CA1091688A - Pyrrolidine and piperidine prostaglandin analogues - Google Patents
Pyrrolidine and piperidine prostaglandin analoguesInfo
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- CA1091688A CA1091688A CA345,592A CA345592A CA1091688A CA 1091688 A CA1091688 A CA 1091688A CA 345592 A CA345592 A CA 345592A CA 1091688 A CA1091688 A CA 1091688A
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Abstract
ABSTRACT OF THE DISCLOSURE
Compounds of formula (I):
(I) wherein: m is 1 or 2; n is 4 to 8; X is CO, protected CO, or CROH
wherein R is hydrogen or C1-4 alkyl and wherein the OH moiety may be protected; R1 is hydrogen or CO2R1 represents an ester group in which the R1 moiety contains from 1 to 12 carbon atoms; R3 is hydroxy, or protected hydroxy; R2 and R4 are separately hydrogen, C1-9 alkyl, C5-8 cycloalkyl, C5-8 cycloalkyl-C1-6 alkyl, phenyl, phenyl C1-6 alkyl, naphthyl, naphthyl C1-6 alkyl, any of which phenyl or naphthyl moieties may be substituted by one or more halogen, trifluoromethyl, C1-6 alkyl, C1-6 alkoxy or nitro groups; or R2 and R4 taken with the carbon atom to which they are joined represen? a C5-8 cycloalkyl group; and salts thereof; except that when one of R2 and R4 is hydrogen or C1-4 alkyl then the other of R2 and R4 cannot be hydrogen or C1-9 alkyl; have useful pharmacological properties including anti-gastric secretion, bronchodilator and platelet aggregation inhi-bition activities.
Compounds of formula (I):
(I) wherein: m is 1 or 2; n is 4 to 8; X is CO, protected CO, or CROH
wherein R is hydrogen or C1-4 alkyl and wherein the OH moiety may be protected; R1 is hydrogen or CO2R1 represents an ester group in which the R1 moiety contains from 1 to 12 carbon atoms; R3 is hydroxy, or protected hydroxy; R2 and R4 are separately hydrogen, C1-9 alkyl, C5-8 cycloalkyl, C5-8 cycloalkyl-C1-6 alkyl, phenyl, phenyl C1-6 alkyl, naphthyl, naphthyl C1-6 alkyl, any of which phenyl or naphthyl moieties may be substituted by one or more halogen, trifluoromethyl, C1-6 alkyl, C1-6 alkoxy or nitro groups; or R2 and R4 taken with the carbon atom to which they are joined represen? a C5-8 cycloalkyl group; and salts thereof; except that when one of R2 and R4 is hydrogen or C1-4 alkyl then the other of R2 and R4 cannot be hydrogen or C1-9 alkyl; have useful pharmacological properties including anti-gastric secretion, bronchodilator and platelet aggregation inhi-bition activities.
Description
~{~tis~
This application .is a divisional o:E S.N. 263,9~.0, E:llod October 22, 1976, and is directed to the preparation of intermediates according to Formula XIII defined herein and the intermedia-tes so produced. The parent application is directed to the preparation of compounds within the scope of Formula I defined herein and the compounds so produced.
, .
This invention relates to novel compounds having pharmacological activity, to a process for their preparation, to intermediates useful in that process, and to pharmaceutical compositions containing them.
More specifically, the invention relates to cyclic amides in which 10 the nitrogen atom is substituted by an aliphatic or aliphatic-aromatic group and one a-carbon atom is substituted by an aliphatic group.
Natural prostglandins and analogues thereof are known to possess a wide variety of pharmacological activities.
Offenlegungsschrift No. 2323193 discloses that pyrazolidine derivatives of the formula (I)':
y ) N~ CH2(A)m(cH2)nC2R
<
`Il-- ' CH2 - CH2cH(cH2)pcH3 (I)' OH
wherein A is CH=CH or C-C; R is H, an alkali metal, an amine salt, or an ~
12C hydrocarbon or chlorohydrocarbon residue; m is O or 1; n is 0-6; p is 0-6;
and Y and Z are O or H2 except that Y and Z are not both O; have similar 20 biological properties to the prostaglandins or are antagonists of prostaglandins.
A paper by Bolliger and Muchowski (Tet. Letters, 1975, 2931) describes the preparation of ll-desoxy-8-
This application .is a divisional o:E S.N. 263,9~.0, E:llod October 22, 1976, and is directed to the preparation of intermediates according to Formula XIII defined herein and the intermedia-tes so produced. The parent application is directed to the preparation of compounds within the scope of Formula I defined herein and the compounds so produced.
, .
This invention relates to novel compounds having pharmacological activity, to a process for their preparation, to intermediates useful in that process, and to pharmaceutical compositions containing them.
More specifically, the invention relates to cyclic amides in which 10 the nitrogen atom is substituted by an aliphatic or aliphatic-aromatic group and one a-carbon atom is substituted by an aliphatic group.
Natural prostglandins and analogues thereof are known to possess a wide variety of pharmacological activities.
Offenlegungsschrift No. 2323193 discloses that pyrazolidine derivatives of the formula (I)':
y ) N~ CH2(A)m(cH2)nC2R
<
`Il-- ' CH2 - CH2cH(cH2)pcH3 (I)' OH
wherein A is CH=CH or C-C; R is H, an alkali metal, an amine salt, or an ~
12C hydrocarbon or chlorohydrocarbon residue; m is O or 1; n is 0-6; p is 0-6;
and Y and Z are O or H2 except that Y and Z are not both O; have similar 20 biological properties to the prostaglandins or are antagonists of prostaglandins.
A paper by Bolliger and Muchowski (Tet. Letters, 1975, 2931) describes the preparation of ll-desoxy-8-
- 2 - ii3 r azapros~aglandln El, but s~ates only that one eplmer thereof was more active in several biological assays tha~ the other epimer.
Our copending Canadian Application No 240,725 discloses that compounds of the formula (I)!~:
CH2 - Y - (CH2)n ~ Rl (CH2~ ~ 2 ( ) wherein:
X is CO, protected CO, CROH in which R is hydro~en or Cl 4 alkyl and in which the OH moiety may be protected;
Y is CH2CH2 or CH=CH; Z is CO or CH2; n is 1 to 8; m is 1, 2 or 3; Rl is hydrogen, CH20H, CH20H in which the OH moiety is protected, C02W wherein W is hydrogen or C02W repre-sents an ester group in which the ester moiety contains from 1 to 12 carbon atoms, or CONH2;R2 is hydrogen7 Cl 4 ~ alkyl, or taken together with R3 and the carbon atom to : 15 which it is attached represents a carbonyl group; R3 is hydrogen, hydroxy or protected hydroxy; R4 is hydrogen or Cl g alkyl; and salts thereof; have useful pharmacological activity. This subject matter was first published in Belgium Patent No. 835989 on the 26th May 1976, a date later than the filing dates of the two U.K. Applications Nos: 43990/75 and 21278/76 from which priority has been ~91~;8f~
.
claimed for the ~resent invention.
A novel class of compounds having useful pharma-cological activity has now been discovered, which compounds are structurally distinct from the prior art referred to above.
The present invention provides a compound of the formula (I):
( CH2 ) nC2Rl (CH2~/~R4 wherein:
m is l or 2;
n is 4 to 8;
X is CO, protected CO, or CROH wherein R is hydrogen or Cl 4 alkyl and wherein the OH moiety may be protected;
Rl is hydrogen or C02R1 represents an ester group in which the Rl moiety contains from 1 to 12 carbon atoms;
R3 is hydroxy, or protected hydroxy;
R2 and R4 ~re separately hydrogen, C1 9 alkyl, C5 ~
cycloalkyl, C5 8 cycloalkyl-Cl 6 alkyl, phenyl, phenyl Cl 6 alkyl, naphthyl, naphthyl Cl 6 alkyl, any of which phenyl or naphthyl moieties may be substituted by one or more halogen, trifluoromethyl, Cl 6 alkyl, Cl 6 alkoxy or nitro groups; or R2 and R4 taken with the carbon atom to which tAey are joined represent a C5 8 cycloalkyl group;
and salts thereof; except that when one of R2 and R4 is hydrogen or Cl_~ alkyl then the other o~ R2 and R~ cannot be hydrogen or Cl g alkyl.
Suitably m is 1 and n is 5, 6 or 7, preferably 6.
Suitable protected hydroxyl groups CROH and R3 include readily hydrolysable groups such as acylated hydroxy groups in which the acyl moiety contains 1 to 4 carbon atoms, for example the acetoxy group; and hydroxy groups etherified by readily removable inert groups such as the benzyl or like groups. Preferably R3 is hydroxy, and the hydroxy moiety in CROH is unprotected.
X may be a protected CO group. Suitable examples of such protected CO groups X include groups formed by conven-tional carbonyl addition and condensation reactions such as ketals, thioketals, hemithioketals, oximes, semicarbazones, hydra70nes and the like. 0~ such groups often the ketal type derivatives will be most useful, for example when X is a group C~O~ .
Examples of suitable groups X include CO, CHOH, C (CH3) OH
and C(C2H5)0H-Preferably X is CO, CHOH or C(CH3) OH, most preferably CO.
Rl is hydrogen or C02Rl represents an ester group in which the Rl moiety contains from 1 to 12 carbon atoms. Ex-amples of Rl include hydrogen, methyl, ethyl, propyl, butyl, phenyl, benzyl, toluyl, and the like, while normally hydrogen or Cl_4 alkyl groups are preferred~
Suitable groups R4 when R4 is an alkyl group include -C4 9 alkyl groups. Such C~ g alkyl groups may be stralght chain alkyl groups, such as n-butyl, _-pentyl, _-hexyl and n-heptyl, or may be alkyl groups branchedby one or two methyl groups (at the same or different carbon atoms). Thus for ex-ample R4 may be a group CH2R5, CH(CH3)R5 or C(CH3) 2R5, whereinR5 iS a straight chain alkyl group such that the carbon con-tent of the resultant group R4 iS 4 to 9.
In general preferred groups R4 when R4 is an alkyl group include straight chain pentyl, hexyl and heptyl groups. Of these, straight chain hexyl is often the most useful. Other preferred groups R4 include groups CH(:CH3)R5 and C(CH3)2R5 wherein R5 is straight chain butyl, pentyl and hexyl.
When R4 is or contains a C5 8 cycloalkyl moiety, the moiety is suitably a cyclohexyl moiety. Examples of suitable Cl 6 alkyl moieties when R4 iS a C5_8 cycloalkyl-Cl 6 alkyl group include methyl, ethyl, propyl, butyl and amyl.
Examples of suitable groups R4 when R4 is an aryl group as previously defined include phenyl, phenylmethyl, phenyl-ethyl, phenyl n-propyl, phenyl _-butyl, naphthyl, naphthyl-methyl, naphthylethyl, naphthyl n-propyl, and naphthyl-n-butyl, and such groups branched in the alkyl moiety by one or two methyl groups (at the same or different carbon atoms). These groups may be substituted in the phenyl or naphthyl moiety by normally one, two or three groups selected from these sub-stituent groups listed herein before. Examples of suitable substituent groups include fluorine, chlorine and bromine ~1~91~;8fl atoms and CF3, methyl, ethyl, n- and iso-propyl, methoxy, ethoxy, _- and iso- propoxy and nitro groups. Preferably the aryl moieties when substituted by such groups will be mono-or di- substituted.
Particularly suitable values for R2 are hydrogen, Cl 4 alkyl and phenyl, for example hydrogen, methyl, ethyl and phenyl. Of these groups preferred groups include methyl and ethyl.
Otherwise R2 can suitably represent groups such as those described above as suitable and preferred groups for R4.
Also, R2 and R4 taken with -the carbon atoms to which they are joined can represent a C5 8 cycloalkyl group, such as the cyclohexyl group.
