilling of' t~e solvent, , the residue is dissolved in water; t.~e r-sulting solution is acidified with dilute hyd~ochloric acid and extracted with diethyl ether. The residue (remaining after evaporating of~ the ether) is recrystallized from ethyl acetate/petrol ether ~1:1) to obtain 8.1 g (73.5% of theory) of 4-[p-chloro-N-~6-methoxybiphenyl-3-yl)-benzamidolbutyric acid, .~P 114 to 116.
; EXAMPLE 14 ' r 20 4-tS~Zoro-Z-metho y-N-(6-me~orybiphenyZ-3-yl)~en2~1~utyrw c 5-chloro-2-methoxyphenyl, A = 6-methoxybiphenyl-3-yl, n = 3 ' Analogously to Example 13, reacting 7.0 g of ethyl 4-(6-methoxybiphenyl-3-yl)aminobutyrate with 4.6 g of ; 25 S-chloro-2-methoxybenzoyl chloride, followed by saponification ~,, ., .
.. . .
, ~.S'',387 of the mtesmediate product, yields 7.1 g (70.1~ of theory) of 4-~5-chloro-2-methoxy-N-~6-methoxybiphenyl-3-yl)benz,lmito]-butyric ac1d, ~ 155 to 156.
EXA~PLE 15 6-~2,~ ch~ iphe~Z-2-ytJb~7sz~0]cc~7roic cci~l Rl ~ 2,4-dichlorophenyl, R - biphenyl-2-yl, n = ;
: Following the procedure of Example 9 , but sub-stituting 2,4-dichlorobenzoyl chloride for p-chlorobenzoyl chloride, yields 6-[2,4-dichloro-~-(biphenyl-2-yl)be.~zamico~-caproic acid, ~P 112 to 113, from ethyl acetate/petrol ether (1:1).
, EXAMPLE 16 .. g-~p-chIoro~ (1',2',3',g',5',~ ~ ¢hyc~robiphenyt-~-y~)ben~ ~ o]outyt~
' eci~
..
~5 Rl ~ D-chlorophenyl, R - 1',2',3',4',5',6'-hexahydrobi?henyl-4-yl, n - 3 Following the procPdure of Example 1 a-c , but substituting p-cyclohexylaniline for 2-ami~o-~iy~enyl, ~-[p-chloro-~-l1',2',3',4',5',6'-hexahydrobiphenyl-4-yl)-benzamido~butyric acid, ~P 75 to 71, is obtaired from isopropyl alcohol/water (1:1).
.
; ~ .
~: - 46 -.,"';
;
i~.';;'3~'7 ~[p-c~ro-lV-~biphzny'-2-y~Jb~ b]vaIs~:o ~ d a) S-[~ iphsnyt-2-yt)¢msnolucts~c 2cid solution of 8.0 g of ethyl 5-(biphenyl-2-yl)amino-valerate ~see ~xample 7 ) in 60 ml of b~nzene i9 mixed with a solution of 2.2 g o~ potassium hydroxide in 20 ml of ethanol. After allowing the resulti~g admix-ture to stand for 24 hours at room temperature, the solvent mixture is dis~illed off ~ vacuo . The residue .. . .
is then dissolved in water; the obtained aaueous solu-tion is washed with diethyl etner and then acidified with dilute hydrochloric acid. The formed precipitate, which is oily at rirst, i3 taken up in dichloromethane.
T~e solvent is then distilled of t and t~e residue l; recrystallized from ethyl acetate/petrol ether (l:l) to obtain 5.6 g (71.3~ of theory) of 5-~N-~biphenyl-2-yl)aminolvaleric acid, .~ 73 to 75.
b) 5-[p~ toro-~ bipnenyZ-2-yZ)benz~do]~JaZe2~,c ac:d 5.4 g of 5-~N-(biphenyl-2-yl)amino]valeric acia is dissolved in 40 ml of 0.2 N caustic soda solution. I3to the resulting clear solution (while vigorously stirring and constantly controlling the pH) 3.5 g of p-chloro-benzoyl chloride is added, drop by drop, while con-currently adding dilute caustic soda solution in order to maintain the pH at between 7 and 8. Af'er ~he addi-tion of acid chloride is complete, the solution is sti_red 1~!5~387 fo¢ a further 30 minutes at pH 8 and then acidt~ied to pR 3 with dilute hydrochloric acid. The precipltat-, which is oily at fi~st cry3tallizes a~ter a time. ~t is ~iltered o~f and recrystalli2ad fro~ isopropyl S alcohol to obtain 7.6 g (93~ of thoery) of 5-~p-chloro-N-~biphenyl-2-yllben2amido]valeric acid, ~P 170 to 173, which is identical with the compaund obtained by the procedure of Example 7 .
A~poules containing 600 mg or 4-t2-chloro-~-(biphenyl-2-yl)benzamido]butyric acid; size or batch: 250 ks.
~;
25.0 kg of 1,2-propyleneglycol and 150.0 kg of double-distilled water ars placed in a vessel to which 15.0 kg of 4-tp-chloro-N-(biphenyl-2-yl)ben2amido]butyric lS acid are added. Then, while stirring, caustic soda solution ~10 percent by weight NaO~) is slowly added. When a solu--; tion is obtained, the pR is adjusted to from 7.5 to 8.0 Sodium pyrosulfite~is added, and the resulting mixture is stirred until all components have dissolvad. Using double-distilled water, the solution is made up to 250 kg. The solution is then charged into 10-ml ampoules and sterili2ed in an.autoclave for 30 minutes at 120.
,., ~mpoules containing 600 mg of 4-tN-(biphenyl-2-yl) crotonoylamido]butyric acid; size of batch: 250 kg.
*) 0.062; kg :
. .
~.~S~387 50.0 kg of 1,2-propyleneglycol and 150.0 ~g of double-distilled water are placed in a ~essel. While stirring,15 kg of 4-~N-(biphenyl-2-yl)crotonoylamido]butyric acid are added theseto. Then cau3tic soda solutlon (10 per 1 5 cant by weight NaO~) is added, and the resulting mi~ture is adjusted to a p~ of 8Ø ~sing double-distilled water, it is made up to 250 ~g. The solution is charged into 10-ml ampoules and sterilized in an autoclave at 120 for - 30 minutes.
Tablets containing ;0 mg of 4-[p-fluoro-N-~bipnenyl-2-yl)benza~ido]butyric acid.
25.0 kg of 4-~p-fluoro-N-(biphenyl-2-yl)benzamido]-butyric acid, 35.0 kg of lactose and 26.0 kg of maize starch are granulated with 21.5 kg or polyvinylpyrrolidone tmole-, - cular weight: approx. 25,000) in about 6 liters of water.
;~ The granulate is passed through a sieve wi~h a mesh width ., i .
~!, of 1.25 mm and, after drying, is a~mixed wi~h 8.0 kg o-carboxymethylcellulose, 2.5 ~g of talcum and 1.0 kg of , 20 magnesium stearate. The dry granulate is pressed into tablets with a diameter of 8 ~m, a weight of 250 mg and a hardness of from 5 to 6 kg.
In a similar manner tablets containing 4-[p-chloro-N-(biphenyl-2-yl)benzamido~butyric acid or 4-~N-(biphenyl-2-yl)crotonoylamido]butyric acid are prepared.
.
: !
' 33~3~
Tablets containinC lOO mq o4 4-~N-(biPhen~l-2-yl) acatamido]butyric acid 40.0 kg of 4-~N-(biphenyl-2-yl)acetamidolbutyric S acid, 24.0 kg of lactose and 16.0 kg of mai2e starch are granulated with 4~0 kg o~ polyvinylpyrrolidone (molecular weight: approx. 25,000) in about 5.5 liters of water a~d then pressed through a sieve with a ~esh width of l.25 mm.
After drying, 10.0 kg of carboxymethylcallulose, 4.0 ~g of talcum and 2.0 kg of magnesiu~ stearate are admix_~
therewith. On an eccentric machine the resulting sranulate is pressed into tablets with a diameter or 9 mm, 2 ~eight of 250 mg and a hardness of from 4 to 5 kg.
.
Tablets containing 300 mg of 4-~p-cAloro-~-biphenyl-2-yl)~enzamido]butyric acid.
60.0 kg of 4-~p-chloro-N-(biphenyl-2-yl)b~zami~o]-butyric acid, 12.0 kg of lactose and 8.0 kg of ai~e starch - are granulated with ~.O kg of polyvinylpyrrolidone (mole-cular weight: approx. 25,000) in about 6 liters of water nd then pressed through a sieve with a mesh wiath of 1.25 mm. After drying, lO.O kg of carboxymethylcellulose, 4.0 kg of talcum and 2.0 ~g of masnesiu~ stearzte are a~muxed _he-e-~ith. On a rotary pelleting machine the resulting granulate ~5;3387 i.s pressed into tablets with a diameter of 11 mm, a weight of 500 mg and a hardness of from 6 to 7 kg.
Analogously, tablets are produced which contain 300 mg of 4-[p-chloro-N-(biphenyl-2-yl)benzamido]caproic zLcid.
~XAMPLE 23 10,000 capsules with an active-principle content of 50 mg are produced from the following components:
'iOO g of 4-[N-(biphenyl-2-yl)crotonoylamido]butyric acid, 495 g of microcrystalline cellulose and 5 g of amorphous silica. The active principle in finely-powdered form, the cellulose and the silica are thoroughly mixed and packed i.nto hard gelatin (size 4) capsules.
. 15 PHARMACOLOGY
The acylbiphenylylamino acids exert a marked protective a.ction on the stomach and liver of rats, and in addition i.ncrease the pancreatic and ~ile secretion of rats, in which t:hey are found to be superior to the known commercial preparations, for example Piprozoline, Carbenoxolone. In a.ddition they bring about an inhibition of the formation of glucose from lactate and pyruvate in the liver of rats, 1~5~387 i.n which they are superior to known commercial preparation for example Buformin, Phenformin.
In the tables which follow, the compounds investigated a.re characterised by a serial number which has been allocated . 5 a.s follows:
Serial No. Name of compound 1 Piprozoline 2 Carbenoxolone 3 Buformin 4 Phenformin : 5 4-[N-(biphenyl-2-yl)-acetamido~-butyric acid 6 4-[p-chloro-N-(biphenyl-4-yl)-benzamido]-butyric acid .~ 7 6-[p-chloro-N-(biphenyl-2-yl)-benzamido]-caproic acid 8 4-~m-trifluoromethyl-N-(biphenyl-2-yl)-benzamido]-butyric acid 9 4-~p-fluoro-N-(biphenyl-2-yl)-benzamido]-: butyric acid 4-[N-(biphenyl-2-yl)-crotonoylamido]-butyric acid 11 5-[p-chloro-N-(biphenyl-2-yl)-benzamido]-valeric acid , .
- ~2 -~ S3387 `:, : ';erial No. Name of compound .
12 6-[2,4-dichloro-N-(biphenyl-2-yl)-benzamido]-caproic acid 13 6-[5-chloro-2-methoxy-N-(biphenyl-2-yl)-benzamido]-caproic acid :~ 14 4-[p-chloro-N-(biphenyl-2-yl)-benzamido]-butyric acid 5-[o-hydroxy-N-(biphenyl-2-yl)-benzamido]-valeric acid 10 16 4-[2-methoxy-5-chloro-N-(biphenyl-2-yl)-benzamido]-butyric acid ` 17 6-~N-(biphenyl-2-yl)-isobutyramido]-caproic acid 18 4-[p-chloro-N-(6-methoxy-biphenyl-3-yl)-benzamido]-butyric acid 19 4-~2-methoxy-5-chloro-N-(6-methoxy-biphenyl-3-yl)-benzamido]-butyric acid 4-[p-chloro-N-(1', 2', 3', 4', 5', 6',-hexahydro-biphenyl-4-yl)-benzamido]-butyric acid.
:
S~,387 `~ Table I shows the stomach protective action (reversal of the stomach ulcer caused by the ligature of the pylorus alnd administering 100 mg/kg of acetylsalicylic acid per os) after intraduodenal application in the rat, the lethal action after intraperitoneal administration in the mouse and also the therapeutical quotient (TQ = LD50/ED50) of re-presentatives of the compounds according to the Invention.
;
: 15 ~S~387 ; Table I
'`tomach protection actlon . Antiulcerogenlc ; Toxicityaction/rat ED50*) ,erialLD50 (mg/kg)denally LD50/ED50 2 120 50 2.4 . 5 750 55 13.6 6 120 14 8.6 : 7 130 22 5.9 . 9 210 40 5.3 300 ~ 40 ~ 7.5 . 11 140 30 4.7 : 13~ 400 **) 10 ~40 . 15 14 180 20 9 15 ~400 ~10 ~40 18 120 ~ 10 ~12 : 19 190 21 9 .
. _ *) Dose which reduces the mean ulcer index by 50 %
*~) per os, i.p. not applicable .
. - 55 _ .;
:
~`
:.
'3R7 Table II shows investlgations regardlng the anti.-hepatotoxic action (ED25j50) of the compounds according to t:he Invention after oral application to waking rats and the i.ethal action after intraperitoneal application on the S mouse (LD50) as well as the therapeutical quotients (TQ = LD50/ED25 and LD50/ 50 Table II
Antihepatotoxic effect, toxicity and ther~peutical quotient Toxicity Antihepatotocix effect TQ
';erialLD50(mg/kg) ED25*) 50*) 50/ LD50/
10No.mouse i.p. mg/kg per.os Rat ED25 ED50 _ __ 11070**) 200 >300 5.4 ~3.6 750 ~3 15 ?250 50 . 6 120 15 22 8 5.5 - 15 7 130 ~ 9 14 ~14.4 9.3 .. 8 110 10 30 11 3.7 9 210 1.6 2.8 131.3 75 300 1.6 2.8 187.5 107.1 11 140 3 12 46.7 11.7 2013>400***) 10 >40 . 14 180 '1 3.5 >180 51.4 17 260 ~30 > 8.7 ~150 ~10 ~15 ;
`` i~.~3387 Explanations to Table II:
~`') ED25 or ED50 = dose which shortens the hexobarbltal , narcosis by 25 and 50% respectlvely of rats suffering from liver damage from CCl4.
~'*) LD50 (per os) cited from Herrmann et al. Arzneim.-Forsch. 27 (1977) 467 ; ~'**) E3er os, i.p. not applicable Table III shows for representatives of the compounds according to the Invention the influence on the bile secre-1:ion (choleresis) of narcosed rats after the intraduodenalapplication (ED50) and the lethal action on the mouse (LD50) after intraperitoneal application and also the thera-peutical quotient (TQ = LD50/ED50).
Table III
-Bile secretion, toxicity and therapeutical quotient ToxicityBile secretion TQ
Serial LD50 (mg/k5)50***) (mg/kg) 50 50 (Mouse i.p.) (Rat i.d.) _ 1 1070** 40 26.8 750 ~15 ~ 50 300 ~10 ~V30 ***) ED50 = dose which brings about an increase in the bile ~.~!5;33~7 :`
, secretion (liquid volume; ~O-min. eraction) by a `I maximum of 50%
~'*) LD50 (P~~) cited from Herrmann et al. Arzneim.-Forsch.
