Dipeptides with neurokinin-antagonistic activity

Details Dipeptides with neurokinin-antagonistic activity Dipeptides with neurokinin-antagonistic activity

1999-12-01

2001-05-15

Higel, Floyd D. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C514S252130, C514S414000, C544S372000, C548S467000

Reexamination Certificate

active

06232468

ABSTRACT:

The invention relates to new amino acid derivatives of general formula I
R
1
—R
11
—A
1
—A
2
—NR
2
R
3
  (I)
and the pharmaceutically acceptable salts thereof, processes for preparing them and pharmaceutical compositions containing these compounds. The compounds are valuable neurokinin (tachykinin)-antagonists.
European Patent Applications EP 394 989 and EP 443 132 and WO 94/05693 describe peptides having a neurokinin antagonistic activity. The compounds according to the invention differ from these compounds essentially in the components R
1
, A
2
, R
5
and NR
2
R
3
.
The abbreviations used for the amino acids in this specification and in the claims correspond to the usual three-letter code as described, for example, in Europ. J. Biochem., 138, 9 (1984). The other abbreviations are explained as follows:
Boc
= t-butoxycarbonyl
Bzl
= benzyl
CDI
= carbonyldiimidazole
Cha
= 3-cyclohexylalanine
DCCI
= dicyclohexylcarbodiimide
DCH
= dicyclohexylurea
HOBt
= 1-hydroxybenzotriazo1e
Hpa
= homophenylalanine
Hyp
= (2S,4R)-hydroxyproline
Pal
= 3-(1-pyrrolyl)alanine
THF
= tetrahydrofuran
TFA
= trifluoroacetic acid
Z
= benzyloxycarbonyl
Me
= methyl
Ac
= acetyl
Et
= ethyl
DMF
= dimethylformamide
DPPA
= diphenylphosphorylazide
PPA
= polyphosphoric acid
RT
= room temperature
Mtr
= 4-methoxy-2,3,6-trimethylbenzene
 sulphonyl
Trp(for)
= formyl-protected tryptophan
Met(0)
= methionine in which S is oxidised to
 form the sulphoxide
Bum
= N(&pgr;)-tert · butoxymethyl
The term amino acid (unless expressly stated otherwise in the text which follows) covers natural and unnatural amino acids, both the D- and the L-forms, particularly &agr;-amino acids, and the isomers thereof.
If an amino acid is given without a prefix, this denotes the L-form of the amino acid. The D-form is specifically given.
A simplified representation is used for the formulae. When representing the compounds, all the CH
3
substituents are indicated by a dash, thus, for example:
The invention relates to new amino acid derivatives of general formula I
R
1
—R
11
—A
1
—A
2
—NR
2
R
3
  (I)
and the pharmaceutically acceptable salts thereof, wherein
R
1
is (a) adamantyl or noradamantyl which is unsubstituted or substituted by X
1
or by one or 2 oxo groups, wherein X
1
denotes halogen, COOH, C(O)NH
2
, C(O)Oalkyl, C(O)NHalkyl, C(O)N(alkyl)
2
[wherein alkyl denotes methyl, ethyl, propyl, butyl or pentyl],
CH
2
, NH-alkyl, CH
2
N(alkyl)
2
[wherein alkyl denotes methyl, ethyl, propyl, butyl or pentyl],
NH(Sch) [wherein Sch denotes methyloxycarbonyl, ethyloxycarbonyl or phenyl (C
1 or 2
-alkyl)oxycarbonyl, in which the phenyl is unsubstituted or substituted by halogen, (C
1-5
)alkyl or (C
1-5
)alkoxy]; or
(b) a saturated 6-membered ring having 6 carbon atoms or 5 carbon atoms and one N-atom, which has a —CH
2
—CH
2
-bridge between two carbon atoms in the p-position, which is unsubstituted or substituted by X
2
and/or one or two oxo groups; wherein X
2
denotes halogen, alkyl, OH, —O-alkyl, —C(O)Oalkyl, —COOH, —C(O)NH
2
, —C(O)NHalkyl, —C(O)N(alkyl)
2
[wherein alkyl denotes methyl, ethyl, propyl, butyl or pentyl], CN, NH
2
or NH(Sch) [wherein Sch denotes methyloxycarbonyl, ethyloxycarbonyl or phenyl (C
1 or 2
-alkyl)oxycarbonyl, in which the phenyl is unsubstituted or substituted by halogen, (C
1-5
)alkyl or (C
1-5
)alkoxy]; or
(c) one of the rings
(d) if R
11
is —C(C
5
H
10
)—C(O)—, R
1
can represent phenyl;
R
11
denotes
—C(O)—, —CH
2
—C(O)—, —C(C
5
H
10
)—C(O)—, —NH—C(O)— or O—C(O)—;
A
1
denotes
D- or L-serine (Ser), D- or L-threonine (Thr), D- or L-allothreonine, D- or L-proline (Pro), D- or L-didehydroproline (&Dgr;Pro) such as, for example, 3,4-didehydroproline (&Dgr;(3,4)-Pro), D- or L-hydroxyproline (Pro(OH)) such as for example 3-hydroxyproline (Pro(30H)) and 4-hydroxyproline (Pro(40H)), D- or L-thiazolidine-4-carboxylic acid, D- or L-aminoproline (Pro(NH
