Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-11-19
2001-12-11
Seaman, D. Margaret (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S310000, C514S311000, C514S313000, C546S153000, C546S154000, C546S155000, C546S156000, C546S157000, C546S158000, C546S165000, C546S166000, C546S168000, C546S169000, C546S170000
Reexamination Certificate
active
06329389
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel amine compounds, production thereof and a pharmaceutical composition comprising them. In further detail, the present invention relates to a compound which has a somatostatin receptor binding inhibition activity, and is useful for preventing and/or treating diseases associated with somatostatin.
BACKGROUND ART
Somatostatin was found to be a growth hormone inhibiting factor (somatotropin release inhibiting factor; SRIF) in 1973.
Somatostatin receptors were found to comprise five subtypes and named as SSTR1, SSTR2, SSTR3, SSTR4 and SSTR5 respectively (e.g., Endocrinology, vol. 136, pp.3695-3697, 1995; Trends in Pharmacological Sciences, pp.87-94, 1997; Life Science, Vol.57, pp.1249-1265, 1995).
Somatostatin is known to inhibit production and/or secretion of various hormones, growth factors, and physiologically active substances. As the hormones inhibited by somatostatin, mentioned are growth hormone (GH), thyroid-stimulating hormones (TSH), prolactin, insulin, and glucagon. Therefore, somatostatin has various functions in endocrine systems, exocrine systems and nerve systems, and drugs targeting somatostatin are being developed (e.g., Endocrinology, vol.136, p.3695-3697, 1995; Trends in Pharmacological Sciences, pp.87-94, vol.18, 1997).
Diseases caused by somatostatin include life-style related diseases such as diabetes; central nervous system diseases, immune system diseases, and hormone-dependent tumors. Trials to develop somatostatin itself or somatostatin analogues as a drug have been conducted. For instance, octreotide known as a somatostatin receptor agonist has been marketed as a drug for treating hormone-dependent tumors.
As a compound having a somatostatin receptor binding activity, especially a selective SSTRL antagonist activity, there is known a compound represented by the formula:
wherein X represents O or H, H; Y represents —CH
2
—, —O—, —NH— or —S—; R
1
represents H or C
1-4
alkyl; R
2
represents H, benzyl, etc.; R
3
represents H, C
1-4
alkyl, etc.; R
4
represents hydrogen atom or halogen (WO97/03054).
As a compound which has a selective SSTR4 binding activity and is expected to have a glaucoma treating activity, there is known a compound represented by the formula:
(J. Am. Chem. Soc., vol.120, pp.1368-1373, 1998; WO97/43728).
On the other hand, the following compounds are known as amine compounds.
1) J. Med. Chem., vol.34, pp.2624-2633, 1991 describes, as a compound having a weak analgesic activity, a compound represented by the following formula:
2) JP-A 8(1996)-176087 describes 3-(N,N-dimethylaminomethyl)-1,2,3,4-tetrahydroquinoline as a synthetic intermediate of a compound represented by the formula:
wherein R
1
represents arylamino such as
A represents a direct bond, methylene, ethylene, imino, oxy or thio; R
9
represents C
1-4
alkoxycarbonylamino-C
1-4
alkyl, etc,; R
10
represents hydrogen or C
1-4
alkyl; R
11
represents hydrogen or halogen; etc.; X represents carbonyl, etc.; R
2
and R
3
represent hydrogen, etc.; R
5
represents hydroxyl, etc.; R
6
represents hydrogen, etc.; R
7
represents hydrogen, etc.; R
8
represents aliphatic group, etc., which is described to be useful in the treatment of hypertension.