The compounds of the formula (Il may form conventional -acid salts when Rl is hydrogen. Such salts include those with alkali and alkaline earth metals, suitably sodium and potas-sium, and ammonium and substituted ammonium salts.
A group of compounds within the compounds of the formula (I) as defined are those wherein X is CO, or CROH wherein R is hydrogen or Cl 4 alkyl and wherein the OH moiety may be pro-tected; R2 is hydrogen, Cl 4 alkyl or phenylj and R4 is hydrogen, Cl g alkyl, phenyl, phenyl Cl 4 alkyl, naphthyl, naphthyl Cl 4 alkyl, any of which phenyl or naphthyl moieties may be substituted by one or more halogen, trifluoromethyl, Cl_6 alkyl, Cl_6 alkoxy or nitro r fl g~
.
groups; e~cept tha-t when R2 is hydrogen or Cl L~ alkyl, R4 must b~ other than hydrogen or Cl g alkyl; and salts thereo~.
One particularly suitable sub-group of compounds within such compounds of the formula (I) include those of the formula (II):
( CH2 ) pC o2R
(CH2 ~ 2 (II) wherein:
m is as defined in formula (I);
p is 6 or 8;
X' is CO, CHOH or C(CH~)OH;
Rll is hydrogen or Cl 4 alkyl;
R12 is hydrogen, methyl or ethyl; and R14 is a group of formula (III):
W
-S ~ (III) Y Z
wherein S is a bond, or a Cl 6 alkylene group which maybe straight chain or branched by one or two methyl groups at the same or different carbon--atoms;and W, Y and Z are each hydrogen or fluorine, chlorine or bromine atoms, or CF3, methyl, ethyl, _- or iso-propyl, methoxy, ethoxy, n-or iso-propoxy or nitro groups; and salts thereof.
-~ot3 ~
Of~e~ S will be a group ~(CH2)q~ wherein q is O to 4.
In formula (II) m is most suitably 1, p is mostsuitably 6, X' is most suitabl~ CO, and R12 is most suitably methyl or ethyl. Also, ~1 is most suitably hydrogen.
A second interesting sub-group of compounds within such compounds o~ formula (I) include those of formula (IV):
(C~2)pC2Rll (CH~ ~ RR224 ( T~J ) wherein m, p, X', Rll and R12 are as defined in formula (II), and R24 is a group of formula (V):
--S~
>.=~ (V) ~,~ . .
10 . wherein ~, W, Y and Z are as defined in formula (III);
and salts thereof.
Often S will be a group ~(CH2)q~ wherein q is O to 4.
In formula (IV) m is most suitably 1, p is most suitably 6, Xl is most suitably CO and R12 is most suitably methyl or ethyl.
A third sub-group of compounds within such compounds of formula (I) of particular interest are those of formula(VI):
~ 31~
(CH2)pC02R 1 ~ ~ 34 (VI) wherein m, p, Xl and Rll are as defined in formula (II), and R34 is a group of formula (.III), a group of formula (V) or a C4 9 alkyl group; and salts thereof.
The most suitable values for m and p in formula (VI) are 1 and 6 respectively, and Xl is most suitably CO.
When R34 is a C4 9 alkyl group, suitable and preferred straight chain and branched groups R34 include those previous-ly described as suitable and preferred for the group R4 when R4 is C4 9 alkyl group. Such preferred groups R34 include straigh.t chain pentyl, hexyl and h.eptyl, and of these normally the most useful is straight chain hexyl. Other preferred groups R 4 include CH(CH3~R 5 and CCCH3)2R 5 wherein R 5 is straight chain butyl, pentyl or hexyl.
A fourth sub-group of compounds that is within formula (I) is of formula (VIII):
2Q (CH2)pC02R 1 (CH2 ~ ~ N ~ Rl (VII) wherein:
p,m,X , R 1 and R 2 are as defined in formula (II)i and 1~91~
RaL~ is a group of ~ormula (VIII):
r(~H2)r (VIII) -S-\ /
wherein S is as de~inod in formula (III) and r is O to 3;
and salts thereof.
Often S will be a group ~(CH2)q~ wherein q is O to 6.
In formula (VII) we prefer that p is 6. Most suitably xl is CO, R12 is methyl or eth~Jl, a~d m is 1.
A ~ h sub-group o~ compounds within formula (I) of interest is of formula (IX):
( CH2 ) pCO~Rll ~CH2 ~ Rb4 (IX) wherein:
p, m, Xl and Rll are as defined in formula (II); R 2 and Rb4 are separately C5 9 alkyl, or groups of formula (III), (V) or (VIII) as defined; or Rb2 and Rb4 ta~en together wi~h the carbon atom to which they are joined represent C5 8 cycloalkyl; and salts thereof.
In formula (IX) we prefer that p is 6. Most suitably xl is CO and m is 1.
Compounds of the formula (II), (IV), (VI), (VII), or (IX) as defined, but wherein Xl is a protected CO
group, are also of particular utility.
The compounds of the ~ormula (I) have asymmetric centres, .f'' ` ~91~388 and thUS are capable oP ~xis~ing in a number of 5tero-isomeric forms. The invention extends to each of these stereoisomeric for~s, and to mixtures thereof. The di~ferent stereoisomeric forms may be separated one from the other by the usual me-thods.
The generally preferred group of compounds according to the invention within formula (I) (CH2 ) nC2Rl / ~/
( H2) ~ I ~ R2 (I) are those wherein M is 1 or 2 N is 4 to 8 X is CO, protected CO or CROH wherein R may be hydrogen or C1-4 alkyl and wherein the OH moiety may be protect-ed;
Rl is C1-4 alkyl;
R3 is hydroxy or protected hydroxy;
P~2 is hydrogen, Cl 4 alkyl, phenyl or phenyl substi-tuted by one or more halogen, trifluoromethyl Cl_6 alkyl, C1-6 alkoxy or nitro groups;
R4 is C4_9 alkyl, cyclohexyl, phenyl, phenyl C1-6 alkyl or phenyl or phenyl C1-6 alkyl substitu-ted with one or more halogen, trifluoromethyl, Cl 6 alkyl, C1-6 alkoxy or nitro groups;
~ 316~3~
- or CR2R~ is C5_8 cycloalkyl;
except when R2 is hydrogen or Cl ~ alkyl, the R4 is not C4 9 alkyl.
~ .
- -12a-The lnven-tlon also provldes a process for the pre-paration of -the compounds o~ the formul~ (I), which process comprises decarboxylating a compound of the formula (X): O
H02C~(CH2 )nC2Rl R (X) (CH2)m- ~ N ~ R4 wherein m, n, Rl, R2, R3 and R4 are as defined in for~ula (I), to yield a compound of the ~ormula (I) wherein X is CO; and thereafter if desired protecting X, or converting X in the thus formed compound to CROH by reduction when R
is hydrogen or by reaction with a Cl 4 alkyl Grignard reagent or Cl 4 alkyl metallic complex when R is Cl 4 alkyl 7 ard then optionally protecting the CROH hydroxy moiety.
The decarboxylation reaction may be brought about under basic, acid or neutral conditions in conventional manner. For example when m = 1 the reaction is con-veniently effected by leaving the chosen compound of the formula (X) in an inert solvent, for e~ample o~Jernight.
After the reaction Rl may be varied by conYentional de-esteri~icatior. and/or esterification reactions.
Similarly protected CROH and R3 hydroxy moieties may be deprotected by conventional methods. For example, when R3 is a benzylox~J group, the benzyl group may readily be 1~9~G~3 removed by hydrogenolysis. Thus i-t may be seen tha-t 'pro-tected hydroxy' compounds of the formula (II are useful inter-mediates in the preparation of the corresponding 'free hydroxy' compounds of the formula (I).
The conversion of a compound of the formula (I) wherein X is CO to the corresponding compound wherein X is protected CO may be carried out under conventional reaction conditions for, for example, carbonyl addition and condensation reactions.
The conversion of a compound of the formula (I~ wherein X is CO to the corresponding compound wherein X is CHOH may be carried out by conventional methods for reducing a ketone to an alcohol, for example by sodium borohydride reduction.
The conversion of a compound of the formula tI) wherein X is CO to the corresponding compound wherein X is CROH in which R is Cl 4 alkyl may be carried out by conventional Grignard or alkyl metal, (suitably alkyl lithium) reactions.
When Rl is hydrogen, salts of compounds of the formula (I) may be prepared in conventional manner, for example by reacting the chosen compound of the formula (I) with the re-~uired base.
It is frequently convenient however to generate the de-sired compound of the formula (I~ directly from an ester of the formula tXI), and often this will in fact be the pre-ferred route:
~ 14 -'3i~
( CH2 ) n~O2RI
R62~ ~ ~ R2 (XI) (CH2)m-1 ~ ~ 4 where CO2R6 is a conventional ester yroup. In such a case R6 is preferably a benzyl group or a lower alkyl group such as ethyl or the like. Thus treatment of a compound of the formula (XI) with, for example, lithium iodide dihydrate and col]idine in anydrous solvents brings about simultaneous de-esterification and decarboxylation. In cases where m =
1, the compound of formula (XI) can be de-es-terified and de-carboxylated by leaving the compound standing in an inert solvent, e.g. overnight, or by heating the compound alone or in a high boiling solventsuch as toluene or xylene.
It will be appreciated that compounds of the formulae (X) and (XI) are useful intermediates and as such form a use-ful aspect of this invention.
The compounds of formula (XI) may be prepared by the ring closure of the corresponding diester of formula ~XII)~
R 0 C ~ (CH2)nC2Rl (XII) (CH2)m~ ~ ~ R4 wherein m, n, Rl, R2, R3, and R4 are as defined in formula (I), R6 is as defined in formula (XI), and R7 is a group such that CO2R7 is an ester group-.
Our copending Canadian Application No 240,725 discloses that compounds of the formula (I)!~:
CH2 - Y - (CH2)n ~ Rl (CH2~ ~ 2 ( ) wherein:
X is CO, protected CO, CROH in which R is hydro~en or Cl 4 alkyl and in which the OH moiety may be protected;
Y is CH2CH2 or CH=CH; Z is CO or CH2; n is 1 to 8; m is 1, 2 or 3; Rl is hydrogen, CH20H, CH20H in which the OH moiety is protected, C02W wherein W is hydrogen or C02W repre-sents an ester group in which the ester moiety contains from 1 to 12 carbon atoms, or CONH2;R2 is hydrogen7 Cl 4 ~ alkyl, or taken together with R3 and the carbon atom to : 15 which it is attached represents a carbonyl group; R3 is hydrogen, hydroxy or protected hydroxy; R4 is hydrogen or Cl g alkyl; and salts thereof; have useful pharmacological activity. This subject matter was first published in Belgium Patent No. 835989 on the 26th May 1976, a date later than the filing dates of the two U.K. Applications Nos: 43990/75 and 21278/76 from which priority has been ~91~;8f~
.
claimed for the ~resent invention.
A novel class of compounds having useful pharma-cological activity has now been discovered, which compounds are structurally distinct from the prior art referred to above.
The present invention provides a compound of the formula (I):
( CH2 ) nC2Rl (CH2~/~R4 wherein:
m is l or 2;
n is 4 to 8;
X is CO, protected CO, or CROH wherein R is hydrogen or Cl 4 alkyl and wherein the OH moiety may be protected;
Rl is hydrogen or C02R1 represents an ester group in which the Rl moiety contains from 1 to 12 carbon atoms;
R3 is hydroxy, or protected hydroxy;
R2 and R4 ~re separately hydrogen, C1 9 alkyl, C5 ~
cycloalkyl, C5 8 cycloalkyl-Cl 6 alkyl, phenyl, phenyl Cl 6 alkyl, naphthyl, naphthyl Cl 6 alkyl, any of which phenyl or naphthyl moieties may be substituted by one or more halogen, trifluoromethyl, Cl 6 alkyl, Cl 6 alkoxy or nitro groups; or R2 and R4 taken with the carbon atom to which tAey are joined represent a C5 8 cycloalkyl group;
and salts thereof; except that when one of R2 and R4 is hydrogen or Cl_~ alkyl then the other o~ R2 and R~ cannot be hydrogen or Cl g alkyl.