27 (1977) 467 Table IV shows, for representatives of the compounds according to the Invention, the influence on the pancreatic secretion of narcotized rats after the intraduodenal appli-i c:ation (ED50) and the lethal action on the mouse (LD50) after intraperitoneal application, as well as the therapeu-tical quotient (TQ - LD50/ ED50).
.
' : .
i~ 33~7 ..i n able IV
I?ancreatic secretion, toxicity and therapeutical quotient :
Toxicity Pancreatic secretion TQ
',erialLD50 [mg/kg] ED50*)[m5/kg~ [LD50/ED50]
(Mouse, i.p.) (Rat, i.d.) 1. 5 _ , 11070**) 35 31 ~ 5 750 ~ 2 ~ 375 : 6 120 1 120 210 2.5 84 12 ~ 250 1.7 ~ 147 13~400***) ~ 1.0 > 400 ; 16 170 2 85 15 18 120 1.5 80 , 19 190 5 38 ~150 1.5 ~100 *) ED50 = dose which brings about an increase in the pancreat_c secretion (liquid volume; 30-min. fraction) Of a maximum of 50~
- **) LD50 (per os) cited from Herrmann et al. Arzneim.-Forsch. 27 (1977) 467.
***) per os, i.p. not applicable .~, Table V shows the results of the lnvestlgatlon of the :lnfluence of representatives of the compounds according.
l:o the Invention on the formation of glucose from lactate and pyruvate in the isolated perfused liver of fasting rats, S 1he inhibition of the glucose-formation being shown for a "~l substance concentration of 0.2 mmole/litre in the perfusate and the ED50 ~ determined from 4 concentrations in the range -~ from 0.02 to 1.00 mmol/litre - and the lethal action on the mouse (LD50) after intraperitoneal application.
- 10 Table V
]:nhibition of the formation of glucose from lactate and : pyruvate in the isolated perfused rat liver and toxicity on the mouse : ',erial Glucose formation 50 ) LD50 (i.p;) No. % change *)(mg/l) (mg/kg) 3 -1 ?1000 213***) ; 4 -3 ~1000 150****) . 14 -79 43 180 .. 7 -99 23 130 ~-: 9 -51 76 21Q .
12 -93 23 ~-250 .
. -'', ~.
1.15~1387 Explanations to Table V:
i~) substance concentration of 0.2 mmol/litre ln the perfusate ~*~ ED50 = dose which brings about an lnhlbltlon of the glucose formation of a maximum of 50%
~**) cited from Soling H.D., Creutzfeldt, W., Int.Biguanid Symp., Aachen 1960, Stuttgart, Thieme Verlag ~***) cited from Bertarelli, P., Boll.chim.farm. 97(1958)396 The compounds according to the Invention are characterised as compared with the cc,mparison compounds 3 and 4 by a considerably stronger inhibition of the formation of glucose from lactate and pyruvate. Whereas 3 and 4 exert practically no inhibition at the concentrations used, with the compounds according to the Invention it is possible to achieve inhi-bition effects of up to 99%.
:, The determination of the pharmacologicalproperties was carried out by the following methods:
Influence on the pancrea~ic and bile secretion of the narcotized rat Execution of experiment:
Male Sprague-Dawley rats (body weight 250-300 g) are narcotized with 1.2 g/kg urethane i.m. Then the abdominal cavity is opened medially, the bile duct is ligatured ; shortly above the place where it leads into the duodenum -:`
and also near to the hepatic duct, and both sectlons are catheterised towards the liver.
As in the rat all the pancreatic ducts lead out into the central sectlon of the bile duct, it is possible in 1:his way to discharge separately the pancreatic secretion from the distal (ligatured) section and the bile from the proximal section of the bile duct.
The quantities of pancreatic juice and bile juice secreted are measured at intervals of 30 minutes over a period from 2 hours before to 3 hours after the intraduo-denal administration of the compounds to be tested (quantity of liquid administered 5 ml/kg).
The body temperature of the animals is maintained at 36 to 38C by means of electric blankets and radiation;
the temperature is monitored rectally.
Evaluation:
The liquid volumes of the 30-minute fractions after the administration of the substance are r-elated in each case to the quantitiy of bile or pancreatic juice secreted prior to the application of the substance (= 100~, mean of the last two measurements). The maximum percentage increase in the pancreatic or bile secretion is represented according to the dose and from this the ED50 is determined by interpolation.
.
:' ' 33~7 Test for antihepatotoxic effect .i _ I~nfluence on the hexobarbital sleePlng perlod of the rat _Eter liver damage by CCl4 _xecution of test:
On the basis of VOGEL et al. (Arzneim.-Forsch.25(1975)82) l:iver cell damage is produced in fasting female Sprague-Dawley rats (190-10 g body weight, 10 animals/dose per test batcH) i by the oral administration of carbon tetrachloride (0.15 ml/kg CC14 in 2.5 ml/kg olive oil), and the extent of this 10 damage is determined by the prolongation of the sleeping period induced by hexobarbital sodium (50 mg/ml/kg i.v.;
caudal vein, duration of injection 45 - 60 seconds) 47 hours ater the administration of the CCl4. The compounds to be tested are administered 1 hour prior to the administration 15 of CC14 orally in a liquid volume of 10 ml/kg.
Evaluation:
_ The antihepatotoxic effect of the compounds to be ; tested (sodium salts in aqueous solution) is determined by ; the reduction of the prolongation of the sleeping period r 20 caused by the CC14 liver cell damage in the groups treated as compared with the prolongation of the sleeping period of the CCl4 control group (= 100%). The ED50 is determined by ~- interpolation from the dose/effect curve.
~;3~87 Testing the antiulcerogenic action The ulcer provocation is carried out on rats which have been made to fast for 24 hours (female, 180 - 200 g) by ligature of the pylorus (under ether narcosis) and the oral application of 100 mg/10ml/kg acetylsalicylic acid. The admini-stration of the substances was carried out intraduodenally (2.5 ml/kg) immediately after the ligature of the pylorus.
The closure of the wound was carried out by means of Michel clamps. 4 hours after this, the animals were destroyed whilst inebriated with ether by dislocation of the atlas and the stomach was resected. The stomach opened longitudinally is fixed on a cork board, and using a stereomicroscope with an enlargement of 10 X the number and size (= diameter) of any ulcers present were determined. The product of the degree of severity (according to the following scale of points) and the number of ulcers was used as the individual ulcer index.
~5;3387 Scale of points:
, No ulcer 0 ~ Diam. 0.1 - 1.4 mm .! ~ 1.5 - 2.4 mm 2 2.5 - 3.4 mm 3 3.5 - 4.4 mm 4 4.5 - 5.4 mm 5 ~5.5 mm 6 As a measure of the antiulcerogenic effect one used the reduction in the mean ulcer index of each treated group as compared with that of the control group (= 100~).
Determination of the inhibition of the formation of glucose in the isolated prefused rat liver ; For this purpose one uses young male Sprague-Dawley 1~ rats (160 to 200 g). The rats are kept in cages of up to 5 animals in a temperature-controlled room (23C) with a fixed day/night rhythm (12/12 hours).
Food is withheld from the animals 20 to 22 hours prior to the operation. They are allowed to take water ad lib.
The operation and the perfusion of the liver are carried out using the technique of R.Scholz et al. (Eur.J.Biochem.
38(1973)64-72). The perfusion liquid used is Krebs-Henseleit . , .
'''` ` ' ' 33~37 ~ bicarbonate buffer (pH 7.4), which is saturated wlth an - oxygen/carbon dioxide mixture (9S/5) and contains 1.6 mmol/litre of L-lactate and 0.2 mmol/litre pyruvate. The perfusion liquid is pumped into the liver via a cannula inserted into the portal vein. The effluent perfusion liquid is collected via a cannula inserted into the Vena cava. The liver is perfused for approximately 2 hours. The test com-pounds are infused for 16 minutes each from the 32nd to the 80th minute after the perfusion in increasing concentrations (0-02 to 1.00 mmol/litre).
Samples of the effluent perfusion liquid are collected at one-minute intervals and analysed for glucose, lactate and pyruvate using standard enzymatic methods. The percentages shown in Table V relate to the condition occuring before and after the administration of the compounds, the changes ` caused solely by lactate and pyruvate being set as being equal to 100%.
, Determination of toxicity The toxicity investigationsare carried out on female NMRI mice (body weight 22-26 g). The animals (5 animals per dose) are given food and water ad lib. Different doses of the substances are administered intraperitoneally. The dura-.
.,.
, ;: .
:, .
;;1387 tion of observation is 14 days. The LD50, i.e. the dose at which 50~ of the animals die, is determined graphically from the dose/effect curve.
. ~ .
~ .
''', . .
.~, .
~ , .
` `' ~
, ., :`:
.
.J
1:~L5;~3e~7 Preferred representatives of the compounds according to the Invention are 4-~4-chloro-N-(biphenyl-2-yl)-benzamido]-butyric acid, 4-GN-(biphenyl-2-yl)-acetamido]-butyric acid, 4-~4 fluoro-N-(biphenyl-2-yl)-benzamido~-butyric acid, 4-[N-(biphenyl-2-yl)-crotonoylamido]-butyric acid, `. 6-[4-chloro-N-(biphenyl-2-yl)-benzamido]-caproic acid, 6-~2,4-dichloro-N-(biphenyl-2-yl)-benzamido]-caproic acid, . 6-[5-chloro-2-methoxy-N-(biphenyl-2-yl)-benzamido]-caproic acid, 5-[2-hydroxy-N-(biphenyl-2-yl)-benzamido]-valeric acid and.their salts.
; The compounds according to the Invention display valuable pharmacological properties which make them commer-: 15 cially utilisable. In warm-blooded animals they develop a protective action for stomach and liver, and in addition they bring about an increase in the secretion of the pancreas and liver (bile). In addition they bring about an inhibition of the formation of glucose from lactate and pyruvate in the : 20 liver.
Because of their advantageous activity, the acylbiphenyl-ylaminoalkanoic acids are suitable for the treatment and prophy-` laxis of diseases which are attributa~le to disorders of the stomach or intestine or to reduced performances of the pancreas, .'--':
:
.
', .
.
~1~153387 bile and/or liver. For example one treats qastric or intes~lnal ulcers, ~illroth II, pancreatic insufficiency, sprue, lndl-gestions and malabsorptions of different aetiology, acute and chronic pancreatitis, indirect disorders of the pancreatic function (supporting of the production of secretin and pancreozymin), as weIl as gall bladder and bile duct inflam-mations, disorders of the bile flow, motility disorders of the bile ducts, a feeling of repletion, flatulence, consti-pation, upper abdominal complaint, hepato-biliar functional disorders, acute and chronic hepatitis, intoxications of the liver, fatty degeneration of the liver, diabetes (maturity - onset diabetes), insulin deficiency diabetes in the form ~of i'brittle diabetes", late diabetic damage The Invention thus furthermore relates to a process for the treatment of mammals suffering from one or more of the above-mentioned diseases. The process is characterised in ~hat a therapeutically active and pharmacologically tolerated amount of one or more compounds of the yeneral formulae I, I*, I**, I*** and I**** and/or salts thereof is administered to the sick mammal. The Invention also relates to the use of the compounds according to the Inven-tion in combating the illnesses indicated above. The Invention likewise comprises the use of the compounds according to the Invention for the preparation of medicaments which are ``:
., ~
.~., .
1~5;~387 employed for combating the illnesses listed.
The Invention further relates to pharmaceutical pro-ducts which contain one or more of the acylbiphenylylamino-alkanoic acids of the general formula I
R1 _ C0 - N - C H - C00~ (I), l n 2n in which R signifies an aliphatic or alicyclic hydrocarbon radical or an optionally substituted phenyl group, A signifies an optionally substituted and/or hydrogenated biphenylyl radical, n signifies a positive whole number from 3 to 5, and/or their pharmacologically compatible salts of inorganic or organic bases.
Forms of embodiment of the pharmaceutical products are those which contain acylbiphenylylaminoalkanoic acids of the formulae I*, I**, I***, I**** or their preferred re-presentatives and/or their pharmacologically compatible salts of inorganic or organic bases.
The pharmaceutical products are produced according to known processes. As pharmaceutical products the new compounds can be used as such or if desired in combination with suitable pharmaceutical carriers. If the new pharmaceutical ~l~S;33~37 preparations in addition to the active principles contain pharmaceutical carriers, the active principle content of these mixtures is 1 to 9S, preferably 15 to 85 per cent by weight of the total mixture.
In accordance with the Invention it is posslble in the field of human and veterinary medicine to use the active principles in any desired form, for example systemic, pro-vided that the formation or maintenance of adequate blood or tissue levels or local concentrations of active principle is ensured. This can either be carried out by oral, rectal or parenteral administration in suitable doses. More advan-tageously the pharmaceutical preparation of the active principle occurs in the form of unit doses which are designed for the particular form of administration desired. A unit dose can be, for example, a tablet, a pill, a capsule, a suppo-sitory, or a measured volume of a powder, a granulate, a solution, an emulsion, a suspension, a sol or a gel.
" Unit dose" in the sense of the present Invention is to be understood to mean a physically determined unit which contains an individual quantitiy of the active component in combination with a pharmaceutical carrier, the active -~ principle content of which corresponds to a fraction or .. .
:
.
, :
.
~:~LS3387 multiple of the therapeutical individual dose. An individual dose preferably contains the quantity of active princlple which is dispensed in a single applicatlon and which corresponds usually to a whole, a half or a third or a quarter of the daily dose.~ If for an individual therapeu-tical administration only a fraction, such as a half or a quarter of the unit dose is required, the unit dose is advantageously divisible, for example in the form of a tablet with a notch for breaking.
The pharmaceutical preparations according to the Invention, if they occur in unit doses and are intended for application, for example to human beings, may contain 0.5 to 1000 mg, advantageously 1 to 750 mg and especially 5 to 500 mg of active principle.
;
Generally speaking, it has been found advantageous both in human medicine and in veterinary medicine, to administer the active principle or principles in oral administration , in a daily dose of 0.01 to 40, preferably 0.1 to 30, especially - 0.2 to 20 mg/kg body weight, possibly in the form of s~veral, ;-~; 20 preferably 2 to 3 individual administrations, in order to , ;~.
achieve the desired results. An individual administration contains the active principle or principles in quantities of 0.0: to 20, preferably o.l to 15, especially 0.2 to 10 mg/kg ' ~53387 body weight.
In a parenteral treatment, for example intramuscular or intravenous application, it is possible to use similar dosages With this therapy one applies 50 to 1000 mg of active 5 principle.
The therapeutical administration of the pharmaceutical preparation is carried out in the case of long-term medication generally at fixed points of time, such as 1 to 4 times a day, for example before or after meals and/or in the evening.
