Pyridine derivatives

Details Pyridine derivatives Pyridine derivatives

1994-07-28

2001-01-16

Jones, Dwayne C. (Department: 1614)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S300000, C546S323000

Reexamination Certificate

active

06175016

ABSTRACT:

The present invention relates to pyridine derivatives, processes for their production and their use in diagnosis to detect bone and other connective tissue disorders in humans and animals.
Compounds of formula IA
wherein
X
1
is H or OH, and
X
2a
⊖
is a chloride or acetate ion
have been extracted from urine either by hydrolysis with 6M HCl at about 108° C. for approximately 24 hours (see Eyre et al., Ann. Rev. Biochem., 1984, 53, 717-748) or by chromatography using acetic acid as eluant (see D. R. Eyre et al. Anal. Biochem. 137, 380-388 (1984). Compounds of formula IA have been disclosed as an index of collagen degradation in metabolic bone and cartilage diseases based on the quantitating of their concentration in urine excretion over a fixed period (see Wu and Eyre, Biochemistry, 1984, 23, 1850; Robins et al., Analytical Biochem., 1988, 169, 197-203; D. Uebelhart et al., Bone and Mineral, 1990, 8, 87-96).
Interest in these compounds (referred to in literature as pyridinoline [X
1
═OH] and deoxypyridinoline [X
1
═H] crosslinks) as a marker for connective tissue metabolism abnormalities e.g. for measurements of bone resorption in human, is growing.
However, as the compounds of formula IA are until now natural compounds obtained by extraction, they do not meet the requirements for running standardized reproducible, reliable and non time-consuming assays.
There is a high need for defined standard pyridinoline crosslinks.
It is the purpose of the present invention to provide new pyridine derivatives and their production by chemical synthesis including the production of a compound of formula IA, in a substantially pure form in order to allow bone turn-over measurements under well standardized conditions.
More particularly, the present invention provides a compound of formula I
wherein
each of X, Y and Z, independently is C
1-8
alkyl; C
1-8
alkyl interrupted by one or two heteroatoms selected from O, N and S; C
5-7
cycloalkyl; C
5-7
cycloalkyl-C
1-4
alkyl; (C
1-4
alkyl)-C
5-7
cycloalkyl; (C
1-4
alkyl)-C
5-7
cycloalkylene-C
1-4
alkyl; optionally substituted aryl; optionally substituted heteroaryl; (C
1-4
alkyl)-aryl; (C
1-4
alkyl)-heteroaryl; (C
1-4
alkyl)-arylene-C
1-4
alkyl; (C
1-4
alkyl)-heteroarylene-C
1-4
alkyl; aryl-C
1-4
alkyl; heteroaryl-C
1-4
alkyl, the aryl or heteroaryl moieties of the above mentioned groups being optionally substituted;
R
3
is COOH or a functional derivative thereof; CHO; CN; C
1-8
alkoxy; SO
2
; —PO
3
H or a functional derivative thereof; —SO
3
H or a functional derivative thereof; a primary, secondary or tertiary amino group; a saturated or unsaturated cyclic amino group; or a radical of formula (a)
wherein
R
5
is a primary, secondary or tertiary amino group or a saturated or unsaturated cyclic amino group, and
R
6
is —COOH or a functional derivative thereof or —CO—Y
2
-R
9
wherein Y
2
is a spacer and R
9
is a secondary amino group;
each of R
1
and R
2
, independently, is hydrogen or has one of the significances given for R
3
,
R
4
is hydroxy; C 6alkoxy; or polyalkylenoxy;
X
1
is H or OH, and
X
2
⊖
is an anion
with the proviso that
i) when both X and Y comprise an alkyl moiety, the chain length of the alkyl moiety in —Y — is at least one carbon atom shorter than the alkyl moiety in —X—, and
ii) X
2
is other than Cl
⊖
or CH
3
COO
⊖
when each of —X—R
1
and —Z—R
3
is
 —Y—R
2
is
 and R
4
is hydroxy.
C
1-8
alkyl is preferably C
1-6
alkyl, more particularly C
1-4
alkyl, especially C
1-2
alkyl.
Preferably aryl means phenyl or 1- or 2-naphthyl, particularly phenyl. Aryl may be substituted, e.g. mono- di- or trisubstituted by hydroxy, C
1-4
alkyl, C
1-4
alkoxy and/or halogen. Preferably aryl is unsubstituted or monosubstituted phenyl.
Preferably heteroaryl means a saturated or unsaturated 5- or 6-membered heterocyclic ring, e.g. imidazolyl, thiazolyl, piperidinyl, piperazinyl or phthaloyl. When substituted, it may be mono-, di- or trisubstituted by hydroxy, C