2
)) such as for example 3-aminoproline (Pro(3NH
2
)) and 4-aminoproline (Pro(4NH
2
)), D- or L-pyroglutamic acid (pGlu), D- or L-hydroxypiperidinocarboxylic acid such as, for example, 5-hydroxypiperidino-2-carboxylic acid, in which any hydroxy and amino groups contained therein may be protected by conventional protecting groups (e.g. acyl, carbamoyl or aralkyl (especially benzyl);
A
2
is
a lipophilic &agr;-amino acid which contains a phenyl, mono-, di- or tri-substituted phenyl, heteroaryl or a naphthyl group, and this cyclic group is separated from the backbone of the amino acid by —CH
2
— or —CH
2
—CH
2
—, (while the substituents of the phenyl group may, independently of one another, be halogen, trihalomethyl, alkoxy or alkyl);
R
2
and R
3
independently of each other denote alkyl, arylalkyl or heteroarylalkyl (wherein aryl denotes phenyl, mono-, di- or tri-substituted phenyl or naphthyl; the substituents of the phenyl group independently of one another denote halogen, trihalomethyl, alkoxy, alkyl, alkylthio, hydroxy, trifluoromethoxy, dialkylamino or cyano or 2 adjacent positions of the phenyl group are linked by —O—(CH
2
)
1 or 2
-O—; heteroaryl denotes indolyl, pyridyl, pyrrolyl, imidazolyl or thienyl; and the alkyl or alkoxy group contains 1 to 3 carbon atoms) or the group
denotes a ring of general formula
wherein s is 2 or 3,
(wherein aryl denotes phenyl, mono-, di- or tri-substituted phenyl or naphthyl; the substituents of the phenyl group independently of one another denote halogen, trihalomethyl, alkoxy, alkyl, cyano, hydroxy, nitro, —CO
2
CH
3
, —CO
2
C
2
H
5
or alkylthio or 2 adjacent positions of the phenyl group are linked by —O—(CH
2
)
1-2
—O— and alkyl contains 1 to 3 carbon atoms).
The compounds according to the invention are valuable neurokinin (tachykinin)-antagonists which have both substance P-antagonism and neurokinin A- and neurokinin B-antagonistic properties. They are useful for the treatment and prevention of neurokinin-mediated diseases.
Compounds of general formula I may have acid groups, chiefly carboxyl groups, or phenolic hydroxy groups, and/or basic groups such as for example guanidino- or aminofunctional groups. Compounds of general formula I may therefore occur either as internal salts, as salts with pharmaceutically useful inorganic acids such as hydrochloric acid, sulphuric acid, phosphoric acid, or sulphonic acid or organic acids (such as for example maleic acid, fumaric acid, citric acid, tartaric acid or acetic acid) or as salts with pharmaceutically useful bases such as alkali or alkaline earth metal hydroxides or carbonates, zinc or ammonium hydroxides or organic amines such as for example diethylamine, triethylamine, triethanolamine and the like.
The chiral centres in the new amino acid derivatives may be of R-, S- or R,S-configuration.
The term “heteroaryl group” used in the definition of A
2
denotes a mono-, di- or tri-cyclic aromatic ring system which contains 1 or 2 heteroatoms, namely one or two nitrogen atoms or one nitrogen and one sulphur atom. If desired, the group may contain 1 or 2 substituents (C
1-3
alkyl) or an oxo group or an alkoxy group containing 1 to 3 carbon atoms.
Examples of suitable heteroaryl groups are
It should be noted that the heteroaryl groups mentioned above may also be bonded to the —CH
2
—CH
2
— group in positions other than those specified.
The —CH
2
CH
2
— group is bonded to the &agr;-carbon atom of the amino acid (A
2
).
Of the compounds of formula I according to the invention, the preferred ones are those wherein
R
1
and R
11
are as hereinbefore defined, and
A
1
is proline, 4-hydroxyproline or thiazolidine-4-carboxylic acid (thioproline), preferably 4-hydroxyproline of 2-S-configuration, particularly
and/or
A
2
denotes a lipophilic alpha-amino acid which contains naphthyl, indolyl or N-methylindolyl, which group is separated from the back bone of the amino acid group by —CH
2
— or —CH
2
—CH
2
—, with A
2
preferably being the group
w

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