Suitably m is 1 and n is 5, 6 or 7, preferably 6.
Suitable protected hydroxyl groups CROH and R3 include readily hydrolysable groups such as acylated hydroxy groups in which the acyl moiety contains 1 to 4 carbon atoms, for example the acetoxy group; and hydroxy groups etherified by readily removable inert groups such as the benzyl or like groups. Preferably R3 is hydroxy, and the hydroxy moiety in CROH is unprotected.
X may be a protected CO group. Suitable examples of such protected CO groups X include groups formed by conven-tional carbonyl addition and condensation reactions such as ketals, thioketals, hemithioketals, oximes, semicarbazones, hydra70nes and the like. 0~ such groups often the ketal type derivatives will be most useful, for example when X is a group C~O~ .
Examples of suitable groups X include CO, CHOH, C (CH3) OH
and C(C2H5)0H-Preferably X is CO, CHOH or C(CH3) OH, most preferably CO.
Rl is hydrogen or C02Rl represents an ester group in which the Rl moiety contains from 1 to 12 carbon atoms. Ex-amples of Rl include hydrogen, methyl, ethyl, propyl, butyl, phenyl, benzyl, toluyl, and the like, while normally hydrogen or Cl_4 alkyl groups are preferred~
Suitable groups R4 when R4 is an alkyl group include -C4 9 alkyl groups. Such C~ g alkyl groups may be stralght chain alkyl groups, such as n-butyl, _-pentyl, _-hexyl and n-heptyl, or may be alkyl groups branchedby one or two methyl groups (at the same or different carbon atoms). Thus for ex-ample R4 may be a group CH2R5, CH(CH3)R5 or C(CH3) 2R5, whereinR5 iS a straight chain alkyl group such that the carbon con-tent of the resultant group R4 iS 4 to 9.
In general preferred groups R4 when R4 is an alkyl group include straight chain pentyl, hexyl and heptyl groups. Of these, straight chain hexyl is often the most useful. Other preferred groups R4 include groups CH(:CH3)R5 and C(CH3)2R5 wherein R5 is straight chain butyl, pentyl and hexyl.
When R4 is or contains a C5 8 cycloalkyl moiety, the moiety is suitably a cyclohexyl moiety. Examples of suitable Cl 6 alkyl moieties when R4 iS a C5_8 cycloalkyl-Cl 6 alkyl group include methyl, ethyl, propyl, butyl and amyl.
Examples of suitable groups R4 when R4 is an aryl group as previously defined include phenyl, phenylmethyl, phenyl-ethyl, phenyl n-propyl, phenyl _-butyl, naphthyl, naphthyl-methyl, naphthylethyl, naphthyl n-propyl, and naphthyl-n-butyl, and such groups branched in the alkyl moiety by one or two methyl groups (at the same or different carbon atoms). These groups may be substituted in the phenyl or naphthyl moiety by normally one, two or three groups selected from these sub-stituent groups listed herein before. Examples of suitable substituent groups include fluorine, chlorine and bromine ~1~91~;8fl atoms and CF3, methyl, ethyl, n- and iso-propyl, methoxy, ethoxy, _- and iso- propoxy and nitro groups. Preferably the aryl moieties when substituted by such groups will be mono-or di- substituted.
Particularly suitable values for R2 are hydrogen, Cl 4 alkyl and phenyl, for example hydrogen, methyl, ethyl and phenyl. Of these groups preferred groups include methyl and ethyl.
Otherwise R2 can suitably represent groups such as those described above as suitable and preferred groups for R4.
Also, R2 and R4 taken with -the carbon atoms to which they are joined can represent a C5 8 cycloalkyl group, such as the cyclohexyl group.
The compounds of the formula (Il may form conventional -acid salts when Rl is hydrogen. Such salts include those with alkali and alkaline earth metals, suitably sodium and potas-sium, and ammonium and substituted ammonium salts.
A group of compounds within the compounds of the formula (I) as defined are those wherein X is CO, or CROH wherein R is hydrogen or Cl 4 alkyl and wherein the OH moiety may be pro-tected; R2 is hydrogen, Cl 4 alkyl or phenylj and R4 is hydrogen, Cl g alkyl, phenyl, phenyl Cl 4 alkyl, naphthyl, naphthyl Cl 4 alkyl, any of which phenyl or naphthyl moieties may be substituted by one or more halogen, trifluoromethyl, Cl_6 alkyl, Cl_6 alkoxy or nitro r fl g~
.
groups; e~cept tha-t when R2 is hydrogen or Cl L~ alkyl, R4 must b~ other than hydrogen or Cl g alkyl; and salts thereo~.
One particularly suitable sub-group of compounds within such compounds of the formula (I) include those of the formula (II):
( CH2 ) pC o2R
(CH2 ~ 2 (II) wherein:
m is as defined in formula (I);
p is 6 or 8;
X' is CO, CHOH or C(CH~)OH;
Rll is hydrogen or Cl 4 alkyl;
R12 is hydrogen, methyl or ethyl; and R14 is a group of formula (III):
W
-S ~ (III) Y Z
wherein S is a bond, or a Cl 6 alkylene group which maybe straight chain or branched by one or two methyl groups at the same or different carbon--atoms;and W, Y and Z are each hydrogen or fluorine, chlorine or bromine atoms, or CF3, methyl, ethyl, _- or iso-propyl, methoxy, ethoxy, n-or iso-propoxy or nitro groups; and salts thereof.
-~ot3 ~
Of~e~ S will be a group ~(CH2)q~ wherein q is O to 4.
In formula (II) m is most suitably 1, p is mostsuitably 6, X' is most suitabl~ CO, and R12 is most suitably methyl or ethyl. Also, ~1 is most suitably hydrogen.
A second interesting sub-group of compounds within such compounds o~ formula (I) include those of formula (IV):
(C~2)pC2Rll (CH~ ~ RR224 ( T~J ) wherein m, p, X', Rll and R12 are as defined in formula (II), and R24 is a group of formula (V):
--S~
>.=~ (V) ~,~ . .
10 . wherein ~, W, Y and Z are as defined in formula (III);
and salts thereof.
Often S will be a group ~(CH2)q~ wherein q is O to 4.
In formula (IV) m is most suitably 1, p is most suitably 6, Xl is most suitably CO and R12 is most suitably methyl or ethyl.
A third sub-group of compounds within such compounds of formula (I) of particular interest are those of formula(VI):
~ 31~
(CH2)pC02R 1 ~ ~ 34 (VI) wherein m, p, Xl and Rll are as defined in formula (II), and R34 is a group of formula (.III), a group of formula (V) or a C4 9 alkyl group; and salts thereof.
The most suitable values for m and p in formula (VI) are 1 and 6 respectively, and Xl is most suitably CO.
When R34 is a C4 9 alkyl group, suitable and preferred straight chain and branched groups R34 include those previous-ly described as suitable and preferred for the group R4 when R4 is C4 9 alkyl group. Such preferred groups R34 include straigh.t chain pentyl, hexyl and h.eptyl, and of these normally the most useful is straight chain hexyl. Other preferred groups R 4 include CH(CH3~R 5 and CCCH3)2R 5 wherein R 5 is straight chain butyl, pentyl or hexyl.
A fourth sub-group of compounds that is within formula (I) is of formula (VIII):
2Q (CH2)pC02R 1 (CH2 ~ ~ N ~ Rl (VII) wherein:
p,m,X , R 1 and R 2 are as defined in formula (II)i and 1~91~
RaL~ is a group of ~ormula (VIII):
r(~H2)r (VIII) -S-\ /
wherein S is as de~inod in formula (III) and r is O to 3;
and salts thereof.
Often S will be a group ~(CH2)q~ wherein q is O to 6.
In formula (VII) we prefer that p is 6. Most suitably xl is CO, R12 is methyl or eth~Jl, a~d m is 1.
A ~ h sub-group o~ compounds within formula (I) of interest is of formula (IX):
( CH2 ) pCO~Rll ~CH2 ~ Rb4 (IX) wherein:
p, m, Xl and Rll are as defined in formula (II); R 2 and Rb4 are separately C5 9 alkyl, or groups of formula (III), (V) or (VIII) as defined; or Rb2 and Rb4 ta~en together wi~h the carbon atom to which they are joined represent C5 8 cycloalkyl; and salts thereof.
In formula (IX) we prefer that p is 6. Most suitably xl is CO and m is 1.
Compounds of the formula (II), (IV), (VI), (VII), or (IX) as defined, but wherein Xl is a protected CO
group, are also of particular utility.
The compounds of the ~ormula (I) have asymmetric centres, .f'' ` ~91~388 and thUS are capable oP ~xis~ing in a number of 5tero-isomeric forms. The invention extends to each of these stereoisomeric for~s, and to mixtures thereof. The di~ferent stereoisomeric forms may be separated one from the other by the usual me-thods.
The generally preferred group of compounds according to the invention within formula (I) (CH2 ) nC2Rl / ~/
( H2) ~ I ~ R2 (I) are those wherein M is 1 or 2 N is 4 to 8 X is CO, protected CO or CROH wherein R may be hydrogen or C1-4 alkyl and wherein the OH moiety may be protect-ed;
Rl is C1-4 alkyl;
R3 is hydroxy or protected hydroxy;
P~2 is hydrogen, Cl 4 alkyl, phenyl or phenyl substi-tuted by one or more halogen, trifluoromethyl Cl_6 alkyl, C1-6 alkoxy or nitro groups;
R4 is C4_9 alkyl, cyclohexyl, phenyl, phenyl C1-6 alkyl or phenyl or phenyl C1-6 alkyl substitu-ted with one or more halogen, trifluoromethyl, Cl 6 alkyl, C1-6 alkoxy or nitro groups;
~ 316~3~
- or CR2R~ is C5_8 cycloalkyl;
except when R2 is hydrogen or Cl ~ alkyl, the R4 is not C4 9 alkyl.
~ .
- -12a-The lnven-tlon also provldes a process for the pre-paration of -the compounds o~ the formul~ (I), which process comprises decarboxylating a compound of the formula (X): O
H02C~(CH2 )nC2Rl R (X) (CH2)m- ~ N ~ R4 wherein m, n, Rl, R2, R3 and R4 are as defined in for~ula (I), to yield a compound of the ~ormula (I) wherein X is CO; and thereafter if desired protecting X, or converting X in the thus formed compound to CROH by reduction when R
is hydrogen or by reaction with a Cl 4 alkyl Grignard reagent or Cl 4 alkyl metallic complex when R is Cl 4 alkyl 7 ard then optionally protecting the CROH hydroxy moiety.
The decarboxylation reaction may be brought about under basic, acid or neutral conditions in conventional manner. For example when m = 1 the reaction is con-veniently effected by leaving the chosen compound of the formula (X) in an inert solvent, for e~ample o~Jernight.
After the reaction Rl may be varied by conYentional de-esteri~icatior. and/or esterification reactions.
Similarly protected CROH and R3 hydroxy moieties may be deprotected by conventional methods. For example, when R3 is a benzylox~J group, the benzyl group may readily be 1~9~G~3 removed by hydrogenolysis. Thus i-t may be seen tha-t 'pro-tected hydroxy' compounds of the formula (II are useful inter-mediates in the preparation of the corresponding 'free hydroxy' compounds of the formula (I).
The conversion of a compound of the formula (I) wherein X is CO to the corresponding compound wherein X is protected CO may be carried out under conventional reaction conditions for, for example, carbonyl addition and condensation reactions.