10 In the case of acute attacks the medication is carried out u at varying points of time. Under certain circumstances it may be necessary to differ from the said dosages, namely accor-ding to the nature, the body weight and the age of the patient to be treated, the nature and severity of the disease, the 15 nature of the preparation and the application of the drug as well as the period of time or interval within which the admini-stration takes place. Thus in some cases it may be sufficient to manage with less than the above-mentioned quantity of active principle, whereas in other cases the quantity of 20 active principle mentioned above must be exceeded. The deter-mination of the optimum dosage and type of application of the acti~e principles necessary in each case can at any times be ;~
carried out by the expert on tbe basis of his technical know--~- ledge.
"
; - 18 -,.~
''' :
-,~
~S~3387 The pharmaceutical preparations conslst as a rule of theactive principles according to the Invention and non-toxic pharmaceutically compatible dru~ excipients which are used as an admixture agent, for example in the form of a capsule, a tablet coating, a bag or another container, for the thera-peutically active component. An excipient can, for example, serve as a vehicle for the uptake of the medicament by the body, as a formulation aid, as a sweetening agent, as a flavour corrector, as a colouring material or as a preserva-tive. The carriers are in each instance adapted by the - specialist to the diseases which are to be treated with the pharmaceutical preparations.
For oral-use it is possible to use, for example, tablets, ; pills, hard and soft capsules, for example of gelatine, disper-sible powders, granulates, aqueous and oily suspensions, emulsions, solutions or syrups.
., Tablets can contain inert diluents, for example calcium carbonate, calcium phospnate, sodium phosphate or lactose;
granulating and distributing agents, for example maize starch or alginates; binders such as for example starch, gelatine or gum acacia; and lubricants, such as for example aluminium or magnesium stearate, talcum or silicone oil. They can also ~- be provided with a coating which can alsG be designed in such a way that it gives a delayed dissolution and resorption ,:' 1~533~37 of the drug in the gastrointestinal tract and therefore ensures, for example, a better compatibility, protraction or retarding. Gelatine capsules can contain the pharmaceu-. tical product mixed with a solid diluent, for example calcium : 5 carbonate or kaolin, or an oily diluent, for example olive oil, groundnut oil or liquid paraffin.
Aqueous suspensions can contain suspension agents, for f example sodium carboxymethylcellulose, methylcellulose,hydroxypropylcellulose, sodium alginate, polyvinylpyrrolidone, - 10 gum dragon or gum acacia; dispersants and wetting agents, for example polyoxyethylene stearate, heptadecaethylene oxycetanol, polyoxyethylene sorbitol monooleate, polyoxy-' ethylene sorbitan monooleate or lecithin; preservatives, .j . such as for example methyl or propyl hydroxybenzoates;
~ 15 :flavouring materials; sweetening agents, for example sodium ;~ cyclamate, saccharin.
Oily suspensions cancontain for example groundnut oil, olive oil, sesame oil, coconut oil or liquid paraffin and . thickeners such as for example beeswaxr paraffin wax or cetyl alcohol; also they may contain sweeteners, flavouring materials and anti-oxidants.
. Powders and granulates which are dispersible in water can contain the pharmaceutical products in admixture with ispersants, wetting agents and suspending agents, for example '' ~ - 20 - ~
' : i ~ 1 S33R7 t:hose mentioned above, as well as sweeteners, flavouring materials and colouring materials.
Emulsions can contain, for example, olive oil, ground-nut oil or liquid paraffin as well as emulsifiers, such as for example gum acacia, gum dragon, phosphatides, sorbitan mono~
oleate, polyoxyethylene sorbitan monooleate, and sweeteners and flavouring materials.
For rectal use of the pharmaceutical products one uses suppositories, which are produced with the help of binders which melt at rectal temperature, for example cocoa butter or polyethyleneglycols.
For parenteral use of the pharmaceutical products one uses sterile injectable aqueous suspensions, isotonic saline solutions or other solutions which can contain dispersants or wetting agents and/or pharmacologically compatible diluents, for example propyleneglycol or butyleneglycol.
The active principle or principles can if desired be formulated with one or more of the said carrier materials or additives also in a microencapsulated form.
If the acylbiphenylylaminoalkanoic acids according to the In~ention and/or their salts are to be used for the treatment of diseases which are based on disorders of the stomach or intestine or on reduced performances of the pancreas, bile and/or liver, the pharmaceutical preparations can also contain ~53387 :
one or more other pharmacologlcally actlve components of other groups of pharmaceutical products, such as antacids, for example aluminium hydroxide, magnesium aluminate; tran-` guilizers, such as benzodiazeplnes, for example Diazepam;
`~ 5 spasmolytics, such as for example Bietamiverin, Camylofin;
anticholinergics, such as for example oxyphencyclimine, phencarbamide; despumation agents, for example dimethylpoly-s;iloxane; laxatives, for example Bisacodyl; swelling agents;
~; if desired also ferments, bile acids, antibiotics, vitamins, amino acids or fatty acid mixtures.
If the acylbiphenylylaminoalkanoic acids and/or their salts are formulated as antidiabetic products, the pharma-ceutical preparations can also contain one or more pharma-cologically active components belonging to different groups of pharmaceutical products, such as additional antidiabetics Isulphonamides, sulphonyl ureas), for example carbutamide, i~
t:olbutamide, chlorpropamide, glibenclamide, glibornuride, glis-oxepide, gliquidone, glymidine, or hypolipidaemics, such as benzafibrat or nicotinic acid as well as their derivatives and salts.
A further object of the Invention is a process for the production of acylbiphenylylaminoalkanoic acids of the general formula I
.~
~' ,,.
.
: , 115;~3~37 R1 _ C0 ~ ~ ~ Cn~I2n ~ COOH (I), . :Ln which R signifies an aliphatic or alicyclic hydrocarbon radical or an optionally substituted phenyl group, ~ signifies an optionally substituted and/or hydrogenated biphenylyl radical, n signifies a positive whole number from 3 to 5, .~ and their salts of inorganic and organic bases, which is .' 10 c:haracterised by the fact that a) a biphenylylaminoalkanoic acid of the general formula II
A NH n 2n (II), i.n which A and n habe the meanings given above, if desired with protection of the carboxyl group, is acylated with an acyl ~` 15 clerivative of the general formula III
R1 _ C0 - R (III), i.n which R7 signifies a leaving group or a R1-C0-0- group, and R1 has the meaning given above, and if desired is then con-verted into a salt or else b) a biphenylylaminoalkenoic acid of the general formula IV
R1 _ C0 - Nl ~ CnH2n-2 ~IV), A
:Ln which R1, A and n have the meanings given above, is hydro-genated, if desired with protection of the carboxyl group, :
.~
~ 15,~-~3~37 and if desired is then converted into a salt or c~ a functional acylbiphenylylaminoalkanoic acld derlvatlve o~ the general formula V
1 _ C0 - N - C H2 - G (V), A
in which R1, A and n have the meanings given above and G
; s:ignifies a functional derivative of a carboxyl group, i!; solvolysed and if desired is then converted into a salt.
For the production of the compounds of modifications I~, I**, I*** or I**** corresponding initial materials Il*, II**, II*** or II****; III*, III**, III*** or III****;
IV*, IV**, IV*** or rv**** or V*, V**, V*** or V**** in which the substituents have the corresponding meaning, are reacted.
If the biphenylylaminoalkanoic acids of the formula 15 I r are reacted with the protection of the carboxyl group, those representatives are used the protective groupsof which do not react with the acyl derivatives III. Suitable represen-tatives are for example esters of alkanols, including those with 1 to 5 carbon atoms, or phenalkanols, such as methyl, propyl, butyl, benzyl or phenethyl esters, possibly also solutions with inorganic or organic bases, such as alkali or alkaline earth metal hydroxides, ammonia, tertiary nitro-. .
- ~4 -~S;3~3~7 ! ~en bases (for example triethylamine, pyrldlne).
In the acyl derivatives III a leaving group R is for example a hydroxy group, a halogen atom, preferably a chlorine or bromine atom, an alkylsulphonyloxy or benzenesulphonyl-oxy gro~p, such as a mesyloxy or p-tolylsulphonyloxy group, ; an alkoxy group, preferably a methoxy or ethoxy group, an alkylmercapto group, such as a methylmercapto or ethylmer-apto group.
The reaction of the biphenylylaminoalkanoic acids II
with the acyl derivatives III is carried out by known processes. The reaction is carried out in suitable solvents, ;such as water or hydrocarbons, for example benzene, toluene, xylene, or ethers, for example tetrahydrofuran, dioxan, 1,2-dimethoxyethane, or ketones, for example methylethyl-ketone, or amides, for example dimethylformamide, orsulphoxides, for example dimethylsulphoxide.
Expediently the acylation, if R signifies a leaving group, is carried out in the presence of an acid-binding agent (proton acceptor). Suitable as such one may mention by way of example alkali metal hydroxides such as sodium hydro-xide, potassium hydroxide, or alkali metal carbonates sucn as sodlum carbonate, potassium carbonate, or tertiary amines such as pyridine, triethylamine, ethyldiisopropylamine.
i33R7 :[f the acyl derivatives III are acid anhydrides, that is to say if R signifies the R -C0-0- group, it is also sufficient 1:o heat the compounds II and III in an inert solvent.
',The reaction can be varied within wide limits, for example --20 to ~100C, temperatures around room temperature (10 to :30 C) being preferred. If the compounds II are acylated with 1:he protection of the carboxyl group, then after the acylation the protective group is split off again in the ~usual manner. If salts are used as protective group, the libera-:10 tion of the acids I obtained is effected by reaction with a suitable mineral acid, such as hydrochloric acid, or sul-phuric acid. If esters are used as protective groups, the acylation is followed by the saponification of the reaction product to give compounds of the formula I. The saponification i.s preferably carried out with an alcoholic (for example ethanolic) alkali metal hydroxide (for example potassium hydroxide) solution at room temperature, optionally with the addition of an inert diluent such as dioxan or benzene.
The initial compounds of the formula II are produced by various processes which are in themselves known. Thus, t:hey are obtained by reacting halogenalkanoic acids of the - formula VI, preferably with the protection of the carboxyl ';
~ - 26 -', , :, .
. .
5~33~37 ., group as an ester group, with a biphenylylamlne of the i.ormula VII
R n 2n A - NH2 ~ VI) (VII), :Ln which n and A have the meanings given above and R8 signifies a halogen atom, preferably a chlorine or bromine atom. The reaction is expediently carried out in the presence of an inert solvent, for example benzene, cyclohexane, diethyl ether, with the addition of a proton acceptor. One may use for this purpose, for example, an excess of the amine VII used for the reaction. If desired, however, it is also possible to add a different proton acceptor.
The starting products II are also obtained by reacting an alkenoic acid ester VIII
15CH2 = CH ~Cn-2H2n-4 (VIII), ; i.n which n has the meaning given above and R signifies an alkyl group with 1 to 5 carbon atoms or a benzyl group, ~lith a biphenylylamine VII. The reaction is expediently c:arried out in the presence of an inert solvent, such as hydrocarbons, for example benzene, toluene, xylene or ethers, ,' .
~`l . .
for example tetrahydrofuran, dioxan, 1,2-dimethoxyethane, or ]cetones, for example methylethylketone, or amides, for example dimethylformamide, or sulphoxides, for example dimethylsul-phoxlde, or nitriles, for example acetonitrile. Expediently the reactants are heated in the solvent, for example by boiling under reflux.
The protective group R is expediently split off only after the reaction of the resultant intermediate products II with the acyl derivatives III so as to obtain the end ~ 10 products I.
;~ The initial compounds II are also obtained by the sol-volysis of functional biphenylylaminoalkanoic acid derivatives of the general formula IX
` A - NH - C H - G (IX), - 15 in which A, n and G have the meanings given above, by ; means of processes which are known to the technician.
- E:xpedient forms of execution are described under process - variant c).
~ The starting products II are further obtained by :
reacting biphenylylamines VII with lactones of the general formula X
CnH2n C=O (X), r; ~ O
; - 28 -.
1~S~3~37 in which n has the meaning glven above, ln a known manner.
The reactlon ls carrled out for example by heatlng the reactants VII and X (e.g. to the boiling polnt of the solvent) i.n inert solvents such as ethers, for example diethyl ether, t:etrahydrofuran or nitriles, for example acetonitrile. The acid obtained can then be converted if desired into the corresponding esters, for example by heating in the corres-ponding alcohols in the presence of a mineral acid, such as hydrochloric acid or sulphuric acid.
The intermediate products II are alternatively obtained in a known manner by the hydrogenation of biphenylyliminoal-~:anoic acids XI
A - N = CH - (CH2)n-1 (XI) in which A and n have the meaning given above, optionally with the protection of the carboxyl group in a known manner.
l'he hydrogenation is carried out for example with Raney nickel under hydrogen pressures of 1 to 250 atmospheres at room temperature in absolute ethanol.
The acids XI are accessible by reacting the biphenyl-ylamines VII with oxo-acid esters XII
0 = CH ~ (CH2)n 1 ~ C0 - 0 - R (XII), - in which n and R have the meanings given above.
; - 29 -~ \
;~
533~37 .
The hydrogenation accordlng to process varlant b) ls c:arried out accoxding to methods such as are known to the t:echnician, Thus the biphenylylaminoalkenoic aclds IV are hydrogenated with hydrogen in the presence of a transition ~, 5 metal or noble metal catalyst or ~he corresponding oxides or :, j complexes in inert solvents. Suitable metals, for example, ~-j are platinum, palladium, iridium, rhodium. A summary of the i hydrogenation process is to be found inter alia in Kirk-Othmer 11, 418-462; Ullmann 10, 109-114, 541-555i 14, . , .
630-649. The splitting off of any protective group which may be present is carried out in the usual manner.
The alkenoic acids IV are obtained for example from t:he halogenalkenoic acid esters XIII
R _ C H2n 2 ~ C0 - 0 - R (XIII), in which R and n have the meanings given above and R10 ~;ignifies a halogen atom, preferably a bromine atom, by amination with a biphenylylamine VII, acylation with an acyl ;. clerivative IIIand if desired subsequent saponification.
r' l'he production is carried out by known methods, halogenation ~production of XIII) and amination, for example analogous to J.Heterocycl.Chem. 8 (1971) 21; acylation and saponifi-cation are carried out analogously to the description of ~' . .
~ , . .
... .
:, :
. .
: . .
~lS~ 7 the present Application.
The halogenalkanolc acids VI and blphenylylamlnes VII are known compounds or are produced by analogy processes;
` for example the halogenalkanoic acids VI are accessible by `1 5 solvolysis, such as hydrolysis or alcoholysis, of the corresponding lactones and subsequent halogenation. Thebiphenylyl-~ amines VII are obtained by the reduction of corresponding ; nitro compounds which are accessible by the nitration of corresponding biphenyls.
` 10 The solvolysis according to process variant c) is carried - out by processes known to the technician. A functional acid derivative in this case is understood to mean a derivative whose functional group G can be converted by solvolysis into 1:he free carboxyl group. Typical representatives are for ~xample those in which G signifles a -~N group or a-C y group, in which signifies an ox~gen or a sulphur atom or a substituted nitrogen atom, especially an imino, alkylimino or hydroxy-imino group and Y signifies a hydroxy group or a monovalent eliminable electrophilic radical, especially a free or substituted amino group, preferably a monoalkyl or dialkyl or aryl ' ... ' .
