JPH0631212B2 - Chromanole derivative, process for its production and pharmaceutical composition containing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to novel compounds having pharmacological activity, a process for their preparation, pharmaceutical compositions containing them and their use in the treatment of mammals.

[Conventional technology]

U.S. Patent No. 4,110,347, U.S. Patent No. 4,251,532, U.S. Patent No. 4,446,113, European Patent Publication No. 9912.
, European Patent Publication No. 28064 and European Patent Publication No. 76075, 4-wherein the amino functional groups and their OH or alkyl or acyl derived groups are trans to each other.
The group of aminochroman-3-ols is described. The compounds are described as having blood pressure lowering activity.

[Problems to be solved by the invention]

A group of chroman derivatives in which the amino function and its OH or alkyl or acyl derivative are cis was found and these compounds were also found to have blood pressure lowering activity.

[Means for solving problems]

Therefore, the present invention has the formula (I) [Wherein _one of R ₁ and R ₂ is hydrogen and the other is C _1-6
Alkylcarbonyl, C _1-6 alkoxycarbonyl, C
_1-6 alkylcarbonyloxy, C _1-6 alkylhydroxymethyl, nitro, cyano, chlorine, trifluoromethyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, C _1-6 alkoxysulfinyl, C _1-6 alkoxysulfonyl, C _1-6 alkylcarbonylamino, C _1-6 alkoxycarbonylamino, C _1-6 alkyl-thiocarbonyl, C _1-6 alkoxy-thiocarbonyl, C _1-6 alkyl-thiocarbonyloxy , C _1-6 alkyl-thiolmethyl, formyl or aminosulfinyl,
Aminosulfonyl or aminocarbonyl whose amino moiety may be substituted by one or two C _1-6 alkyl groups or C _1-6 alkylsulfinylamino, C _1-6 alkylsulfonyl Amino, C _1-6 alkoxysulfinylamino or C _1-6 alkoxysulphonylamino or ethylenyl terminally substituted by C _1-6 alkylcarbonyl, nitro or cyano, or —C (C _{1- 6} alkyl) NOH or —C (C _1-6 alkyl) NNH ₂ or _one of R ₁ and R ₂ is nitro, cyano or C _1-3 alkylcarbonyl and the other is methoxy Or an amino optionally substituted by 1 or 2 C _1-6 alkyl or by a C _2-7 alkanoyl; one of R ₃ and R ₄ is hydrogen or C _1-4 alkyl and the other is C _{1 -4} alkyl or R ₃ and R _{4 taken} together are C _2-5 polymethylene; R ₅ is hydrogen, C _1-3 alkyl or C _1-8 acyl; R ₆ is hydrogen or C be _1-6 alkyl; and R ₇ is or hydroxy is hydrogen, C _1-6 alkoxy, by or a halogen a C _1-6 alkoxycarbonyl or C _1-6 alkyl optionally substituted by carboxy Substituted C _1-6 alkyl or C _2-6 alkenyl; substituted by amino optionally substituted by one or two C _1-6 alkyl groups which may be the same or different and whether it is C _1-6 alkyl; C _1-6 alkyl or C _1-6
Substituted by a C _1-6 alkanoyl group optionally substituted by an alkenyl group or by up to 3 halogen atoms or by a phenyl group optionally substituted by a C _1-6 alkyl, C _1-6 alkoxy or halogen Optionally amino; or C _1-6 alkoxy or C _1-6 alkyl, C _1-6 alkoxy or phenoxy optionally substituted by halogen; aryl or heteroaryl Each is C _1-6 alkyl,
C _1-6 alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, C _1-12 carboxyl acyl or amino or aminocarbonyl (substituted by 1 or 2 C _1-6 alkyl May be substituted by one or more groups or atoms selected from the group of the following); or when X is oxygen, R ₇ is carboxy, C _1-6 alkoxycarbonyl, or the same or different. Is selected from the group of aminocarbonyl optionally substituted by one or two C _1-6 alkyl groups; or R ₆ and R ₇ together are C _3-4 polymethylene; X is Is oxygen or sulfur; and the R ₆ NCXR ₇ and OR ₅ moieties are cis or are pharmaceutically acceptable when one or the other of R ₁ and R ₂ and / or R ₇ is amino or an amino-containing group. A compound] To provide.

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and X are as defined above and R ₇ is hydrogen or hydroxy, C _1-6 alkoxy,
C _1-6 alkoxy or carbonyl or C _1-6 alkyl or is C _2-6 alkenyl substituted by or is halogen and C _1-6 alkyl optionally substituted by carboxy; or R ₆ Together there is a group of compounds within formula (I) which are C _3-4 polymethylene.

When _one of R ₁ and R ₂ is hydrogen, the other is often C _1-6 alkylcarbonyl, C _1-6 alkoxycarbonyl, C _1-6 alkylcarbonyloxy, C _1-6 alkylhydroxymethyl, nitro, cyano or chlorine. Selected from the group. Especially when one of R ₁ and R ₂ is hydrogen, the other is preferably nitro,
Cyano, C _1-6 alkylcarbonyl or C _1-6 alkoxycarbonyl, most preferably nitro or cyano.

When _one of R ₁ and R ₂ is hydrogen, it is preferred that R ₂ is hydrogen.

When _one of R ₁ and R ₂ is nitro, cyano or C _1-3 alkylcarbonyl, the other is preferably 1 or 2 C _1-6
Amino optionally substituted by alkyl or by C _2-7 alkanoyl. In particular when _one of R ₁ and R ₂ is nitro, cyano or C _1-3 alkylcarponyl, the other is amino, methylamino, dimethylamino or acetylamino. Most preferably one of R ₁ and R ₂ is nitro or cyano and the other is amino.

When _one of R ₁ and R ₂ is nitro, cyano or C _1-3 alkylcarbonyl, R ₁ is preferably nitro, cyano or C _1-3 alkylcarbonyl.

The alkyl part of the alkyl-containing group or the alkyl group for R ₁ or R ₂ is preferably methyl or ethyl.

Preferably both R ₃ and R ₄ are methyl, ethyl or n-
Alkyl having 1 to 4 carbon atoms, including propyl. In particular they are both methyl or ethyl, preferably both methyl.