The conversion of a compound of the formula (I~ wherein X is CO to the corresponding compound wherein X is CHOH may be carried out by conventional methods for reducing a ketone to an alcohol, for example by sodium borohydride reduction.
The conversion of a compound of the formula tI) wherein X is CO to the corresponding compound wherein X is CROH in which R is Cl 4 alkyl may be carried out by conventional Grignard or alkyl metal, (suitably alkyl lithium) reactions.
When Rl is hydrogen, salts of compounds of the formula (I) may be prepared in conventional manner, for example by reacting the chosen compound of the formula (I) with the re-~uired base.
It is frequently convenient however to generate the de-sired compound of the formula (I~ directly from an ester of the formula tXI), and often this will in fact be the pre-ferred route:
~ 14 -'3i~
( CH2 ) n~O2RI
R62~ ~ ~ R2 (XI) (CH2)m-1 ~ ~ 4 where CO2R6 is a conventional ester yroup. In such a case R6 is preferably a benzyl group or a lower alkyl group such as ethyl or the like. Thus treatment of a compound of the formula (XI) with, for example, lithium iodide dihydrate and col]idine in anydrous solvents brings about simultaneous de-esterification and decarboxylation. In cases where m =
1, the compound of formula (XI) can be de-es-terified and de-carboxylated by leaving the compound standing in an inert solvent, e.g. overnight, or by heating the compound alone or in a high boiling solventsuch as toluene or xylene.
It will be appreciated that compounds of the formulae (X) and (XI) are useful intermediates and as such form a use-ful aspect of this invention.
The compounds of formula (XI) may be prepared by the ring closure of the corresponding diester of formula ~XII)~
R 0 C ~ (CH2)nC2Rl (XII) (CH2)m~ ~ ~ R4 wherein m, n, Rl, R2, R3, and R4 are as defined in formula (I), R6 is as defined in formula (XI), and R7 is a group such that CO2R7 is an ester group-.
3~
In the process of the inven-tion the group CO2Rl in -the intermediates of formula (X), (XI) and (XII) will normally represent an ester group, and if acids of the formula ( I ) (wherein Rl is hydrogen) are required they will be obtained by de-esterification of the corresponding compound of the formula (I) wherein CO2R1 is an ester group. Usually the ester group CO2R7 in formula (XII) will be the same ester group as CO2Rl, and for the sake of convenience the ester group CO2R6 will also normally be the same estergroup as CO2Rl. l'he ester groups CO2Rl/R6/R7 are suitably Cl_4 alkyl esters such as methyl and ethyl esters.
Generally, the ring closure takes place in a dry organic solvent using a strong base such as sodium hydride or sodium ethoxide (or other OR6 or OR7 group) to bring about the initial proton abstraction from the ~-methylene group.
It has been found that sodium ethoxide in benzene, or potassium t-butoxide in toluene, benzene or hexamethyl-phosphoramide give good results.
Compoundsofformula (XII) are novel useful intermediates and as such, form an aspect of this invention.
Compounds of formula (XII) may be prepared by the ester-ification of a corresponding acid or by the reaction of a compound of the formula (XIII):
2C ~ CH2)n 2 1 ~2 -(XIII) ~3~ 3 with a reactive acylating deriva-tive of an acid of the formula HO2C ~ (CH2)m CO2~I (XIV) or an ester thereof.
Suitable reactive acyla-ting derivatives include (a) compounds of the formula (:XV):
R602C - (,CH2)m - CO - Z (XV) where z is a readily displaceable group such as Cl, Br, 2 3' 2 6 4CH3, OCO(CH2)mCO2R6 or like, (b) compounds of the formula (XV) wherein Z is OH in the presence of di-cyclohexyl.carbodiimide as a condensing agent, and (c) a cyclic anhydride such as:
o ~0 The reaction of the compound ~XIII) with the compound (XIV) and (XV) occurs under conventional acylation conditions.
The novel substituted amino acids (XIII) are highly use-ful intermediates and form an important aspect of the present invention.
The compounds (XIII) may be prepared by the reaction of an amine of the formula (XVI):
H2N - CH2CH2CR2R3R4 (XVI) with a compound of the formula (.XVIII:
R7O2C - ICH - (-CH2)nC2Rl (XVII) Q
~t31~
where Q is a group readily disp:Laceable by an electron rich group.
Suitable yroups Q include I, Br, Cl, O.SO2.CH3, O.SO2C6H4CH3 and other conventional groups.
The displacement reaction occurs under conventional reaction conditions, for example, in an alcoholic solvent in the presence of Na2CO3 or pyridine.
When R2 is hydrogen or lower alkyl then the amine CXVI) can be prepared by conventional methods. However when R2 and R4 are higher alkyl or cyclic groups as defined in formula (I), then the amine is best prepared by the following reaction scheme, or a scheme chemically analogous thereto:
R2 liquid \ 13 ammonia ~C=O+CH3CN ~ C-CH2CN
/ strong base R4 or LiNH2; orreduce e.g.
lithium in hexamethyl- 4 phosphoramide (containing \ /
diethylamine~/benzene/
THF; opt. protect.
H2N-CH2cH2cR2R3R4 (XVI) Of the intermediate compounds discussed, a generally pre-ferred group according to the invention are those of formulae XII and XIII wherein m (formula XII) is 1 or 2, 16~
and in both n is 4 to 8 X is CO, protected CO or CROH wherein R may be hydrogen or Cl 4 alkyl and wherein the OH moiety may be protected;
Rl is Cl_4 alkyl;
R3 is hydroxy or protected hydroxy;
R2 is hydrogen, Cl 4 alkyl, phenyl or phenyl substituted by one or more halogen, trifluoromethyl Cl 6 alkyl, Cl 6 alkoxy or nitro groups;
R4 is C4 9 alkyl, cyclohexyl, phenyl, phenyl Cl 6 alkyl or phenyl or phenyl Cl 6 alkyl substituted with one or more halogen, trifluoromethyl, Cl 6 alkyl, Cl 6 alkoxy or nitro groups;
or CR2R4 is C5 8 cycloalkyl;
except when R2 is hydrogen or Cl 4 alkyl, the R4 is not C4 9 alkyl;
and R7 is Cl_4 alkyl--18a-~9~
Compoundswithin the .~ormula (I~ have useful pha.rmaco-logical activity. For example compounds within the formula (I). have anti-gastric secretion activity, cardiovascular activity e.g. anti-hypertensive activity, platelet aggre-gration inhibition activity, effect the respiratory tract e.g. bronchodilator activity, and have antifertility and smooth muscle activity.
In general it may be said that compounds within the formula (I) have a range of pharmacological activities simiLar to those shown by the natural prostaglandins, but that these activities tend to be rather more selective.
The invention therefore also provides a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable carrier.
Clearly the formulation of the said pharmaceutical com-position will depend on the nature of the activity shown by the chosen compound of the formula (I), and on other factors such as a preference in a particular area of therapy for a particular mode of administration.
20. The compositions may be in the form of tablets, capsules, powders, granules, lozenges or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents; for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrollidone;
.
~gl~8 filler for example lac~ose, suyar, maize-starch, calcium phosphate, sorbitol or gylcine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or ac-ceptable wetting agents such as sodium lauryl sulphate.
The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspen-sions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats, emulsify-ing agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oilsl, for example almond oil, fractionated coconut oil, oily esters such as glycerine, propylene gylcol, or ethyl alcohol; pre-2n servatives, for example methyl or propyl _-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colour-ing agents. The compounds of the formula (I~ may also if desired be incorporated in a food-stuff, for example in the form of a biscuit.
For parenteral administration, fluid unit dosage forms are prepared utilizing the compound of the formula (I) and a ~ .
~1~9~ti~3fl sterile vehicle. The compound, depending on the vehicle and concentration used, can be either suspe~dedor dissolved in the vehicle. In preparing solutions the compound can be dis-solved for injection and filter sterilized before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anesthetic, preservatives and buf-fering agents can be dissolved in the vehicle. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead lQ of being dissolved and sterilization cannot be accomplished by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle.
Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
When appropriate, the compositions of this invention may be presented for aerosol or oral administration, or as a microfine powder for insufflation.
As is common practice, the compositions will usually be accompanied by written or printed directions forusein the medical treatment concerned.
It has been found that a number of the compounds of the formula (I) are potent inhibitors of gastric secretion, and thus have commercial utility as anti-ulcer agents. In treat-ment of this nature, the composition containing the formula (I) will preferably be formulated in a manner to allow oral 1~3i~
administration. Normally . 01 m~/ky to 500 my/ky per day, most suitably .1 to 100 my/kg per ~ay, of the compound of the formula (I) in composition form will be administered in such treatment.
Also a number of compounds of the formula (I) have particularly useful activity on the respiratory tract, and thus find utility as for example bronchodilators. Normally compositions containing such compounds of the formula (I) will be formulated ~or aerosol or oral administrationl or as a microfine powder for insuf~lation, and the treatment will comprise the administration of from .001 mg/kg to 100 mg/kg per day of the compound in composition form.
Further, a number of compounds of the formula (I) are particularly potent inhibitors of platelet aggregration, and thus compositions containing such compounds are useful inter alia for administration to humans and animals to prevent clot formation for example after surgery to prevent postoperative thrombosis; in geriatric patients to prevent transient cerebral ischemic attacks; and long-term prophylaxis following myo-2Q cardial infarcts and strokes - and in general in the treatment or prophylaxis of any disorder caused by an over pronounced tendency of blood platelets to aggregrate. Such compositions also have applications in the storage of whole blood in blood banks, and whole blood to be used in heart-lung machines, or to be circulatedthrough organs, e.g. heart and kidneys, which have been removed from a cadaver and prior to transplant.
- 22 ~
9~
It will of course be realised that the preci~e dosage used in the treatment of any of the hereinbefore described disorders will depend on the actual compound of the formula (I) used, and also on other factors such as the seriousness of the disorder being treated.
The invention also provides a method of treatment and/or propylaxis of disorders in human beings which comprises the - administration to the sufferer of an effective amount of a compound of the formula (II.
It will be realised that when the compound of the formula (I) exhibits platelet aggregration inhibition activity then the invention also provides a method of inhibiting such ag-gregration ln vitro.
It will also be realised that when a compound of formula (I) exhibits anti-fertility activity, then the invention also provides a method of preventing pregnancy comprising the ad-ministration to the person or animal of an effective amount of the corpound of the formula (I).
The following Examples illustrate the preparation of com-pounds of the formula (Il and their pharmacological properties.
~1~9~161~3 N~N-Dibenzyl-2-aminoethyl methyl ketone Freshly distilled methyl vinyl ketone (70.5 g) was added dropwise with stirring to a solution of dibenzylamine (197 g) in dry ethanol (50 ml) and the mixture was stirred for 30 minutes.
The solvent was evaporated and the solid residue washed with a small amount of ethanol to give N~N-diben~yl-2-aminoethyl methyl ketone as a pale yellow solid (211.6 g, 79% yield), m.p. 58-59.
N~N-Dibenzyl-2-aminoethyl ethyl ketone was similarly prepared as a yellow oil from ethyl vinyl ketone and dibenzylamine.
I.R. spectrum - carbonyl absorption at 1700 cm 1.
NMR spectrum - 10 proton singlet at 2.7~ [(C6H5CH2)2N-]
In the process of the inven-tion the group CO2Rl in -the intermediates of formula (X), (XI) and (XII) will normally represent an ester group, and if acids of the formula ( I ) (wherein Rl is hydrogen) are required they will be obtained by de-esterification of the corresponding compound of the formula (I) wherein CO2R1 is an ester group. Usually the ester group CO2R7 in formula (XII) will be the same ester group as CO2Rl, and for the sake of convenience the ester group CO2R6 will also normally be the same estergroup as CO2Rl. l'he ester groups CO2Rl/R6/R7 are suitably Cl_4 alkyl esters such as methyl and ethyl esters.