~5;~.3~7 amino group, a hydroxyamino or hydrazino group, a hydra-zobenzene group, a 2-hydroxyethylamino group, a free or substituted mercapto group, preferably an alkylthio group, a substituted hydroxy group, preferably an alkoxy group, an azido, a chloro or bromo radical, a morpholino group or a piperidino group, in which Y is not a hydroxy group if X represents an oxygen atom.
An alkyl radical of an alkylimino, a monoalkylamino, a dialkylamino, an alkylthio and an alkoxy group is to be understood to mean an alkyl radical with up to 5 carbon atoms, whilst an aryl radical of an arylamino group is to be understood to mean an aryl radical with up to 10 carbon atoms.
Preferred representatives of the acid derivative V are those in which G signifies a -CN group or a -C y group, :in which ; ,Y signifies an oxygen atom, a sulphur atom or an imino group and ; Y signifies an amino, monoalkylamino, dialkylamino, phenyl-amino, alkoxy, alkylthio, chloro or bromo radical.
Particularly preferred representatives of the acid derivative V are the corresponding acid amides, alkyl esters t)f the acid and nitriles, that is to say those compounds :`
of the formula V in which G represents a -C0-NH2l -C0-NH-R
-C0-NR 2~ -C0-0-R or -CN group and R has the meaning given above. They constitute valuable intermediate products for the production of the compounds I and their salts.
For the solvolysis of the functional carboxylic acid derivatives V one uses a medium which gives off water, which consists wholly or partly of water or of agents which split off water under hydrolysis conditions. The reaction can be carried out as a homogeneous reaction, in which case one usually operates in the presence of a polar organic sol-; vent or a solutizer. Advantageously one uses as solvent, for example, low-molecular alcohols, dioxan, acetone, low-molecular carboxylic acids, N-methylpyrrolidone, sulpholan or dimethylsulphoxide. However, it is also possible to carry out the hydrolysis as a heterogeneous reaction. The pH of the medium which splits off water depends upon the chemical nature of the acid derivative used, but also on the nature of the compound of the general formula I which is desired and it can therefore be neutral, acid or basic. It is adjusted to the desired value with acids, bases or buffers.
The hydrolysis temperatures are between 0C and the boiling point of the medium which splits off water, generally 1.15~ 7 ¦ between 0 and 150 C, and especially between 20 and 120 C.
The hydrolysis temperatures depend individually also on whether one operates under pressure or without pressure.
The reaction times are between 10 minutes and 20 hours according to the charge, the reaction temperatures and other reaction parameters. After the hydrolysis has ended, the acids :r are isolated by using the usual methods, for example by recrystallisation or by the acidification of their solutions, :Lf desired with the concentration of their solutions.
~ 10 In order to purify it, their alkaline solution can be ; extracted with an organic solvent which is not miscible with the alkaline solution , for example diethyl ether, benzene, chlorobenzene, chloroform or methylene chloride.
The carboxylic acid derivatives V are obtained by methods which are current to the technician. For example they are obtained by the reaction of functional halogenalkanoic acid clerivatives XIV
R ~ (CH2)n ~ G (XIV), i.n which R8, n and G have the meanings giv~en above, with 20 biphenylylamines VII followed by acylation with acyl derivatives ; III.
The conversion of the acids of the general formula I
or of the modifications I*, I**, I***, I*** into their salts J~lS3387 .1 can be carried out by direct alkaline hydrolysls of the acld derivatives of the formula V. As alkaline reactant one uses the particular inorganic or organic base whose salt is c~esired. However, one also obtains the salts if one reacts ; 5 l_he acids of the general formula I with the stoichiometrical equivalent of corresponding base, for example sodium hydroxide or sodium alcoholate, or else readily soluble salts are con-verted by double decomposition into sparingly soluble salts, or else any salts are converted into pharmacologically com-patible salts.
The following Examples illustrate the Invention in greater detail, but without restricting it. The abbreviations ~IP and BP signify melting point and boiling point respectively.
. .
, - 35 -~ ~5;33~7 EXAMPLE
~-~p-chtoro-lV-t~ipha~yI-2-yZJ~cmi~]butyr~o aoid Rl - p-chlorophenyl, A ~ ~iphenyl-2-yl, n ~ 3 a) ~:yt ~-fbiphsny?,-2-yZ)~rn7toou~yrat2 ~ 5 30.0 g of 2-amLnobiphenyl, 23.4 g of ethyl ciisoprooyl-amine and 35.4 g o ethyl 4-bromobutyrate are heated together to 1~0 for 3 hours while s~irr_ng. After cooling, ~he reaction pro~uct is sti-r2d with die~yl - ether, the precipitated salt is filtered ofr, and the residue ~remaining after evaporating of~ the ether) is recrystallized from isopropyl alcohol to obt~in 32.0 g (63.7% of theory) o~ ethyl g-(biphenyl-2-yl)amino-butyrate, ,u~ 60 to 62.
~) 2~:yZ 4-~cn~ro-.~-tbiphenyZ-2-yZ~b~r.z~r~dolDu~yl~crte 9.8 g of p-chlorobenzoyl chloride is added drop by drop at ~oom t~mper~tur_ (while stirring and withi~ 30 minutes) to a solution of 16.0 g of ethyl 4-~biphenyl-2-yl)-; aminobutyrate and 7.3 g of ethyl diisoprooyl~mine in 70 ~1 of benzene. After a further hour, ~he precipitate is ~iltered o'f, the filtrate is evaporated, and the evaporation residue is recrystallized from cyclohexane to obtain 18.0 g (75.6% o theory) o ethyl 4-[(p-chloro-N-(biphenyl-2-yl)benzamido]butyrate, ~P 100 to 102~.
c) ~-~p-ch~oro-~Y-(biph2nyZ-2-ytJbenzomido3b~yric c~id 15.0 g of ethyl 4-[p-chloro-N-~biphenyl-2-yl)benzamido]-butyrate is dissolved in 100 ml of benzene and, after the addi~ion thereto of a solution of 2.8 g of potassium hydroxide in 20 ml of ethanol, is then stirred at room temperature ~or S hours. The solvent is then distilled off *n v~c~o, and the obtained residue is dissolved in water. The resulting aqueous solution is acidi'ied with - dilute hydrochloric acid, and the precipitate, wnic~
; 10 separates out, is taken up in methyle~e chloride. The residue remai.~ing, after drying and distilling o~ he methylene chloride, is recrystallized from an et~anol/
water mixture ~2:1) to obtain 10.1 g ~72.1~ o- tneory) o~ 4-~?-chloro-N-(biphenyl-2-yl)ber.zamido]butyric acid, '~ 135 to 137.
~-[m-triJ7 oromet~y~ -fbipher.yl-2^yZ)ben2c~i~o]butyric ccid Rl = ~,a,~-trifluoro-m-tolyl, A = bipheryl-2-yl, n = 3 a) EthyZ ~-[n~-trif~wrome~.yZ-~Y-~oiDhe7~yZ-2-yZ)benz ~ o]Duty~ct Anal~gously to Example I b, 11.8 g of ethyl 4-(biphenyl-2-yl)aminobutyrate and 5.4 g of ethyldiisopropyl~mine are reacted in 70 ml of benzene with 8.7 g of m-tri-fluoromethylbenzoyl chloride. The reaction product is recrystallized from a mixture of iso?ropyl alcohol and water (1:1) to obtain 16.0 g (8~.4% of theory) of ' "
'. :
:
,:
. .
`:
1~5;33t37 .
ethyl-4-~m-trifluoromethyl-N-~biphenyl-2-yl)benzamido]-butyrate, .~P 65 to 67.
b,l 4- ~m-t2~J~wr~m~thy~-tV-tbiph~ny~-2-ylJb~nzam~o~ty2~:a ~o*d 16.0 g o~ et.iyl-4-~m-~rlfluoromethyl-N-(biphenyl-2-yl)-benzamido]butyrate in 50 ml of benzene are ~ixed with a solution of 3.4 g of potassium hydroxide in 25 ml of ethanol and sti~red at roo~ temperature for 8 hours.
'~hen further processed analogously to Exa~ple 1 c, ; 13.1 g ~91.3% of ~Iheory) of 4-~m-trifluoro~et~yl-~-io (biphenyl-2-yl)benzamidolbutyric acid, .~P 156 to 15~, are obtained.
, ~-~[p-J^Zuoro-~-(Dip~nyt-2-yZ)benz ~i~olsu~yr~c ~ci~
L
R' - p-fluorophenyl, A = biphenyl-2-yl, n = 3 a'l ~ yI 4-~p-f~ ipkenyZ-Z-uI)be?~zc7ndo]butyratz Analogously to Example 1 b 10.0 g of ethyl 4-(biphenyl-2-yl)aminobutyrate and 4.6 g of ethyldiisopro2ylamir.e ~n 50 ml of benzene are reactod with 5. 6 g of p-fluorobenzoyl chloride. The reaction product is recrystallized from cyclohexane to obtain 12.1 g ~84.6% of theory) of ethyl 4-tp-fluoro-N-(bi2he~yl-2-yl) benzamido butyrate, MP 83 to 84.
~ .
.' ' '.,~ ' .
'' ', , i~S~33~37 b) Ç-[p-fZwro-,~ ipheny~-2-ylJ~nzam~o]butyric c~id 11.2 g of ethyl 4-~p-~luoro-N-(biphenyl-2~yl)~enzamido]-butyrate in S0 ml of benzene is m~xed with a solution o~
2.2 g of potassium hydroxide in 20 ml o~ ethanol and S stirred at room temperat~re for 8 hours. When prccessed analogously to Example 1 c, 7.1 g t71.7~ of theory) of 4-~p-fluoro-N-(biphenyl-2-yl)benzamido]butyric acid, ~P 120 to 122, are obtaine~.
4 [ S-cnIoro- 2-metnosy-~- ~b:Dne~y 1, - 2-y ZJ oen~c:~ ] ou~;~ric a~d R-L ~ S-chloro-2-metho~yphenyl, A - biphenyl-2-yl, n = 3 Analosously to Exa~ple 1 , 10.0 5 of ethyl 4-(:biphenyl-2-yl)aminobutyrate and 4.6 g of ethyldiisopropyl-~In;ne in 50 ~1 of benzene are reacted with a solution of .3 g of 5-chloro-2-methoxybenzoyl chloride in 20 ml o benzene to obtain, as reaction ?roduct, 1;.0 g (94.1~ of theory) Oc ethyl 4-[S-chloro-2-methoxy-N-(bi2henyl-2-vl)benz-amido]butyrate as a viscous non-distillable oil. ~e saponification of this ester yields 12.4 g (88~ of theory~
c,f 4-[5-chloro-2-methoxy-N-(biphenyl-2-yl)benzamido]butyric z.cid, MP 160 to 162.
- 3~ -~, ., ~1533R7 , ~- [N- ~b~ph~nyl-2-yt)ccs~o ] ~u~yria aoid -C~3, A ~ biphenyl-2-yl, n ~ 3 Analogously to Exampla 1, 16.0 g of ethyl 4-(biphenyl-2-yl)aminobutyrate and 7.3 g of ethyldiisopropyl- -am~ne in 70 ml of benzene are reacted with 4.4 g o~ acetyl chlo~ide to obtain, as reaction product, 14.0 g ~76.2~ or theory) of ethyl 4-[N-(biphenyl-2-yl)acetamido]butyrate as a viscous non-distillable oil. The saponification of this ~ . 10 ester and recrystallization of the crude product obtained ; f~om isopropyl alcohol yields 10.1 g (79.03 of theory) of 4-[~J-~bipnenyl-2-yl)acet~;do3bu~yric acid, .~P 12~ to 125.
" .
-~i2h2nyI-2-yZJoro~m~y~s~b]~utyr~c ~ d .~
; Analogo~sly to Example 1, 10.0 g of ethyl 4-(biphenyl-2-yl)aminobutyrate and 4.6 g o~ ethyldiisopropyl-amine in 70 ml of benzene are reacted with 3.8 g of crotonyl chloride to obtain, as reaction product, 10.1 g (81.5% of theory) of ethyl 4-tN-tbiphenyl-2-yl)crotonoylamido]butyrate - as a viscous non-distillable oil. The saponification of this ester and recrystallization of the crude prodt~ct . obtained from isopropyl alcohol yields 5.1 g (55~ of theory) of 4~ biphenyl-2-yl)crotonoylamido]butyric acid, ,~P 127 to 128.
....
~ 40 -,. .
.~ . , ., .
~S''.3~7 E~AMPLE 7 5-~(p-ahZoro-lY-fbiphen~Z-2-yZ)be*~m~do~va1eric oc%d p-chlorophenyl, A - biphenyl-2-yl, n - 4 50.0 g of 2-am~nobiphenyl, 33.2 g of ethyldiiqopro-: S pylamlne and 61.9 g of ethyl 5-bromovalerate ars reacted : analo~ously to Example 1 a to obtain 80.0 g of ethyl S-~biphenyl-2-yl)aminovalerate a~ a non-crystallizin~ oil.
30.0 g o~ this est~r is reacted, analogously to Example 1 b , with 13.1 g of ethyldiisopropylamine and 17.1 g o~ lor~2~yl chloride in 10 ml of benzene; the ethyl S-[p-c~loro--~-tbiphenyl~2-yl)benz~mldo]valerate obtained as an oily ntermediate product is then saponifi~d analo-gously to ~xample 1 c to obtain 22.1 g ;53.7~ of theory) .` of 5[p-c~loro-~-(biphenyl-2-yl)benz ido]~aleric acid, .~ 15 ~P 170 to 173.
5-[o-hyd~o2y-~V-(b%phenyZ-2-u?,)berl2~dD]vol,eric ccid o-hydroxyohenyl, A = biohenyl-2-yl, n = 4 ~ 15.0 g or ethyl 5-~biphenyl-2-yl)aminovaleratP is : 20 reacted, analogously to Example 1 b, with 6.6 g of ethyl-r' diisopropylamine and 10.0 g of o-acetoxybenzoylchloride in 70 ml of benzene to obtain, as reaction product, 17.0 S
(73O4~ of theory) of ethyl 5-[o-ac~toxy-N-(biphenyl-2-yl)-benzamidolvalerate as a viscous non-dist-llable oil. The . 25 saponification of this ester yields 9.1 g (63.2% of theory) ~: of 5-[o-hydIoxy-N-(biphenyl-2-yl)bænzamldo]valeric acid, 138 to 139.
,,: , .; - 41 -:
.
.
. .
."'' ~
S;~31 37 6-~p~htoro-1V-tbiphenyt-2-yt)benz~o]c~pro*o aci,~l Rl p-chlorophenyl, A 8 biphenyl-2-yl, n - S
20.0 g of 2-aminobiphenyl, 15.3 g of ethyldiiso-propylamine and 26.3 g of ~thyl 6-bromocaproate are reacted, analosously to Example 1 a , to obtain 36.0 g of ethyl 5-~biphenyl-2~yl)aminocaproate as a non-crystallizing oil.