1 4
alkyl, C
1
alkoxy and/or halogen. Preferably heteroaryl is unsubstituted.
When R
1
, R
2
, R
3
or R
5
is a secondary amino group, it is preferably —NHR
a
wherein R
a
is C
1-8
alkyl; C
1-8
alkyl optionally substituted by COOH or functional derivative thereof; C
2-8
alkenyl; C
3 7
cycloalkyl; C
3-7
cycloalkyl-C
1-8
alkyl; phenyl; phenyl-C
1
alkyl; or R
a
is a radical —Y
a
or —Z
a
—Y
b
wherein Y
a
is a protecting group or a group capable of covalently reacting with an antigen or a protecting group, Z
a
is a spacer and Y
b
is a protecting or antigenic group, biotinyl or a group derived from a molecule capable of forming a complex with another molecule like the biotin-avidin tool.
When R
1
, R
2
, R
3
or R
5
is a tertiary amino group, it is preferably —NR
a
R
a
′ wherein R
a
is as defined above and R
a
′ has independently one of the significances given for R
a
; preferably R
a
and R
a
′ are two substituents which do not hinder each other.
N-protecting groups as Y
a
or Y
b
include such groups as e.g. disclosed in “Protective Groups in Organic Synthesis”, T. W. Greene, J. Wiley & Sons NY (1981), 219-287, for example acyl such as formyl, acetyl, trifluoroacetyl, methoxysuccinyl, hydroxysuccinyl or benzoyl optionally substituted on the phenyl ring with e.g. p-methoxycarbonyl, p-methoxy, p-nitro or p-phenylsulfonamidocarbonyl; alkoxycarbonyl such as t-butyloxycarbonyl, isobutyloxycarbonyl or methoxycarbonyl; allyl-oxycarbonyl; arylmethoxycarbonyl such as 9-fluorenylmethoxycarbonyl or benzyloxy carbonyl optionally substituted on the phenyl ring with p-methoxy, p-nitro, o- or p-chloro, m-phenyl or 3,4-dimethyl; trityl; arylmethyl such as benzyl optionally ring substituted with p-methoxy, p-nitro or p-chloro; or arylsulfonyl such as phenylsulfonyl optionally ring substituted with p-methyl or p-methoxy, or naphthylsulfonyl optionally ring substituted with e.g. amino or di(C
1-4
alkyl)amino.
Examples of carboxylic acid functional derivatives are acid halides, acid anhydrides (including mixed acid anhydrides), active esters, active amides, etc. Among the acid halides, acid chloride is the most frequently used. Examples of the acid anhydrides include cyclic anhydrides and mixed anhydrides, such as dialkylphosphoric acid mixed anhydrides, dialkylphosphorous acid mixed anhydride etc. Examples of activated esters as R
1
, R
2
, R
3
or R
6
include C
1-8
alkyl ester, e.g. methyl ester or ethyl ester, cyanomethyl ester, p-nitrophenyl ester, an ester with N-hydroxysuccinimide, optionally ring-substituted phenyl or benzyl ester, or fluorenylmethyl ester. Examples of active carboxylic acid amides as R
1
, R
2
, R
3
or R
6
include amides with imidazole, dimethyl-imidazole or triazole. Carboxylic amide groups as R
1
, R
2
, R
3
or R
6
may also be e.g. —CONH
2
, —CONHR
a
or —CONR
a
R
a
′ as defined above.
Examples of functional derivatives of —SO
3
H or —PO
3
H are e.g. C
1-6
alkyl, benzyl, phenyl, allyl or trimethylsilyl esters, acid halides, e.g. acid chloride, or lower dialkyl amides, e.g. diethyl or diisopropyl amides. Preferred are (alkoxy)(diamino)phosphines, e.g. such a phosphine wherein “alcoxy” is methoxy, butoxy, allyloxy or benzoxy and “diamino” is diethylamino, dipropylamino or diisopropylamino.
R
9
in R
6
is preferably —NHR
c
wherein R
c
is a functional group capable of covalently reacting with an antigen, an antigenic group or
wherein R
10
is OH or C
1-8
alkoxy and R
11
is C
1-6
alkyl. OR
11
is preferably in para.
When R
6
is a COOH functional derivative, it may also be —CONHR
c
wherein R
c
is as defined above.
Examples of an anion X
2
⊖
include e.g. OH
⊖
, Cl
⊖
, Br
⊖
, I
⊖
, CH
3
COO
⊖
, CF
3
COO
⊖
, citrate.
Suitable spacer groups as Z
a
or Y
2
include e.g. a radical of formula (b)
—R
7
—X
3
—  (b)
wherein
X
3
is a divalent group derived from a functional moiety capable of covalently reacting with a protecting group or an antigen, and
R
7
is C
1-6
alkylene optionally interrupted by one

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