Generally, the ring closure takes place in a dry organic solvent using a strong base such as sodium hydride or sodium ethoxide (or other OR6 or OR7 group) to bring about the initial proton abstraction from the ~-methylene group.
It has been found that sodium ethoxide in benzene, or potassium t-butoxide in toluene, benzene or hexamethyl-phosphoramide give good results.
Compoundsofformula (XII) are novel useful intermediates and as such, form an aspect of this invention.
Compounds of formula (XII) may be prepared by the ester-ification of a corresponding acid or by the reaction of a compound of the formula (XIII):
2C ~ CH2)n 2 1 ~2 -(XIII) ~3~ 3 with a reactive acylating deriva-tive of an acid of the formula HO2C ~ (CH2)m CO2~I (XIV) or an ester thereof.
Suitable reactive acyla-ting derivatives include (a) compounds of the formula (:XV):
R602C - (,CH2)m - CO - Z (XV) where z is a readily displaceable group such as Cl, Br, 2 3' 2 6 4CH3, OCO(CH2)mCO2R6 or like, (b) compounds of the formula (XV) wherein Z is OH in the presence of di-cyclohexyl.carbodiimide as a condensing agent, and (c) a cyclic anhydride such as:
o ~0 The reaction of the compound ~XIII) with the compound (XIV) and (XV) occurs under conventional acylation conditions.
The novel substituted amino acids (XIII) are highly use-ful intermediates and form an important aspect of the present invention.
The compounds (XIII) may be prepared by the reaction of an amine of the formula (XVI):
H2N - CH2CH2CR2R3R4 (XVI) with a compound of the formula (.XVIII:
R7O2C - ICH - (-CH2)nC2Rl (XVII) Q
~t31~
where Q is a group readily disp:Laceable by an electron rich group.
Suitable yroups Q include I, Br, Cl, O.SO2.CH3, O.SO2C6H4CH3 and other conventional groups.
The displacement reaction occurs under conventional reaction conditions, for example, in an alcoholic solvent in the presence of Na2CO3 or pyridine.
When R2 is hydrogen or lower alkyl then the amine CXVI) can be prepared by conventional methods. However when R2 and R4 are higher alkyl or cyclic groups as defined in formula (I), then the amine is best prepared by the following reaction scheme, or a scheme chemically analogous thereto:
R2 liquid \ 13 ammonia ~C=O+CH3CN ~ C-CH2CN
/ strong base R4 or LiNH2; orreduce e.g.
lithium in hexamethyl- 4 phosphoramide (containing \ /
diethylamine~/benzene/
THF; opt. protect.
H2N-CH2cH2cR2R3R4 (XVI) Of the intermediate compounds discussed, a generally pre-ferred group according to the invention are those of formulae XII and XIII wherein m (formula XII) is 1 or 2, 16~
and in both n is 4 to 8 X is CO, protected CO or CROH wherein R may be hydrogen or Cl 4 alkyl and wherein the OH moiety may be protected;
Rl is Cl_4 alkyl;
R3 is hydroxy or protected hydroxy;
R2 is hydrogen, Cl 4 alkyl, phenyl or phenyl substituted by one or more halogen, trifluoromethyl Cl 6 alkyl, Cl 6 alkoxy or nitro groups;
R4 is C4 9 alkyl, cyclohexyl, phenyl, phenyl Cl 6 alkyl or phenyl or phenyl Cl 6 alkyl substituted with one or more halogen, trifluoromethyl, Cl 6 alkyl, Cl 6 alkoxy or nitro groups;
or CR2R4 is C5 8 cycloalkyl;
except when R2 is hydrogen or Cl 4 alkyl, the R4 is not C4 9 alkyl;
and R7 is Cl_4 alkyl--18a-~9~
Compoundswithin the .~ormula (I~ have useful pha.rmaco-logical activity. For example compounds within the formula (I). have anti-gastric secretion activity, cardiovascular activity e.g. anti-hypertensive activity, platelet aggre-gration inhibition activity, effect the respiratory tract e.g. bronchodilator activity, and have antifertility and smooth muscle activity.
In general it may be said that compounds within the formula (I) have a range of pharmacological activities simiLar to those shown by the natural prostaglandins, but that these activities tend to be rather more selective.
The invention therefore also provides a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable carrier.
Clearly the formulation of the said pharmaceutical com-position will depend on the nature of the activity shown by the chosen compound of the formula (I), and on other factors such as a preference in a particular area of therapy for a particular mode of administration.
20. The compositions may be in the form of tablets, capsules, powders, granules, lozenges or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents; for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrollidone;
.
~gl~8 filler for example lac~ose, suyar, maize-starch, calcium phosphate, sorbitol or gylcine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or ac-ceptable wetting agents such as sodium lauryl sulphate.
The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspen-sions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats, emulsify-ing agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oilsl, for example almond oil, fractionated coconut oil, oily esters such as glycerine, propylene gylcol, or ethyl alcohol; pre-2n servatives, for example methyl or propyl _-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colour-ing agents. The compounds of the formula (I~ may also if desired be incorporated in a food-stuff, for example in the form of a biscuit.
For parenteral administration, fluid unit dosage forms are prepared utilizing the compound of the formula (I) and a ~ .
~1~9~ti~3fl sterile vehicle. The compound, depending on the vehicle and concentration used, can be either suspe~dedor dissolved in the vehicle. In preparing solutions the compound can be dis-solved for injection and filter sterilized before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anesthetic, preservatives and buf-fering agents can be dissolved in the vehicle. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead lQ of being dissolved and sterilization cannot be accomplished by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle.
Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
When appropriate, the compositions of this invention may be presented for aerosol or oral administration, or as a microfine powder for insufflation.
As is common practice, the compositions will usually be accompanied by written or printed directions forusein the medical treatment concerned.
It has been found that a number of the compounds of the formula (I) are potent inhibitors of gastric secretion, and thus have commercial utility as anti-ulcer agents. In treat-ment of this nature, the composition containing the formula (I) will preferably be formulated in a manner to allow oral 1~3i~
administration. Normally . 01 m~/ky to 500 my/ky per day, most suitably .1 to 100 my/kg per ~ay, of the compound of the formula (I) in composition form will be administered in such treatment.
Also a number of compounds of the formula (I) have particularly useful activity on the respiratory tract, and thus find utility as for example bronchodilators. Normally compositions containing such compounds of the formula (I) will be formulated ~or aerosol or oral administrationl or as a microfine powder for insuf~lation, and the treatment will comprise the administration of from .001 mg/kg to 100 mg/kg per day of the compound in composition form.
Further, a number of compounds of the formula (I) are particularly potent inhibitors of platelet aggregration, and thus compositions containing such compounds are useful inter alia for administration to humans and animals to prevent clot formation for example after surgery to prevent postoperative thrombosis; in geriatric patients to prevent transient cerebral ischemic attacks; and long-term prophylaxis following myo-2Q cardial infarcts and strokes - and in general in the treatment or prophylaxis of any disorder caused by an over pronounced tendency of blood platelets to aggregrate. Such compositions also have applications in the storage of whole blood in blood banks, and whole blood to be used in heart-lung machines, or to be circulatedthrough organs, e.g. heart and kidneys, which have been removed from a cadaver and prior to transplant.
- 22 ~
9~
It will of course be realised that the preci~e dosage used in the treatment of any of the hereinbefore described disorders will depend on the actual compound of the formula (I) used, and also on other factors such as the seriousness of the disorder being treated.
The invention also provides a method of treatment and/or propylaxis of disorders in human beings which comprises the - administration to the sufferer of an effective amount of a compound of the formula (II.
It will be realised that when the compound of the formula (I) exhibits platelet aggregration inhibition activity then the invention also provides a method of inhibiting such ag-gregration ln vitro.
It will also be realised that when a compound of formula (I) exhibits anti-fertility activity, then the invention also provides a method of preventing pregnancy comprising the ad-ministration to the person or animal of an effective amount of the corpound of the formula (I).
The following Examples illustrate the preparation of com-pounds of the formula (Il and their pharmacological properties.
~1~9~161~3 N~N-Dibenzyl-2-aminoethyl methyl ketone Freshly distilled methyl vinyl ketone (70.5 g) was added dropwise with stirring to a solution of dibenzylamine (197 g) in dry ethanol (50 ml) and the mixture was stirred for 30 minutes.
The solvent was evaporated and the solid residue washed with a small amount of ethanol to give N~N-diben~yl-2-aminoethyl methyl ketone as a pale yellow solid (211.6 g, 79% yield), m.p. 58-59.
N~N-Dibenzyl-2-aminoethyl ethyl ketone was similarly prepared as a yellow oil from ethyl vinyl ketone and dibenzylamine.
I.R. spectrum - carbonyl absorption at 1700 cm 1.
NMR spectrum - 10 proton singlet at 2.7~ [(C6H5CH2)2N-]
4 proton broad multiplet at 7.3~ (,N-CH2CH2-) 3 proton triplet at 9.05r, J = 7cps (-CCH2CH3) ~1~9~L6~3 3-Methyl-l-(N,N-dibenzvlamlno)-5-phenyl-pentan-3-oL
2-Phenylethyl magnesium bromide was prepared under nitrogen from magnesium (8.04 g) and 2-bromoethyl benzene (54.8 g) in dry tetrahydrofuran (100 ml).
A solution of N,N-dibenzyl-2-aminoethyl methyl ketone (50 g) in dry tetrahydrofuran (200 ml) was added dropwise to the Grignard reagent. The mixture was stirred and refluxed overnlght.
A saturated solution of ammonium chloride was added and the product extracted three times with ether. The organic fractions were combined, dried over magnesium sulphate and evaporated in vacuo to gi~e 3-methyl-1-(Nl~dibenzylamino)-5-phenyl-pentan-3-ol as a yellow oil (75.6 g).
I.R. spectrum - broad OH absorption at 3330 cm 1, absence of carbonyl absorption.
The compounds shown in Table 1 were similarly prepared.
Table 1 (PhCH2)2NcH2cH2 C R~
Compound Precursor R~ OH absorption 1 Bromobenzene C6H5 3300 2 Benzyl bromide CH2C6H5 3300 3 1-Bromo-3-phenyl propane (CH2)3C6~15 3300 4 . !3-Bromo-isopropyl benzene CH2CH(CH3)C6H53330 2-Bromoethyl-4'-fluorobenzene ( 2)2 ~CH 3350 _ l-Bromo-3-(2'-methoxyphenyl)-propane (CH2)3 ~ 3350 ~1~)91~;~8 l-Amino-3-methyl-5-phenyl-pentan-3-ol A solution of 3-methyl-1-(N,N-dlbenzylamino)-5-phenyl-pentan-3-ol (75.5 g) in ethanol (200 ml) was added to a slurry of 1070 Pd/C (8 g) in ethanol. The mixture was hydrogenated at 200 psi and 70 for three days.
The mixture was filtered through kieselguhr and evaporated. The oily produced was fractionally distilled to give l_amino-3-methYl-5-phen~l-pentan-3-ol as a colourless liquld (15.8 g, 40% yield), b.p. 136/
0.3 mm Hg.
The compounds shown in Table 2 were similarly prepared.