18.0 g of this ester are reacted, analogously to Ex~mple 1 b , with 7.5 g of ethyldiisopropylamine and ~0.1 g of p-chlorobenzoyl chloride in ~0 ml of b~nzene. The resulting reaction product is purified chromatographically o~er a silica gel column (eluent: methylene chloride) to obtain 11.5 g (44.2~ of theory) of ethyl 6-~p-chloro-~-(biphenyl-2-yl)benzamido]caproate as a viscous non-distillable oil.
Sap~nification of this ester yields 8.1 g (75.1~ of theory) of 6-[p-chloro-N-(biphenyl-2-yl)benzamido]caproic acid, ~P 93 to 95~.
6-[5-c;~toro-2-me~h.o~J-iY-tbiphsnyt-2-yt)benz~n~o]caproic ac~d 8.0 g of ethyl 6-tbiphenyl-2-yl)aminocaproate and 3.3 g of ethyldiisopropylamine in S0 ml of benzene a~e ,.
re~cted with a solution of 5.3 g of 5-chloro-2-.~et~oxy-benzoyl chloride in 20 ml of benzene, analogously to Example 1 a, to obtain, as _eaction product, 11.1 g . ~ . .
., .
: ' /
5,~33~7 I ~90~ of theory) of ethyl 6-~S-cbloro-2-methoxy-N-(~iphenyl-2-yl)benzamudolcaproate as a visco~s non-distillable oil.
The saponi~ication of this ester yields 7.0 g ~67~ o~
theory) of 6-tS-chloro-2-methoxy-N-~biphenyl-2-yl)bcnzamido]-caproic acid, r~ 164 to 165.
, 6-[D-~biphenyt^2-yl)isobutyrcmidb]c3~roic c^i~
Rl ~ -C~(Ca3)2, A - biphenyl-2-yl, n s ;
~ Analogously to Example 10 10.0 5 of ethyl `: 10 6-(biphenyl-2-yl)a~inocaproate, 4.2 g of ethyldiisooropyl-a~ine a~d 3.4 isobutyryl chloride n 70 .~1 of benzene yields 8.~ g (72.6~ of ~heory) or ethyl 6^~N-(biphenyl-2-yl)iso-buty.~ido]caproate as a ~iscous non distillable oil. The saponification of this ester yields 6.1 g ~74~ of t~eory) l; of 6-~N-(biphenyl-2-yl)isobutyr~mido]caproic ac d, MP 120 to 121.
:' .
s-~p-~htoro~ bipnenyt-~-yZ)benzcm*~o]ou~yr~c c~ d .. Rl ~ p-chlorophenyl, A = biphenyl-4-yl, n = 3 a) Ethyl 4-(biphenyI-4-ylJc~ nob%~ityr2te : 24.0 g (57.3~ of theory) of ethyl 4-(biphenyl-4-yl)-- aminobutyrate, ~ 82 to 84, are obtained analogously ,, .,` ` ' ..' . i .~., ..
31.~ 3~7 to Example 1 b , from 25.0 g o. 4-aminobiphenyl, 19.2 g of ethyldiisopropylamine and 28.9 g of ethyl 4-bro -butyrate.
b) 4^~p-cn~ tY-(biphenyI-~-y?,~benz~rr~do]bu~yrw cci~l S ~nalogously to Example 1 b, 10.0 g of ethyl 4-(bi?henyl-4-yl)aminobutyrate and 4.6 g of ethyldiisopropylamine Ln ~0 ml o~ ber.zene are reactad with 6.2 g of p-chloro-benzoyl chloride to obtain 9.4 g (62.9% of theory1 Of ethyl 4-tp-chloro-~-~biphenyl-4-yl)benza~ido]butyrate as a viscous non-distillable oil. Saponification of this ester, analogously to Example 1 a- , vields 7.0 g (79.7% of theory) of 4-[p-chloro-N-~biphenyl-4-vl)-benzamido]butyric acid, ~P 192 to 194.
~_{p-c~loro-~-(6-metho~y-oip~enyZ-3-yl)oe~zomi~o]o~tyq-~c aci~
'.
Rl , p-chlorophenyl, A - 6-methoxybiphenyl-3-yl, n = 3 a) 2ti~yI 4-~6-metno~ ipner~yZ-3-yt)~rwtoo~yrat~
; 29.; g of 5-amino-2-methoxybiphenyl, 19.2 g of ethyl-diisopropylamine and 28.9 g of ethyl 4-bromobutyrate are heated together (while stirring) for 4 hours at 125. After cooling, the resulting reaction ?roauc~
~ is stirred with diethyl ether and filtered from the ;; precipitated salt. The residue (remaining after evapora--~ ting off the ether) is recrystallized from isopropyl .' . . .
~.15;~3~37 alcohol to obtain 22.5 g t48.5~ of theory) of ethyl 4-~6-methoxybiphenyl-3-yl)aminobutyrate, .~P ~1 to 72.
b) 4- [p~hloro-.V-~6~ho~ybip~enyZ-3-yI)b~ do]~utyr~ ¢oid 8.0 g of ethyl 4-(6-methoxybiphenyl-3-yl)a~lnobutyrate and, 3.3 g of ethyldiisopropylamine in S0 ml of benzene are reacted, analogously to Example 1 b , with 4.6 g of p-chlorobenzoyl chloride. The reaction product is dissolved in 50 ml of benzene a~d, after the acdi~ion thereto of a solution of 2.3 g of potassium hydroxide ~10 in 20 ml o~ ethanol, is t~en stirred for 8 hours at room temperature. ~fter distilling of' t~e solvent, , the residue is dissolved in water; t.~e r-sulting solution is acidified with dilute hyd~ochloric acid and extracted with diethyl ether. The residue (remaining after evaporating of~ the ether) is recrystallized from ethyl acetate/petrol ether ~1:1) to obtain 8.1 g (73.5% of theory) of 4-[p-chloro-N-~6-methoxybiphenyl-3-yl)-benzamidolbutyric acid, .~P 114 to 116.
; EXAMPLE 14 ' r 20 4-tS~Zoro-Z-metho y-N-(6-me~orybiphenyZ-3-yl)~en2~1~utyrw c 5-chloro-2-methoxyphenyl, A = 6-methoxybiphenyl-3-yl, n = 3 ' Analogously to Example 13, reacting 7.0 g of ethyl 4-(6-methoxybiphenyl-3-yl)aminobutyrate with 4.6 g of ; 25 S-chloro-2-methoxybenzoyl chloride, followed by saponification ~,, ., .
.. . .
, ~.S'',387 of the mtesmediate product, yields 7.1 g (70.1~ of theory) of 4-~5-chloro-2-methoxy-N-~6-methoxybiphenyl-3-yl)benz,lmito]-butyric ac1d, ~ 155 to 156.
EXA~PLE 15 6-~2,~ ch~ iphe~Z-2-ytJb~7sz~0]cc~7roic cci~l Rl ~ 2,4-dichlorophenyl, R - biphenyl-2-yl, n = ;
: Following the procedure of Example 9 , but sub-stituting 2,4-dichlorobenzoyl chloride for p-chlorobenzoyl chloride, yields 6-[2,4-dichloro-~-(biphenyl-2-yl)be.~zamico~-caproic acid, ~P 112 to 113, from ethyl acetate/petrol ether (1:1).
, EXAMPLE 16 .. g-~p-chIoro~ (1',2',3',g',5',~ ~ ¢hyc~robiphenyt-~-y~)ben~ ~ o]outyt~
' eci~
..
~5 Rl ~ D-chlorophenyl, R - 1',2',3',4',5',6'-hexahydrobi?henyl-4-yl, n - 3 Following the procPdure of Example 1 a-c , but substituting p-cyclohexylaniline for 2-ami~o-~iy~enyl, ~-[p-chloro-~-l1',2',3',4',5',6'-hexahydrobiphenyl-4-yl)-benzamido~butyric acid, ~P 75 to 71, is obtaired from isopropyl alcohol/water (1:1).
.
; ~ .
~: - 46 -.,"';
;
i~.';;'3~'7 ~[p-c~ro-lV-~biphzny'-2-y~Jb~ b]vaIs~:o ~ d a) S-[~ iphsnyt-2-yt)¢msnolucts~c 2cid solution of 8.0 g of ethyl 5-(biphenyl-2-yl)amino-valerate ~see ~xample 7 ) in 60 ml of b~nzene i9 mixed with a solution of 2.2 g o~ potassium hydroxide in 20 ml of ethanol. After allowing the resulti~g admix-ture to stand for 24 hours at room temperature, the solvent mixture is dis~illed off ~ vacuo . The residue .. . .
is then dissolved in water; the obtained aaueous solu-tion is washed with diethyl etner and then acidified with dilute hydrochloric acid. The formed precipitate, which is oily at rirst, i3 taken up in dichloromethane.
T~e solvent is then distilled of t and t~e residue l; recrystallized from ethyl acetate/petrol ether (l:l) to obtain 5.6 g (71.3~ of theory) of 5-~N-~biphenyl-2-yl)aminolvaleric acid, .~ 73 to 75.
b) 5-[p~ toro-~ bipnenyZ-2-yZ)benz~do]~JaZe2~,c ac:d 5.4 g of 5-~N-(biphenyl-2-yl)amino]valeric acia is dissolved in 40 ml of 0.2 N caustic soda solution. I3to the resulting clear solution (while vigorously stirring and constantly controlling the pH) 3.5 g of p-chloro-benzoyl chloride is added, drop by drop, while con-currently adding dilute caustic soda solution in order to maintain the pH at between 7 and 8. Af'er ~he addi-tion of acid chloride is complete, the solution is sti_red 1~!5~387 fo¢ a further 30 minutes at pH 8 and then acidt~ied to pR 3 with dilute hydrochloric acid. The precipltat-, which is oily at fi~st cry3tallizes a~ter a time. ~t is ~iltered o~f and recrystalli2ad fro~ isopropyl S alcohol to obtain 7.6 g (93~ of thoery) of 5-~p-chloro-N-~biphenyl-2-yllben2amido]valeric acid, ~P 170 to 173, which is identical with the compaund obtained by the procedure of Example 7 .
A~poules containing 600 mg or 4-t2-chloro-~-(biphenyl-2-yl)benzamido]butyric acid; size or batch: 250 ks.
~;
25.0 kg of 1,2-propyleneglycol and 150.0 kg of double-distilled water ars placed in a vessel to which 15.0 kg of 4-tp-chloro-N-(biphenyl-2-yl)ben2amido]butyric lS acid are added. Then, while stirring, caustic soda solution ~10 percent by weight NaO~) is slowly added. When a solu--; tion is obtained, the pR is adjusted to from 7.5 to 8.0 Sodium pyrosulfite~is added, and the resulting mixture is stirred until all components have dissolvad. Using double-distilled water, the solution is made up to 250 kg. The solution is then charged into 10-ml ampoules and sterili2ed in an.autoclave for 30 minutes at 120.
,., ~mpoules containing 600 mg of 4-tN-(biphenyl-2-yl) crotonoylamido]butyric acid; size of batch: 250 kg.
*) 0.062; kg :
. .
~.~S~387 50.0 kg of 1,2-propyleneglycol and 150.0 ~g of double-distilled water are placed in a ~essel. While stirring,15 kg of 4-~N-(biphenyl-2-yl)crotonoylamido]butyric acid are added theseto. Then cau3tic soda solutlon (10 per 1 5 cant by weight NaO~) is added, and the resulting mi~ture is adjusted to a p~ of 8Ø ~sing double-distilled water, it is made up to 250 ~g. The solution is charged into 10-ml ampoules and sterilized in an autoclave at 120 for - 30 minutes.
Tablets containing ;0 mg of 4-[p-fluoro-N-~bipnenyl-2-yl)benza~ido]butyric acid.
25.0 kg of 4-~p-fluoro-N-(biphenyl-2-yl)benzamido]-butyric acid, 35.0 kg of lactose and 26.0 kg of maize starch are granulated with 21.5 kg or polyvinylpyrrolidone tmole-, - cular weight: approx. 25,000) in about 6 liters of water.
;~ The granulate is passed through a sieve wi~h a mesh width ., i .
~!, of 1.25 mm and, after drying, is a~mixed wi~h 8.0 kg o-carboxymethylcellulose, 2.5 ~g of talcum and 1.0 kg of , 20 magnesium stearate. The dry granulate is pressed into tablets with a diameter of 8 ~m, a weight of 250 mg and a hardness of from 5 to 6 kg.
In a similar manner tablets containing 4-[p-chloro-N-(biphenyl-2-yl)benzamido~butyric acid or 4-~N-(biphenyl-2-yl)crotonoylamido]butyric acid are prepared.
.
: !
' 33~3~
Tablets containinC lOO mq o4 4-~N-(biPhen~l-2-yl) acatamido]butyric acid 40.0 kg of 4-~N-(biphenyl-2-yl)acetamidolbutyric S acid, 24.0 kg of lactose and 16.0 kg of mai2e starch are granulated with 4~0 kg o~ polyvinylpyrrolidone (molecular weight: approx. 25,000) in about 5.5 liters of water a~d then pressed through a sieve with a ~esh width of l.25 mm.
After drying, 10.0 kg of carboxymethylcallulose, 4.0 ~g of talcum and 2.0 kg of magnesiu~ stearate are admix_~
therewith. On an eccentric machine the resulting sranulate is pressed into tablets with a diameter or 9 mm, 2 ~eight of 250 mg and a hardness of from 4 to 5 kg.
.
Tablets containing 300 mg of 4-~p-cAloro-~-biphenyl-2-yl)~enzamido]butyric acid.
60.0 kg of 4-~p-chloro-N-(biphenyl-2-yl)b~zami~o]-butyric acid, 12.0 kg of lactose and 8.0 kg of ai~e starch - are granulated with ~.O kg of polyvinylpyrrolidone (mole-cular weight: approx. 25,000) in about 6 liters of water nd then pressed through a sieve with a mesh wiath of 1.25 mm. After drying, lO.O kg of carboxymethylcellulose, 4.0 kg of talcum and 2.0 ~g of masnesiu~ stearzte are a~muxed _he-e-~ith. On a rotary pelleting machine the resulting granulate ~5;3387 i.s pressed into tablets with a diameter of 11 mm, a weight of 500 mg and a hardness of from 6 to 7 kg.
Analogously, tablets are produced which contain 300 mg of 4-[p-chloro-N-(biphenyl-2-yl)benzamido]caproic zLcid.
~XAMPLE 23 10,000 capsules with an active-principle content of 50 mg are produced from the following components:
'iOO g of 4-[N-(biphenyl-2-yl)crotonoylamido]butyric acid, 495 g of microcrystalline cellulose and 5 g of amorphous silica. The active principle in finely-powdered form, the cellulose and the silica are thoroughly mixed and packed i.nto hard gelatin (size 4) capsules.