Suitable examples when R ₅ is C _1-3 alkyl include methyl, ethyl, n- and iso-propyl, preferably methyl.

Suitable examples when R ₅ is acyl include acyl carboxylates such as acetyl, propionyl and benzoyl.

R ₅ is preferably hydrogen.

Suitable groups for R ₆ when R ₇ and R ₆ are not taken together to form C _3-4 polymethylene are hydrogen, methyl, ethyl, n-
And iso-propyl, n-, secondary- and tertiary-butyl. Preferably R ₆ is hydrogen or methyl most preferably hydrogen.

Examples of R ₇ when R ₇ and R ₆ together are not C _3-4 polymethylene include:

Hydrogen, methyl, ethyl, n- and iso-propyl, n-
Methyl or ethyl secondary or tertiary butyl or substituted by carboxy or chlorine, vinyl, prop-1-enyl, prop-2-enyl, 1-methylvinyl, but-1-enyl, butene. The-2-enyl, bute-3-
Enyl, 1-methylenepropyl, 1-methylprope-1
-Enyl, 1-methylprop-2-enyl (their E and Z forms when stereoisomerism is present), methyl or ethyl terminally substituted by hydroxy or methoxy. Preferably R ₇ is methyl, ethyl, n- or iso-propyl or vinyl, especially methyl, hydroxymethyl and methoxymethyl. Preferably R ₇ is methyl.

The group (CH ₂ ) pNR ₈ R ₉ (wherein p is 1 to 6 and R ₈ and R ₉ are each independently hydrogen or C _1-6 alkyl). Examples of p include 1 and 2, especially 1. Preferably R ₈ and R ₉ are each independently selected from hydrogen and methyl.

Optionally substituted by an alkyl or trichloroacetyl group such as methyl, ethyl, propyl or butyl, or optionally by a methyl, methoxy or chlorine group or a phenyl group optionally substituted by an atom Amino, especially amino, methylamino and phenylamino optionally substituted on the phenyl ring by one methyl, methoxy or chlorine group or atom.

Methoxy, ethoxy, n- and iso-propoxy and phenoxy optionally substituted by one methyl, ethyl, methoxy, ethoxy, chlorine or bromine group or atom, preferably methoxy, ethoxy and one methyl, Phenyloxy optionally substituted by methoxy or chlorine groups or atoms, especially ethoxy, where X is preferably oxygen.

Carboxyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl and dimethylaminocarbonyl when X is oxygen, especially ethoxycarbonyl or aminocarbonyl.

Examples of R ₇ aryl include phenyl and naphthyl, of which phenyl is preferred.

A sub-group of R ₇ heteroaryl is 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heteroaryl, of which 5- or 6-membered monocyclic heteroaryl is preferred. In addition, the 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heteroaryl preferably contains 1, 2 or 3 heteroatoms which are selected from the group of oxygen, nitrogen and sulfur and 1 Identical or different if more than one heteroatom is present.

1, 2, or 3 selected from the group of oxygen, nitrogen and sulfur
Examples of 5- or 6-membered monocyclic heteroaryl containing 4 heteroatoms include furanyl, thiofenyl, pyryl, oxazolyl, thiazolyl, imidazolyl and thiadiazolyl and pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl. Preferred examples of these groups include furanyl, thiophenyl, pyryl and pyridyl, especially 2- and 3-furanyl, 2- and 3-pyryl, 2- and 3-thiophenyl and 2-, 3- and 3-pyridinyl.

1, 2, or 3 selected from the group of oxygen, nitrogen and sulfur
Examples of 9- or 10-membered bicyclic heteroaryl containing 4 heteroatoms include benzofuranyl, benzothiophenyl, indolyl and indazolyl, quinolinyl and isoquinolinyl and quinazoninyl. Preferred examples of these groups are 2
-And 3-benzofuranyl, 2- and 3-benzothiophenyl and 2- and 3-indolyl and 2- and 3-quinolinyl.

Preferably the number of groups or atoms for any substitution of aryl or heteroaryl is 1, 2, 3 or 4.

Preferred examples of groups or atoms for any substitution of an arule or heteroaryl are methyl, methoxy, hydroxy,
Contains chlorine, nitro or cyano.

A subgroup of R ₇ is phenyl or naphthyl or 5- or 6-
Membered monocyclic or 9- or 10-membered bicyclic heteroaryl wherein the phenyl or heteroaryl group is C _1-6 alkyl, C
_1-6 1, 2, 3, or 4 selected from the group of alkoxy, halogen, trifluoromethyl, nitro or cyano
May be substituted by individual groups or atoms.

Preferred subgroups of phenyl optionally substituted as defined above are phenyl, 4-substituted phenyl, 3-
Substituted phenyl, 3,4-disubstituted phenyl and 3,4,5-trisubstituted phenyl. Specific examples of phenyl which may be substituted as defined above are phenyl, 4-hydroxyphenyl, 4-fluorophenyl, 4-cyanophenyl, 3-nitrophenyl, 3,4-dichlorophenyl and 3 Contains 4,4,5-trimethoxyphenyl.

5- or 6 optionally substituted as defined above
A preferred subgroup of -membered monocyclic or 9- or 10-membered bicyclic heteroaryl is unsubstituted or monosubstituted 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heteroaryl, especially unsubstituted 5
It is a 6-membered monocyclic or a 9- or 10-membered bicyclic heteroaryl.

X is preferably of formula (II) Where n is 1 or 2 and the remaining substituents are of formula (I)
Are as defined under), and a preferred group of compounds of formula (I)

Suitable and preferred groups for the substituents are as described for formula (I).

Formula (III) Wherein _{one of} R ₁ ¹ and R ₂ ¹ is hydrogen and the other is cyano or nitro and the remaining substituents are as defined in formula (I) It will be appreciated that there are preferred subgroups.

Suitable and preferred groups for the substituents are as described under formula (I).

From the above, formula (IV) It will be appreciated that there are preferred compounds within formula (III) where lactam and hydroxy groups are cis with respect to each other.

Other examples of compounds of formula (I) include the compounds prepared in the Examples below.

Formula (V) Wherein _{one of} R ₁ ² and R ₂ ² is cyano or nitro, the other is amino optionally substituted as defined, and the remaining substituents are as defined in formula (I). There is another subgroup of compounds within formula (II)

Preferably R ₁ ² is is R ₂ ² is cyano or nitro amino. Suitable and preferred groups for the remaining substituents are of the formula
As described under (I).