Table 2 H2NCH2cH2~c~R~
NH2, OH absorption Compound R"B.p. (cm~l) 7 6 5 _ 3300 8 H2C6 595-105~/0.6 mm _ 9 (CH2)3C6H5130/0.2 mm _ CH2CH(CH3)C6H5 _ 3330 11 ~ _ 3350 12 ( 2)3~3 3350 r~
1~916 EX~MPLE 4 Acetonitrile (7 g) in dry ether (30 ml) was added dropwise to a suspension of sodamide (9.97 g) in liquid ammonia (500 ml). The mlxture was stirredfor 10 minutes, then a solution o~ phenylamyl-ketone (30 g) ln dry ether (30 ml) was added dropwise. After stirring for an additional hour solid ammonium chloride (14 g) was added. The ammonia was evaporated and during the evaporatlon ether (50 ml) was added. The residue was treated with water (150 ml) and the ether layer was separated. The aqueous phase was extrated with ether and the combined ether phase was washed with brine until the washings were neutral, then was dried o~er magnesium sulphate and evaporated in vacuo to give a yellow oil. The unchanged starting materials were removed by vacuum distillation, and the residue which solidified on standing~ was reasonably pure 3-hydroxy-3-phenyl-n-octanitrile (12.5 g) I.R. spectrum - CN absorption at 2250 cm 1.
OH absorption at 3430 cm 1 l-Hvdroxv-l-cvanomethyl-cyclohexane, b.p. L01/0.1 mm was similarly prepared.
3-Hydroxy-3-phenyl-n-octanitrile ~12.45 g) in dry ether (50 ml) was added dropwise to a stirred suspension of lithium aluminium hydride (2.18 g) in dry ether (300 ml). Reflux occurred and this was maintained by external heating for 45 minutes after the final addition. The mixture was cooled (ice-bath) and water (2.5 ml), 157O NaOH solution (2.5 ml) and water (7.5 ml) were added dropwise in sequence. The resulting mixture was stirred for half-an-hour at room temperature, then was filtered through Kieselguhr. The resulting solution was dried over magnesium sulphate, and evaporated in vacuo to give 3-hydroxy-3-phenyl-n-octylamine (12.1 g, 977O crude yield).
I.R. spectrum - strong absorption 3000-3500 cm 1 due to OH, NH2 absence of CN absorption.
l-Hydrox~-1-(2'-aminoethyl)-cyclohexane, b.p. 81/0.15 mm, was similarly prepared.
~IL0~ LG~8 Diethyl 2-(N-3'-hydroxy-3'-methyl-5'-phenyl-n-pentyl)-aminoazelate Diethyl 2-bromoazelate (9.7 g) in dry ethanol (50 ml) was added dropwise to a refluxing solution of l-amino-3-methyl-5-phenyl-pentan-3-ol (5 g) in dry ethanol (150 ml) containing a suspension of anhydrous sodium carbonate (2.7 g). The mixture was refluxed overnight.
The mixture was filtered and the filtrate e~aporated in ~acuo.
The residue was taken up in ether and the ethereal solution was ~ashed with water until the washings were neutral, dried over magnesium sulphate and evaporated in vacuo to give diethyl 2-(N-3'-hydroxY-3'-methyl-5'-phenyl-n-pentyl)-amino-azelate as a pale yellow oil (10.4 g).
I.R. spectrum - broad OH, NH absorption at 3300 cm 1.
ester carbonyl absorption at 1730 cm 1 The compounds shown in Table 3 were similarly prepared:
Table 3 EtO2C ~ (CH2)6C02Et HN~
OH
Compound R~
CH3 (CH2)3C6H5 16 CH3 CH2CH(CH3)C6H5 17 CH3 (CH2) ~ F
cont ...
::aa~
Table 3 (contd ) Compound R~ R
18 CH3 (CH2)3 In each case, the I.R. spectrum showed a broad OH, NH absorption at .3300 cm 1 and an ester carbonyl absorption at 1730 cm 1.
-- ~0 --~ 16~8 Diethyl 2-[N-3'-hvdrox~-3'-methyl-5'-phenyl-n-pentyl)-N-ethoxycarbonyl-acetyl]-aminoazelate A solution of monoethyl malonate (2.9 g) in dry methylene chloride (50 ml) was added to a solution of diethyl 2-(N-3'-hydroxy-3'-methyl-5'-phenyl-n-pentyl)-aminoazelate (10.4 g) in dry methylene chloride (50 ml).
The mixture was stirred at room temperature and a solution of dicyclo-hexylcarbodiimide (5.0 g) in dry methylene chloride (25 ml) was added dropwise Stirring was continued overnight.
The mixture was filtered and the filtrate evaporated in vacuo. The residue was taken up in ether and the ethereal solution was washed with dilute hydrochloric acid, sodium bicarbonate solution and then with sodium chloride solution until the washings were neutral. The ether layer was dried over magnesium sulphate and evaporated in vacuo to give diethyl 2-~N-3'-hydroxy-3l-methyl-5l-phenyl-n-Dentyl)-N-ethoxvcarbonylacetyl]-amin azelate as a yellow oil (11.9 g).
I.R. spectrum - broad OH absorption at 3400 cm carbonyl absorptions at 1730 cm 1 and 1640 cm 1.
The compounds shown in Table 4-were similarly prepared.
~ 31 -~g 3L~
Table 4 EtO2C~(CH2)6C02Et 2 ~ N
o ( CH2 ) 2CR,;~R~I, OH
Compound R~ R~
22 CH3 CH2C6~l5 23 CH3 (CH2)3C6 5 24 CH3 CH2CH(CH3)C6H5 CH3 (CH2)2 ~ F
26 CH3 (CH2)3 In each case, the I.R. spectrum showed a broad OH absorption at 3400 cm 1 together with carbonyl absorptions at 1730 cm 1 and 1640 cm 1.
- 1~91~;~fl EX~PLE 8 2-(6'-EthoxycarbonYl-n-hexyl)-1-(3"-hydroxy-3"-methyl-5"-Dhenyl-n-pentyl)-pyrrolidin-3~5-dlone Potassium tert-butoxide (2.18 g) was added in small portions over one hour to a warm solution of diethyl 2-[N-(3'-hydroxy-3'-methyl-5'-phenyl-n-pentyl~-N-ethoxycarbonylacetyl]-aminoazelate (11.9 g) in dry toluene (100 ml).
The mixture was gently refluxed for 2 hours.
The solvent was evaporated in vacuo and the residue taken up in water.
The solution was extracted twice with ether and the aqueous layer was acidified with dilute hydrochloric acid and extracted with ether. This ethereal solution was washed with brine and dried over magnesium sulphate to give a solution of 4-ethoxycarbonyl-2-(6'-ethoxycarbonyl-n-bexyl)-1-(3"-hydroxy-3"-methyl-5"-phenyl-n-pentyl)-pyrrolidin-3,5-dione. The product decarboxylated on standing in ether solution overnight. The solvent was evaporated in vacuo to give 2-(6'-ethoxycarbonvl-n-hex~l)-l-(3"-hydroxy-3"-methyl-5"-phenyl-n-pentyl-pyrrolidin-3.5-dione as a yellow oil (4.7 g).
I.R. spectrum - broad OH absorption at 3430 cm 1 carbonyl absorptions at 1760 cm 1, 1720 cm 1 and 1680 cm l.
~ 33 - `
f' - ~0'31G~3~
The compounds shown in Table 5 were similarly prepared.
Table 5 o ~ ( 2)6 2 O N~
( 2)21 ~ 4 OH
_ _ _ I.R. spectrum Compound R~ R~ OH absorption carbonyl absorptions cm~lcm~l _ _, 29 CH3 C6H5 34001675 ? 1720, 1760 CH3 CH2C6H5 34001675, 1720, 1760 31 CH3 (CH2)3C6 5 34001675, 1720, 1760 32 CH3 CH2CH(CH3)C6H5 3450 1680, 1720, 1760 33 CH3 (CH2)2 ~ F 34501680, 1725, 1765 34 CH3 (CH2)3 ~ 34001680, 1720, 1760 C6H5 C5Hll 34001675, 1725, 1760 36 O 34501680, 1725, 1760 i6~fl 2-(6'-Ethoxycarbonyl-n-hexyl)-3-hydroxv-1-(3"-hydroxy-3"-methvl-6"-phenvl-n-he~y1)-pyrrolidin-S-one Sodium borohydride (290 mg) was added portionwlse to a solution of 2-(6'-ethoxycarbonyl-n-hexyl)-1-(3"-hydroxy-3"-methyl-6"-phenyl-n-hexyl)-pyrrolidin-3,5-dione (2.5 g) in dry ethanol (50 ml). The mixture was stirred at room temperature ~or 2 hours.
The sol~ent was evaporated in vacuo and the residue was taken up in ether. The ethereal solution was washed with very dilute hydrochloric acid and with water, dried over magnesium sulphate, and evaporated in vacuo to give a colourless oil. The product was purified by column chromatography to give 2-(6'-ethoxycarbonvl-n-hexyl)-3-hydroxy-1-(3"-hydroxy-3"-methyl-6"-phenyl-n-hexyl)-pyrrolidin-5-one as a colourless oil (1.5 g, 60% yield).
I.R. spectrum - broad OH absorption at 3400 cm l carbonyl absorptions at 1725 cm l and 1665 cm 1.
The compounds shown in Table 6 were similarly prepared.
f' ~9i~
Table 6 OH
~(CH2)6c02Et N~
(CH2)2C1 ~ 4 OH
_ .
I.R. spectrum Compound R~, R~ OH abmolption carbonyl absorptions 37CH3 C6H5 3400 1670, 1720 38CH3 CH2C6H5 3400 1670, 1720 39CH3 (CH2)2C6 5 3400 1670, 1720 3 ( 2)2~ 3430 1670, 1725 41CH3 (CH2)3~3 3400 1665, 1725 ,~ A
~916~3~
PHAR~lACOLOGICAL ~ATA
Anti-secretory activity The anti-secretory activity of the compounds was determined by their inhibition of pentagastrin-stimulated gastric acid secretion in the perfused rat stomach preparation (Ghosh and Schild preparation).
2-(6'-Ethoxycarbonyl-n-hexyl)-1-(3"-hydroxy-3"-methyl-6"-phenyl-n-hexyl)-pyrrolidin-3,5-dione inhibited acid secretion with an approximate ED50 of 850 ~g/kg, intravenously.
Inhibition of pLatelet aggregation The compounds were examined for their ability to inhibit guinea pig platelet aggregation induced, Ln vitro, by 5.45 x 10 M adenosine diphosphate.
2-(6'-Ethoxycarbonyl-n-hexyl)-1-(3"-hydroxy-3"-methyl-6"-phenyl-n-hexyl~-pyrrolidine-3,5-dione inhibited platelet aggregation with an IC50 of 1.6 x 10 M.
Bronchodilation activity .
The compounds were examined for their ability to inhibit 5-hydroxy-tryptamine-induced bronchoconstriction in the anaesthetised artificially respired guinea pig (Konæett-Rossler preparation).
2-(6'-Ethoxycarbonyl-n-hexyl)-1-(3"-hydroxy-3"-methyl-6"-phenyl-n-hexyl)-pyrrolidin-3,5-dione inhibited bronchoconstriction with an IC50 of 137 ~g/kg, intravenously.
- ~7 -~91t~
Antifertility activity The antifertility activity of the compounds was determined by their abillty to inhibit pregnancy in mated hamsters, 2-(6'-Ethoxycarbonyl-n-hexyl)-3-hydroxy-1-(3"-hydroxy-3"-methyl-5"-phenyl-n-pentyl)-pyrrolidin-5-one completely inhibited pregnancy in hamsters when dosed at 25 mg/kg, subcutaneously, on days 6, 7 and 8 after mating.
Toxicity No apparent side effects were observed after administration of 2-(6'-ethoxycarbonyl)-n-hexyl)-l-(3"-hydroxy-3"-methyl-6"-phenyl-n-hexyl)-pyrrolidin-3,5-dione at 100 mg/kg subcutaneously in the hamster and I.D.
in the rat.
2-Phenylethyl magnesium bromide was prepared under nitrogen from magnesium (8.04 g) and 2-bromoethyl benzene (54.8 g) in dry tetrahydrofuran (100 ml).