. 15 PHARMACOLOGY
The acylbiphenylylamino acids exert a marked protective a.ction on the stomach and liver of rats, and in addition i.ncrease the pancreatic and ~ile secretion of rats, in which t:hey are found to be superior to the known commercial preparations, for example Piprozoline, Carbenoxolone. In a.ddition they bring about an inhibition of the formation of glucose from lactate and pyruvate in the liver of rats, 1~5~387 i.n which they are superior to known commercial preparation for example Buformin, Phenformin.
In the tables which follow, the compounds investigated a.re characterised by a serial number which has been allocated . 5 a.s follows:
Serial No. Name of compound 1 Piprozoline 2 Carbenoxolone 3 Buformin 4 Phenformin : 5 4-[N-(biphenyl-2-yl)-acetamido~-butyric acid 6 4-[p-chloro-N-(biphenyl-4-yl)-benzamido]-butyric acid .~ 7 6-[p-chloro-N-(biphenyl-2-yl)-benzamido]-caproic acid 8 4-~m-trifluoromethyl-N-(biphenyl-2-yl)-benzamido]-butyric acid 9 4-~p-fluoro-N-(biphenyl-2-yl)-benzamido]-: butyric acid 4-[N-(biphenyl-2-yl)-crotonoylamido]-butyric acid 11 5-[p-chloro-N-(biphenyl-2-yl)-benzamido]-valeric acid , .
- ~2 -~ S3387 `:, : ';erial No. Name of compound .
12 6-[2,4-dichloro-N-(biphenyl-2-yl)-benzamido]-caproic acid 13 6-[5-chloro-2-methoxy-N-(biphenyl-2-yl)-benzamido]-caproic acid :~ 14 4-[p-chloro-N-(biphenyl-2-yl)-benzamido]-butyric acid 5-[o-hydroxy-N-(biphenyl-2-yl)-benzamido]-valeric acid 10 16 4-[2-methoxy-5-chloro-N-(biphenyl-2-yl)-benzamido]-butyric acid ` 17 6-~N-(biphenyl-2-yl)-isobutyramido]-caproic acid 18 4-[p-chloro-N-(6-methoxy-biphenyl-3-yl)-benzamido]-butyric acid 19 4-~2-methoxy-5-chloro-N-(6-methoxy-biphenyl-3-yl)-benzamido]-butyric acid 4-[p-chloro-N-(1', 2', 3', 4', 5', 6',-hexahydro-biphenyl-4-yl)-benzamido]-butyric acid.
:
S~,387 `~ Table I shows the stomach protective action (reversal of the stomach ulcer caused by the ligature of the pylorus alnd administering 100 mg/kg of acetylsalicylic acid per os) after intraduodenal application in the rat, the lethal action after intraperitoneal administration in the mouse and also the therapeutical quotient (TQ = LD50/ED50) of re-presentatives of the compounds according to the Invention.
;
: 15 ~S~387 ; Table I
'`tomach protection actlon . Antiulcerogenlc ; Toxicityaction/rat ED50*) ,erialLD50 (mg/kg)denally LD50/ED50 2 120 50 2.4 . 5 750 55 13.6 6 120 14 8.6 : 7 130 22 5.9 . 9 210 40 5.3 300 ~ 40 ~ 7.5 . 11 140 30 4.7 : 13~ 400 **) 10 ~40 . 15 14 180 20 9 15 ~400 ~10 ~40 18 120 ~ 10 ~12 : 19 190 21 9 .
. _ *) Dose which reduces the mean ulcer index by 50 %
*~) per os, i.p. not applicable .
. - 55 _ .;
:
~`
:.
'3R7 Table II shows investlgations regardlng the anti.-hepatotoxic action (ED25j50) of the compounds according to t:he Invention after oral application to waking rats and the i.ethal action after intraperitoneal application on the S mouse (LD50) as well as the therapeutical quotients (TQ = LD50/ED25 and LD50/ 50 Table II
Antihepatotoxic effect, toxicity and ther~peutical quotient Toxicity Antihepatotocix effect TQ
';erialLD50(mg/kg) ED25*) 50*) 50/ LD50/
10No.mouse i.p. mg/kg per.os Rat ED25 ED50 _ __ 11070**) 200 >300 5.4 ~3.6 750 ~3 15 ?250 50 . 6 120 15 22 8 5.5 - 15 7 130 ~ 9 14 ~14.4 9.3 .. 8 110 10 30 11 3.7 9 210 1.6 2.8 131.3 75 300 1.6 2.8 187.5 107.1 11 140 3 12 46.7 11.7 2013>400***) 10 >40 . 14 180 '1 3.5 >180 51.4 17 260 ~30 > 8.7 ~150 ~10 ~15 ;
`` i~.~3387 Explanations to Table II:
~`') ED25 or ED50 = dose which shortens the hexobarbltal , narcosis by 25 and 50% respectlvely of rats suffering from liver damage from CCl4.
~'*) LD50 (per os) cited from Herrmann et al. Arzneim.-Forsch. 27 (1977) 467 ; ~'**) E3er os, i.p. not applicable Table III shows for representatives of the compounds according to the Invention the influence on the bile secre-1:ion (choleresis) of narcosed rats after the intraduodenalapplication (ED50) and the lethal action on the mouse (LD50) after intraperitoneal application and also the thera-peutical quotient (TQ = LD50/ED50).
Table III
-Bile secretion, toxicity and therapeutical quotient ToxicityBile secretion TQ
Serial LD50 (mg/k5)50***) (mg/kg) 50 50 (Mouse i.p.) (Rat i.d.) _ 1 1070** 40 26.8 750 ~15 ~ 50 300 ~10 ~V30 ***) ED50 = dose which brings about an increase in the bile ~.~!5;33~7 :`
, secretion (liquid volume; ~O-min. eraction) by a `I maximum of 50%
~'*) LD50 (P~~) cited from Herrmann et al. Arzneim.-Forsch.
27 (1977) 467 Table IV shows, for representatives of the compounds according to the Invention, the influence on the pancreatic secretion of narcotized rats after the intraduodenal appli-i c:ation (ED50) and the lethal action on the mouse (LD50) after intraperitoneal application, as well as the therapeu-tical quotient (TQ - LD50/ ED50).
.
' : .
i~ 33~7 ..i n able IV
I?ancreatic secretion, toxicity and therapeutical quotient :
Toxicity Pancreatic secretion TQ
',erialLD50 [mg/kg] ED50*)[m5/kg~ [LD50/ED50]
(Mouse, i.p.) (Rat, i.d.) 1. 5 _ , 11070**) 35 31 ~ 5 750 ~ 2 ~ 375 : 6 120 1 120 210 2.5 84 12 ~ 250 1.7 ~ 147 13~400***) ~ 1.0 > 400 ; 16 170 2 85 15 18 120 1.5 80 , 19 190 5 38 ~150 1.5 ~100 *) ED50 = dose which brings about an increase in the pancreat_c secretion (liquid volume; 30-min. fraction) Of a maximum of 50~
- **) LD50 (per os) cited from Herrmann et al. Arzneim.-Forsch. 27 (1977) 467.
***) per os, i.p. not applicable .~, Table V shows the results of the lnvestlgatlon of the :lnfluence of representatives of the compounds according.
l:o the Invention on the formation of glucose from lactate and pyruvate in the isolated perfused liver of fasting rats, S 1he inhibition of the glucose-formation being shown for a "~l substance concentration of 0.2 mmole/litre in the perfusate and the ED50 ~ determined from 4 concentrations in the range -~ from 0.02 to 1.00 mmol/litre - and the lethal action on the mouse (LD50) after intraperitoneal application.
- 10 Table V
]:nhibition of the formation of glucose from lactate and : pyruvate in the isolated perfused rat liver and toxicity on the mouse : ',erial Glucose formation 50 ) LD50 (i.p;) No. % change *)(mg/l) (mg/kg) 3 -1 ?1000 213***) ; 4 -3 ~1000 150****) . 14 -79 43 180 .. 7 -99 23 130 ~-: 9 -51 76 21Q .
12 -93 23 ~-250 .
. -'', ~.
1.15~1387 Explanations to Table V:
i~) substance concentration of 0.2 mmol/litre ln the perfusate ~*~ ED50 = dose which brings about an lnhlbltlon of the glucose formation of a maximum of 50%
~**) cited from Soling H.D., Creutzfeldt, W., Int.Biguanid Symp., Aachen 1960, Stuttgart, Thieme Verlag ~***) cited from Bertarelli, P., Boll.chim.farm. 97(1958)396 The compounds according to the Invention are characterised as compared with the cc,mparison compounds 3 and 4 by a considerably stronger inhibition of the formation of glucose from lactate and pyruvate. Whereas 3 and 4 exert practically no inhibition at the concentrations used, with the compounds according to the Invention it is possible to achieve inhi-bition effects of up to 99%.
:, The determination of the pharmacologicalproperties was carried out by the following methods:
Influence on the pancrea~ic and bile secretion of the narcotized rat Execution of experiment:
Male Sprague-Dawley rats (body weight 250-300 g) are narcotized with 1.2 g/kg urethane i.m. Then the abdominal cavity is opened medially, the bile duct is ligatured ; shortly above the place where it leads into the duodenum -:`
and also near to the hepatic duct, and both sectlons are catheterised towards the liver.
As in the rat all the pancreatic ducts lead out into the central sectlon of the bile duct, it is possible in 1:his way to discharge separately the pancreatic secretion from the distal (ligatured) section and the bile from the proximal section of the bile duct.
The quantities of pancreatic juice and bile juice secreted are measured at intervals of 30 minutes over a period from 2 hours before to 3 hours after the intraduo-denal administration of the compounds to be tested (quantity of liquid administered 5 ml/kg).
The body temperature of the animals is maintained at 36 to 38C by means of electric blankets and radiation;
the temperature is monitored rectally.
Evaluation:
The liquid volumes of the 30-minute fractions after the administration of the substance are r-elated in each case to the quantitiy of bile or pancreatic juice secreted prior to the application of the substance (= 100~, mean of the last two measurements). The maximum percentage increase in the pancreatic or bile secretion is represented according to the dose and from this the ED50 is determined by interpolation.
.
:' ' 33~7 Test for antihepatotoxic effect .i _ I~nfluence on the hexobarbital sleePlng perlod of the rat _Eter liver damage by CCl4 _xecution of test:
On the basis of VOGEL et al. (Arzneim.-Forsch.25(1975)82) l:iver cell damage is produced in fasting female Sprague-Dawley rats (190-10 g body weight, 10 animals/dose per test batcH) i by the oral administration of carbon tetrachloride (0.15 ml/kg CC14 in 2.5 ml/kg olive oil), and the extent of this 10 damage is determined by the prolongation of the sleeping period induced by hexobarbital sodium (50 mg/ml/kg i.v.;
caudal vein, duration of injection 45 - 60 seconds) 47 hours ater the administration of the CCl4. The compounds to be tested are administered 1 hour prior to the administration 15 of CC14 orally in a liquid volume of 10 ml/kg.
Evaluation:
_ The antihepatotoxic effect of the compounds to be ; tested (sodium salts in aqueous solution) is determined by ; the reduction of the prolongation of the sleeping period r 20 caused by the CC14 liver cell damage in the groups treated as compared with the prolongation of the sleeping period of the CCl4 control group (= 100%). The ED50 is determined by ~- interpolation from the dose/effect curve.
~;3~87 Testing the antiulcerogenic action The ulcer provocation is carried out on rats which have been made to fast for 24 hours (female, 180 - 200 g) by ligature of the pylorus (under ether narcosis) and the oral application of 100 mg/10ml/kg acetylsalicylic acid. The admini-stration of the substances was carried out intraduodenally (2.5 ml/kg) immediately after the ligature of the pylorus.
The closure of the wound was carried out by means of Michel clamps. 4 hours after this, the animals were destroyed whilst inebriated with ether by dislocation of the atlas and the stomach was resected. The stomach opened longitudinally is fixed on a cork board, and using a stereomicroscope with an enlargement of 10 X the number and size (= diameter) of any ulcers present were determined. The product of the degree of severity (according to the following scale of points) and the number of ulcers was used as the individual ulcer index.
~5;3387 Scale of points:
, No ulcer 0 ~ Diam. 0.1 - 1.4 mm .! ~ 1.5 - 2.4 mm 2 2.5 - 3.4 mm 3 3.5 - 4.4 mm 4 4.5 - 5.4 mm 5 ~5.5 mm 6 As a measure of the antiulcerogenic effect one used the reduction in the mean ulcer index of each treated group as compared with that of the control group (= 100~).
Determination of the inhibition of the formation of glucose in the isolated prefused rat liver ; For this purpose one uses young male Sprague-Dawley 1~ rats (160 to 200 g). The rats are kept in cages of up to 5 animals in a temperature-controlled room (23C) with a fixed day/night rhythm (12/12 hours).
Food is withheld from the animals 20 to 22 hours prior to the operation. They are allowed to take water ad lib.
The operation and the perfusion of the liver are carried out using the technique of R.Scholz et al. (Eur.J.Biochem.
38(1973)64-72). The perfusion liquid used is Krebs-Henseleit . , .
'''` ` ' ' 33~37 ~ bicarbonate buffer (pH 7.4), which is saturated wlth an - oxygen/carbon dioxide mixture (9S/5) and contains 1.6 mmol/litre of L-lactate and 0.2 mmol/litre pyruvate. The perfusion liquid is pumped into the liver via a cannula inserted into the portal vein. The effluent perfusion liquid is collected via a cannula inserted into the Vena cava. The liver is perfused for approximately 2 hours. The test com-pounds are infused for 16 minutes each from the 32nd to the 80th minute after the perfusion in increasing concentrations (0-02 to 1.00 mmol/litre).
Samples of the effluent perfusion liquid are collected at one-minute intervals and analysed for glucose, lactate and pyruvate using standard enzymatic methods. The percentages shown in Table V relate to the condition occuring before and after the administration of the compounds, the changes ` caused solely by lactate and pyruvate being set as being equal to 100%.
, Determination of toxicity The toxicity investigationsare carried out on female NMRI mice (body weight 22-26 g). The animals (5 animals per dose) are given food and water ad lib. Different doses of the substances are administered intraperitoneally. The dura-.
.,.
, ;: .
:, .
;;1387 tion of observation is 14 days. The LD50, i.e. the dose at which 50~ of the animals die, is determined graphically from the dose/effect curve.
. ~ .
~ .
''', . .
.~, .
~ , .