3) WO97/12860 describes, as a compound having an acyl-coenzyme A: cholesterol acyltransferase inhibiting activity and a lipid peroxidation inhibiting activity, a heterocyclic compound represented by the formula:
wherein at least one of R
1
, R
2
and R
5
represents alkyl or alkenyl which is substituted by hydroxy, an acidic group, alkoxycarbonyl or —NR
9
R
10
wherein R
9
and R
10
respectively represent hydrogen atom or lower alkyl, etc., and the remaining two groups independently represent hydrogen atom, lower alkyl or lower alkoxy; either of R
2
and R
5
represents a group represented by the formula: —NHCOR
7
wherein R
7
represents alkyl, etc., and the remaining groups represent hydrogen atom, lower alkyl or lower alkoxy; R
6
represents alkyl, alkenyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl or arylalkyl; Z represents nitrogen atom substituted by R
6
, or a combined group forming 5-membered ring or 6-membered ring together with a carbon atom of benzene ring attached to the nitrogen atom and a carbon atom adjacent to the carbon atom, or a pharmaceutically acceptable salt thereof.
Conventional somatostatin and its analogues are all peptides. They are problematic in their oral absorbability, pharmacokinetics, etc. and are therefore unsatisfactory as medicines. It is desired to develop a compound which is different from conventional known compounds in its chemical structure, and which has a selective or nonselective affinity to somatostatin receptor subtypes, or an excellent somatostatin receptor binding inhibiting activity, and which has satisfactory properties as a medicine.
DISCLOSURE OF INVENTION
The present inventors have studied various compounds having a somatostatin receptor binding inhibiting activity, and, as a result, have succeeded in, for the first time, the production of a compound represented by the formula (I):
wherein Ar represents an aromatic group which may be substituted;
X represents methylene, S, SO, SO
2
or CO;
Y represents a spacer having a main chain of 2 to 5 atoms;
n represents an integer of 1 to 5;
i) R
1
and R
2
each represents a hydrogen atom or a lower alkyl which may be substituted,
ii) R
1
and R
2
form, taken together with the adjacent nitrogen atom, a nitrogen-containing heterocyclic ring which may be substituted, or
iii) R
1
or R
2
together with —(CH
2
)
n
—N═ form, bonded to a component atom of Ring B, a spiro-ring which may be substituted;
Ring A represents an aromatic ring which may be substituted;
Ring B represents a 4- to 7-membered nitrogen-containing non-aromatic ring which may be further substituted by alkyl or acyl,
with a proviso that X represents S, SO, SO
2
or CO when Ring A has as a substituent a group represented by the formula:
—NHCOR
11
where R
11
represents alkyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl or a group represented by the formula:
—NHR
12
where R
12
represents alkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, or a salt thereof [hereafter sometimes referred to as compound (I)], which is characterized by the chemical structure in that the nitrogen atom of Ring B in the skeletal structure represented by the formula:
wherein symbols have the same meanings as above, is substituted by the group represented by the formula:
—X—Y—Ar
where each symbol has the same meaning as above.
We have found for the first time that based on its specific chemical structure, compound (I) has an unexpectedly excellent somatostatin receptor binding inhibiting activity, etc., that a compound of the formula (I′):
wherein X′ represents methylene, S, SO, SO
2
or CO, other symbols have the same meanings as above, or a salt thereof [hereinafter sometimes referred to as compound (I′)] also has an unexpectedly excellent somatostatin receptor binding inhibiting activity, and that these compounds have low toxicity and are therefore satisfactory as medicines. Compound (I) is within the scope of compound (I′). On the basis of these findings, the inventors have completed the present invention.
Specifically, the present invention relates to:
(1) compound (I),
(2) a compound of the above (1), wherein Ring B represents a 4- to 7-membered nitrogen-containing non-aromatic ring which may be substituted by alkyl;
(3) a compound of the above (1), wherein Ar represents an aromatic ring assembly group which may be substituted or a fused aromatic group which may be substituted;
(4) a compound of the above (1), wherein X represents CO;
(5) a compound of the above (1), wherein Y represents a C
2-5
alkylene which may be substituted;
(6) a compound of the above (5), wherein the substituent of the C
2-5
alkylene represented by Y is acylamino;
(7) a compound of the above (1), wherein n represents 1 or 2;
(8) a compound of the above (1), wherein R
1
Endo Satoshi
Kato Kaneyoshi
Suzuki Nobuhiro
Takekawa Shiro
Terauchi Jun
Chao Mark
Philippe Y. Riesen
Seaman D. Margaret
Takeda Chemical Industries Ltd.
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