A solution of N,N-dibenzyl-2-aminoethyl methyl ketone (50 g) in dry tetrahydrofuran (200 ml) was added dropwise to the Grignard reagent. The mixture was stirred and refluxed overnlght.
A saturated solution of ammonium chloride was added and the product extracted three times with ether. The organic fractions were combined, dried over magnesium sulphate and evaporated in vacuo to gi~e 3-methyl-1-(Nl~dibenzylamino)-5-phenyl-pentan-3-ol as a yellow oil (75.6 g).
I.R. spectrum - broad OH absorption at 3330 cm 1, absence of carbonyl absorption.
The compounds shown in Table 1 were similarly prepared.
Table 1 (PhCH2)2NcH2cH2 C R~
Compound Precursor R~ OH absorption 1 Bromobenzene C6H5 3300 2 Benzyl bromide CH2C6H5 3300 3 1-Bromo-3-phenyl propane (CH2)3C6~15 3300 4 . !3-Bromo-isopropyl benzene CH2CH(CH3)C6H53330 2-Bromoethyl-4'-fluorobenzene ( 2)2 ~CH 3350 _ l-Bromo-3-(2'-methoxyphenyl)-propane (CH2)3 ~ 3350 ~1~)91~;~8 l-Amino-3-methyl-5-phenyl-pentan-3-ol A solution of 3-methyl-1-(N,N-dlbenzylamino)-5-phenyl-pentan-3-ol (75.5 g) in ethanol (200 ml) was added to a slurry of 1070 Pd/C (8 g) in ethanol. The mixture was hydrogenated at 200 psi and 70 for three days.
The mixture was filtered through kieselguhr and evaporated. The oily produced was fractionally distilled to give l_amino-3-methYl-5-phen~l-pentan-3-ol as a colourless liquld (15.8 g, 40% yield), b.p. 136/
0.3 mm Hg.
The compounds shown in Table 2 were similarly prepared.
Table 2 H2NCH2cH2~c~R~
NH2, OH absorption Compound R"B.p. (cm~l) 7 6 5 _ 3300 8 H2C6 595-105~/0.6 mm _ 9 (CH2)3C6H5130/0.2 mm _ CH2CH(CH3)C6H5 _ 3330 11 ~ _ 3350 12 ( 2)3~3 3350 r~
1~916 EX~MPLE 4 Acetonitrile (7 g) in dry ether (30 ml) was added dropwise to a suspension of sodamide (9.97 g) in liquid ammonia (500 ml). The mlxture was stirredfor 10 minutes, then a solution o~ phenylamyl-ketone (30 g) ln dry ether (30 ml) was added dropwise. After stirring for an additional hour solid ammonium chloride (14 g) was added. The ammonia was evaporated and during the evaporatlon ether (50 ml) was added. The residue was treated with water (150 ml) and the ether layer was separated. The aqueous phase was extrated with ether and the combined ether phase was washed with brine until the washings were neutral, then was dried o~er magnesium sulphate and evaporated in vacuo to give a yellow oil. The unchanged starting materials were removed by vacuum distillation, and the residue which solidified on standing~ was reasonably pure 3-hydroxy-3-phenyl-n-octanitrile (12.5 g) I.R. spectrum - CN absorption at 2250 cm 1.
OH absorption at 3430 cm 1 l-Hvdroxv-l-cvanomethyl-cyclohexane, b.p. L01/0.1 mm was similarly prepared.
3-Hydroxy-3-phenyl-n-octanitrile ~12.45 g) in dry ether (50 ml) was added dropwise to a stirred suspension of lithium aluminium hydride (2.18 g) in dry ether (300 ml). Reflux occurred and this was maintained by external heating for 45 minutes after the final addition. The mixture was cooled (ice-bath) and water (2.5 ml), 157O NaOH solution (2.5 ml) and water (7.5 ml) were added dropwise in sequence. The resulting mixture was stirred for half-an-hour at room temperature, then was filtered through Kieselguhr. The resulting solution was dried over magnesium sulphate, and evaporated in vacuo to give 3-hydroxy-3-phenyl-n-octylamine (12.1 g, 977O crude yield).
I.R. spectrum - strong absorption 3000-3500 cm 1 due to OH, NH2 absence of CN absorption.
l-Hydrox~-1-(2'-aminoethyl)-cyclohexane, b.p. 81/0.15 mm, was similarly prepared.
~IL0~ LG~8 Diethyl 2-(N-3'-hydroxy-3'-methyl-5'-phenyl-n-pentyl)-aminoazelate Diethyl 2-bromoazelate (9.7 g) in dry ethanol (50 ml) was added dropwise to a refluxing solution of l-amino-3-methyl-5-phenyl-pentan-3-ol (5 g) in dry ethanol (150 ml) containing a suspension of anhydrous sodium carbonate (2.7 g). The mixture was refluxed overnight.
The mixture was filtered and the filtrate e~aporated in ~acuo.
The residue was taken up in ether and the ethereal solution was ~ashed with water until the washings were neutral, dried over magnesium sulphate and evaporated in vacuo to give diethyl 2-(N-3'-hydroxY-3'-methyl-5'-phenyl-n-pentyl)-amino-azelate as a pale yellow oil (10.4 g).
I.R. spectrum - broad OH, NH absorption at 3300 cm 1.
ester carbonyl absorption at 1730 cm 1 The compounds shown in Table 3 were similarly prepared:
Table 3 EtO2C ~ (CH2)6C02Et HN~
OH
Compound R~
CH3 (CH2)3C6H5 16 CH3 CH2CH(CH3)C6H5 17 CH3 (CH2) ~ F
cont ...
::aa~
Table 3 (contd ) Compound R~ R
18 CH3 (CH2)3 In each case, the I.R. spectrum showed a broad OH, NH absorption at .3300 cm 1 and an ester carbonyl absorption at 1730 cm 1.
-- ~0 --~ 16~8 Diethyl 2-[N-3'-hvdrox~-3'-methyl-5'-phenyl-n-pentyl)-N-ethoxycarbonyl-acetyl]-aminoazelate A solution of monoethyl malonate (2.9 g) in dry methylene chloride (50 ml) was added to a solution of diethyl 2-(N-3'-hydroxy-3'-methyl-5'-phenyl-n-pentyl)-aminoazelate (10.4 g) in dry methylene chloride (50 ml).
The mixture was stirred at room temperature and a solution of dicyclo-hexylcarbodiimide (5.0 g) in dry methylene chloride (25 ml) was added dropwise Stirring was continued overnight.
The mixture was filtered and the filtrate evaporated in vacuo. The residue was taken up in ether and the ethereal solution was washed with dilute hydrochloric acid, sodium bicarbonate solution and then with sodium chloride solution until the washings were neutral. The ether layer was dried over magnesium sulphate and evaporated in vacuo to give diethyl 2-~N-3'-hydroxy-3l-methyl-5l-phenyl-n-Dentyl)-N-ethoxvcarbonylacetyl]-amin azelate as a yellow oil (11.9 g).
I.R. spectrum - broad OH absorption at 3400 cm carbonyl absorptions at 1730 cm 1 and 1640 cm 1.
The compounds shown in Table 4-were similarly prepared.
~ 31 -~g 3L~
Table 4 EtO2C~(CH2)6C02Et 2 ~ N
o ( CH2 ) 2CR,;~R~I, OH
Compound R~ R~
22 CH3 CH2C6~l5 23 CH3 (CH2)3C6 5 24 CH3 CH2CH(CH3)C6H5 CH3 (CH2)2 ~ F
26 CH3 (CH2)3 In each case, the I.R. spectrum showed a broad OH absorption at 3400 cm 1 together with carbonyl absorptions at 1730 cm 1 and 1640 cm 1.
- 1~91~;~fl EX~PLE 8 2-(6'-EthoxycarbonYl-n-hexyl)-1-(3"-hydroxy-3"-methyl-5"-Dhenyl-n-pentyl)-pyrrolidin-3~5-dlone Potassium tert-butoxide (2.18 g) was added in small portions over one hour to a warm solution of diethyl 2-[N-(3'-hydroxy-3'-methyl-5'-phenyl-n-pentyl~-N-ethoxycarbonylacetyl]-aminoazelate (11.9 g) in dry toluene (100 ml).
The mixture was gently refluxed for 2 hours.
The solvent was evaporated in vacuo and the residue taken up in water.
The solution was extracted twice with ether and the aqueous layer was acidified with dilute hydrochloric acid and extracted with ether. This ethereal solution was washed with brine and dried over magnesium sulphate to give a solution of 4-ethoxycarbonyl-2-(6'-ethoxycarbonyl-n-bexyl)-1-(3"-hydroxy-3"-methyl-5"-phenyl-n-pentyl)-pyrrolidin-3,5-dione. The product decarboxylated on standing in ether solution overnight. The solvent was evaporated in vacuo to give 2-(6'-ethoxycarbonvl-n-hex~l)-l-(3"-hydroxy-3"-methyl-5"-phenyl-n-pentyl-pyrrolidin-3.5-dione as a yellow oil (4.7 g).
I.R. spectrum - broad OH absorption at 3430 cm 1 carbonyl absorptions at 1760 cm 1, 1720 cm 1 and 1680 cm l.
~ 33 - `
f' - ~0'31G~3~
The compounds shown in Table 5 were similarly prepared.
Table 5 o ~ ( 2)6 2 O N~
( 2)21 ~ 4 OH
_ _ _ I.R. spectrum Compound R~ R~ OH absorption carbonyl absorptions cm~lcm~l _ _, 29 CH3 C6H5 34001675 ? 1720, 1760 CH3 CH2C6H5 34001675, 1720, 1760 31 CH3 (CH2)3C6 5 34001675, 1720, 1760 32 CH3 CH2CH(CH3)C6H5 3450 1680, 1720, 1760 33 CH3 (CH2)2 ~ F 34501680, 1725, 1765 34 CH3 (CH2)3 ~ 34001680, 1720, 1760 C6H5 C5Hll 34001675, 1725, 1760 36 O 34501680, 1725, 1760 i6~fl 2-(6'-Ethoxycarbonyl-n-hexyl)-3-hydroxv-1-(3"-hydroxy-3"-methvl-6"-phenvl-n-he~y1)-pyrrolidin-S-one Sodium borohydride (290 mg) was added portionwlse to a solution of 2-(6'-ethoxycarbonyl-n-hexyl)-1-(3"-hydroxy-3"-methyl-6"-phenyl-n-hexyl)-pyrrolidin-3,5-dione (2.5 g) in dry ethanol (50 ml). The mixture was stirred at room temperature ~or 2 hours.
The sol~ent was evaporated in vacuo and the residue was taken up in ether. The ethereal solution was washed with very dilute hydrochloric acid and with water, dried over magnesium sulphate, and evaporated in vacuo to give a colourless oil. The product was purified by column chromatography to give 2-(6'-ethoxycarbonvl-n-hexyl)-3-hydroxy-1-(3"-hydroxy-3"-methyl-6"-phenyl-n-hexyl)-pyrrolidin-5-one as a colourless oil (1.5 g, 60% yield).
I.R. spectrum - broad OH absorption at 3400 cm l carbonyl absorptions at 1725 cm l and 1665 cm 1.
The compounds shown in Table 6 were similarly prepared.
f' ~9i~
Table 6 OH
~(CH2)6c02Et N~
(CH2)2C1 ~ 4 OH
_ .
I.R. spectrum Compound R~, R~ OH abmolption carbonyl absorptions 37CH3 C6H5 3400 1670, 1720 38CH3 CH2C6H5 3400 1670, 1720 39CH3 (CH2)2C6 5 3400 1670, 1720 3 ( 2)2~ 3430 1670, 1725 41CH3 (CH2)3~3 3400 1665, 1725 ,~ A
~916~3~
PHAR~lACOLOGICAL ~ATA
Anti-secretory activity The anti-secretory activity of the compounds was determined by their inhibition of pentagastrin-stimulated gastric acid secretion in the perfused rat stomach preparation (Ghosh and Schild preparation).