Formula (VI) (Wherein R ₆ ¹ is R ₇ ¹ is hydrogen or C _1-6 alkyl optionally substituted by hydroxy or methoxy C _1-6
There is another group of compounds within formula (I) of formula (I) wherein alkyl and the remaining substituents are as defined in formula (I).

Suitable and preferred groups for the substituents are as described for the corresponding substituents in formula (I).

Formula (VII) Wherein R ₁ ¹ and R ₂ ¹ are as defined in formula (III) and the remaining substituents are as defined in formulas (I) and (VI) There are preferred subgroups.

Suitable and preferred groups for the substituents are as described for the corresponding substituents under formula (I).

Preferred subgroups of compounds within formula (VII) are formula (VIII) Wherein R ₇ ² is C _1-4 alkyl, preferably methyl, and preferably R ₅ is hydrogen.

The compounds of formula (I) are asymmetric and therefore may exist as stereoisomers. The present invention includes all such stereoisomers individually and as a mixture eg racemic modification.

The present invention also provides formula (IX) And (i) R ₇ ² COQ ₁ [wherein the R ₆ ² NH and OR ₅ ′ moieties are cis; and R ₁ ′
And R ₂ 'is a group or atom capable of converting R ₁ and R ₂ or in each; R _5' is a group or atom capable of converting R ₅ or it; R ₆ ² is hydrogen or C _1-6 alkyl in it, when R ₇ ² is either a group capable of conversion thereto R ₇ or other than amino optionally substituted as defined in the range paragraph (1) of claims or (R ₆ ² is hydrogen ) Q ₂ (CH ₂ ) n + 2 ⁻ or a metal salt thereof; Q ₁ and Q ₂ are leaving groups]; and then R ₇ ² is a compound of claim (1).
When it is a group that can be converted to R ₇ which is other than amino which may be substituted as defined in paragraph (7), R ₇ ² is substituted as defined in claim (1). Also substituted with another R ₇ other than amino; R ₇ ² is Q ₂ (CH ₂ ) n + 2
^- cyclizing the compound formed when a; (ii) or or three formula _{X = C = N · R 10} ( wherein R ₁₀ is hydrogen, C _1-6 alkyl, C _1-6 alkenyl C _1-6 alkanoyl optionally substituted by halogen atoms within or C _1-6 alkyl, C _1-6 alkoxy or phenyl optionally substituted by halogen; and X is oxygen or sulfur. reacting a compound of the it); and then may be converted to R ₁₀ when R ₁₀ is hydrogen; then (i) or (ii) R ₁ followed '
Or if R ₂ ′ is a group or atom convertible to R ₁ or R ₂ , then convert the group or atom to R ₁ or R ₂ ; R ₁ in the resulting compound of formula (I), R ₂ or R ₅ may be converted to another R ₁ , R ₂ or R ₅ ; when R ₆ ² is hydrogen it is converted to C _1-6.
May be converted to alkyl; and R ₇ is carboxy,
Any R _{6 in} the resulting compounds of formula (I) which is C _1-6 alkoxycarbonyl or other than aminocarbonyl optionally substituted as defined in claim (1) The carbonyl group of NCOR ₇ may be thiatized to give other compounds of formula (I) in which X is sulfur; and when the resulting compound of formula (I) contains a salifiable group There is provided a process for the preparation of compounds of formula (I) which may optionally form a pharmaceutically acceptable salt.

In the modified method (i), the leaving group Q ₁ is a group which can be substituted with a primary or secondary amino nucleophilic group. Examples of these groups are C _2-9
Acyloxy such as C _1-4 alkylcarbonyloxy,
And preferably it contains halogens such as chlorine and bromine.
When the leaving group Q ₁ is any of these examples, the acylating agent is either an acid anhydride or an acid halide. When it is an acid anhydride it may be a mixed or single acid anhydride. If it is a mixed anhydride, it may be prepared in situ from a carboxylic acid and an acid halide, although this is much less preferred than using the halide itself.
Another example of a leaving group Q ₁ is a hydroxy group, which is less preferred than the aforementioned leaving group.

R ₇ ² when R ₇ substituted alkyl group which R ₇ is as defined in the in the desired compound of formula (I) in process variant (i) is a group which can be converted to R ₇ substituted alkyl group as defined above Particularly preferred is C _1-6 alkyl substituted by halogen, especially bromine. The R ₇ ² halogen substituent in the resulting compound of process variant (i) may be converted into an R ₇ substituent which is defined above by conventional amination reactions with ammonia or the corresponding alkyl- or dialkylamine. And optionally substituted amino.

Less preferably R ₇ ² is also C _1-6 alkyl substituted by protected amino, protected C _1-6 alkylamino or amino substituted by two independent C _1-6 alkyl groups. Often it is necessary to protect the R ₇ amino function in process variant (i). A particular example of these groups R ₇ ² is the group (CH ₂ ) pNR ₈ ′ R ₉ ′, where R ₈ ′ and R ₉ ′, where p is 1-6, are together a divalent protecting group. R ₈ 'and R _9'
One of which is methyl and the other is a monovalent protecting group or each of R ₈ ′ and R ₉ ′ is methyl). R
₆ NCOR _{7 The} following R ₇ ² to R ₇ without breaking the amide bond
Suitable protecting groups and deprotection conditions to effect the conversion to will be readily apparent to those skilled in the art.

When the acylating agent is an anhydrous acid, acylation of the compound of formula (IX) is preferably carried out using anhydrous acid as a solvent in the presence of an acid acceptor such as sodium acetate or preferably triethylamine.

When the acylating agent is an acid halide, the acylation of the compound of formula (IX) is preferably an acid acceptor such as triethylamine,
It is carried out in a medium such as chloroform or dichloromethane in the presence of trimethylamine, pyridine, picoline or calcium, potassium or sodium carbonate.

In the modified method (i), when R ₇ ² is C _1-6 alkoxy, phenoxy which may be substituted as defined above, or C _1-6 alkoxycarbonyl, an example of the leaving group Q ₁ is halogen such as chlorine or Contains bromine. Acylation is then preferably carried out under the reaction conditions described above for the corresponding Q ₁ group.