Claims (14)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Process for the preparation of an acylbiphenyl-ylaminoalkanoic acid conforming to the general formula I
(I), wherein R1 signifies an aliphatic or alicyclic hydrocarbon radical or an optionally substituted phenyl.group, A signifies an optionally substituted and/or hydrogenated biphenylyl radical, and n signifies a positive whole number from 3 to 5, or a pharmaceutically acceptable salt thereof with an inorganic or organic base, characterized in that a) a biphenylylaminoalkanoic acid of the general formula II
A - NH - CnH2n - COOH (II), in which A and n have the meanings given above, optio-nally with the protection of the carboxyl group, is acylated with an acyl derivative of the general formula III
R1 - CO - R7 (III), in which R7 is a leaving group or a R1-CO-O-group and R1 has the meaning given above, and if desired is then converted into a corresponding pharmaceutically acceptable salt or b) a biphenylylaminoalkenoic acid of the general formula IV
(IV), in which R1, A and n have the meanings given above, optionally with the protection of the carboxyl group, is hydrogenated and if desired is then coverted into a corresponding pharmaceutically acceptable salt, or c) a functional acylbiphenylylaminoalkanoic acid derivative of the general formula V
(V), in which R1, A and n have the meanings given above and G signifies a functional derivative of a carboxyl group, is solvolysed and if desired is then converted into a corresponding pharmaceutically acceptable salt.
(I), wherein R1 signifies an aliphatic or alicyclic hydrocarbon radical or an optionally substituted phenyl.group, A signifies an optionally substituted and/or hydrogenated biphenylyl radical, and n signifies a positive whole number from 3 to 5, or a pharmaceutically acceptable salt thereof with an inorganic or organic base, characterized in that a) a biphenylylaminoalkanoic acid of the general formula II
A - NH - CnH2n - COOH (II), in which A and n have the meanings given above, optio-nally with the protection of the carboxyl group, is acylated with an acyl derivative of the general formula III
R1 - CO - R7 (III), in which R7 is a leaving group or a R1-CO-O-group and R1 has the meaning given above, and if desired is then converted into a corresponding pharmaceutically acceptable salt or b) a biphenylylaminoalkenoic acid of the general formula IV
(IV), in which R1, A and n have the meanings given above, optionally with the protection of the carboxyl group, is hydrogenated and if desired is then coverted into a corresponding pharmaceutically acceptable salt, or c) a functional acylbiphenylylaminoalkanoic acid derivative of the general formula V
(V), in which R1, A and n have the meanings given above and G signifies a functional derivative of a carboxyl group, is solvolysed and if desired is then converted into a corresponding pharmaceutically acceptable salt.
2. Processes for the preparation of an acylbiphenyl-ylaminoalkanoic acid conforming to the general formula I*
(I*), wherein R1* signifies an aliphatic hydrocarbon radical with 1 to 7 carbon atoms, an alicyclic hydrocarbon radical with 3 to 10 carbon atoms or a phenyl radical A* signifies a group of the formula , or n* signifies a positive whole number from 3 to 5, R2*, R3* and R4* are the same or different and signify a hydrogen atom, a halogen atom, a hydroxy group, an alkyl group with 1 to 4 carbon atoms, an alkoxy group with 1 to 4 carbon atoms, an alknoyloxy group with 2 to 5 carbon atoms, a nitro group or a trifluoro-methyl group, and R5* and R6* are the same or different and signify a hydrogen atom, a halogen atom, a methyl group, a methoxy group, a hydroxy group or a nitro group, or a pharmaceutically acceptable salt thereof with an inorganic or organic base, characterized in that a) a biphenylylaminoalkanoic acid of the general formula II*
A* - NH - Cn*H2n* - COOH (II*), in which A* and n* have the meanings given above, optionally with the protection of the carboxyl group, is acylated with an acyl derivative of the general formula III*
R1* - CO - R7* (III*), in which R7* is a leaving group or a R1*-CO-O-group and R1* has the meaning given above, and if desired is then converted into a corresponding pharmaceutically acceptable salt or b) a biphenylylaminoalkenoic acid of the general formula IV*
(IV*), in which R1*, A* and n* have the meanings given above, optionally with the protection of the carboxyl group, is hydrogenated and if desired is then converted into a corresponding pharmaceutically acceptable salt, or c) a functional acylbiphenylylaminoalkanoic acid derivative of the general formula V*
(V*), in which R1*, A* and n* have the meanings given above and G* signifies a functional derivative of a carboxyl group, is solvolysed and if desired is then converted into a corresponding pharmaceutically acceptable salt.
(I*), wherein R1* signifies an aliphatic hydrocarbon radical with 1 to 7 carbon atoms, an alicyclic hydrocarbon radical with 3 to 10 carbon atoms or a phenyl radical A* signifies a group of the formula , or n* signifies a positive whole number from 3 to 5, R2*, R3* and R4* are the same or different and signify a hydrogen atom, a halogen atom, a hydroxy group, an alkyl group with 1 to 4 carbon atoms, an alkoxy group with 1 to 4 carbon atoms, an alknoyloxy group with 2 to 5 carbon atoms, a nitro group or a trifluoro-methyl group, and R5* and R6* are the same or different and signify a hydrogen atom, a halogen atom, a methyl group, a methoxy group, a hydroxy group or a nitro group, or a pharmaceutically acceptable salt thereof with an inorganic or organic base, characterized in that a) a biphenylylaminoalkanoic acid of the general formula II*
A* - NH - Cn*H2n* - COOH (II*), in which A* and n* have the meanings given above, optionally with the protection of the carboxyl group, is acylated with an acyl derivative of the general formula III*
R1* - CO - R7* (III*), in which R7* is a leaving group or a R1*-CO-O-group and R1* has the meaning given above, and if desired is then converted into a corresponding pharmaceutically acceptable salt or b) a biphenylylaminoalkenoic acid of the general formula IV*
(IV*), in which R1*, A* and n* have the meanings given above, optionally with the protection of the carboxyl group, is hydrogenated and if desired is then converted into a corresponding pharmaceutically acceptable salt, or c) a functional acylbiphenylylaminoalkanoic acid derivative of the general formula V*
(V*), in which R1*, A* and n* have the meanings given above and G* signifies a functional derivative of a carboxyl group, is solvolysed and if desired is then converted into a corresponding pharmaceutically acceptable salt.
3. Process for the preparation of an acylbiphenyl-ylaminoalkanoic acid conforming to the general formula I**
(I**), wherein R1** signifies an aliphatic hydrocarbon radical with 1 to 5 carbon atoms, an alicyclic hydrocarbon radical with 5 to 7 carbon atoms or a phenyl radical A** signifies a group of the formula or n** signifies a positive whole number from 3 to 5, R2** signifies a hydrogen atom, R 3** and R4** are the same or different and signify a hydrogen atom, a halogen atom, a hydroxy group, a methoxy group, a methyl group, an alkanoyloxy group with 2 to 5 carbon atoms, a nitro group or a triflu-oromethyl group, and one of the substituents R5** or R6** signifies a hydrogen atom and the other signifies a hydrogen atom, a halogen atom, a methyl group, a methoxy group, a hydroxy group or a nitro group, or a pharmaceutically acceptable salt thereof with an inorganic or organic base, characterized in that a) a biphenylylaminoalkanoic acid of the general formula II**
A** - NH - Cn**H2n** - COOH (II**), in which A** and n** have the meanings given in above, optionally with the protection of the carboxyl group, is acylated with an acyl derivative of the general formula III**
R1** - CO - R7** (III**), in which R7** is a leaving group or a R1**-CO-O-group and R1** has the meaning given above, and if desired is then converted into a corresponding pharmaceutically acceptable salt or b) a biphenylylaminoalkenoic acid of the general formula IV**
(IV**), in which R1**, A** and n** have the meanings given above, optionally with the protection of the carboxyl group, is hydrogenated and if desired is then converted into a corresponding pharmaceutically acceptable salt, or c) a functional acylbiphenylylaminoalkanoic acid derivative of the general formula V**
(V**), in which R1**, A** and n** have the meanings given above and G** signifies a functional derivative of a carboxyl group, is solvolysed and if desired is then converted into a corresponding pharmaceutically acceptable salt.
(I**), wherein R1** signifies an aliphatic hydrocarbon radical with 1 to 5 carbon atoms, an alicyclic hydrocarbon radical with 5 to 7 carbon atoms or a phenyl radical A** signifies a group of the formula or n** signifies a positive whole number from 3 to 5, R2** signifies a hydrogen atom, R 3** and R4** are the same or different and signify a hydrogen atom, a halogen atom, a hydroxy group, a methoxy group, a methyl group, an alkanoyloxy group with 2 to 5 carbon atoms, a nitro group or a triflu-oromethyl group, and one of the substituents R5** or R6** signifies a hydrogen atom and the other signifies a hydrogen atom, a halogen atom, a methyl group, a methoxy group, a hydroxy group or a nitro group, or a pharmaceutically acceptable salt thereof with an inorganic or organic base, characterized in that a) a biphenylylaminoalkanoic acid of the general formula II**
A** - NH - Cn**H2n** - COOH (II**), in which A** and n** have the meanings given in above, optionally with the protection of the carboxyl group, is acylated with an acyl derivative of the general formula III**
R1** - CO - R7** (III**), in which R7** is a leaving group or a R1**-CO-O-group and R1** has the meaning given above, and if desired is then converted into a corresponding pharmaceutically acceptable salt or b) a biphenylylaminoalkenoic acid of the general formula IV**
(IV**), in which R1**, A** and n** have the meanings given above, optionally with the protection of the carboxyl group, is hydrogenated and if desired is then converted into a corresponding pharmaceutically acceptable salt, or c) a functional acylbiphenylylaminoalkanoic acid derivative of the general formula V**
(V**), in which R1**, A** and n** have the meanings given above and G** signifies a functional derivative of a carboxyl group, is solvolysed and if desired is then converted into a corresponding pharmaceutically acceptable salt.
4. Processes for the preparation of an acylbiphenylyl-aminoalkanoic acid conforming to the general formula I***
(I***), wherein R1*** signifies an aliphatic hydrocarbon radical with 1 to 3 carbon atoms or a phenyl radical A*** signifies a group of the formula or n*** is a positive whole number from 3 to 5, R2*** signifies a hydrogen atom, R3*** and4*** are the same or different and signify a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxy group, a methoxy group or a trifluoro-methyl group, and one of the substituents R5*** or R6*** signifies a hydrogen atom and the other signifies a hydrogen atom or a methoxy group, or a pharmaceutically acceptable salt thereof with an inorganic or organic base, characterized in that a) a biphenylylaminoalkanoic acid of the general formula II***
A*** - NH - Cn***H2n*** - COOH (II***), in which A*** and n*** have the meaning given above, optionally with the protection of the carboxyl group, is acylated with an acyl derivative of the general formula III***
R1*** - CO - R7*** (III***), in which R7*** is a leavlng gxoup or a R1*** -CO-O-group and R1*** has the meaning given above, and if desired is then converted into a corresponding pharmaceutically acceptable salt or b) a biphenylylaminoalkenolc acid of the general formula IV***
(IV***), in which R1***, A*** and n*** have the meanings given above, optionally with the protection of the carboxyl group, is hydrogenated and if desired is then converted into a corresponding pharmaceutically acceptable salt, or c) a functional acylbiphenylylaminoalkanoic acid derivative of the general formula V***
(V***), in which R1***, A*** and n*** have the meanings given above and G*** signifies a functional derivative of a carboxyl group, is solvolysed and if desired is then converted into a corresponding pharmaceutically acceptable salt.
(I***), wherein R1*** signifies an aliphatic hydrocarbon radical with 1 to 3 carbon atoms or a phenyl radical A*** signifies a group of the formula or n*** is a positive whole number from 3 to 5, R2*** signifies a hydrogen atom, R3*** and4*** are the same or different and signify a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxy group, a methoxy group or a trifluoro-methyl group, and one of the substituents R5*** or R6*** signifies a hydrogen atom and the other signifies a hydrogen atom or a methoxy group, or a pharmaceutically acceptable salt thereof with an inorganic or organic base, characterized in that a) a biphenylylaminoalkanoic acid of the general formula II***
A*** - NH - Cn***H2n*** - COOH (II***), in which A*** and n*** have the meaning given above, optionally with the protection of the carboxyl group, is acylated with an acyl derivative of the general formula III***
R1*** - CO - R7*** (III***), in which R7*** is a leavlng gxoup or a R1*** -CO-O-group and R1*** has the meaning given above, and if desired is then converted into a corresponding pharmaceutically acceptable salt or b) a biphenylylaminoalkenolc acid of the general formula IV***
(IV***), in which R1***, A*** and n*** have the meanings given above, optionally with the protection of the carboxyl group, is hydrogenated and if desired is then converted into a corresponding pharmaceutically acceptable salt, or c) a functional acylbiphenylylaminoalkanoic acid derivative of the general formula V***
(V***), in which R1***, A*** and n*** have the meanings given above and G*** signifies a functional derivative of a carboxyl group, is solvolysed and if desired is then converted into a corresponding pharmaceutically acceptable salt.
5. Processes for the preparation of an acylbiphenyl-ylaminoalkanoic acid conforming to the general formula I****
(I****), wherein R1**** signifies an alkyl group with 1 to 3 carbon atoms, an alkenyl radical with 2 or 3 carbon atoms, or a phenyl group A**** signifies a group of the formula n**** signifies a positive whole number from 3 to 5, R2**** signifies a hydrogen atom, R3**** signifies a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxy group, a methoxy group or a trifluoromethyl group, R4**** signifies a hydrogen atom or a chlorine atom, and one of the substituents R5**** or R6**** signifies a hydrogen atom and the other signifies a hydrogen atom or a methoxy group, or a pharmaceutically acceptable salt thereof with an inorganic or organic base, characterized in that a) a biphenylylaminoalkanoic acid of the general formula II****
A**** - NH - Cn****H2n**** - COOH (II****), in which A**** and n**** have the meanings given above, optionally with the protection of the carboxyl group, is acylated with an acyl derivative of the general formula III****
R1****- CO - R7**** (III****), in which R7**** is a leaving group or a R1****-CO-O-group and R1**** has the meaning given above, and if desired is then converted into a corresponding pharmaceutically acceptable salt or b) a biphenylylaminoalkenoic acid of the general formula IV****
(IV****), in which R1****, A**** and n**** have the meanings given above, optionally with the protection of the carboxyl group, is hydrogenated and if desired is then converted into a corresponding pharmaceutically acceptable salt, or c) a functional acylbiphenylylaminoalkanoic acid derivative of the general formula V****
(V****), in whlch R1****, A**** and n**** have the meanings given above and G**** signifies a functional derivative of a carboxyl group, is solvolysed and if desired is then converted into a corres-ponding pharmaceutically acceptable salt.
(I****), wherein R1**** signifies an alkyl group with 1 to 3 carbon atoms, an alkenyl radical with 2 or 3 carbon atoms, or a phenyl group A**** signifies a group of the formula n**** signifies a positive whole number from 3 to 5, R2**** signifies a hydrogen atom, R3**** signifies a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxy group, a methoxy group or a trifluoromethyl group, R4**** signifies a hydrogen atom or a chlorine atom, and one of the substituents R5**** or R6**** signifies a hydrogen atom and the other signifies a hydrogen atom or a methoxy group, or a pharmaceutically acceptable salt thereof with an inorganic or organic base, characterized in that a) a biphenylylaminoalkanoic acid of the general formula II****
A**** - NH - Cn****H2n**** - COOH (II****), in which A**** and n**** have the meanings given above, optionally with the protection of the carboxyl group, is acylated with an acyl derivative of the general formula III****
R1****- CO - R7**** (III****), in which R7**** is a leaving group or a R1****-CO-O-group and R1**** has the meaning given above, and if desired is then converted into a corresponding pharmaceutically acceptable salt or b) a biphenylylaminoalkenoic acid of the general formula IV****
(IV****), in which R1****, A**** and n**** have the meanings given above, optionally with the protection of the carboxyl group, is hydrogenated and if desired is then converted into a corresponding pharmaceutically acceptable salt, or c) a functional acylbiphenylylaminoalkanoic acid derivative of the general formula V****
(V****), in whlch R1****, A**** and n**** have the meanings given above and G**** signifies a functional derivative of a carboxyl group, is solvolysed and if desired is then converted into a corres-ponding pharmaceutically acceptable salt.