2-(6'-Ethoxycarbonyl-n-hexyl)-1-(3"-hydroxy-3"-methyl-6"-phenyl-n-hexyl)-pyrrolidin-3,5-dione inhibited acid secretion with an approximate ED50 of 850 ~g/kg, intravenously.
Inhibition of pLatelet aggregation The compounds were examined for their ability to inhibit guinea pig platelet aggregation induced, Ln vitro, by 5.45 x 10 M adenosine diphosphate.
2-(6'-Ethoxycarbonyl-n-hexyl)-1-(3"-hydroxy-3"-methyl-6"-phenyl-n-hexyl~-pyrrolidine-3,5-dione inhibited platelet aggregation with an IC50 of 1.6 x 10 M.
Bronchodilation activity .
The compounds were examined for their ability to inhibit 5-hydroxy-tryptamine-induced bronchoconstriction in the anaesthetised artificially respired guinea pig (Konæett-Rossler preparation).
2-(6'-Ethoxycarbonyl-n-hexyl)-1-(3"-hydroxy-3"-methyl-6"-phenyl-n-hexyl)-pyrrolidin-3,5-dione inhibited bronchoconstriction with an IC50 of 137 ~g/kg, intravenously.
- ~7 -~91t~
Antifertility activity The antifertility activity of the compounds was determined by their abillty to inhibit pregnancy in mated hamsters, 2-(6'-Ethoxycarbonyl-n-hexyl)-3-hydroxy-1-(3"-hydroxy-3"-methyl-5"-phenyl-n-pentyl)-pyrrolidin-5-one completely inhibited pregnancy in hamsters when dosed at 25 mg/kg, subcutaneously, on days 6, 7 and 8 after mating.
Toxicity No apparent side effects were observed after administration of 2-(6'-ethoxycarbonyl)-n-hexyl)-l-(3"-hydroxy-3"-methyl-6"-phenyl-n-hexyl)-pyrrolidin-3,5-dione at 100 mg/kg subcutaneously in the hamster and I.D.
in the rat.
Claims (12)
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a compound of the formula (XIII) wherein n is 4 to 8;
R1 is C1-4 alkyl;
R3 is hydroxy or protected hydroxy;
R2 is hydrogen, C1-4 alkyl, phenyl or phenyl substituted by one or more halogen, trifluoromethyl, C1-6 alkyl, C1-6 alkoxy or nitro groups;
R4 is C4-9 alkyl, cyclohexyl, phenyl, phenyl C1-6 alkyl, or phenyl or phenyl C1-6 alkyl substituted with one or more halogen, trifluoromethyl, C1-6 alkyl, C1-6 alkoxy or nitro groups;
or CR2R4 is C5-8 cycloalkyl;
except when R2 is hydrogen or C1-4 alkyl, then R4 is not C4-9 alkyl; and R7 is C1-4 alkyl, which comprises reacting a compound of formula (XVI) wherein R2, R3 and R4 are as defined with a compound of the formula (XVII) where n, R1 and R7 are as defined and Q is a group readily dis-placeable by an electron rich group and recovering the required compound of formula (XIII).
R1 is C1-4 alkyl;
R3 is hydroxy or protected hydroxy;
R2 is hydrogen, C1-4 alkyl, phenyl or phenyl substituted by one or more halogen, trifluoromethyl, C1-6 alkyl, C1-6 alkoxy or nitro groups;
R4 is C4-9 alkyl, cyclohexyl, phenyl, phenyl C1-6 alkyl, or phenyl or phenyl C1-6 alkyl substituted with one or more halogen, trifluoromethyl, C1-6 alkyl, C1-6 alkoxy or nitro groups;
or CR2R4 is C5-8 cycloalkyl;
except when R2 is hydrogen or C1-4 alkyl, then R4 is not C4-9 alkyl; and R7 is C1-4 alkyl, which comprises reacting a compound of formula (XVI) wherein R2, R3 and R4 are as defined with a compound of the formula (XVII) where n, R1 and R7 are as defined and Q is a group readily dis-placeable by an electron rich group and recovering the required compound of formula (XIII).
2. The process of claim 1 wherein Q in formula (XVII) is I, Br, Cl, O.SO2.CH3, or O.SO2C6H4CH3.
3. A process as claimed in claim 1 wherein n is 6 in formula (XVII).
4. A process as claimed in claim 3 wherein R2 in formula (XVI) is H, C1-4 alkyl or phenyl.
5. A process as claimed in claim 4 wherein R4 in formula (XVI) is phenyl, phenyl C1-6 alkyl, or those groups substituted with a halogen, trifluoromethyl, C1-6 alkyl, C1-6 alkoxy or nitro group.
6. A process as claimed in claim 4 wherein R2 in formula (XVI) is H, methyl or ethyl.
7. A process as claimed in claim 4, 5 or 6 wherein R2 in formula (XVI) is methyl.
8. A compound of the formula (XIII) wherein n is 4 to 8;
R1 is C1-4 alkyl;
R3 is hydroxy or protected hydroxy;
R2 is hydrogen, C1-4 alkyl, phenyl or phenyl substituted by one or more halogen, trifluoromethyl C1-6 alkyl, C1-6 alkoxy or nitro groups;
R4 is C4-9 alkyl, cyclohexyl, phenyl, phenyl C1-6 alkyl, or phenyl or phenyl C1-6 alkyl substituted with one or more halogen, trifluoromethyl, C1-6 alkyl, C1-6 alkoxy or nitro groups;
or CR2R4 is C5-8 cycloalkyl;
except when R2 is hydrogen or C1-4 alkyl, then R4 is not C4-9 alkyl; and R7 is C1-4 alkyl, when prepared by the process of claim 1 or 2 or an ob-vious chemical equivalent thereof.
R1 is C1-4 alkyl;
R3 is hydroxy or protected hydroxy;
R2 is hydrogen, C1-4 alkyl, phenyl or phenyl substituted by one or more halogen, trifluoromethyl C1-6 alkyl, C1-6 alkoxy or nitro groups;
R4 is C4-9 alkyl, cyclohexyl, phenyl, phenyl C1-6 alkyl, or phenyl or phenyl C1-6 alkyl substituted with one or more halogen, trifluoromethyl, C1-6 alkyl, C1-6 alkoxy or nitro groups;
or CR2R4 is C5-8 cycloalkyl;
except when R2 is hydrogen or C1-4 alkyl, then R4 is not C4-9 alkyl; and R7 is C1-4 alkyl, when prepared by the process of claim 1 or 2 or an ob-vious chemical equivalent thereof.
9. A process for the preparation of the compound diethyl-2-(N-3'-hydroxy-3'-methyl-5'-phenyl-n-pentyl)-aminoazelate which comprises reacting diethyl-2-bromoazelate with 1-amino-3-methyl-5-phenyl-pentan-3-ol in a solvent in the presence of a base and recovering the required compound.
10. Diethyl-2-(N-3'-hydroxy-3'-methyl-5'-phenyl-n-pentyl)-aminoazelate when prepared by the process of claim 9 or an ob-vious chemical equivalent.
11. A process for the preparation of a compound of the group diethyl-2-(N-3'-hydroxy-3'-methyl-3'-phenyl-n-propyl)-amino-azelate, diethyl-2-(N-3'-hydroxy-3'-methyl-4'-phenyl-n-butyl)-aminoazelate, diethyl-2-(n-3'-hydroxy-3'-methyl-6'-phenyl-n-hexyl)-aminoazelate, diethyl-2-(N-3'-hydroxy-3'-methyl-5'-methyl-5'-phenyl-n-pentyl)-aminoazelate, diethyl-2-(N-3'-hydroxy-3'-methyl-5-(p-fluorophenyl)-n-pentyl)-aminoazelate, diethyl-2-(N-3'-hydroxy-3'-methyl-6'-(o-methoxyphenyl)-n-hexyl)-aminoazelate, diethyl-2-(N-3'-hydroxy-3'-phenyl-n-oct-1-yl)-aminoazelate, and 2-diethyl-2-[N-(1'-hydroxycyclohex-1'yl)ethyl]aminoazelate.
which comprises reacting diethyl-2-bromoazelate in a solvent in the presence of a base with the corresponding compound of the group 1-amino-3-methyl-3-phenyl-propan-3-ol 1-amino-3-methyl-4-phenyl-n-butan-3-ol 1-amino-3-methyl-6-phenyl-n-hexan-3-ol 1-amino-3-methyl-5-methyl-5-phenyl-n-pentan-3-ol 1-amino-3-metnyl-5-(p-flurorophenyl)-n-pentan-3-ol 1-amino-3-methyl-6-(o-methoxyphenyl)-n-hexan-3-ol 1-amino-3-phenyl-n-octan-3-ol 1-amino-2-(1'-hydroxycyclohex-1'-yl)ethane and recovering the required compound.
which comprises reacting diethyl-2-bromoazelate in a solvent in the presence of a base with the corresponding compound of the group 1-amino-3-methyl-3-phenyl-propan-3-ol 1-amino-3-methyl-4-phenyl-n-butan-3-ol 1-amino-3-methyl-6-phenyl-n-hexan-3-ol 1-amino-3-methyl-5-methyl-5-phenyl-n-pentan-3-ol 1-amino-3-metnyl-5-(p-flurorophenyl)-n-pentan-3-ol 1-amino-3-methyl-6-(o-methoxyphenyl)-n-hexan-3-ol 1-amino-3-phenyl-n-octan-3-ol 1-amino-2-(1'-hydroxycyclohex-1'-yl)ethane and recovering the required compound.
12. A compound of the group diethyl-2-(N-3'-hydroxy-3'-methyl-3'-phenyl-n-propyl)-aminoazelate, diethyl-2-(N-3'-hydroxy-3'-methyl-4'-phenyl-n-butyl)-aminoazelate, diethyl-2-(N-3'-hydroxy-3'-methyl-6'-phenyl-n-hexyl)-aminoazelate, diethyl-2-(N-3'-hydroxy-3'-methyl-5'-methyl-5'-phenyl-n-pentyl) -aminoazelate, diethyl-2-(N-3'-hydroxy-3'-methyl-5-(p-fluorophenyl)-n-pentyl)-aminoazelate, diethyl-2-(N-3'-hydroxy-3'-methyl-6'-(o-methoxyphenyl)-n-hexyl)-aminoazelate, diethyl-2-(N-3'-hydroxy-3'-phenyl-n-oct-1-yl)-aminoazelate, and 2-diethyl-2-[N-(1'-hydroxycyclohex-1'-yl)ethyl]-aminoazelate when prepared by the process of claim 11 or an obvious chemical equivalent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA345,592A CA1091688A (en) | 1975-10-25 | 1980-02-13 | Pyrrolidine and piperidine prostaglandin analogues |
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB43990/75 | 1975-10-25 | ||
| GB43990/75A GB1572184A (en) | 1975-10-25 | 1975-10-25 | 12-azaprostaglandins |
| GB21278/76 | 1976-05-22 | ||
| GB2127876 | 1976-05-22 | ||
| CA263,940A CA1085856A (en) | 1975-10-25 | 1976-10-22 | Pyrrolidine and piperidine prostaglandin analogues |
| CA345,592A CA1091688A (en) | 1975-10-25 | 1980-02-13 | Pyrrolidine and piperidine prostaglandin analogues |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1091688A true CA1091688A (en) | 1980-12-16 |
Family
ID=27425949
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA345,592A Expired CA1091688A (en) | 1975-10-25 | 1980-02-13 | Pyrrolidine and piperidine prostaglandin analogues |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1091688A (en) |
-
1980
- 1980-02-13 CA CA345,592A patent/CA1091688A/en not_active Expired
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| MKEX | Expiry |