When R ₅ 'in the compound of formula (IX) in process variant (i) is hydroxy, there is a risk of side reactions between the hydroxy group and the acylating agent, which leads to reaction at relatively low temperatures, eg below 10 ° C. Can be minimized by doing Alternatively R ₅ 'may be C _1-7 acyloxy in the compound of formula (IX) and may be converted to hydroxy as described below after reaction with the acylating agent. But the reaction just preferably only amines R ₆ NH- is controlled as usual as described above as acylated.

R ₇ ² is _{Q 2 (CH 2) n +} 2 - acylation reaction when is preferably carried out in an inert solvent such as tetrahydrofuran.

R ₇ ² is Q ₂ (CH ₂₎ sodium salt if the metal salt is used when n + 2 is preferred.

In process variant (ii), R ₁₀ is C _1-6 alkyl or C _1-6 alkanoyl optionally substituted as defined above or substituted as defined above. When good phenyl, the reaction of the compound of formula (IX) is preferably carried out in a solvent such as methylene chloride below room temperature, especially below 10 ° C.

The reaction of the compound of formula (IX) when R ₁₀ is hydrogen preferably uses that of the corresponding alkali metal cyanate or thiocyanate such as sodium or potassium in an aqueous medium which may be methanolic acidified with a mineral acid such as dilute hydrochloric acid. Is done. A slightly higher temperature, for example 50 to 90 ° C, is preferable.

The conversion of aromatic groups or atoms into one of the groups of substituents defined above is generally known. For example, it is preferable to protect any unsubstituted terminal amino moiety when carrying out the reaction, for example to protect with a protecting agent when R ₁ / R ₂ is amino. Examples of protective agents include an acyl group such as acetyl. Removal of the acyl protecting agent is performed by base hydrolysis.

If it is desired to protect the amino group in the presence of a cyano group, a more preferred method is to use a trifluoroacetyl protecting group which can be removed by mild hydrolysis.
Another suitable method for deprotecting a protected amino group in the presence of a cyano group is to use a benzyloxycarbonyl or p-nitrobenzyloxycarbonyl protecting group, which group is removed by mild catalytic hydrogenolysis. Can be done.
The benzyloxycarbonylamino and p-nitrobenzyloxycarbonylamino groups may be formed by reaction of the appropriate chloride with the free amine functionality.

Furthermore, the hydrogen atom may be nitrated in a known manner by a compound of formula (V) in which _{one of} R ₁ 'and R ₂ ' is hydrogen and the other is acetamide, and then the compound is hydrolyzed. By converting the obtained amine into a diazonium salt and finally decomposing it to obtain a compound of formula (I), wherein one of R ₁ and R ₂ is hydrogen and the other is nitro. It can be replaced by a nitro group.

However, any conversion is preferably done in the early stages described below.

The R ₆ ² hydrogen atom is converted to the R ₆ ² C _1-6 alkyl group by conventional amine alkylation using an alkyl halide in an inert solvent such as dimethylformamide under basic conditions using a base such as potassium carbonate for example. Can be done. However, a more preferred method is by conventional reductive amination with the corresponding alkanoyl halide followed by reduction with sodium cyanoborohydride.

Preferably the R ₅ alkylating agent is an alkyl iodide and the reaction is carried out in an inert solvent such as toluene in the presence of a base such as potassium t-butoxide.

Preferably the R ₅ acylating agent is a carboxylic acid or derivative thereof such as an anhydride and the reaction is carried out in a non-hydroxyl solvent in the presence of a condensation promoter such as dicyclohexyl-carbodiimide or triethylamine.

R ₅ ′ may be a protecting group such as a C _1-6 alkyl or C _1-6 acyl group or more preferably tetrahydropyran-2-yl. These groups may be removed by conventional hydrolysis.

The leaving group Q ₂ is a group which can be displaced by a secondary amino nucleophilic group adjacent to the carbonyl function. A preferred example is chlorine.

The thiation reaction is preferably carried out with conventional thiation agents such as hydrogen sulfide, phosphorus pentasulfide and Lawesson's reagent (p-methoxyphenylthiophosphine sulfide dimer).
The use of hydrogen sulfide and phosphorus pentasulfide is susceptible to side reactions and is therefore
The use of Lawesson's reagent is preferred.

The thiation reaction conditions are conventional for the thiating agent used. For example, the use of hydrogen sulfide is preferably acid catalyzed in a polar solvent such as acetic acid or ethanol, eg with hydrogen chloride. The preferred use of Lawesson's reagent is carried out in a dry solvent such as toluene or methylene chloride at temperatures from room temperature to reflux.

When X is sulfur and R ₁ or R ₂ is a carbonyl-containing group in formula (I), the compound of formula (V) (wherein R ₁ ′ or R ₂ ′ is a protected carbonyl-containing group during the thiation reaction Is present) and then the protected carbonyl-containing group is R ₁
Alternatively, it is preferably converted into a necessary carbonyl-containing group for R ₂ . Without such protection, the additional carbonyl groups are likely to cause competing side reactions. Examples of preferred carbonyl protecting groups include ketalizing agents, which are added and removed in the usual way.

When _one of R ₁ and R _{2 in} the resulting compound of formula (I) is amino or an amino-containing group, any formation of its pharmaceutically acceptable salt will be carried out according to the usual manner.

Intermediates of formula (IX) where R ₆ is hydrogen are of formula (X) Prepared from its alkylated or acylated derivative of or trans bromohydrin, which upon reaction with sodium azide in dimethylformamide gives the corresponding cis hydroxy- / acyloxy- / alkoxy-azitos, preferably with hydrogen / palladium Reduction by catalytic reduction gives the compound of formula (IX).

R ₅ 'is preferably other than hydrogen is namely R ₅ a hydrogen atom in the formula (X) is protected by alkylation or acylation, or other protecting groups. One preferred example of a protecting group is tetrahydropyran-2-yl. Protecting groups are usually removed after the reduction step.

If R ₅ 'is hydrogen in formula (X), a mixture of cis and trans hydroxy azides is formed which can then be routinely separated by conventional chromatography.

Compound of R ₆ ² is other than hydrogen the formula (IX) may be formed by reduction in conventional amine alkylation or acylation following.

Compounds of formula (X) R ₅ 'is hydrogen Formula (XI) It is produced by reacting the compound of 1 with hydrogen bromide. R ₅ ′
Compounds of formula (X) other than hydrogen will be prepared by conventional alkylation / acylation methods as described above.

The intermediates of formula (IX) are new and thus form an aspect of the present invention.

Compounds of formula (XI) are known and may be prepared according to the methods described in the aforementioned US patents and European patent publications.

As mentioned above, the compounds of formula (I) exist in optically active forms and the process of the present invention produces mixtures of these forms.
The individual isomers will be separated from each other by chromatography using a chiral phase.

As mentioned above, the compounds of formula (I) have been found to have blood pressure lowering activity. They are therefore useful in treating hypertension.

Accordingly, the present invention provides a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier. In particular, the present invention provides an antihypertensive pharmaceutical composition comprising an antihypertensive effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier.

The composition is preferably administered orally. However, they may be administered in other ways, for example parenterally for patients with heart disease.

The compositions of the invention are preferably in unit dosage form in order to obtain consistent dosage. Suitable unit dosage forms include tablets, capsules and powders in bags or vials. Such unit dosage form is from 1 to 100 mg of the compound of the invention and more usually from 2 to 50 mg, eg 5 to 25 mg eg 6,1.
It will contain 0, 15 or 20 mg. This composition is 1 per day
~ 6 times usually 2 to 4 times daily with daily dose of 75
5 to 200 mg and more particularly 10 per kg adult
It will be administered in the manner of ~ 100 mg.

The compositions according to the invention will be formulated with the customary auxiliaries, such as fillers, disintegrants, binders, lubricants, perfumes. They are processed in the usual way, for example with known antihypertensives, diuretics and β-
It is formulated in a manner similar to that used in blockers.

The present invention further provides compounds of formula (I) for use in the treatment of hypertension.

The present invention also provides a method of treating hypertension in mammals, including humans, which method comprises providing a mammal with an illness in an anti-hypertensive effective amount of a compound of formula (I) or a pharmaceutical composition of the invention. Is administered.

The following examples relate to the preparation of compounds of formula (I) and the following reference examples relate to the preparation of their intermediates.

Reference Example 1 trans-4-bromo-6-cyano-3,4-dihydro-2,2-dimethyl-2H-benzo [b] pyran-3-
All 6-Cyano-3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H- in carbon tetrachloride (500 m)
45% HBr (40 m) was added dropwise at room temperature into a stirred solution of benzo [b] pyran (20.1 g, the preparation of which is described in European Patent Specification No. 0009912). After 2 hours of stirring carbon tetrachloride was washed with water and sodium bicarbonate solution and then dried over anhydrous magnesium sulfate. A pale yellow solid (24.6g) was obtained upon evaporation and evaporation. A small portion of this was recrystallized from ethyl acetate / pentane to give trans-4-bromo-6-cyano-3,4-dihydro-2,2 as pale yellow crystals having a melting point of 111 to 112 ° C.
-Dimethyl-2H-benzo [b] pyran-3-ol was obtained.

Bromohydrin (12 g), dihydropyran (25 m
) And concentrated HCl (3 drops) were stirred for 2 days at room temperature. The mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with water and sodium bicarbonate solution and dried over anhydrous magnesium sulfate. The gum was evaporated and evaporated to give a gum which was treated with pentane to give the crude title compound as a viscous white solid (14.25g).

Reference Example 2 4-azido-6-cyano-3,4-dihydro-2,2-
Dimethyl-2H-benzo [b] pyran-3-ol tetrahydropyranyl ether Crude tetrahydropyranyl bromide of Reference Example 1 (14 g)
And sodium azide (4 g) were stirred in N, N-dimethylformamide (50 m) for 24 hours. The mixture was poured into water and extracted with ethyl acetate. The ethyl acetate was washed with water and brine and dried over anhydrous magnesium sulfate. Removal of the desiccant and evaporation gave the compound of Reference Example 2 as an oil (13.5g). IR (film) 2100,2
225 cm ^-1 . The oil was treated with pentane and solidified.

Reference Example 3 4-amino-6-cyano-3,4-dihydro-2,2-dimethyl-2H-benzo [b] pyran-3-ol tetrahydropyranyl ether Azide of Reference Example 2 (7.50 in ethanol (150 m))
g) was shaken for 25 hours with 5% pd / C (500 mg) in an atmosphere of hydrogen. Yellow foam (6.29 due to excess and evaporation)
g) was obtained. 2 in the compound of Reference Example 2 by IR
It showed a trace of absorption at 100 cm ^-1 .

Mass spectrum MH ⁺ (at m / z) 303.1707.

Calculated as C ₁₇ H ₂₂ N ₂ O ₃ · H ⁺ 303.1708.

Reference Example 4 cis-4-amino-6-cyano-3,4-dihydro-2,2-
Dimethyl-2H-benzo [b] pyran-3-ol Trans-4-bromo-6-cyano-3,4-dihydro-
2,2-Dimethyl-2H-benzo [b] pyran-3-ol (3.94g, prepared as described in Reference Example 1) was treated with sodium azide (3.0g) in dimethylformamide (30m) at room temperature for 2 hours. ) And stirred. The reaction mixture was poured with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine and then dried over anhydrous magnesium sulfate. A gum (3.85 g) was obtained by filtration and evaporation.

The hydroxy-azide (1.5 g) was dissolved in dimethylformamide (10 m) and concentrated HCl (2 m) and treated with zinc dust (1 g) for 10 minutes. The mixture was passed, diluted with water and extracted with ethyl acetate. The aqueous phase is made basic and extracted with ethyl acetate to give a basic fraction which is chromatographed (chromatrone,
Increasing concentrations (30 → 100%) of ethyl acetate in pentane, flow rate 6 ml / min, silica gel) gave the title compound (305 mg) as a powdery solid from ethyl acetate, mp 143-144 °.

Mass spectrum M ⁺ 218.1054 at m / z.

Calculated as _{C 12 H 14 N 2 O 2} 218.1055.

The other major fraction contained the trans isomer (350 mg) previously described in European Patent Application No. 0076075.

〔Example〕

Example 1 6-Cyano-3,4-dihydro-2,2-dimethyl-cis-4
-(2-oxo-1-pyrrolidinyl) -2H-benzo [b] pyran-3-ol E (1) The protected amine of Reference Example 3 (5.91 g) and triethylamine (2.18 m) were stirred in dichloromethane (60 m) while cooling to 0 ° C. Chlorobutyryl chloride (2.25
m) was added dropwise and upon completion of addition the reaction was stirred at room temperature for 2 hours. Water was added and the layers were separated then the organic layer was washed with brine. The organic layer was dried over anhydrous MgSO _{4 and} then it was evaporated to give an oil (7.35 g).

This material was treated with concentrated HCl in ethanol (25 m) for 2 hours.
Treated with (2m) and water (2m). The solution is poured into water and extracted with ethyl acetate to give a yellow gum (4.50g)
Got It was purified by chromatography and recrystallized from ethyl acetate to give the 4- (4'-chlorobutyrylamino) compound as crystals with a melting point of 172-173 ° C.

The crude chlorobutylamino compound (484 mg) was dissolved in dry tetrahydrofuran (25 m) and treated with sodium hydride (48 mg, 80% dispersion in oil) under nitrogen. After 4 hours at room temperature the reaction mixture was carefully added with water (2
00m). Extraction with ethyl acetate gave a cream colored solid (340 mg). Recrystallization from ethyl acetate gave the title compound (1
73 mg) was obtained.

IR (KBr disk) 2235, 1680 cm ^-1 .

Mass spectrometry _{^{M + -H 2 O (m /}} z) 268.1212.

Calculated as C ₁₆ H ₁₈ N ₂ O ₃ 268.1212.

NMR (CDCl ₃ ) δ1.36 (3H); 1.49 (3H); 2.12 (2H, m); 2.54 (2H, m); 2.79 (1H, br m, exchangeable) 3.34 (1H, m) 3.74 (1H) , M) 3.88 (1H, q, collapsed to d3.5Hz by adding D ₂ O) 5.41 (1H, d, J = 3.5H)
z) 6.94 (1H, d, J = 8.5H
z) 7.24 (1H, small m) 7.48 (1H, m, J = 8.5Hz
Visible).

Example 2 Cis-4-acetylamino-6-cyano-3,4-dihydro-2,2-dimethyl-2H-benzo [b] pyran-3-ol (E2) Acetyl chloride (0.104 m) was added to cis-amino alcohol (313 mg) and triethylamine (0.21 m) obtained in Reference Example 4 and others in dichloromethane (20 m) with vigorous stirring. Stirring was continued for 0.5 hours, the reaction mixture was washed with water and dried over anhydrous magnesium sulfate.
A yellow foam is obtained by filtration and evaporation, which is chromatographed (chromatotron, ethyl acetate / pentane gradient elution,
The mixture was purified by silica gel) and recrystallized from ethyl acetate to obtain the title compound (53 mg) having a melting point of 193-194 ° C.

Mass spectrum M ⁺ 18 (m / z) 242.1057.

Calculated as _{C 14 H 16 N 2 O 3} 242.1055.

Example 3 cis-4-benzoylamino-6-cyano-3,4-dihydro-2,2-dimethyl-2H-benzo [b] pyran-3-
All The compound of Example 3 was prepared in a similar manner as described in Example 2 using benzoyl chloride. Recrystallization of the crude product with ethyl acetate pentane, mp 158-159.
The compound of Example 3 was obtained as crystals at 5 ° C.

NMR (CDCl ₃ ) δ 1.38 (3H, s) 1.53 (3H, s) 2.46 (1H, irregular m) D ₂
Exchangeable with O 3.83 (1H, irregular m) D ₂
Decays to d, J = 4Hz by addition of O 5.60 (1H, q, J = 8.4H
z) Very slow exchange with D ₂ O to produce d, J = 4Hz 6.92 (1H, d, J = 9Hz)
Overlap 7.05 (1H, d, J = 8Hz) by
Very late exchange with D ₂ O 7.33-8.05 (7H, m series) Mass Spec M ⁺ -18 (m / z) 304.1222.

Calculated as C ₁₉ H ₁₆ N ₂ O ₂ 304.1212.

Example 4 cis-6-Cyano-3,4-dihydro-2,2-dimethyl-4
-(N-methylureido) -2H-benzo [b] pyran-3-ol The cis-amino alcohol (0.20) of Reference Example 4 dissolved in dichloromethane (10 m) and cooled in an ice bath.
Methylene isocyanate (0.05 g) was added to g). The stirred solution was allowed to come to room temperature and stirring was continued for 68 hours. The solution was evaporated and the obtained solid was recrystallized from ethyl acetate / pentane to give the title compound (63 mg) having a melting point of 135 to 137 ° C.

NMR (CDCl ₃ + D ₂ O) δ1.34 (3H, s) 1.48 (3H, s) 2.83 (3H, s) 3.70 (1H, d, J = 4Hz) 5.23 (1H, d, J = 4Hz) 6.87 (1H, d, J = 9Hz) 7.45 (1H, q, J = 9.2H
z) 7.56 (1H, small m) mass spectrum M ⁺ -18 (m / z) 257.1160.

Calculated as C ₁₄ H ₁₅ N ₃ O ₂ 257.1164.

〔effect〕

Pharmacological data systolic blood pressure IMClaxton, MGpalfreymanRHpoyser, RLWhi
ting, European Journal of pharmacology, 37,179 (1976)
It was recorded by a modification of the tail-cuff method described by. Pulses were shown using a W + W BP recorder (model 8005). Prior to all measurements, rats were placed in a heated environment (33.5 ± 0.5 ° C) and then transferred to a restrained cage. Each measurement of blood pressure was the average of at least 6 readings. Spontaneously hypertensive rats with systolic blood pressure> 170 mmHg (12-18 weeks old) were considered hypertensive.

Toxicity No toxicity was found in the above test.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁵ Identification number Office reference number FI technical display location // C07D 407/12 309 8829-4C

Claims (8)

[Claims] 1. A formula (I) [Wherein R ₁ is C _1-6 alkylcarbonyl, C _1-6 alkoxycarbonyl, C _1-6 alkylcarbonyloxy, C _1-6
Alkyl hydroxymethyl, nitro, cyano, chlorine, trifluoromethyl, C _1-6 alkylsulfinyl, C _1-6
Alkylsulfonyl, C _1-6 alkoxysulfinyl,
C _1-6 alkoxysulfonyl, C _1-6 alkylcarbonylamino, C _1-6 alkoxycarbonylamino, C _1-6 alkyl-thiocarbonyl, C _1-6 alkoxy-thiocarbonyl, C _1-6 alkyl-thiocarbonyloxy , C _1-6 alkyl-thiolmethyl, formyl or aminosulfinyl, aminosulfonyl or aminocarbonyl, the amino moiety of which is substituted by one or two C _1-6 alkyl groups. Well or C _1-6 alkylsulfinylamino, C _1-6 alkylsulphonylamino,
C _1-6 alkoxysulfinylamino or C _1-6 alkoxysulphonylamino or C _1-6 alkylcarbonyl, ethylenyl terminally substituted by nitro or cyano or —C (C _1-6 alkyl) ) NOH or-
Is selected from the group of C (C _1-6 alkyl) NNH ₂ or _one of R ₁ and R ₂ is nitro, cyano or C _1-3 alkylcarbonyl and the other is methoxy or one or Is amino optionally substituted by two C _1-6 alkyl or by C _2-7 alkanoyl; R ₂ is hydrogen; R ₃ and R ₄ are C _1-4 alkyl; R ₅ is R ₆ is hydrogen; and R ₇ is hydrogen or hydroxy, C _1-6 alkoxy,
C _1-6 alkoxy or carbonyl or C _1-6 alkyl substituted by or is halogen or C _2-6 alkenyl and C _1-6 alkyl optionally substituted by carboxy; be the same or different or C _1-6 alkyl substituted by amino optionally substituted by one or two C _1-6 alkyl optionally; or 3 by C _1-6 alkyl or C _1-6 alkenyl group With an amino optionally substituted by a C _1-6 alkanoyl group optionally substituted by a halogen atom or by a C _1-6 alkyl, C _1-6 alkoxy or a phenyl group optionally substituted by a halogen. Or C _1-6 alkoxy or C _1-6 alkyl, C
_1-6 alkoxy or phenoxy optionally substituted by halogen; aryl or heteroaryl, each of which is C _1-6
Alkyl, C _1-6 alkoxy, hydroxy, halogen,
Trifluoromethyl, nitro, cyano, C _1-12 carboxylate acyl or amino or aminocarbonyl (1
Or optionally 2 or more C _1-6 alkyl) may be substituted by one or more groups or atoms selected from the group of the following; or when X is oxygen, R ₇ is carboxy, Is selected from the group of aminocarbonyl which is C _1-6 alkoxycarbonyl or which may be substituted by one or two C _1-6 alkyl groups which may be the same or different; or R ₆ and R ₇ Are together C _3-4 polymethylene; X is oxygen; and the R ₆ NCXR ₇ and OR ₅ moieties are cis or one or the other of R ₁ and R ₂ and / or R ₇ is amino. Or an amino-containing group, which is a pharmaceutically acceptable salt thereof]. 2. Formula (II) The compound according to claim (1), wherein n is 1 or 2 and the other variable groups are as defined in claim (1). 3. Formula (III) (Wherein R ₁ ¹ is cyano or nitro, R ₂ ¹ is hydrogen, and the remaining variables are compounds according to claim (2). 4. Formula (VI) Wherein R ₆ ¹ is hydrogen, R ₇ ¹ is C _1-6 alkyl _optionally substituted by hydroxy or methoxy and the remaining variables are as defined in claim (1). The compound according to claim (1). 5. Formula (VII) (Wherein the variable groups are as defined in claims (1) and (3)), and the compound according to claim (4). 6. The compound is 6-cyano-3,4-dihydro-2,2-dimethyl-cis-4- (2-oxo-1-pyrrolidinyl) -2H-benzo [b] pyran-3-ol, Cis-4-acetylamino-6-cyano-3,4-dihydro-2,2-dimethyl-2H-benzo [b] pyran-
3-ol, cis-4-benzoylamino-6-cyano-3,4-dihydro-2,2-dimethyl-2H-benzo [b] pyran-3-ol, or cis-6-cyano-3,4- Dihydro-2,2-dimethyl-4- (N-methylureido) -2H-benzo [b]
The compound according to claim (1), which is pyran-3-ol. 7. Formula (I) [Wherein R ₁ is C _1-6 alkylcarbonyl, C _1-6 alkoxycarbonyl, C _1-6 alkylcarbonyloxy, C _1-6
Alkyl hydroxymethyl, nitro, cyano, chlorine, trifluoromethyl, C _1-6 alkylsulfinyl, C _1-6
Alkylsulfonyl, C _1-6 alkoxysulfinyl,
C _1-6 alkoxysulfonyl, C _1-6 alkylcarbonylamino, C _1-6 alkoxycarbonylamino, C _1-6 alkyl-thiocarbonyl, C _1-6 alkoxy-thiocarbonyl, C _1-6 alkyl-thiocarbonyloxy , C _1-6 alkyl-thiolmethyl, formyl or aminosulfinyl, aminosulfonyl or aminocarbonyl, the amino moiety of which is substituted by one or two C _1-6 alkyl groups. Well or C _1-6 alkylsulfinylamino, C _1-6 alkylsulphonylamino,
C _1-6 alkoxysulfinylamino or C _1-6 alkoxysulphonylamino or C _1-6 alkylcarbonyl, ethylenyl terminally substituted by nitro or cyano or —C (C _1-6 alkyl) ) NOH or-
Selected from the group of C (C _1-6 alkyl) NNH ₂ ; R ₂ is hydrogen; R ₃ and R ₄ are C _1-4 alkyl; R ₅ is hydrogen; R ₆ is hydrogen R ₇ is hydrogen or hydroxy, C _1-6 alkoxy,
C _1-6 alkoxy or carbonyl or C _1-6 alkyl substituted by or is halogen or C _2-6 alkenyl and C _1-6 alkyl optionally substituted by carboxy; be the same or different or C _1-6 alkyl substituted by amino optionally substituted by one or two C _1-6 alkyl optionally; or 3 by C _1-6 alkyl or C _1-6 alkenyl group With an amino optionally substituted by a C _1-6 alkanoyl group optionally substituted by a halogen atom or by a C _1-6 alkyl, C _1-6 alkoxy or a phenyl group optionally substituted by a halogen. Or C _1-6 alkoxy or C _1-6 alkyl, C
_1-6 alkoxy or phenoxy optionally substituted by halogen; aryl or heteroaryl, each of which is C _1-6
Alkyl, C _1-6 alkoxy, hydroxy, halogen,
Trifluoromethyl, nitro, cyano, C _1-12 carboxylate acyl or amino or aminocarbonyl (1
Or optionally 2 or more C _1-6 alkyl) may be substituted by one or more groups or atoms selected from the group of the following; or when X is oxygen, R ₇ is carboxy, Is selected from the group of aminocarbonyl which is C _1-6 alkoxycarbonyl or which may be substituted by one or two C _1-6 alkyl groups which may be the same or different; or R ₆ and R ₇ Are together C _3-4 polymethylene; X is oxygen; and the R ₆ NCXR ₇ and OR ₅ moieties are cis or one or the other of R ₁ and R ₂ and / or R ₇ is amino. Or an amino-containing group which is a pharmaceutically acceptable salt thereof], a compound of formula (IX) And (i) the formula R ₇ ² COQ _{1 wherein the} R ₆ ² NH and OR ₅ ′ moieties are cis; and R ₁ ′ and R ₂ ′ may be converted to R ₁ and R ₂ or to them, respectively. is a group or atom; R ₅ 'is a group or atom capable of converting R ₅ or it; R ₆ ² is hydrogen; R ₇ ² may be optionally substituted as defined in formula (I) (when R ₆ ² is hydrogen) or a R ₇ or a group capable of conversion to their non-amino or _{Q 2 (CH 2) n +} 2 - be metal salts thereof; Q ₁ and Q ₂ a leaving group reacting a certain]; and then R ₇ ² is wherein the R ₇ ² when a group capable of conversion to R ₇ is other than amino optionally substituted as defined in formula (I) be substituted as defined in (I) was replaced to other R ₇ ² is other than be an amino; R ₇ ² is _{Q 2 (CH 2) n +} 2 - der Or cyclizing the compound formed when, or (ii) formula _{X = C = N · R 10} ( wherein R ₁₀ is hydrogen, C _1-6 alkyl, or 3 or fewer is a C _1-6 alkenyl A C _1-6 alkanoyl optionally substituted by a halogen atom, or C _1-6 alkyl, C _1-6 alkoxy or phenyl optionally substituted by a halogen; and X is oxygen). May be converted to R ₁₀ when R ₁₀ is hydrogen; and (i) or (ii) then R ₁ ′ or R ₂ ′ is R ₁ or R ₂ If a group or atom capable of conversion into the converted the substrate or atom into R ₁ or R _2; R ₁ in the resulting compound of formula (I), R ₂ or R ₅ to another R ₁ , may be converted to R ₂ or R _5; pharmaceutically when and the obtained compounds of formula (I) contain a group capable of chloride Process for preparing a compound of consists in may form acceptable salts formula (I). 8. The formula (I) [Wherein R ₁ is C _1-6 alkylcarbonyl, C _1-6 alkoxycarbonyl, C _1-6 alkylcarbonyloxy, C _1-6
Alkyl hydroxymethyl, nitro, cyano, chlorine, trifluoromethyl, C _1-6 alkylsulfinyl, C _1-6
Alkylsulfonyl, C _1-6 alkoxysulfinyl,
C _1-6 alkoxysulfonyl, C _1-6 alkylcarbonylamino, C _1-6 alkoxycarbonylamino, C _1-6 alkyl-thiocarbonyl, C _1-6 alkoxy-thiocarbonyl, C _1-6 alkyl-thiocarbonyloxy , C _1-6 alkyl-thiolmethyl, formyl or aminosulfinyl, aminosulfonyl or aminocarbonyl, the amino moiety of which is substituted by one or two C _1-6 alkyl groups. Well or C _1-6 alkylsulfinylamino, C _1-6 alkylsulphonylamino,
C _1-6 alkoxysulfinylamino or C _1-6 alkoxysulphonylamino or C _1-6 alkylcarbonyl, ethylenyl terminally substituted by nitro or cyano or —C (C _1-6 alkyl) ) NOH or-
Is selected from the group of C (C _1-6 alkyl) NNH ₂ or _one of R ₁ and R ₂ is nitro, cyano or C _1-3 alkylcarbonyl and the other is methoxy or one or Is amino optionally substituted by two C _1-6 alkyl or by C _2-7 alkanoyl; R ₂ is hydrogen; R ₃ and R ₄ are C _1-4 alkyl; R ₅ is R ₆ is hydrogen; and R ₇ is hydrogen or hydroxy, C _1-6 alkoxy,
C _1-6 alkoxy or carbonyl or C _1-6 alkyl substituted by or is halogen or C _2-6 alkenyl and C _1-6 alkyl optionally substituted by carboxy; be the same or different or C _1-6 alkyl substituted by amino optionally substituted by one or two C _1-6 alkyl optionally; or 3 by C _1-6 alkyl or C _1-6 alkenyl group With an amino optionally substituted by a C _1-6 alkanoyl group optionally substituted by a halogen atom or by a C _1-6 alkyl, C _1-6 alkoxy or a phenyl group optionally substituted by a halogen. Or C _1-6 alkoxy or C _1-6 alkyl, C
_1-6 alkoxy or phenoxy optionally substituted by halogen; aryl or heteroaryl, each of which is C _1-6
Alkyl, C _1-6 alkoxy, hydroxy, halogen,
Trifluoromethyl, nitro, cyano, C _1-12 carboxylate acyl or amino or aminocarbonyl (1
Or optionally 2 or more C _1-6 alkyl) may be substituted by one or more groups or atoms selected from the group of the following; or when X is oxygen, R ₇ is carboxy, Is selected from the group of aminocarbonyl which is C _1-6 alkoxycarbonyl or which may be substituted by one or two C _1-6 alkyl groups which may be the same or different; or R ₆ and R ₇ Are together C _3-4 polymethylene; X is oxygen; and the R ₆ NCXR ₇ and OR ₅ moieties are cis or one or the other of R ₁ and R ₂ and / or R ₇ is amino. Or a pharmaceutically acceptable salt of the amino-containing group] or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.