6. Process according to claim 4 in which A***
is a 2-biphenylyl radical.
is a 2-biphenylyl radical.
7. Process according to claim 5 in which A****
is a 2-biphenylyl radical.
is a 2-biphenylyl radical.
8. Process according to claim 5 in which R3****
is a fluorine atom, a chlorine atom, a hydroxy group or a methoxy group and R5**** and R6****
are hydrogen atoms.
is a fluorine atom, a chlorine atom, a hydroxy group or a methoxy group and R5**** and R6****
are hydrogen atoms.
9. Process according to claim 5, in which A****
is a 2-biphenylyl radical, R3**** is a fluorine atom, a chlorine atom, a hydroxy group or a methoxy group and R5**** and R6**** are hydrogen atoms.
is a 2-biphenylyl radical, R3**** is a fluorine atom, a chlorine atom, a hydroxy group or a methoxy group and R5**** and R6**** are hydrogen atoms.
10. An acylbiphenylylaminoalkanoic acid of the general formula I
(I), wherein R1 signifies an aliphatic or alicyclic hydrocarbon radical or an optionally substituted phenyl group, A signifies an optionally substituted and/or hydrogenated biphenylyl radical, and n signifies a positive whole number from 3 to 5, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.
(I), wherein R1 signifies an aliphatic or alicyclic hydrocarbon radical or an optionally substituted phenyl group, A signifies an optionally substituted and/or hydrogenated biphenylyl radical, and n signifies a positive whole number from 3 to 5, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.
11. An acylbiphenylylaminoalkanoic acid of the general formula I*
(I*) wherein R1* signifies an aliphatic hydrocarbon radical with 1 to 7 carbon atoms, an alicyclic hydrocarbon radical with 3 to 10 carbon atoms or a phenyl radical.
A* signifies a qroup of the formula or n* signifies a positive whole number from 3 to 5, R2*, R3* and R4* are the same or different and signify a hydrogen atom, a halogen atom, a hydroxy group, an alkyl group with 1 to 4 carbon atoms, an alkoxy group with 1 to 4 carbon atoms, an alkanoyloxy group with 2 to 5 carbon atoms, a nitro group or a trifluoro-methyl group, and R5* and R6* are the same or different and signify a hydrogen atom, a halogen atom, a methyl group, a methoxy group, a hydroxy group or a nitro group, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 2 or by an obvious chemical equivalent thereof.
(I*) wherein R1* signifies an aliphatic hydrocarbon radical with 1 to 7 carbon atoms, an alicyclic hydrocarbon radical with 3 to 10 carbon atoms or a phenyl radical.
A* signifies a qroup of the formula or n* signifies a positive whole number from 3 to 5, R2*, R3* and R4* are the same or different and signify a hydrogen atom, a halogen atom, a hydroxy group, an alkyl group with 1 to 4 carbon atoms, an alkoxy group with 1 to 4 carbon atoms, an alkanoyloxy group with 2 to 5 carbon atoms, a nitro group or a trifluoro-methyl group, and R5* and R6* are the same or different and signify a hydrogen atom, a halogen atom, a methyl group, a methoxy group, a hydroxy group or a nitro group, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 2 or by an obvious chemical equivalent thereof.
12. An acylbiphenylylaminoalkanoic acid of the general formula I**
(I**), wherein R1** signifies an aliphatic hydrocarbon radical with 1 to 5 carbon atoms, an alicyclic hydrocarbon radical with 5 to 7 carbon atoms or a phenyl radical A** signifies a group of the formula or n** signifies a positive whole number from 3 to 5, R2** signifies a hydrogen atom, R3** and R4 are the same or different and signify a hydrogen atom, a halogen atom, a hydroxy group, a methoxy group, a methyl group, an alkanoyloxy group with 2 to 5 carbon atoms, a nitro group or a triflu-oromethyl group, and one of the substituents R5** or R6** signifies a hydrogen atom and the other signifies a hydrogen atom, a halogen atom, a methyl group, a methoxy group, a hydroxy group or a nitro group, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 3 or by an obvious chemical equivalent thereof.
(I**), wherein R1** signifies an aliphatic hydrocarbon radical with 1 to 5 carbon atoms, an alicyclic hydrocarbon radical with 5 to 7 carbon atoms or a phenyl radical A** signifies a group of the formula or n** signifies a positive whole number from 3 to 5, R2** signifies a hydrogen atom, R3** and R4 are the same or different and signify a hydrogen atom, a halogen atom, a hydroxy group, a methoxy group, a methyl group, an alkanoyloxy group with 2 to 5 carbon atoms, a nitro group or a triflu-oromethyl group, and one of the substituents R5** or R6** signifies a hydrogen atom and the other signifies a hydrogen atom, a halogen atom, a methyl group, a methoxy group, a hydroxy group or a nitro group, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 3 or by an obvious chemical equivalent thereof.
13. An acylbiphenylylaminoalkanoic acid of the general formula I***
(I***), wherein R1*** signifies an aliphatic hydrocarbon radical with 1 to 3 carbon atoms or a phenyl radical A*** signifies a group of the formula or n*** is a positive whole number from 3 to 5, R2*** signifies a hydrogen atom, R3*** and R4*** are the same or different and signify a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxy group, a methoxy group or a trifluoro-methyl group, and one of the substltuents R5*** or R6*** signifies a hydrogen atom and the other signifies a hydrogen atom or a methoxy group, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 4 or by an obvious chemical equivalent thereof.
(I***), wherein R1*** signifies an aliphatic hydrocarbon radical with 1 to 3 carbon atoms or a phenyl radical A*** signifies a group of the formula or n*** is a positive whole number from 3 to 5, R2*** signifies a hydrogen atom, R3*** and R4*** are the same or different and signify a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxy group, a methoxy group or a trifluoro-methyl group, and one of the substltuents R5*** or R6*** signifies a hydrogen atom and the other signifies a hydrogen atom or a methoxy group, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 4 or by an obvious chemical equivalent thereof.
14. An acylbiphenylylaminoalkanoic acid of the general formula I****
(I****), wherein R1**** signifies an alkyl group with 1 to 3 carbon atoms, an alkenyl radical with 2 or 3 carbon atoms, or a phenyl group A**** signifies a group of the formula n**** signifies a positive whole number from 3 to 5, R2**** signifies a hydrogen atom, R3**** signifies a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxy group, a methoxy group or a trifluoromethyl group, R4**** signifies a hydrogen atom or a chlorine atom, and one of the substituents R5**** or R6**** signifies a hydrogen atom and the other signifies a hydrogen atom or a methoxy group, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 5 or by an obvious chemical equivalent thereof.
(I****), wherein R1**** signifies an alkyl group with 1 to 3 carbon atoms, an alkenyl radical with 2 or 3 carbon atoms, or a phenyl group A**** signifies a group of the formula n**** signifies a positive whole number from 3 to 5, R2**** signifies a hydrogen atom, R3**** signifies a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxy group, a methoxy group or a trifluoromethyl group, R4**** signifies a hydrogen atom or a chlorine atom, and one of the substituents R5**** or R6**** signifies a hydrogen atom and the other signifies a hydrogen atom or a methoxy group, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 5 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH650478 | 1978-06-14 | ||
| CH6504/78-7 | 1978-06-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1153387A true CA1153387A (en) | 1983-09-06 |
Family
ID=4310656
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000329666A Expired CA1153387A (en) | 1978-06-14 | 1979-06-13 | Substituted amino acids, their use and production and pharmaceutical products containing same |
Country Status (18)
| Country | Link |
|---|---|
| EP (1) | EP0006218B1 (en) |
| JP (1) | JPS54163558A (en) |
| AT (1) | ATE1093T1 (en) |
| AU (1) | AU525423B2 (en) |
| BE (1) | BE876933A (en) |
| CA (1) | CA1153387A (en) |
| DE (2) | DE2962949D1 (en) |
| DK (1) | DK244979A (en) |
| ES (1) | ES481492A1 (en) |
| FR (1) | FR2432501A1 (en) |
| GB (1) | GB2024813A (en) |
| GR (1) | GR65292B (en) |
| IE (1) | IE48514B1 (en) |
| IL (1) | IL57554A0 (en) |
| NZ (1) | NZ190722A (en) |
| PL (1) | PL216292A1 (en) |
| PT (1) | PT69762A (en) |
| ZA (1) | ZA792943B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3042482A1 (en) * | 1980-11-11 | 1982-06-24 | A. Nattermann & Cie GmbH, 5000 Köln | N-BENZOYL- (OMEGA) -ANILINOALCANCARBONIC ACIDS, SALTS AND -ESTERS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM |
| US4440941A (en) * | 1980-12-22 | 1984-04-03 | Usv Pharmaceutical Corporation | Aroyl-aminoacids, amides and esters thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3697563A (en) * | 1970-06-29 | 1972-10-10 | Inst Chemioterapico Italiano S | (3,4,5-trimethoxy-benzamido)-alkanoic acids for prophylaxis and treatment of cardiac disorders |
-
1979
- 1979-06-12 DE DE7979101912T patent/DE2962949D1/en not_active Expired
- 1979-06-12 EP EP79101912A patent/EP0006218B1/en not_active Expired
- 1979-06-12 BE BE6/46861A patent/BE876933A/en unknown
- 1979-06-12 PL PL21629279A patent/PL216292A1/xx unknown
- 1979-06-12 AT AT79101912T patent/ATE1093T1/en not_active IP Right Cessation
- 1979-06-12 JP JP7315079A patent/JPS54163558A/en active Pending
- 1979-06-12 DE DE19792923731 patent/DE2923731A1/en not_active Withdrawn
- 1979-06-12 DK DK244979A patent/DK244979A/en not_active Application Discontinuation
- 1979-06-12 PT PT69762A patent/PT69762A/en unknown
- 1979-06-12 GB GB7920409A patent/GB2024813A/en not_active Withdrawn
- 1979-06-12 GR GR59321A patent/GR65292B/en unknown
- 1979-06-12 AU AU47978/79A patent/AU525423B2/en not_active Ceased
- 1979-06-12 FR FR7914946A patent/FR2432501A1/en not_active Withdrawn
- 1979-06-12 ES ES481492A patent/ES481492A1/en not_active Expired
- 1979-06-13 CA CA000329666A patent/CA1153387A/en not_active Expired
- 1979-06-13 IL IL57554A patent/IL57554A0/en unknown
- 1979-06-13 ZA ZA792943A patent/ZA792943B/en unknown
- 1979-06-14 NZ NZ190722A patent/NZ190722A/en unknown
- 1979-08-08 IE IE1129/79A patent/IE48514B1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ZA792943B (en) | 1980-06-25 |
| PT69762A (en) | 1979-07-01 |
| PL216292A1 (en) | 1980-03-24 |
| EP0006218A1 (en) | 1980-01-09 |
| AU4797879A (en) | 1979-12-20 |
| DE2923731A1 (en) | 1980-01-03 |
| EP0006218B1 (en) | 1982-05-26 |
| JPS54163558A (en) | 1979-12-26 |
| AU525423B2 (en) | 1982-11-04 |
| IL57554A0 (en) | 1979-10-31 |
| ES481492A1 (en) | 1980-03-01 |
| ATE1093T1 (en) | 1982-06-15 |
| IE791129L (en) | 1979-12-14 |
| GR65292B (en) | 1980-08-01 |
| DE2962949D1 (en) | 1982-07-15 |
| FR2432501A1 (en) | 1980-02-29 |
| NZ190722A (en) | 1981-11-19 |
| BE876933A (en) | 1979-12-12 |
| GB2024813A (en) | 1980-01-16 |
| IE48514B1 (en) | 1985-02-20 |
| DK244979A (en) | 1979-12-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JPH0825977B2 (en) | N- (2 ''-aminophenyl) -benzamide derivative, process for producing the same and pharmaceutical composition containing the same | |
| US4476137A (en) | [1-(2-Benzoxazolyl)hydrazino]alkyl nitrile derivatives | |
| CA1130800A (en) | N-SUBSTITUTED .omega.-AMINOALKANOYL-.omega.-AMINOALKANOIC ACIDS, THEIR USE AND PROCESS FOR THEIR PRODUCTION AS WELL AS PHARMACEUTICAL PRODUCTS CONTAINING THESE COMPOUNDS | |
| US4512998A (en) | Anthelmintic benzimidazole carbamates | |
| US3908013A (en) | Pharmaceutical aromatic guanidine compositions and methods of using same | |
| US4243678A (en) | Acylhydrocarbylaminoalkanoic acids, compositions and uses | |
| US3912756A (en) | New phenoxyalkyl-carboxylic acid compounds and therapeutic compositions | |
| GB1570140A (en) | Tumour-resolving and histolytic medicaments comprising dehydrooligropeptides | |
| US3165550A (en) | N-substituted p-benzenedisulfonamides | |
| HU184271B (en) | Process for preparing imidazolidine derivatives | |
| CA1066714A (en) | Pharmaceutical n-phenyloxamic acid derivatives | |
| CA1153387A (en) | Substituted amino acids, their use and production and pharmaceutical products containing same | |
| GB2024814A (en) | Acyl (bicyclic aryl) - aminoalkanoic acids | |
| US4285935A (en) | Dehydropeptide compounds, their production and their medical use | |
| CA1123433A (en) | Acylhydrocarbylaminoalkanoic acids, their production and use as well as pharmaceutical products containing same | |
| FR2563519A1 (en) | IMINOTHIAZOLIDINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME | |
| US3156699A (en) | Nu-(5-nitro-thiazolyl-2) 2, 4-dinitropyrrole-1-acetamide | |
| ES2366396T3 (en) | PEPTIDE DESFORMILASA INHIBITORS. | |
| JPH05508170A (en) | Novel difluoroquinolones, their synthesis methods, and pharmaceuticals containing them | |
| JPS62246553A (en) | Novel substituted benzamides, manufacture and therapeutic use | |
| JPS6056142B2 (en) | New derivatives of thiazoline and their pharmaceutical applications | |
| US4128550A (en) | 1-Methyl-4-piperidyl 5-phenyl-2-furoates | |
| JPS63126860A (en) | Guanidinomethylbenzoic acid derivative | |
| US5091547A (en) | Phenylacetic acid derivative and process for making same | |
| US4333938A (en) | Imino derivatives of 5-aminobenzodioxole-1,3 which are useful as medicaments |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |